UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C.  20549

 

 

Form 10-K

 

 

(Mark One)

 

☒ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

 

For the fiscal year ended DECEMBER 31, 2018

 

Or

 

☐TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

 

For the transition period from              TO              

 

Commission File Number: 001-36046

 

AXOGEN, INC.

(Exact name of registrant as specified in its charter)

 

 

Registrant’s telephone number, including area code: (386)462-6800

 

 

Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒

 

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐ No ☒

 

Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐

 

Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§ 232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes ☒ No ☐

 

Indicate by check mark if disclosure of delinquent filers pursuant to Item 405 of Regulation S-K (§ 229.405 of this chapter) is not contained herein, and will not be contained, to the best of registrant’s knowledge, in definitive proxy or information statements incorporated by reference in Part III of this Form 10-K or any amendment to this Form 10-K. ☒

 

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company.  See the definitions of “large accelerated filer,” “accelerated filer”, “smaller reporting company” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

 

 

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act ☐

 

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act). Yes ☐ No ☒

 

As of June 30, 2018, the aggregate market value of the voting and non-voting common equity held by non-affiliates of the Registrant was approximately $1,498,135,561 based upon the last reported sale price of our common stock on the Nasdaq Capital Market.

 

The number of shares outstanding of the Registrant’s common stock as of February 22, 2019 was 38,945,029 shares.

 

DOCUMENTS INCORPORATED BY REFERENCE

 

Portions of the Registrant’s definitive proxy statement to be filed pursuant to Regulation 14A within 120 days after the end of the Registrant’s fiscal year are incorporated by reference into Part III of this Form 10-K.

 

 

TABLE OF CONTENTS

 

 

 

 

 

 

 

FORWARD-LOOKING STATEMENTS

 

From time to time, in reports filed with the U.S. Securities and Exchange Commission (including this Form 10-K), in press releases, and in other communications to shareholders or the investment community, Axogen, Inc. (including Axogen, Inc.’s wholly owned subsidiaries, Axogen Corporation, Axogen Processing Corporation and Axogen Europe GmbH, the “Company”, “Axogen”, “we”, “our”, or “us”) may provide forward-looking statements, as defined in the Private Securities Litigation Reform Act of 1995, concerning possible or anticipated future results of operations or business developments. Words such as "expects", "anticipates", "intends", "plans", "believes", "seeks", "estimates", "projects", "forecasts", "continue", "may", "should", "will", “goals,” variations of such words and similar expressions are intended to identify such forward-looking statements. The forward-looking statements may include, without limitation, statements regarding our assessment of our internal controls over financial reporting, our growth, our 2019 guidance, product development, product potential, financial performance, sales growth, product adoption, market awareness of our products, data validation, and our visibility at and sponsorship of, conferences and educational events. The forward-looking statements are and will be subject to risks and uncertainties, which may cause actual results to differ materially from those expressed or implied in such forward-looking statements. Forward-looking statements contained in this Form 10-K should be evaluated together with the many uncertainties that affect the Company’s business and its market, particularly those discussed in the risk factors and cautionary statements set forth in the Company’s filings with the U.S. Securities and Exchange Commission, including as described in “Risk Factors” included in Item 1A of this Form 10-K. Forward-looking statements are not guarantees of future performance, and actual results may differ materially from those projected. The forward-looking statements are representative only as of the date they are made and,  except as required by applicable law, the Company assumes no responsibility to publicly update or revise any forward-looking statements, whether as a result of new information, future events, changed circumstances or otherwise.

 

PART I

 

ITEM 1.  BUSINESS

 

General 

Axogen  is the leading company focused specifically on the science, development and commercialization of technologies for peripheral nerve regeneration and repair. We are passionate about helping to restore peripheral nerve function and quality of life to patients with physical damage or transection to peripheral nerves by providing innovative, clinically proven and economically effective repair solutions for surgeons and health care providers. Peripheral nerves provide the pathways for both motor and sensory signals throughout the body. Every day, people suffer traumatic injuries or undergo surgical procedures that impact the function of their peripheral nerves. Physical damage to a peripheral nerve, or the inability to properly reconnect peripheral nerves, can result in the loss of muscle or organ function, the loss of sensory feeling, or the initiation of pain.

 

Axogen's platform for peripheral nerve repair features a comprehensive portfolio of products, including Avance® Nerve Graft, a biologically active off-the-shelf processed human nerve allograft for bridging severed peripheral nerves without the comorbidities associated with a second surgical site; Axoguard® Nerve Connector, a porcine submucosa extracellular matrix (“ECM”) coaptation aid for tensionless repair of severed peripheral nerves; Axoguard® Nerve Protector, a porcine submucosa ECM product used to wrap and protect damaged peripheral nerves and reinforce the nerve reconstruction while preventing soft tissue attachments; and Avive® Soft Tissue Membrane, a minimally processed human umbilical cord membrane that may be used as a resorbable soft tissue covering to separate tissue layers and modulate inflammation in the surgical bed. Along with these core surgical products, Axogen also offers Axotouch® Two-Point Discriminator, used to measure the innervation density of any surface area of the skin, and Acroval® Neurosensory & Motor Testing System, an evaluation and measurement tool to assist health care professionals in detecting changes in sensation, assessing return of sensory, grip, and pinch function, evaluating effective treatment interventions, and providing feedback to patients on peripheral nerve function. The Axogen portfolio of products is available in the United States, Canada, the United Kingdom, and several other European and international countries.

 

Nerves can be damaged in a number of ways. When a nerve is cut due to a traumatic injury or surgery, functionality of the nerve may be compromised, causing the nerve to no longer carry the signals to and from the brain to the muscles and skin and reducing or eliminating functionality.  Nerve damage or transection of this type generally requires a surgical repair. Traditionally, the standard has been to either suture the nerve ends together directly without tension or to bridge the gap between the nerve ends with a less important nerve surgically removed from elsewhere in the patient’s own body, referred to as nerve autograft. Nerves that are not repaired or heal abnormally can form a complication called a neuroma which may send altered signals to the brain resulting in the sensation of pain. This abnormal section of nerve can, under certain circumstances, be surgically cut out and the resulting gap repaired.  In addition, compression on a nerve, blunt force trauma or other physical irritations to a nerve can cause nerve damage that may alter the signal conduction of the nerve, result in pain, and may in some instances require surgical intervention to address the resulting nerve compression and inflammation.    Finally, when a woman undergoes a mastectomy due to breast cancer or prophylactically due to a genetic predisposition for breast cancer, the nerves are cut to allow the removal of the breast tissue.  This can result in a loss of sensation and the potential risk of a symptomatic neuroma.  When a women chooses an autologous breast reconstruction after a mastectomy, sensation can,    in certain cases, be returned through surgical intervention. 

 

In order to improve the options available for the surgical repair and regeneration of peripheral nerves, Axogen has developed and licensed regenerative medicine technologies. Axogen’s innovative approach to regenerative medicine has resulted in first-in-class products that it believes are redefining the peripheral nerve repair market.    Axogen’s products are used by surgeons during surgical interventions to repair a wide variety of physical nerve damage or transection throughout the body, which can range from a simple laceration of a finger to a complex brachial plexus injury (an injury to the network of nerves that originate in the neck) as well as nerve injuries caused by dental, orthopedic and other surgical procedures. Avance® Nerve Graft provides surgeons an implant with the micro-architecture of a human nerve. This structure is essential and allows for bridging nerve gaps or transections up to 70mm in length. Additionally, Avance® Nerve Graft has product and distribution synergies with Axoguard® Nerve Protector, Axoguard® Nerve Connector and Avive® Soft Tissue Membrane.  Axoguard® products provide the unique features of pliability, suturability,

and translucence for visualization of the underlying nerve, while also allowing the extracellular matrix to remodel utilizing the patient’s own cells.  Avive® Soft Tissue Membrane is minimally processed human umbilical cord membrane that may be used as a resorbable soft tissue covering to separate tissues and modulate inflammation in the surgical bed.

 

Regenerative Medical Products Industry

 

Regenerative medical products enable the repair, restoration, replacement or regeneration of tissue or organ systems of the body.  Regenerative medical products are becoming common in various medical arenas because they have been shown to be effective repairing injured or defective tissues, such as bone, tendons, dermis and other tissues of the body.  Surgeons utilize regenerative medical products because they can provide the complex structure required for implant integration and regeneration in the body.

 

Axogen believes the primary driver of sustained growth in the regenerative medical product market is continued favorable efficacy as compared to autograft tissue and synthetic medical products, and a wider understanding of this advantage by practitioners. Repair with nerve autograft requires a secondary recovery procedure to remove tissue from another location of the patient’s body to repair the injured area and results in loss of function at the site of donation. Further, nerve autograft may also be costly and time consuming and may result in complications at the second surgical site such as infection.  In addition to processed nerve allograft (Avance® Nerve Graft), alternatives to nerve autograft include hollow-tube synthetic or collagen-based medical products that are designed to provide some restoration of function but may be limited by mechanisms of nerve healing and/or biocompatibility with the body. Regenerative medical products often provide more desirable conditions for reconstruction and regeneration of tissue, creating a superior solution for patients and physicians.  Axogen follows this trend, providing regenerative medical products for peripheral nerve repair.

 

Regenerative medicine products typically consist of and rely on:

 

 

Axogen’s Avance® Nerve Graft, Axoguard® Nerve Protector and Axoguard® Nerve Connector are ECM scaffolds, and utilize the patients’ own cells to remodel or regenerate these scaffolds.  Avive® Soft Tissue Membrane is a resorbable soft tissue covering to separate tissues and modulate inflammation in the surgical bed.

 

Peripheral Nerves and Their Regeneration

 

The peripheral nervous system, or PNS, consists of nerves that either extend outside of, or reside outside of, the central nervous system (primarily the brain and spinal cord).  Peripheral nerves provide the pathway for signals between the central nervous system and target organs, regulating movement (motor nerves) and touch (sensory nerves).  Therefore, if a peripheral nerve is crushed, severed, or otherwise physically damaged, its ability to deliver signals to or from the target organs is eliminated, or significantly reduced, and could result in a loss of sensation and/or motor functionality.  The axon portion of the nerve cell, consisting of cell cytoplasm and resembling a hair-like fiber, carries signals between the cell body and the target organ.  Axons can be quite long, even exceeding one meter, but are only a few micrometers in diameter.  A typical nerve consists of hundreds of axons that lie within long, thin tubes (endoneurial tubes).  Analogous to a wiring cable, these endoneurial tubes are bundled together in groups called fascicles, and each nerve may contain numerous fascicles.  This sheath structure provides protection for the axons and support for regeneration in the event of damage or transection.  Nerve damage or transection occurs when a sufficient number of axons have been crushed or transected (severed), thereby disrupting signals to or from the target motor or sensory organ.

 

Given the right conditions, peripheral nerves have the ability to regenerate.  Regenerating axons require the proper environmental conditions including structure and guidance of axons in a tension and compression free environment.  In an untreated severe crush injury or transected nerve, errant axons that are not guided by the nerve sheath structure, or other mechanism, can form painful and ineffective nerve proliferation (neuromas).  This condition can require revision surgery to relieve pain or bring back sensory and/or motor functionality. Therefore, the surgical treatment of peripheral

nerves due to damage or transection is typically focused on restoring nerve functionality by providing structural guidance to regenerating axons, minimizing the formation of neuromas and protecting the nerve to alleviate compression.    

 

Inflammation can impair tissue regeneration and result in irritation and compression of the nerve.  Trauma and surgical interventions can trigger the body’s repair response which can result in inflammation in the surgical arena (nerve and/or surrounding tissue).  When this occurs it can compromise the surgical outcomes of nerve repair.  Avive® Soft Tissue Membrane is a resorbable soft tissue covering to separate tissues and modulates inflammation in the surgical bed.

 

Peripheral Nerve Regeneration Market Overview

 

Peripheral nerve injury (“PNI”) through damage or transection is a major source of physical disability impairing the ability to move muscles or to feel normal sensations.  Failure to treat peripheral nerve damage or transection can, in severe cases, lead to full loss of sensation and/or function, pain and, sometimes, amputation.  Many peripheral nerve patients who receive treatment do not optimally recover. They may suffer from both reduced, or no, muscle strength, and reduced, or no, sensitivity and pain.

 

Every day patients suffer traumatic bodily injuries resulting in damage or transection to peripheral nerves severe enough to require surgical treatment, including injuries from motor vehicle accidents, power tool injuries, gunshot wounds, dislocations, fractures, lacerations, or other forms of penetrating trauma.  The peripheral nerves commonly damaged or transected from these traumas include the digital, median, ulnar, radial, facial, spinal accessory and brachial plexus nerves. The “Trauma” portion of the Total Addressable Market (as defined below) encompasses the traumatic PNI described above but excludes the OMF, Upper Extremity Compressions and Breast (as such terms are defined below) portions of the Total Addressable Market. 

 

Beyond the physical damage or transection to peripheral nerves resulting from traumatic bodily injuries described above, peripheral nerve damage or transection also occurs due to surgical intervention.  Nerve damage or transection can occur during dental and oral surgery procedures such as third molar extractions, placement of dental implants, removal of tumors, orthognathic surgery and mandibular resection during which one or more sections of the trigeminal nerve can be damaged or transected (“OMF”).  This can result in numbness in certain areas of the face and mouth.

 

Breast reconstruction neurotization (“Breast”) is another portion of the Total Addressable Market.  Currently, when a woman undergoes autologous breast reconstruction after a mastectomy, she receives the shape of a natural breast, but oftentimes without experiencing any return of sensory feeling.  This forfeiture of sensation can have a profound effect on the woman’s quality of life.  In certain cases, sensation can be returned to the breast area with the use of the Company’s products through an innovative surgical technique we call ReSensation℠.  The Company believes that the ideal breast reconstruction should restore breast Size, Shape, Symmetry, Softness as well as Sensation – without the potential risks and co-morbidity associated with autograft.  The Company believes the ReSensation℠  technique incorporates a patients’ desire for the opportunity to return sensation in their breasts with a reproducible and efficient surgical approach for reconstructive plastic surgeons.

 

Finally, peripheral nerves are also damaged due to compression injuries.  For instance, severe and recurrent carpal and cubital tunnel cases may result in complications and damage to the peripheral nerve that requires surgical intervention and protection of the peripheral nerve.  PNI caused by recurrent carpal tunnel syndrome and cubital tunnel syndrome constitutes the “Upper Extremity Compression” portion of the Total Addressable Market.

 

In the cases where a peripheral nerve is severed and the gap between its two ends is extremely small, the surgeon may be able to reconnect the peripheral nerve without tension through direct suturing as a coaptation aid (“Primary Repair”). When the gap in the nerve tissue is more than a few millimeters in length, the surgeon typically needs to use material to bridge the gap between the peripheral nerve ends to ensure a tension-free repair (“Gap Repair”).  Historically for a Gap Repair surgeons have relied on a nerve autotransplantation (autologous nerve grafting or nerve autograft).  In nerve autograft procedures, surgeons remove peripheral nerve from another part of the patient’s body, frequently the sural nerve from the back of the lower leg, to repair the damaged nerve.  Nerve autografting is often effective in

repairing a damaged peripheral nerve, but it presents a tradeoff — the surgeon can attempt to fix the damaged nerve but must create an additional nerve deficit at another location in the body.  For example, a patient may opt to get movement and feeling back in their finger while losing some sensation in their foot. Additionally, Axogen believes the secondary surgery to obtain the needed nerve autograft also:  (1) increases operating time, in a hospital by potentially as much as 30 to 90 minutes (Intra-Service times based on median intra-service times for CPT codes (64885-6, 64890-93, 64895-98, 64910-64911) provided by CMS, Physician Fee Schedule, http://my.clevelandclinic.org/ccf/media/files/Patients/cleveland-clinic-main-charges.pdf and Capek L, Clarke H M, Zuker R M. Endoscopic sural nerve harvest in the pediatric patient. Plast Reconstr Surg. 1996 Oct; 98(5): 884–888), and thus medical expenses, we estimate by $3,200 to $9,500 per procedure (2018 MS-DRG relative weight multiplied by 2-18 rate per IPPS Final Rule, as calculated by MCRA, payment rate will vary by facility. Calculation includes labor, related, non related and capital payment rates), and (2) may result in a 27% (Rappaport WD, Valente J, Hunter GC, Rance NE,et al. Clinical utilization and complications of sural nerve biopsy. Am J Surg. 1993 Sep; 166(3): 252-256) complication rate due to surgical site infection, wound healing and chronic pain. In the case of extreme trauma where multiple peripheral nerves need to be repaired, it may not be possible to recover enough nerve from the patient to complete the Gap Repair.  Further, nerve autograft tissue may not provide an appropriate diameter match with the diameter of the injured nerve stump, an important factor in a successful repair outcome.

 

Drawbacks of repair with autograft nerve eventually led to the development of hollow tube conduits, or hollow tube nerve cuffs for Primary Repair and Gap Repair made of, for instance, bovine collagen or polyglycolic acid.  The hollow tube nerve cuff is typically an absorbable hollow tube that, unlike natural peripheral nerve, does not have internal microarchitecture and endoneurial tubes to support regenerating axons; as a result, it is deficient in the qualities that natural peripheral nerve possesses to support nerve regeneration across a gap.  Hollow-tubes may also lack pliability and structural integrity needed when used around joints and may be difficult to use in a confined space.  Clinical data has demonstrated that hollow tubes are most effective when used in very short gaps, what Axogen defines as Primary Repair, and the reliability of successful nerve recovery diminishes as gap length increases with a 34% to 57% failure rate for hollow tube conduits in repairs with a greater than 5mm gap (Weber RA, Breidenbach WC, Brown RE, Jabaley ME, Mass DP. A randomized prospective study of polyglycolic acid conduits for digital nerve reconstruction in humans. Plast Reconstr Surg. 2000 Oct;106(5):1036-45; discussion 1046-8 and Wangensteen KJ, Kalliainen LK.  Collagen tube conduits in peripheral nerve repair: a retrospective analysis. Hand (N Y). 2010 Sep;5(3):273-7. doi: 10.1007/s11552-009-9245-0. Epub 2009 Nov 24).    

 

Conduits filled with an inner matrix have been announced by competitors. Such filled tube conduits are not currently available for purchase in the United States and the date of such future availability is unknown.  These filled conduits are purported to have greater ability to regenerate after peripheral nerve injury than a hollow tube conduit, but there is very limited data supporting this position. See - “Competition”.

 

The shortcomings of hollow-tubes for peripheral nerve repair limit where they may be used effectively. Thus, Axogen believes the peripheral nerve repair market needs an alternative off-the-shelf product that offers other features such as a natural ECM scaffold and three-dimensional structure of a typical nerve for bridging nerve transections without the comorbidities of an additional surgical site required for harvest of autograft nerve tissue. Axogen believes its Avance® Nerve Graft and Axoguard® Nerve Connector products address the market needs for both Gap Repair and Primary Repair.

 

Compression on a peripheral nerve or blunt force trauma can also cause nerve damage that may require surgical intervention. In these cases, the peripheral nerve is not severed and thus does not create the need for a Primary Repair or Gap Repair.  However, the surgeon may want to protect and isolate the peripheral nerve during the healing process.  In these situations peripheral nerve protection is provided by wrapping the nerve (“Nerve Protection”).

 

Axoguard® Nerve Protector is a porcine submucosa extracellular matrix used for Nerve Protection.  Other Nerve Protection products are usually made from bovine collagen or polyglycolic acid and are typically absorbable. Axoguard® Nerve Protector provides the unique features of pliability, suturability, and translucence for visualization of the underlying peripheral nerve, while also allowing the patient’s own cells to incorporate into the extracellular matrix to remodel and separate the peripheral nerve from the surrounding tissue.

 

Inflammation can impair tissue regeneration and result in irritation and compression of the peripheral nerve.  Trauma and surgical interventions can trigger the body’s repair response which can result in inflammation in the peripheral nerve and/or the surrounding tissue.  When this occurs it can compromise the surgical outcomes of peripheral nerve repair.  Avive® Soft Tissue Membrane can be proactively used in these surgical applications (“Proaction”).  Avive® Soft Tissue Membrane has been specifically designed as a soft tissue covering to modulate inflammation, provide a longer resorption profile to separate the tissue layers for at least 16 weeks and to provide the handling and suturability features the Company believes is favored by peripheral nerve surgeons.  

 

We estimate the United States PNI has a potential total addressable market for our current product portfolio for Trauma, OMF, Breast and Upper Extremity Compression of $2.7 billion (the “Total Addressable Market”).   Estimating the Total Addressable Market for nerve repair is challenging as there is not a simple data source for the incidence of peripheral nerve issues.  This is further complicated by the fact that nerves can be injured in many traumatic and surgical injuries and can be impacted from the head to the toe of a patient.  In addition, we believe nerves are often one of many structures injured in a trauma (i.e. amputation) or in surgery and the incidence of these nerve injuries are often not coded or tracked.  Quantifying the procedures involving nerve repair may also be challenging.  While selected trauma and surgical procedures are dedicated to the repair of nerves (i.e. a pediatric brachial plexus procedure), most of the incidence of nerve repair is a step in a larger trauma (i.e. digital replant) or surgical procedure (i.e. mandible reconstruction).  CPT codes exist for surgeons to code for nerve repair, however, we believe the data substantially underestimates the total number of nerves repaired.  Physicians are encouraged to document all steps of procedures; however, payment guidelines can vary widely across payors, plans and state regulations thus often limiting surgeon payment to a select number of codes per procedure (for example, five codes or less is not uncommon).  Open trauma often involves many surgical steps including wound debridement, skin closure and one or more repairs of tendons, bone or joints, nerves, veins and arteries.  CPT codes are often reported by a hierarchy of reimbursement rates with the highest reimbursable procedures getting listed and subsequent codes often being left out of the procedure coding. As a result, we believe CPT coding underrepresents the total number of nerve repairs performed in trauma.  Because we believe CPT claims are not fully representative of the true volumes of nerve repair surgery, we follow an “empirical” methodology to estimate the Total Addressable Market – using published clinical literature and procedure databases to make what we believe are the most objective assumptions.

 

We estimate that the Trauma portion of the Total Addressable Market is approximately $1.9 billion based upon epidemiological studies regarding the general number of trauma patients, clinical literature review reporting  PNI incidence and physician interviews.    There are almost 137 million emergency department visits in the U.S. each year of which approximately 30 million are related to traumatic injuries (2015 National Hospital Ambulatory Medical Care Survey, Publication of U.S. Department of Health & Human Services).  We believe that this injury population includes more than 1.4 million patients suffering damage or transection to peripheral nerves resulting in over 700,000 nerve repair procedures (Noble, et al. J of Trauma Injury Infection and Critical Care 1998; Portincasa et al: Microsurgery 27:455-462, 2007).  We have estimated the portion of these nerve repair procedures due to trauma that would require Gap Repair, Primary Repair and/or Nerve Protection and applied, as we believed was appropriate in each procedure segment, the number of units and average sales price of Avance® Nerve Graft and the average market price for nerve connectors, nerve protectors and soft tissue membrane products to determine the probable Total Addressable Market.

 

We estimate that the OMF portion of the Total Addressable Market is approximately $300 million, based upon research indicating that approximately 56,000 PNI occur in the U.S. each year related to third molar surgeries, anesthetic injections, dental implants, orthognathic surgery and mandibular resection procedures. (Shih-Yun Wu et al: Systematic Review and Meta-Analysis on Incidence of Altered Sensation of Mandibular Implant Surgery - PLoS ONE 11(4): e0154082;  Souheil Hussaini, Procedure frequency in the jaws related to implant location, Dent Oral Craniofac Res, 2016 Volume 2(2): 230-233;  Nguyen. Et al: Risk  Factors for Permanent  Injury  of Inferior  Alveolar  and  Lingual  Nerves  During Third  Molar  Surgery;  J Oral Maxillofac Surg. 2014 Dec;72(12);  Cheung LK,  Leung  YY,  Chow  LK,  et  al.  Incidence  of neurosensory  deficits  and  recovery  after  lower  third molar  surgery:  a  prospective  clinical  study  of  4338 cases.  Int  J  Oral  Maxillofac  Surg  2010;39:320–6.; Transparency Market Research: Dental Implant Market - Global Industry Analysis and Forecast 2016 – 2024;  Cha et al, Maxillofacial Plastic and Reconstructive surgery (2016) 38:19 - Frequency of bone graft in implant surgery;  Miloro ed. 2012: Text Book on trigeminal  nerve injuries;  Pogrel et al: J Am Dent Assoc. 2000 Jul;131(7):901-7: Permanent nerve involvement resulting from inferior alveolar nerve blocks;  Agbaje et al: Int. J. Oral Maxillofac. Surg. 2015; 44: 447-451, J.O Systematic review of the incidence of inferior

alveolar nerve injury in bilateral sagittal split osteotomy (BSSO) and the assessment of neurosensory disturbance).    We have applied the average sales price of the Avance® Nerve Graft, Axoguard® Nerve Connector and Axoguard® Nerve Protector that address such PNI in order to derive the OMF portion of the Total Addressable Market.

 

In 2017, there were 106,295 breast reconstruction procedures in the US as reported in the 2017 plastic surgery statistic report published by the American Society of Plastic Surgery. The report details 19,316 of these reconstructions procedures were autologous flap reconstruction, and that 66.2% of the reconstructions were bilateral.  Removing those procedures that are not appropriate for neurotization, and based upon the Company’s assumption that approximately 50% of women may elect to have a dual neurotization for each flap, we estimate that the Breast portion of the Total Addressable Market is approximately $250 million.  (2017 ASPS Plastic Surgery Statistics Reports, Includes TRAM, DIEP, and "Other Flaps", Distribution based on 2017 ASPS Data).

 

We estimate that the Upper Extremity Compression portion of the Total Addressable Market is approximately $270 million, or 130,000 procedures.  Extrapolating the 2016 Medicare National HCPCS Aggregate Summary Table to the total US population, we estimate that there are approximately 488,000 primary carpal tunnel and 95,000 primary cubital tunnel relief surgeries performed annually in the U.S. For carpal tunnel, we believe that our addressable procedure is the estimated 20% of carpal tunnel surgeries that require a  revision procedure to address the recurrence of symptoms (Sotereanos et al, Techniques in hand and Upper extremity surgery 1(1):35-40,1997). From the 95,000 primary cubital tunnel surgeries, we estimate that our addressable procedure potential comprise a small proportion of primary interventions and all revisions  (J Seradge et al, Hand Surg 1998; 23A:483-491; Papatheodorou et al, J Hand Surg Am. 2015;40(5):987e992).   As a result, we estimate that approximately 97,500 carpal tunnel revision surgeries and 32,400 total cubital tunnel procedures are addressable each year in the U.S. to mitigate the recurrence of symptoms. These revision and primary surgeries are required due to compression of the peripheral nerve associated with soft tissue attachments from the surrounding tissue or tissue infiltration entrapping the nerve. To prevent additional recurrences, surgeons will opt for a Nerve Protection which includes a product such as the Axoguard® Nerve Protector. In order to derive the Upper Extremity Compression portion of the Total Addressable Market, we multiplied the average market sales price of Axoguard®  Nerve Protectors by the number of estimated procedures.    

 

Although distribution and sales of  products in the Trauma, OMF, Breast and Extremity Compression portions of the Total Addressable Market constitute our primary revenue sources today, market expansion opportunities in lower extremity surgery, head and neck surgery, urology and the surgical treatment for pain offer us new and expanded revenue opportunities.  The Company has announced a planned future expansion into the surgical treatment of pain with an initial focus on traumatic injuries including amputation and orthopedic surgeries such as total hip arthroplasty, total knee arthroplasty, knee arthroscopy, Morton’s neuroma, foot and ankle procedures and wrist arthroscopy. The Company estimates that the incidence of painful injuries in these applications is over 370,000 patients annually.  One of the causes of neuropathic pain is called a neuroma-a tangled mass of disorganized nerve and fibrous tissue resulting in aberrant nerve signals which the brain interprets as pain.  Traditionally these neuromas have been treated  using pain management methods including pharmacological agents which do not address the anatomical cause of the pain.  The surgical treatment of such pain involves a procedure to remove the painful neuroma and, subsequently, repair the resulting Nerve Gap or appropriately terminate the nerve end.  Axogen developed the Axoguard® Nerve Cap to protect a peripheral nerve end and separate the nerve end from the surrounding environment to reduce the development of asymptomatic or painful neuromas (“Neuroma Management”). An example application for Axoguard® Nerve Cap is in a digital amputation whereby the severed nerves may form a neuroma if the nerve end is not properly terminated or capped.  We are currently conducting user evaluations of Axoguard® Nerve Cap and a post-market clinical study of neuroma revision using Axoguard® Nerve Cap.

 

Axogen’s Product Portfolio

 

 

Overview of Axogen’s Products

 

The Axogen surgical solution product portfolio provides surgeons off-the-shelf products for a wide variety of peripheral nerve damage or transection.  The Company’s proprietary products and technologies are designed to overcome fundamental challenges in peripheral nerve repair. Axogen’s Avance® Nerve Graft is the alternative to

autografts and other off-the-shelf peripheral nerve repair products for nerve gaps up to 70mm in length.  Axoguard® Nerve Connector is a coaptation aid for transected peripheral nerve.  Axoguard® Nerve Protector is a protective wrap for peripheral nerves damaged by compression, or where the surgeon wants to protect and isolate the peripheral nerve during the healing process after surgery.  Avive®  Soft Tissue Membrane provides a resorbable covering to keep tissue structures apart while providing the beneficial properties of a  placental membrane.

 

Functional measurements play an important role in the evaluation of peripheral nerve function by assisting the healthcare professionals in detecting changes in sensation or muscle strength, assessing return of sensory or motor function, establishing effective treatment interventions, and providing feedback to the patients.   Standardized evaluation and measurement of peripheral nerve function is also an important part of identifying nerve damage or transection and determining treatment outcomes.  Axogen’s functional measurement products include the Acroval® Neurosensory and Motor Testing System (for sensory and motor function) and the Axotouch® Two-Point Discriminator tool (for sensory function).

 

Avance® Nerve Graft 

 

Avance® Nerve Graft is a biologically active nerve therapy with more than ten years of comprehensive clinical evidence intended for the surgical repair of peripheral nerve transections to support regeneration across the defect (a gap created when the nerve is severed).  It is intended to act as a bridge in order to guide and support axonal regeneration across a peripheral nerve gap caused by traumatic injury or surgical intervention.  Avance® Nerve Graft is decellularized and sterile processed human peripheral nerve tissue.  Axogen developed the Avance® Nerve Graft by following the guiding principle that the human body created the optimal peripheral nerve structure.  Axogen, through its licensing efforts and research, developed the Avance® process, a proprietary method for processing recovered human peripheral nerve tissue in a manner that preserves the essential structure of the ECM while cleansing away cellular and noncellular debris.  Avance® Nerve Graft provides the natural peripheral nerve structure of a nerve including the native laminin to guide the regenerating nerve fibers.  The nerve ECM is additionally processed to remove a natural inhibitor to regeneration called chondroitin sulphate proteoglycan (“CSPG”).     

 

Axogen believes that Avance® Nerve Graft is the first off-the-shelf human nerve allograft for bridging nerve transections. Avance® Nerve Graft is comprised of bundles of small diameter endoneurial tubes that are held together by an outer sheath called the epineurium.  Avance® Nerve Graft has been processed to remove cellular and noncellular factors such as cells, fat, blood, and axonal debris, while preserving the three-dimensional laminin lined tubular bioscaffold (i.e. microarchitecture), epineurium and microvasculature of the peripheral nerve. After processing, Avance® Nerve Graft is flexible and pliable, and its epineurium can be sutured in place allowing for tension-free approximation of the proximal and distal peripheral nerve stumps.  The design results in a product that has clean and clear pathways for the regenerating axons to grow through.  During the healing process, the body revascularizes and gradually remodels the graft into the patient’s own tissue while allowing the processed peripheral nerve allograft to physically support axonal regeneration across the peripheral nerve transection.

 

With lengths up to 70 mm and diameters up to 5 mm, Avance® Nerve Graft allows surgeons to choose and trim the implant to the correct length for repairing the relevant peripheral nerve gap, as well as to match the diameter to the proximal and distal end of the severed peripheral nerve.  Avance® Nerve Graft is stored frozen and utilizes packaging that maintains the graft in a sterile condition.  The packaging is typical for medical products so the surgical staff is familiar with opening the package for transfer of Avance® Nerve Graft into the sterile surgical field. Such packaging also provides protection during shipment and storage and a reservoir for the addition of sterile fluid to aid in thawing the product. Avance® Nerve Graft thaws in less than 10 minutes, and once thawed, it is ready for implantation.

 

Avance® Nerve Graft provides the following key advantages:

 

 

Axoguard® Nerve Connector

 

Axoguard® Nerve Connector is a coaptation aid used to align and connect severed peripheral nerve ends in a tensionless repair. The product is in a tubular shape with an open lumen on each end where the severed peripheral nerve ends are placed.  It is typically used when the gap between the peripheral nerve ends is 5mm or less in length.  Axoguard® Nerve Connector is made from a minimally processed porcine ECM which allows the body’s natural healing process to repair the peripheral nerve while its tube shape isolates and protects the transected nerves during the healing process.  During healing, the patient’s own cells incorporate into the extracellular matrix product to remodel and form a tissue similar to the outermost layer of the peripheral nerve (nerve epineurium).  Axoguard® Nerve Connector is provided sterile, for single use only, and in a variety of sizes to meet the surgeon’s needs.

 

Axoguard® Nerve Connector can be used:

 

 

Axoguard® Nerve Connector has the following advantages:

 

 

Axoguard® Nerve Protector

 

Axoguard® Nerve Protector is a product used to protect and wrap damaged peripheral nerves and reinforce reconstructed nerve gaps while preventing soft tissue attachments. It is designed to protect and isolate the peripheral nerve during the healing process after surgery by creating a barrier between the nerve tissue and the surrounding tissue bed.  The product is delivered in a slit tube format allowing it to be wrapped around peripheral nerve structures.  Axoguard® Nerve Protector is made from a minimally processed porcine ECM.  During healing, the ECM remodels allowing the protector to separate the peripheral nerve from the surrounding tissue.  Axoguard® Nerve Protector competes against off-the-shelf biomaterials such as reconstituted collagen as well as the use of the patient’s own tissue

such as vein and hypothenar fat pad wrapping.  Axoguard® Nerve Protector is provided sterile, for single use only, and in a variety of sizes to meet the surgeon’s needs.

 

Axoguard® Nerve Protector can be used to:

 

 

Axoguard® Nerve Protector has the following advantages:

 

 

Avive® Soft Tissue Membrane

 

Avive® Soft Tissue Membrane is minimally processed human umbilical cord membrane that may be used as a resorbable soft tissue covering to  separate tissues and modulate inflammation in the surgical bed.  Inflammation can impair tissue regeneration and result in irritation and compression of the nerve.  Trauma and surgical interventions can trigger the body’s repair response which can result in inflammation in the surgical arena (peripheral nerve and/or surrounding tissue).  When this occurs it can compromise the surgical outcomes of peripheral nerve repair. 

 

We believe, the medical community has for decades realized the beneficial qualities of human amniotic membrane and continues to utilize this natural tissue in applications across the body.  Avive® Soft Tissue Membrane offers a resorbable anatomical covering to keep tissue surfaces apart.  Avive® Soft Tissue Membrane is provided sterile and in a variety of sizes to meet the surgeon’s surgical needs.

 

Avive® Soft Tissue Membrane:

 

 

Avive® Soft Tissue Membrane has the following advantages:

 

 

 Acroval® Neurosensory and Motor Testing System

 

Acroval® Neurosensory and Motor Testing System is a device for evaluating patients with peripheral nerve conditions.  We believe that an important step for improving patient outcomes is to support the standardized evaluation and measurement of peripheral nerve function.  Today there is little consistency of measurement protocols. With the Acroval® system examiners will have digital, less subjective results for their patients with conditions like peripheral neuropathy, peripheral nerve compression syndromes, and transected peripheral nerves. Ultimately, we believe that standardization of evaluation and measurement techniques will facilitate comparison and interpretation of clinical results leading to better understanding and care for patients with peripheral nerve conditions.

 

Dr. A. Lee Dellon, a world-renowned peripheral nerve expert, developed the peripheral nerve functional evaluation and measurement system over 25 years ago.  We acquired the rights to his device in 2015 and launched the product in March 2016. Acroval® consists of three different devices designed to evaluate hand strength and neurosensory function:

 

 

Acroval® can be used to assist healthcare professionals:

 

 

Acroval® has the following advantages:

 

 

Axotouch® Two Point Discriminator

 

The Axotouch® Two-Point Discriminator tool can be used to measure the innervation density of any surface area of the skin. The discs are useful for determining sensation after damage to a peripheral nerve, following the progression of a repaired peripheral nerve, and during the evaluation of a person with possible peripheral nerve damage, such as compression.

 

The Axotouch® Two-Point Discriminator tool is a set of two aluminum discs each containing a series of prongs spaced between two to 15 millimeters apart. Additionally, 20 and 25 millimeter spacing is provided. A circular depression on either side of the disc allows ease of rotation. The discs can be rotated between a single prong for testing one-point and any of the other spaced prongs for testing two-point intervals.

 

Axotouch® Two-Point Discriminator has the following advantages:

 

 

Tissue Recovery and Processing for Avance® Nerve Graft and Avive® Soft Tissue Membrane

 

Avance® Nerve Graft Processing Overview

 

Axogen has developed the Avance® Process, an advanced and proprietary technique to process Avance® Nerve Graft from donated human peripheral nerve tissue.  The Avance® Process requires special training over several months for each manufacturing associate who processes Avance® Nerve Grafts.  The processing and manufacturing system for Avance® Nerve Graft has required significant capital investment, and we seek to continually improve our manufacturing and quality assurance processes and systems.  Axogen’s Avance® Process is depicted as follows:

 

 

Avance® Nerve Graft and Avive® Soft Tissue Membrane Processing 

 

Axogen’s Avance® Process and SMART processing of Avive® Soft Tissue Membrane consists of several steps, including peripheral nerve tissue, in the case of Avance®, and umbilical cord, in case of Avive®, recovery/acquisition and testing, donor medical review and release, processing, packaging, and sterilization to meet or exceed all applicable U.S. Food and Drug Administration (the “FDA”), state, and international regulations and American Association of Tissue Banks (“AATB”) standards.  We have a number of contracts with recovery and acquisition agencies to supply peripheral nerve tissue and umbilical cord and believe these contracts, and the ability to enter into additional contracts, will provide us with the tissues we require for our Avance® and Avive® implants.   As an FDA registered tissue establishment, Axogen utilizes both its own personnel and a variety of subcontractors for recovery/acquisition, storage, testing, processing and sterilization of the donated peripheral nerve and umbilical cord tissue. Additionally, independent certified laboratories have been contracted by Axogen and its subcontractors to perform testing.  The safety of Avance® Nerve Graft and Avive® Soft Tissue Membrane is supported by donor screening, process validation, process controls, and validated terminal sterilization methods. The Axogen Quality System has built in redundancies that are meant to control the release of each product for implantation only after such product meets our stringent quality control and product requirements.

 

Avance® Nerve Graft and Avive® Soft Tissue Membrane Tissue Recovery/Acquisition and Processing Facility

 

Axogen partners with other FDA registered tissue establishments and AATB accredited recovery/acquisition agencies or recovery/acquisition agencies in compliance with AATB standards for human tissue recovery. After consent for donation is obtained, donations are screened and tested in detail for safety in compliance with the federal regulations and AATB standards on communicable disease transmission.    Axogen processes and packages Avance® Nerve Graft and Avive® Soft Tissue Membrane using its employees and equipment pursuant to a License and Services Agreement,  

as amended (the “CTS Agreement”) with Community Blood Center (d/b/a Community Tissue Services) (“CTS”), Dayton, Ohio. CTS is an FDA registered tissue establishment. 

 

The CTS Agreement terminates December 31, 2021, subject to earlier termination by either party at any time for cause (subject to the non-terminating party’s right to cure, in certain circumstances), or without cause upon 6  months prior notice whereby notice cannot be provided prior to March 1, 2021. Under the CTS Agreement Axogen pays CTS a facility fee for clean room/manufacturing, storage and office space.  CTS also provides services in support of Axogen’s manufacturing such as routine sterilization of daily supplies, providing disposable supplies, microbial services and office support.  The service fee is based on a per donor batch rate.  The CTS facility provides a cost effective, quality controlled and licensed facility.  Axogen’s processing methods and process controls have been developed and validated to ensure product uniformity and quality.  Pursuant to the CTS Agreement, Axogen pays license fees on a monthly basis to CTS (See – Item 8. Financial Statements and Supplementary Data – Notes to Consolidated Financial Statements - Footnote 14. Commitments and Contingencies - Service Agreements).

 

Axogen acquired property which is located near the CTS facility which is comprised of a 70,000 square foot building on approximately 8.6 acres of land.  It is expected that renovations will be completed by the termination date of the CTS Agreement to provide a new processing facility that can be included in our Biologics License Application (“BLA”) for Avance® Nerve Graft.  The capacity of the property once operational, along with the ability for expansion, is expected to provide processing capabilities that will meet our intended sales growth.    Axogen believes it can obtain certain economic incentives from state and local authorities associated with the renovations and additional employment at the facility; such incentives are not expected to be a material offset to the cost of the project as a whole.

 

Avance® Nerve Graft and Avive® Soft Tissue Membrane Packaging

 

After processing, each Avance® Nerve Graft and Avive® Soft Tissue Membrane graft is visually inspected and organized by size into finished product codes. It is then packaged in primary packaging.  The outer pouch is the primary sterility and moisture barrier.  The packaging operation is performed in a controlled environment at CTS. 

 

Avance® Nerve Graft and Avive® Soft Tissue Membrane Sterilization and Labeling

 

After being processed and packaged, Avance® Nerve Graft and Avive® Soft Tissue Membrane are then terminally sterilized and shipped to Axogen’s Burleson, Texas distribution facility (the “Distribution Facility”).  There the products receive their final labels and are released following a final stringent technical and quality review.  Orders for Avance® Nerve Graft and Avive® Soft Tissue Membrane are placed with Axogen’s customer care team and the products are packaged and shipped from the Distribution Facility.

 

Avance® Nerve Graft and Avive® Soft Tissue Membrane Product Release

 

The Axogen Quality System meets the requirements set forth under 21 CFR Part 1271 for Human Cells, Tissues and Cellular and Tissue-Based Products, including Good Tissue Practices (“GTP”) and is compliant with the 21 CFR Part 820 Quality System Regulations (“QSR”).  Axogen has established quality procedures for review of tissue recovery, relevant donor medical record review and release to processing that meet or exceed FDA requirements as defined in 21 CFR Part 1271, state regulations, international regulations and AATB standards.  Furthermore, Axogen utilizes validated processes for the handling of raw material components, environmental control, processing, packaging and terminal sterilization.  In addition to ongoing monitoring activities for product conformity to specifications and sterility, shipping methods have been validated in accordance with applicable industry standards.

 

Manufacturing of Axogen Products Other Than Avance® Nerve Graft and Avive® Soft Tissue Membrane  

 

Manufacturing for the Axoguard® Product Line

 

Axoguard® is manufactured by Cook Biotech Incorporated, West Lafayette, Indiana (“Cook Biotech”), which was established in 1995 to develop and manufacture tissue grafts utilizing porcine extracellular matrix technology.  Axogen decided to expand its portfolio of products and felt that the unique ECM material offered by Cook Biotech provided the

combination of properties needed in nerve reconstruction. Cook Biotech’s ECM material is pliable, capable of being sutured, translucent and allows the patient’s own cells to incorporate into the extracellular matrix to remodel and form a tissue similar to the nerve’s epineurium.  Cook has its own source of the raw material for the ECM material and manufactures Axoguard® products from such sources.  In August 2008, Cook Biotech entered into an agreement, amended in March 2012, with Axogen to distribute its product worldwide in the field of the peripheral and central nervous system, but excluding use of the Axoguard® product in the oral cavity for endodontic and periodontal applications and OMF surgery solely as they relate to dental, soft or hard tissue repair or reconstruction. We believe the exclusion does not limit our identified OMF market, but expansion into certain additional OMF market areas could be limited to the Avance® Nerve Graft.

 

The Cook Biotech agreement was amended on February 26, 2018 to run through June 30, 2027.  It requires certain minimum purchases, although through mutual agreement the parties have not established such minimums and to date have not enforced such provision, and establishes a formula for the transfer cost of the Axoguard® products. Under the agreement, Axogen provides purchase orders to Cook Biotech, and Cook Biotech fulfills the purchase orders.

 

Manufacturing for the Acroval® Neurosensory and Motor Testing System and Axotouch® Two Point Discriminator

 

The Acroval® Neurosensory and Motor Testing System and Axotouch® Two Point Discriminator are contract manufactured by Viron Technologies, doing business as Cybernetics Research Laboratories (“CRL”), Tucson, Arizona.   CRL provides Acroval® to the Company’s Distribution Facility and Axogen performs final inspection and packaging for customer shipment.  CRL provides warranty service on behalf of the Company for the Acroval® and maintains certain levels of spare parts inventory for manufacturing and fulfillment of warranty work. CRL supplies Axotouch unpackaged and it is packaged at the Distribution Facility.

 

We believe CRL has capacity to support any future volumes of Acroval® and Axotouch®. 

 

Sales and Marketing

 

Overview

 

Axogen is focused on the developing market of peripheral nerve repair and regeneration, is committed to improving awareness of new surgical peripheral nerve repair options and is advancing evaluation capabilities for nerve issues, as well as building additional scientific and clinical data to assist surgeons and patients in making informed choices with respect to treatment of peripheral nerve injuries.  Axogen believes that there is an opportunity to rethink current approaches to peripheral nerve repair and that its approach will solidify its position as a leader in the field of peripheral nerve repair products. The following provides the key elements of Axogen’s sales and marketing strategy.

 

Increase Awareness of Axogen’s Products

 

Prior to the introduction of Axogen’s portfolio of peripheral nerve repair products, surgeons had a limited number of options available for the surgical repair of damaged or transected peripheral nerves.  Axogen entered the market to improve the standard of care for patients.   Axogen intends to increase market share by improving awareness and adoption of nerve repair techniques and Axogen’s products through the continued use of educational conferences and presentations, surgical resident and fellow training, scientific publications, and a knowledgeable and professional sales team.  Axogen works to increase usage within active accounts as well as expand the overall customer base by adding new active accounts. Axogen defines an “active account” as an account that has typically gone through the committee approval process, has at least one surgeon who has converted a portion of his or her treatment algorithms of peripheral nerve repair to the Axogen portfolio and has ordered Axogen products at least six times in the last 12 months.  Axogen is focused on plastic reconstructive surgeons and orthopedic and plastic hand surgeons who perform surgeries on patients suffering traumatic nerve damage or transection and who perform hand reconstructive surgeries, certain OMF surgeons who repair damaged oral nerves and certain plastic reconstructive surgeons who perform autologous flap breast reconstruction.

 

Expand Clinical and Scientific Data Regarding the Performance of Axogen Products

 

Generating clinical data is an important component of Axogen’s marketing strategy.  To date Axogen has seventy-seven peer reviewed clinical papers.  Sixty-six of such clinical papers relate to our Avance® Nerve Graft and thirty-one to our Axoguard® Nerve Protector and Axoguard® Nerve Connector products.  Certain of these publications contain data on multiple products. Axogen will continue to accept patients, for which there are more than 1,600 Avance® nerve repairs enrolled to date, in its RANGER® clinical study (defined below in “Government Regulations”), a utilization registry of Avance® Nerve Graft.  An additional arm of the registry study has been initiated tracking neurotization outcomes in breast reconstruction (Sensation-NOW).Five of the above mentioned publications and more than 60 scientific conference presentations have been generated to date from the registry.  A multicenter prospective randomized comparative pilot study of hollow tube conduits and Avance® Nerve Graft has completed subject enrollment and outcome follow-up and has been published (Means et al).  Case series in digital nerve repair have been published from the Mayo Clinic, Georgetown University Medical Center and Philadelphia Hand Center and a case series in OMF have been published from UT Southwestern and University of Illinois-Chicago.  A number of additional investigator initiated case reports, studies and publications have been completed including breast neurotization, compressive neuropathies and the surgical treatment of pain.  Case series in brachial plexus, neurotization of breast reconstruction and the surgical treatment of pain are also being developed.  Axogen also supports outside research and will continue to work with investigators working on grants with a translational focus.

 

Commitment to the Education of Best Practices in Peripheral Nerve Repair

 

Axogen has established educational conferences and presentations and surgical resident and fellow training that we believe has positioned us as a leader in providing peripheral nerve repair best practices. In 2018, we trained two-thirds of hand surgeon fellows through such courses and training.  The Company provides education on peripheral nerve repair through its “Best Practices in Nerve Repair” national programs (“National Programs”) as well as local and regional educational events.  In calendar years  2016, 2017 and 2018, we conducted  13, 15, and 18 National Programs, respectively, and we expect to conduct 25 National Programs in 2019.    These are supported by on-line tools and discussion forums such as Nerve Matters, an on-line community of peripheral nerve surgeons where the surgeons can ask questions, present cases and share findings in the area of peripheral nerve repair. 

 

Execute the Sales Process and Expand the Axogen Sales Team

 

Axogen provides full sales and distribution services through both a direct sales force and a team of independent sales agencies.  As of December 31, 2018,  Axogen had 85 direct sales professionals and 17 independent sales agencies in the U.S. By the end of 2019,  Axogen anticipates the number of direct sales professionals in the U.S. will be more than 115.  Axogen’s product portfolio is available in ten countries outside the U.S. through nine independent distributors.  Axogen provides support and resources for independent agencies and distributors both within and outside the United States and is increasing its direct sales force in selected United States territories.  Axogen provides its products to hospitals, surgery centers and military hospitals, calling on plastic reconstructive surgeons and orthopedic and plastic hand surgeons and certain OMF surgeons to review the benefits of the Axogen products.  While surgeons make the decision to implant the products in appropriate patients, hospitals make the decision to buy the products from Axogen.  In today’s budget constrained environment, hospital committees review new technologies for cost effectiveness as well as quality.  Axogen believes that it has been successful in meeting the needs of these hospital committees by demonstrating the cost/benefit of its products and providing a fair value to the hospital. 

 

Expand the Product Pipeline and Applications in Peripheral Nerve Repair

 

Axogen has developed line extensions and additional products to support surgeons in their needs for repairing damaged or transected peripheral nerves.  Axogen believes additional opportunities exist to develop or acquire complementary products in peripheral nerve repair.  In addition, there exists opportunities to expand the existing portfolio of products in new applications of peripheral nerve repair in lower extremity surgery, head and neck surgery, urology and the surgical treatment for pain.

 

Axogen Strengths

 

Axogen believes that it has the following strengths in the field of peripheral nerve repair and regeneration:

 

Established Peripheral Nerve Repair Expertise

 

Axogen has made a significant investment in understanding peripheral nerve anatomy and surgical peripheral nerve repair and regeneration.  This has been accomplished through interaction with leading academic centers throughout the United States and by striving to build an outstanding internal team of technical and clinical experts.

 

Commitment to the Promotion and Education of Best Practices in Peripheral Nerve Repair

 

Axogen has established educational conferences and presentations and surgical resident and fellow training that we believe is positioning us as a leader in providing peripheral nerve repair best practices. Axogen has developed the programs and speakers to train surgeons currently in practice as well as surgical fellows.

 

Clinical Date

 

Axogen is developing a body of clinical evidence of its implants in real world situations surgeons face when diagnosing and treating their patients with peripheral nerve injuries.  This data provides support for surgeons in their clinical decision making and providing treatment options to their patients.

 

A pivotal multicenter prospective randomized comparative study (RECON) of hollow tube conduits and Avance® Nerve Graft to support the transition to a biological product is in process (See “Government Regulations – Clinical Trials”).  A multicenter, prospective, randomized and subject blinded study of Axoguard® Nerve Cap as compared to neurectomy for the treatment of symptomatic neuroma (REPOSE) and a registry study of Avive® Soft Tissue Membrane in acute trauma have been initiated and are enrolling.  Finally, a pilot study on the repair of the cavernous nerves in prostate cancer patients has completed enrollment, follow-up and data analysis.

 

Surgical Implant Commercialization Experience

 

The Axogen commercialization team consists of sales, marketing, and customer care professionals with backgrounds in the medical device and biotechnology industries. The team has strong experience in the introduction of technologies and has been instrumental in beginning to establish Avance® Nerve Graft, Avive® Soft Tissue Membrane and the Axoguard® product lines as a new standard of care for the surgical treatment of peripheral nerve damage or transections in our core markets.  Axogen believes it can leverage these capabilities in expanding the commercial success of the current Axogen products, future peripheral nerve products and opportunities in new peripheral nerve surgical applications.

 

Avance® Nerve Graft Performance

 

Axogen has worked with leading institutions, researchers and surgeons to support innovation in the field of surgical peripheral nerve repair. We believe Axogen’s RANGER® study (defined below in the section entitled “Government Regulations”) is the largest multi-center clinical study conducted in peripheral nerve gap repair.  Axogen is also conducting a Multicenter, Prospective, Randomized, Subject and Evaluator Blinded Comparative Study of Nerve Cuffs and Avance® Nerve Graft Evaluating Recovery Outcomes for the Repair of Nerve Discontinuities (“RECON”). This study is the phase 3 trial to support its BLA for the Avance® Nerve Graft (See “Government Regulations”).  The January, 2012 edition of Microsurgery and November 2012 edition of The Journal of Hand Surgery, June 2015 edition of Journal of Reconstructive Microsurgery and January 2017 edition of HAND each contain an article summarizing the RANGER® study results. The Brooks et al. publication reported on 55 Avance® Nerve Graft nerve repairs and resulted in meaningful motor and sensory recovery in 87% of nerve transections between 5 and 50 mm.  Additionally, no implant related adverse events were reported.  (Brooks, D. N., Weber, R. V., Chao, J. D., Rinker, B. D., Zoldos, J., Robichaux, M. R., Ruggeri, S. B., Anderson, K. A., Bonatz, E. E., Wisotsky, S. M., Cho, M. S., Wilson, C., Cooper, E. O., Ingari, J. V., Safa, B., Parrett, B. M. and Buncke, G. M. (2012), Processed nerve allografts for peripheral nerve reconstruction: A

multicenter study of utilization and outcomes in sensory, mixed, and motor nerve reconstructions. Microsurgery, 32: 1—14. doi: 10.1002/micr.20975 and Cho, et al. 2012, J Hand Surg Am 37(11):2340-9).  A meta-analysis of available clinical outcomes data from published papers on the leading synthetic collagen conduit showed meaningful improvement in only 40-74% of cases bridging a gap in the nerve. This data was further verified in a review of autograft alternative in the 2016 edition of Hand Clinics.   A similar meta-analysis for nerve autograft reported meaningful improvement in 60-88% of nerve repairs.  Finally, the Company has expanded RANGER® to include an additional study arm called Sensation-NOW™ for breast neurotization.

 

International Opportunity for Revenue

 

Axogen currently focuses on the U.S. market, with additional foreign distribution and sales in Canada, United Kingdom and certain other countries. The need for the surgical repair of damaged or transected nerves is a global issue. Through its ex-U.S. revenue, Axogen has demonstrated the capability to take its current peripheral nerve repair product offering into new geographical markets.  Axogen does not currently have European Union (“E.U.”) wide approval for Avance® Nerve Graft as human tissue is approved in each individual country.  Cook Biotech is currently renewing the Axoguard product CE Mark and until such renewal Axogen is able to sell only those Axoguard© products that are currently in inventory in the E.U., which inventory may not be sufficient to satisfy all product sales prior to obtaining the renewal. Avive® Soft Tissue Membrane, Acroval® Neurosensory and Motor Testing System and Axotouch® Two Point Discriminator are only available in the United States, but Axogen is taking action to introduce them internationally, which introduction is subject to meeting the appropriate regulatory standards of a particular country and any appropriate E.U. wide regulation or directive.  To date, revenue from international distribution and sales have not been material, there are no material risks associated with foreign operations and we do not have dependencies as to international revenue.  See Risk Factors - Axogen’s operations must comply with FDA and other governmental requirements.

 

Research and Development

 

Axogen believes it provides the most extensive product portfolio for peripheral nerve repair available.  Our current development focus is to expand clinical data in both traumatic peripheral nerve repair and other surgical applications.  Additional product line extensions of the Avance® and Axoguard® products and other peripheral nerve repair products may be developed. In this regard, Axogen introduced: (1) an Axoguard® Connector line extension in winter 2014 by providing a new longer 15mm product; (2) Axotouch® in the fall of 2014; (3) Acroval® in March 2016; (4) Avive® Soft Tissue Membrane launched in November 2016; and(5) Axoguard® Nerve Cap which has been developed has its 510(k) premarket clearance from the FDA and is currently available in select locations for clinical and user preference evaluations.

 

 Axogen works with academic institutions in the expansion of treatments for peripheral nerve and is involved in a number of grants from government agencies related to nerve repair or use of our products and/or technologies. For the years ended December 31, 2018, 2017, and 2016, Axogen recognized grant revenue of approximately $195,000, $56,000 and $290,000, respectively.  For the years ended December 31, 2018, 2017, and 2016, Axogen spent approximately $11.8 million, $6.7 million, and $4.2 million, respectively, on total research and development expenses for product and clinical development.

 

Competition

 

The medical device and biotechnology industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products. As such, Axogen cannot predict what products may be offered in the future that may compete with Axogen’s products.  With regard to peripheral nerve function evaluation and measurement there are a number of methods and techniques with little consistency of measurement protocols.  Currently as to peripheral nerve repair products, Axogen competes primarily against all transected and non-transected peripheral nerve repair approaches including direct suture repair, autograft and hollow-tube nerve conduits and materials used to wrap and protect damaged peripheral nerve tissue.  Finally, there are numerous companies that offer amnion products in a variety of formats, primarily in the area of wound care, which could be competitive with Axogen’s Avive® product.

 

Because the requirements of the biomaterials used in peripheral nerve repair can vary based on the severity and location of the damaged nerve, the size and function of the nerve, surgical technique and patient preference, Axogen’s peripheral nerve repair products compete against both autograft materials (nerve in the case of a bridging repair and vein or fat in the case of a nerve protection repair), and a limited number of off-the-shelf alternatives for grafting and protecting.  Competitive aspects of our products focus on the overall value proposition of our products and their suitability for specific applications and can include composition and structure of the material, ease of use, clinical evidence, handling, and price. Axogen’s major competitors for off-the-shelf repair options in hollow-tube conduits and bio-absorbable wraps are the following companies:

 

 

Axogen believes that surgeons use Avance® Nerve Graft because it provides them with the natural three-dimensional structure and familiar handling characteristics of a typical peripheral nerve for bridging peripheral nerve transections (severed peripheral nerves) without the comorbidities and additional surgical site of an autograft as well as confidence in the performance of the product as a result of the growing body of clinical literature.  Axoguard® Nerve Protector and Axoguard® Nerve Connector provide the unique features of pliability, suturability and translucence for visualization of the underlying nerve while also allowing the patient’s own cells to incorporate into the extracellular matrix to remodel. Avive®  Soft Tissue Membrane has what Axogen believes are favorable handling and absorption properties and is a resorbable soft tissue covering to separate tissues and modulate inflammation in the surgical bed.   Acroval® Neurosensory and Motor Testing System is a continuation of Axogen’s commitment to improving patient outcomes.  Axogen believes that the standardization of evaluation and measurement techniques will facilitate comparison and interpretation of clinical results leading to better understanding and care for patients with peripheral nerve damage.

 

Axogen believes any current or future competitors face the following important barriers to entry as it relates to the market for its peripheral nerve repair products.  Axogen’s intellectual property (“IP”), and that of its partners, including patents, patents-pending, trade secrets and know how, is believed to be an important barrier for its Avance® Nerve Graft and Axoguard® products.  Axogen has developed knowledge and experience in understanding and meeting FDA regulatory requirements for Avance® Nerve Graft, including having made a substantial investment in conducting the preclinical and clinical testing necessary to support a submission for a FDA BLA.  Additionally, Axogen believes the ability to offer a portfolio of products focused on peripheral nerve repair and evaluation provides a unique competitive position as to other entities that do not have this breadth of product offering.  However, due to its limited resources, its smaller size and its relatively early stage, Axogen believes it may face competitive challenges from larger entities and market factors that could negatively impact Axogen’s growth, including competitors’ introduction of new products and competitors’ bundling of products to achieve pricing benefits. 

 

Intellectual Property

 

Overview

 

Axogen protects its IP through a combination of patents, trademarks, trade secrets, and copyrights.  In addition, Axogen safeguards its trade secrets and other confidential know-how, and carefully protects these and other IP rights when engaging with third parties.  For example, Axogen requires vendors, contract organizations, consultants, advisors and employees to execute confidentiality and nondisclosure agreements, and to appropriately protect any information disclosed to them by Axogen so as to preserve its confidential and/or trade secret status.  Axogen also requires consultants, advisors and employees to assign to Axogen their rights to any IP arising out of their relationship with Axogen.

 

License Agreements

 

Axogen has entered into license agreements with University of Florida Research Foundation (the “UFRF”) and the University of Texas at Austin (“UTA”). Under the terms of these license agreements, Axogen holds exclusive worldwide licenses to underlying technologies used by Axogen in its Avance® Nerve Graft.  The license agreements include both the right to issued patents and patents pending in the U.S. and international markets.  The effective term of the license agreements extends through the term of the related patents.  In the event of default, licensors may also terminate an agreement (after written notice) if Axogen fails to cure a breach.  The license agreements contain the following key terms:

 

 

Currently, Axogen pays royalties to UFRF and UTA specific to the licensed technologies related to the Avance® Nerve Graft.

 

Patents

 

As of the date of this Form 10-K, Axogen owns or is the exclusive licensee of fifteen issued U.S. patents, about fifteen pending U.S. patent applications (including those for which Axogen has received a notice of allowance) and numerous international patents and patent applications with regard to its peripheral nerve products.  The granted European Patent No. EP1425390 has been validated in France, Germany, Italy, Spain, Sweden, Switzerland, and the United Kingdom. The following table identifies the issued U.S. patents owned or licensed by Axogen with regard to its peripheral nerve products, including the patent number, the title of each patent, and the estimated expiration date of each patent.

 

 

With respect to our Avance® Nerve Graft we have patent protection through at least September 2023 in the United States. In addition we also expect Avance® Nerve Graft will receive Biosimilar Protection that would provide 12 years of data exclusivity. Finally, Axogen has Enforcement Discretion  from FDA allowing continued distribution under controls applicable to Human Cellular and Tissue-based Products (“HCT/P”) with an agreed transition plan to a Biologic Product under a BLA.  We believe a competitive processed peripheral nerve allograft would need to successfully complete BLA Phase I, II and III clinical studies prior to clinical release, the completion of which we believe would take at least 8 years.

 

Additionally, Axogen entered into an exclusive distribution agreement with Cook Biotech in August 2008, as subsequently amended in February 2018, to distribute Cook’s ECM technology in the form of the Surgisis® Nerve Cuff, the form of a nerve wrap or patch, or the form of any other mutually agreed to configuration in the field of peripheral nervous system and central nervous system use, but excluding use of the Axoguard® product in the oral cavity for endodontic and periodontal applications and OMF surgery solely as they relate to dental, soft or hard, tissue repair or reconstruction.  Axogen has subsequently rebranded the Surgisis products under the Axoguard® name.  Cook Biotech believes it has know-how and trade secrets with respect to the ECM technology that provides certain competitive obstacles.

 

Because of the length of time and expense associated with bringing new products through development and the governmental approval process, medical technology companies have traditionally placed considerable importance on obtaining and maintaining patent protection for significant new technologies, products and processes. Axogen’s policy is to seek patent protection for, or where strategically preferable, maintain as trade secret, the inventions that it considers important to its products and the development of its business. Axogen has sought and will continue to seek patent protection for select proprietary technologies and other inventions emanating from its R&D, including with respect to uses, methods, and compositions, in an effort to further fortify its IP stronghold in areas of import to the company and its growing product portfolio. In instances that patent protection is not possible, product value to Axogen’s portfolio can still be derived. 

 

Trademarks, Trade Secrets and Copyrights

 

Axogen holds more than one hundred registered trademarks and has filed more than sixty additional trademark applications worldwide to protect its brand.  This allows Axogen to prevent competitors from, for example, using the same or a confusingly similar company name, or the same or confusingly similar product names which could otherwise wrongfully allow such competitors to capitalize on the Axogen brand, reputation and goodwill, and thereby improperly bolster their sales or reputations through, for example, consumer confusion, a false indication of Axogen’s endorsement, or of a false indication of corporate or contractual relationship with Axogen.  Axogen polices and enforces its marks. 

 

Axogen possesses trade secrets and material know-how in the following general subject matters: nerve and tissue processing, nerve repair, product testing methods, and pre-clinical and clinical expertise.  Axogen has registered copyrights for training tools and artistic renderings.

 

Government Regulations

 

U.S. Government Regulation Overview

 

Axogen’s products are subject to regulation by the FDA, as well as other federal and state regulatory bodies in the U.S. and comparable authorities in other countries. In addition, its Avance® Nerve Graft and Avive® Soft Tissue Membrane must comply with the standards of the tissue bank industry’s accrediting organization, the AATB.

 

Axogen distributes for Cook Biotech the Axoguard® product line. Cook Biotech is responsible for the regulatory compliance of the Axoguard® product line. Axoguard® products are regulated as medical devices and subject to premarket notification requirements under section 510(k) of the Federal Food, Drug, and Cosmetic Act (the “FD&C Act”), 21 CFR Part 820 (“Quality System Regulation”) and related laws and regulations. Cook Biotech has obtained a 510(k) premarket clearance for Axoguard® Nerve Connector from the FDA for the use of porcine (pig) small intestine submucosa for the repair of peripheral nerve transections where gap closure can be achieved by flexion of the extremity. Cook Biotech has also obtained a 510(k) premarket clearance for Axoguard® Nerve Protector for the repair of peripheral nerve damage in which there is no gap or where a gap closure is achieved by flexion of the extremity.  We sell the 510(k) cleared device under the trade name Axoguard® Nerve Protector and Axoguard® Nerve Connector.

 

Axogen is responsible for the regulatory compliance of Avive®  Soft Tissue Membrane.  Avive® Soft Tissue Membrane is processed and distributed in accordance with FDA requirements for Human Cellular and Tissue-based Products (361 HCT/P) under 21 CFR Part 1271 regulations, US State regulations and the guidelines of the AATB.

 

Axogen also distributes Axotouch® Two-Point Discriminator.  This device is manufactured for Axogen and distributed from the Burleson Facility is a Class I device (general controls) that is exempt from premarket notification and the Quality System Regulation requirements except for the Recordkeeping and Complaint file requirements. It is classified by FDA under 21 CFR 882.1200 (Two-point discriminator, product code: GWI).

 

The Acroval® line of devices is manufactured for Axogen and distributed from the Burleson Facility.  The Acroval® devices are regulated as medical devices and in 2018, the FDA changed the notification requirements to be exempt under Section 510(k) of the FD&C Act.  The Acroval® line of devices includes the Acrogrip®, Acropinch® and PSSD®, all of

which received 510(k) clearance by the FDA in the 1990’s.  Acrogrip® was cleared under the name Digi-Grip Sensor, Acropinch® was cleared as Pinch Sensor and PSSD® as the NK Pressure-Specified Sensory Device.

 

In 2007, Axogen began to process and distribute its Avance® Nerve Graft pursuant to Section 361 of the PHS Act and 21 CFR Part 1271 Human Cells, Tissues, and Cellular and Tissue Based Products controls. Such action was based on Axogen’s good faith belief that Avance® Nerve Graft product was an HCT/P tissue product regulated solely under Section 361. From October 2008 through early 2010, Axogen was in communication with the FDA concerning the regulatory status of the Avance® Nerve Graft product. In April 2010, in response to a Request For Designation filed by Axogen, the FDA determined that Avance® Nerve Graft was a biologic product that would be reviewed and regulated by the U.S. FDA Center for Biologics Evaluation and Research (“CBER”) under the requirements of Section 351 of the PHS Act. Section 351 requires, among other things, an approved license to market a biological product.

 

Axogen met with CBER in July 2010 and, between July 2010 and November 2010, provided information to CBER that resulted in the FDA issuing a letter stating the agency’s intent to exercise enforcement discretion with respect to the continued introduction or delivery for introduction into interstate commerce of Avance® Nerve Graft assuming that certain conditions are met relating to the transition of Avance® Nerve Graft from regulation as an HCT/P under Section 361 to a biological product under section 351 of the PHS Act. Specifically, the FDA is permitting Avance® Nerve Graft to be distributed, subject to FDA enforcement discretion, provided that:

 

 

 

 

 

 

 

 

 oIn November 2018, Axogen was audited by the FDA with respect to its Human Tissue Quality System under 21 CFR Part 1271.  Such audit resulted in one Form 483 observation on tissue tracking.  Axogen has taken corrective action to correct this  observation and the FDA has accepted the corrective action plan.

 

 

 

Axogen is working to ensure compliance with the applicable regulations through ongoing discussions with the FDA regarding the transition of the quality system to 21 CFR Parts 210/211 and 600-610 compliance with the FDA and through audits for compliance to 21 CFR Part 1271 and amendments to the IND providing updates to the phase III clinical trial. The final determination of regulatory compliance will be made by the FDA during the pre-license inspection as part of the BLA review.  If the FDA does not find Axogen to be in compliance, or if Axogen is unable to meet the required standards for preclinical studies, clinical studies and Chemistry, Manufacturing, and Controls, the approval of the BLA would be delayed or denied.

 

The FDA will end the period of enforcement discretion upon a final determination of Axogen’s future BLA submission or if prior to the BLA submission, the FDA finds that Axogen does not meet the conditions for the transition plan, or is not exercising due diligence in executing the transition (e.g., study completion, or BLA submission is neither timely nor adequate). If final action on the BLA is negative or Axogen is found to not meet the conditions for the transition plan or its execution, Axogen will not be able to continue to distribute the Avance® Nerve Graft. Axogen continues to work diligently to execute the transition plan, including maintaining regular communication with the FDA, and, in this context, continues to distribute Avance® Nerve Graft.

 

The BLA application of Avance® Nerve Graft, if approved, will require a potentially substantial user fee payment to the FDA, although certain exemptions, waivers and discounts of the user fees may apply, including certain waivers or discounts for small businesses.

 

The Food and Drug Administration Safety and Innovation Act, referred to herein as FDASIA (Public Law 112-144), which was signed into law on July 9, 2012, amended the FD&C Act. FDASIA includes the Prescription Drug User Fee Amendments of 2012 which authorizes the FDA to continue to collect the following user fees from applicants who submit certain new drug and biological product applications and supplements:

 

 

In September 2018 the FDA granted a Regenerative Medicine Advanced Therapy (RMAT) designation for Avance® Nerve Graft. A regenerative medicine therapy is eligible for the designation if it is intended to treat, modify, reverse or cure a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the product has the potential to address unmet medical needs for such a disease or condition. The RMAT designation provides access to a streamlined approval process for regenerative medicine technologies and ensures continued informal meetings with the FDA in support of the BLA for Avance® Nerve Graft.

 

The Company believes that any future, competitive peripheral nerve allograft would be required to follow the standard pathway for biologic licensing, which typically entails multiple clinical trials and takes many years. The FDA provided updated guidance in December 2017 which made clear that any processing that alters the biological characteristics of peripheral nerve tissue would be considered more than minimal manipulation, and therefore require a BLA prior to marketing.

 

The Company has maintained a collaborative dialogue with the FDA and will continue to work closely with the FDA as it progresses towards its BLA submission. Upon BLA approval, Avance® Nerve Graft we believe we will have 12 years of data exclusivity with regard to potential biosimilars.

 

FDA — General

 

FDA regulations govern nearly all the activities that Axogen performs, or that are performed on its behalf, to ensure that medical products distributed domestically or exported internationally are safe and effective for their intended uses. The activities the FDA regulates include the following:

 

 

Failure to comply with applicable FDA regulatory requirements may subject Axogen to a variety of administrative or judicially-imposed penalties or sanctions and/or prevent it from obtaining or maintaining required approvals, clearances or licenses to manufacture and market its products. Such failure to comply with the applicable FDA requirements may subject Axogen to stringent administrative or judicial actions or sanctions, such as agency refusal to approve pending applications, warning letters, product recalls, product seizures, total or partial suspension of production or distribution of products, injunctions, or civil or criminal prosecution.

 

FDA’s Premarket Clearance and Approval Requirements - Medical Devices

 

Unless an exemption applies, each medical device distributed commercially in the U.S. requires either a 510(k) premarket notification submission or a Pre-Market Approval (“PMA”) Application to the FDA. Medical devices are classified into one of three classes—Class I, Class II, or Class III—depending on the degree of risk, the level of control necessary to assure the safety and effectiveness of each medical device and how much is known about the type of device. For devices first intended for marketing after May 28, 1976, pre-market review and clearance by the FDA for Class I and II medical devices is accomplished through the 510(k) pre-market notification procedure by finding a device substantially equivalent to a legally marketed Class I or II device, unless the device is exempt. The majority of Class I medical devices are exempt from the 510(k) premarket notification requirement.  Devices deemed by the FDA to pose the greatest risk, such as life-sustaining, life-supporting or implantable devices for which Class II controls are inadequate to assure safety or effectiveness, and novel devices, including devices deemed not substantially equivalent to a previously cleared 510(k) device, are placed in Class III.  Class III devices generally require an approved PMA prior to marketing.

 

A PMA must be supported by extensive data, including, but not limited to, technical, preclinical, clinical trials, manufacturing and labeling to demonstrate to the FDA’s satisfaction, the safety and effectiveness of the device.

 

FDA’s Premarket Approval Requirements - Biologic Products

 

Biological Product License Application (BLA) Pathway

 

Biological products subject to BLA requirements are approved under the Public Health Service Act.  Biological products require FDA approval of a BLA to be marketed.  In order to be approved, a BLA must demonstrate the safety, purity and potency of the product candidate based on results of preclinical studies and clinical trials. A BLA must also contain extensive CMC and other manufacturing information, and the applicant must pass an FDA pre-approval inspection of the manufacturing facility or facilities at which the biologic product is produced to assess compliance with the FDA’s cGMP. Satisfaction of FDA approval requirements for biologics typically takes several years and the actual time required may vary substantially based on the type, complexity and novelty of the product.  Axogen cannot be certain that any BLA approvals for its products will be granted on a timely basis, or at all.

 

The steps for obtaining FDA approval of a BLA to market a biologic product in the U.S. include:

 

 

Preclinical tests include laboratory evaluations of product chemistry, toxicity and formulation, as well as animal studies. An IND sponsor must submit the results of the preclinical tests, together with manufacturing information and analytical data, to the FDA as part of the IND. Some preclinical testing may continue after the IND is submitted. The

IND must become effective before human clinical trials may begin. An IND will automatically become effective 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions about issues such as the conduct of the trials and or supporting preclinical data as outlined in the IND. In that case, the IND sponsor and the FDA must resolve any outstanding FDA concerns or questions before clinical trials can proceed. In other words, submission of an IND may not result in the FDA allowing clinical trials to commence.

 

Biosimilar Biological Products

 

A regulatory approval pathway for biosimilars was established by The Biologics Price Competition and Innovation Act (“BPCIA”), as part of the Patient Protection and Affordable Care Act of 2010. An important component of the legislation specified that a manufacturer of a reference biological product would be granted 12 years of non-patent data exclusivity before a biosimilar could be approved for marketing in the US. An application for a biosimilar product may not be submitted to FDA until four years after the approval date of the BLA for the reference biological product. BPCIA provides for an abbreviated licensure process for a biosimilar, i.e., a biological product that is highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences compared to the reference product in terms of safety, purity and potency.  At its discretion, the FDA can waive a requirement for any required element in an application for a biosimilar product. In addition, the legislation distinguished approval of a biosimilar from approval of such a product as a substitute for the reference biological products. Where a product is approved as a biosimilar and additionally approved as a substitute for the reference biologic, it is considered an interchangeable product. Approval as interchangeable requires that the product is biosimilar and can be expected to produce the same clinical results as the reference product in any given patient, and if intended for repeat dosing, a demonstration that the risk in terms of safety or diminished efficacy of alternating or switching between the use of the interchangeable and reference product is not greater than the risk of using the reference product without such alternating or switching. Interchangeable products can be substituted for a reference product without intervention of the prescribing healthcare provider.  Most states have enacted or are considering laws that regulate the use and substitution of biosimilar and interchangeable products.   For example, Virginia requires licensure as interchangeable by the FDA for a pharmacist to dispense a biosimilar in place of a prescribed biological product (Virginia § 54.1-3408.04).

 

FDA’s Pre-Approval and Pre-Licensing Requirements

 

Before approving a BLA, the FDA generally inspects the facility or the facilities at which the product is manufactured. The FDA will not approve the product if it finds that the facility does not appear to be in cGMP compliance. If the FDA determines the application, manufacturing process or manufacturing facilities are not acceptable, it will either not approve the application or issue a complete response letter to indicate that the review cycle for an application is complete and that the application is not ready for approval.  The letter will describe specific deficiencies and, when possible, will outline recommended actions the applicant might take to get the application ready for approval. Notwithstanding the submission of any requested additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

 

The testing and approval process requires substantial time, effort and financial resources, and each may take several years to complete. Data obtained from clinical activities are not always conclusive and may be susceptible to varying interpretations, which could delay, limit or prevent regulatory approval. The FDA may not grant approval on a timely basis, or at all. Axogen may encounter difficulties or unanticipated costs in its efforts to secure necessary governmental approvals, which could delay or preclude it from marketing its products. The FDA may limit the indications for use or place other conditions on any approvals that could restrict the commercial application of the products. After approval, some types of changes to the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further testing requirements and FDA review and approval.

 

Post-Approval Requirements

 

After regulatory approval of a product is obtained, Axogen will be required to comply with a number of post-approval requirements. For example, as a condition of approval of a BLA, the FDA may require post marketing testing and surveillance to monitor the product’s continued safety or efficacy. In addition, holders of an approved BLA are required to keep extensive records, to report certain adverse reactions and production problems such as biologic

deviation reports to the FDA, to provide updated safety and efficacy information and to comply with requirements concerning advertising and promotional labeling for their products. Also, quality control and manufacturing procedures must continue to conform to cGMP regulations as well as the manufacturing conditions of approval set forth in the BLA. The FDA periodically inspects manufacturing facilities to assess compliance with cGMP regulations, which impose certain procedural, substantive and recordkeeping requirements. Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain compliance with cGMP and other aspects of regulatory compliance.

 

Future FDA inspections may identify compliance issues at Axogen’s facilities or at the facilities of its contract manufacturers that may disrupt production or distribution, or require substantial resources to correct and prevent recurrence of any deficiencies. In addition, discovery of problems with a product or the failure to comply with applicable requirements may result in restrictions on a product, manufacturer or holder of an approved BLA, including withdrawal or recall of the product from the market or other voluntary, FDA-initiated or judicial action that could delay or prohibit further marketing. Newly discovered or developed safety or effectiveness data may require changes to a product’s approved labeling, including the addition of new warnings and contraindications. Finally, new government requirements, including those resulting from new legislation, may be established that could delay or prevent regulatory approval of Axogen products that are currently under development or regulatory activity.

 

The FDA has broad regulatory compliance and enforcement powers. If the FDA determines that Axogen failed to comply with applicable regulatory requirements, it can take a variety of compliance or enforcement actions, such as issuing a FDA Form 483 notice of inspectional observations, warning letter, or untitled letter, imposing civil money penalties, suspending or delaying issuance of approvals, requiring product recall, imposing a total or partial shutdown of production, withdrawal of approvals or clearances already granted, and pursuing product seizures, consent decrees or other injunctive relief, and criminal prosecution through the U.S. Department of Justice (the “DOJ”). The FDA can also require Axogen to repair, replace or refund the cost of devices that it manufactured or distributed. If any of these events were to occur, it could materially adversely affect Axogen’s business.

 

Clinical Trials

 

Clinical trials are required to support a BLA or PMA and are sometimes required for 510(k) clearance. Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators. Clinical trials are conducted under strict requirements to ensure the protection of human subjects participating in the trial and under protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring and safety, and the effectiveness criteria to be evaluated. Clinical trials for biological products require the submission and FDA acceptance of an IND and clinical trials for medical devices require the submission and FDA approval of an Investigational Device Exemption application, or IDE, unless the device regulations provide for an exemption from the IDE requirement.  Clinical trials for significant risk devices may not begin until the IDE is approved by the FDA and the Institutional Review Board (IRB) overseeing the particular clinical trial. If the product is considered a non-significant risk device under FDA regulations, the trial must only be approved by an IRB prior to its initiation.  A protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND or IDE, for significant risk devices. In addition, for these studies, an IRB at each site at which the study is conducted must approve the protocol, subject consent form and any amendments for each site at which the study is conducted. All research subjects must be informed, among other things, about the risks and benefits of the investigational product and provide their informed consent in writing.

 

Clinical trials under an IND typically are conducted in three sequential phases, but the phases may overlap or be combined.  In Axogen’s case, Axogen believes that the Phase 3 clinical trial study for the Avance® Nerve Graft represents the only new clinical data that will be required to evaluate safety and effectiveness.  Phase 1 clinical trials usually involve the initial introduction of the investigational product into a small group of healthy volunteers (e.g., 10 to 20) to evaluate the product’s safety (dosage tolerance and pharmacokinetics if a biologic product) and, if possible, to gain an early indication of its effectiveness.  Phase 2 clinical trials usually involve controlled trials in a larger but limited patient population (e.g., a few hundred) to:

 

 

Phase 3 clinical trials usually further evaluate clinical efficacy and test further for safety in an expanded patient population (e.g., a hundred to several thousand). Phase 3 clinical trials usually involve comparison with placebo, standard treatments or other comparators. Usually at least one well-controlled large Phase 3 or pivotal clinical trial demonstrating safety and efficacy is required to support a BLA. These trials are intended to establish the overall risk-benefit profile of the product and provide an adequate basis for physician labeling. Phase 3 trials are almost always larger, more time consuming, complex and costly than Phase 1 and Phase 2 clinical trials.  Phase 1, Phase 2 and Phase 3 clinical testing may not be completed successfully within any specified period, if at all. Furthermore, the FDA or Axogen may suspend or terminate clinical trials at any time on various grounds, including a finding that the subjects or patients are being exposed to an unacceptable health risk, have experienced a serious and unexpected adverse event, or that continued use in an investigational setting may be unethical. Similarly, an IRB can suspend or terminate approval of research if the research is not being conducted in accordance with the IRB’s requirements or if the research has been associated with unexpected serious harm to patients.

 

Investigational New Drug Application

 

For a biologic product, an IND must be submitted prior to the initiation of the clinical study.  The IND application must contain information in three broad areas:

 

 

Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials.  During this time, the FDA has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.

 

Axogen Clinical Trials

 

Axogen has an active clinical research program to gather data on Avance® Nerve Graft.  Axogen has completed two clinical studies and is performing two ongoing clinical studies. The ongoing studies are “A Multicenter Retrospective Study of Avance® Nerve Graft Utilization, Evaluations and Outcomes in Peripheral Nerve Injury Repair (“RANGER®”)” and “A Multicenter, Prospective, Randomized, Patient and Evaluator Blinded Comparative Study of Nerve Cuffs and Avance® Nerve Graft Evaluating Recovery Outcomes for the Repair of Nerve Discontinuities (“RECON”)”. Completed studies are “A Multicenter, Prospective, Randomized, Comparative Study of Hollow Nerve Conduit and Avance® Nerve Graft Evaluation Recovery Outcomes of the Nerve Repair in the Hand (“CHANGE”)” and a pilot study to evaluate the use of Avance® Nerve Graft in the reconstruction of nerves following prostatectomy.

 

Axogen will continue to accept patients in the RANGER® clinical study, a utilization registry of Avance® Nerve Graft. Five publications and more than 60 scientific conference presentations have been generated to date from the registry.  The RANGER® Study is an observational study in current enrollment. It is designed to allow enrollment of up to a total of 5,000 subjects over the next several years. The follow-up for the RANGER® Study is standard of care with a target of up to 36 months post peripheral nerve repair. At the time of the BLA submission, Axogen will submit an

interim report in the BLA for the enrolled subjects. In 2013, a Matched Autograft and Tube Conduit Case Control Cohort Arm of RANGER® (“MATCH”) comparative arm was added.  Subjects treated with Avance® Nerve Graft were matched to the peripheral nerve autograft or tube conduit treated groups based on size of gap length. We anticipate having approximately 300 subjects treated with peripheral nerve autograft and/or tube conduit in the comparative arm.  

 

Axogen created  an additional RANGER® Study arm called Sensation Neurotization Outcomes for Women (“Sensation-NOW”).  This registry cohort is designed to assess breast sensation following reconstruction with or without neurotization.  The study is currently enrolling and is designed to enroll up to 2,000 subjects who have undergone mastectomy and breast reconstruction.

 

Axogen has worked with leading institutions, researchers and surgeons to support innovation in the field of surgical peripheral nerve repair.  Axogen believes that RANGER® is currently the largest multi-center observational clinical study conducted in peripheral nerve gap repair.  Axogen’s ongoing RECON study will also continue our clinical work, providing a new multi-center, prospective, randomized, clinical study on Avance® Nerve Graft. The January 2012 edition of Microsurgery, November 2012 edition of The Journal of Hand Surgery June 2015 edition of Journal of Reconstructive Microsurgery and the January 2017 edition of HAND, each contain an article summarizing RANGER® study results (Brooks, et al. Processed nerve allografts for peripheral nerve reconstruction: A multicenter study of utilization and outcomes in sensory, mixed, and motor nerve reconstructions. Microsurgery, 2012 Jan; 32(1): 1-14; and Cho, et al. Functional outcome following nerve repair in the upper extremity using processed nerve allograft. J Hand Surg Am 2012 Nov; 37(11):2340-9 and Rinker, et al. Outcomes of short-gap sensory nerve injuries reconstructed with processed nerve allografts from a multicenter registry study. J Reconstr Microsurg 2015 Jun; 31(5):384-90).  Brooks et al. reported on 55 Avance® Nerve Graft nerve repairs and resulted in meaningful motor and sensory recovery in 87% of nerve transections between 5 and 50 mm.  Cho et al. showed that Avance® Nerve Graft provided 89% meaningful recovery for digital nerve injuries, and 80% meaningful recovery for motor function in mixed and motor nerve injuries. An expanded data milestone was presented at the 5th Vienna Symposium on Surgery of Peripheral Nerves in June 2014 and such expanded RANGER® data provides that of the injuries repaired with the Avance® Nerve Graft 90%, 80% and 87% achieved meaningful recovery for gap lengths of 5-14 mm, 15-29 mm and 30-65 mm, respectively. Rinker et al. reported on a subgroup from the RANGER® registry on sensory recovery of short-gap digital nerve repairs between 5-15 mm using Avance® Nerve Graft.  The study cohort included 24 subjects with 37 digital nerve repairs. Outcomes analysis demonstrated meaningful levels of sensory recovery. No implant related adverse experiences were reported in any of such reports.  In a second publication, Rinker et al. reported on a subgroup from RANGER® with nerve gaps >25 mm.  They found that in the population of 28 subjects, meaningful sensory recovery was reported in 86% of the repairs.  Isaacs and Safa reported on a subgroup of subjects with large diameter nerve injuries repaired with Avance® Nerve Graft.  The study included 15 nerve repairs with 4-5 mm diameter Avance® Nerve Grafts.  Outcomes analysis found that meaningful levels of sensory and motor function were achieved and no safety concerns were reported.

 

The following describes available clinical outcomes data from published papers on the leading synthetic and collagen conduit.  Published papers on the leading synthetic collagen conduit by Weber, et al., 2000 and Wangensteen and Kalliainen, 2009, showed meaningful improvement: 74% in sensory nerves and 43% in sensory, mixed and motor nerves, respectively, of cases bridging a gap in the particular type of nerve. A paper published by Haug, et al., 2013 on the leading synthetic and collagen conduit showed meaningful improvement in 40% sensory nerves using the static 2-point discrimination test. Autograft studies where autograft and direct repair or direct suture were tested by Weber, et al., 2000, Kim and Kline 2001-2006, Frykman and Gramyk, 1991, Frykman and Gramyk, 1991 and Kallio, 1993, as interpreted by Brooks et al. 2012, reported meaningful recovery: 86% in sensory nerves, 67-86% in sensory and mixed nerves, 80% in sensory nerves, 75-78% mixed nerves and 70% sensory nerves, respectively, of cases bridging a gap in the particular type of nerve. Published papers by Kim and Kline 2001-2006 and Frykman and Gramyk, 1991 reported successful recovery in 75% and 78% of mixed and motor nerves, respectively. A study by Kallio et al., 1993 showed recovery in 67% of mixed and motor nerves where recovery was defined as results indicating a classification of useful or better motor and sensory recovery.

 

The RECON study is a prospective, randomized, controlled, patient and evaluator blinded, comparative study of Avance® Nerve Graft and Collagen Nerve Cuffs in the repair of peripheral nerve transections.  The study is a non-inferiority study designed to assess the outcome of peripheral nerve repair originally in approximately 170 subjects in up to 20 centers. Subjects will be followed over the course of 12 months to assess safety and efficacy outcomes with assessments being performed at various defined intervals up to 12 months.  The study completed initial subject enrollment in January 2019. No outcome data is available at this time.  As required by the SPA and agreed to by FDA and Axogen, an independent statistical analysis was conducted to determine if greater study enrollment is appropriate to maintain the planned statistical power of the study.  Axogen is working with the FDA to review the interim analysis findings and obtain agreement on the next phase of the study.    See Risk Factors - Clinical trials can be long, expensive and results are ultimately uncertain, which could jeopardize Axogen’s ability to obtain regulatory approval and continue to market its Avance® Nerve Graft product.

 

 

CHANGE was a prospective randomized controlled pilot study of nerve cuffs and Avance® Nerve Graft for the reconstruction of peripheral nerve transections in male and female subjects that sustained injury to at least one nerve in the hand, distal to the superficial palmar arch that after resection resulted in a nerve gap of >5 mm and ≤20 mm. The study results were published by Means et al in the June 2016 edition of HAND.  The authors randomized 23 participants with 31 digital nerve injuries. Sixteen participants with 20 repairs had at least six months of follow-up while 12-month follow-up was available for 15 repairs. There were no significant differences in participant and baseline characteristics between treatment groups. The average static two point discrimination (s2PD) for the Avance® Nerve Graft was 5 ± 1 mm (n = 6) compared with 8 ± 5 mm (n = 9) for hollow conduits. All injuries randomized to processed nerve allograft returned some degree of s2PD as compared with 75% of the repairs in the conduit group. The authors concluded that in this pilot study, patients whose digital nerve reconstructions were performed with processed nerve allografts had significantly improved and more consistent functional sensory outcomes compared with hollow conduits. 

 

A pilot study on the repair of the cavernous nerves in prostate cancer patients at Vanderbilt with 24 month follow-up has been completed. A total of 12 subjects were enrolled in this single center study. The primary objective of this study was to assess the technical feasibility of using Avance® Nerve Graft for neurovascular bundle (NVB) reconstruction during Robotic Assisted Laparoscopic Prostatectomy (RALP). The secondary objective of the study was to assess the long term safety and efficacy of NVB reconstruction by assessing quality of life and erectile function through validated questionnaires 24 months post-repair.

 

ASM-CP-001 is a registry study to evaluate the role of Avive® Soft Tissue Membrane in the management of nerve injury following acute trauma.  The study is designed to collect safety, functional and healthcare economic outcomes data in a select set of acute trauma injuries.  The study is currently designed to enroll up to 200 subjects.

 

Axogen is conducting REPOSE™, a two-phase study comparing standard neurectomy to Axoguard® Nerve Cap, a porcine small intestine submucosa-based nerve termination cap which leverages Axogen’s patented chambered technology to aid in the management of symptomatic or painful neuroma.  The first phase will include approximately 15 subjects in a non-randomized pilot, while the second phase is a prospective, randomized controlled study planned to enroll up to 101 subjects, with approximately 15 in the open pilot phase followed by 86 in the randomized phase. The study will assess pain scores, quality of life and health outcomes over a 12-month follow-up period. Enrollment has been initiated.

 

In addition to these clinical research programs, Axogen is developing additional clinical trials in peripheral nerve repair, mixed and motor nerve repair, breast neurotization and pain. 

 

Clinical trials are subject to extensive recordkeeping and reporting requirements. Axogen’s clinical trials must be conducted under the oversight of an IRB for the relevant clinical trial sites and must comply with FDA regulations, including but not limited to those relating to good clinical practices. Axogen is also required to obtain the patients’ written informed consent in form and substance that complies with both FDA requirements and state and federal privacy and human subject protection regulations. Axogen, the FDA or the IRB may suspend a clinical trial at any time for various reasons, including a belief that the risks to study subjects outweigh the anticipated benefits. Even if a trial is completed, the results of clinical testing may not adequately demonstrate the safety and efficacy of the biological

product or device, or may otherwise not be sufficient to obtain FDA approval to market the product in the U.S. Similarly, in Europe, the clinical study for a medicine product must be authorized by the Competent Authority in each Member State in which the clinical trial is to be conducted, and must receive a favorable opinion from an ethics committee.

 

Pervasive and Continuing Regulation

 

There are numerous regulatory requirements that apply after a product is cleared or approved. For medical devices, these include, but are not limited to: the FDA’s regulations for device labeling (21 CFR Part 801), medical device reporting (21 CFR Part 803), reporting of corrections and removals (21 CFR Part 806), establishment registration and device listing requirements (21 C.F.R. Part 807); and compliance with the Quality System Regulation (“QSR”) per 21 CFR Part 820.  Distribution of medical devices is also subject to license/registration requirements in some states.  For tissue and biologic products, the regulatory requirements include: the FDA’s registration and listing requirements, donor eligibility requirements and compliance with Good Tissue Practices (“GTP”) in 21 CFR Part 1271 for human tissue products, compliance with the FDA’s cGMP in 21 CFR Parts 210, 211, and 600 for licensed biological products, and postmarket BLA requirements (21 CFR Part 601). Among other things, these regulations require manufacturers, including third party manufacturers to:

 

 

Axogen has not received any reports of adverse events concerning the Avance® Nerve Graft or Avive® Soft Tissue Membrane products.  Six adverse events have been reported for the Axoguard® products (one each in 2013, 2014, 2015 and 2016 and two in 2017). Axogen reported two (2) biological deviations in 2018 for quality system issues related to human tissue distribution (no patient safety issues were involved).  Axogen has not had to submit any Medical Device Reports (“MDRs”) or tissue adverse reaction reports to the FDA. Cook Biotech submitted a MDR for the Axoguard® adverse events in 2013, 2014, 2015, 2016 and 2017.  Although Axogen’s Axoguard® products have had just six adverse events reported to date, there may have been other incidents, including patient deaths, which may have occurred during procedures utilizing Axogen’s products without Axogen being aware of any such incidents.  In addition, there can be no assurance that in the future Axogen’s products will not cause or contribute to an adverse event that would require Axogen to submit MDRs, biological deviation reports, or tissue adverse reaction reports to the FDA.

 

The advertising and promotion of medical products are also regulated by the Federal Trade Commission and by state regulatory and enforcement authorities. Recently, some promotional activities for FDA-regulated products have been the subject of enforcement action brought under healthcare reimbursement laws and consumer protection statutes. In addition, under the Federal Lanham Act and similar state laws, competitors and others can initiate litigation relating to advertising claims.

 

Axogen is registered with the FDA as a tissue establishment for the Avance® Nerve Graft and Avive® Soft Tissue Membrane. The FDA has broad post-market and regulatory enforcement powers. Axogen is subject to unannounced inspections by the FDA to determine compliance with the GTP, GMP and other regulations, and these inspections may also include the manufacturing facilities of suppliers.

 

Failure by Axogen or by Axogen’s suppliers to comply with applicable regulatory requirements can result in enforcement action by the FDA or other federal or state authorities, which may include any of the following sanctions, among others:

 

 

Education Grants, U.S. Anti-kickback, False Claims and Other Healthcare Fraud and Abuse Laws    

 

Educational Grants

 

A medical product manufacturer may provide financial support, including support by way of grants, to third-parties for the purpose of conducting medical educational activities. If these funded activities are considered by the FDA to be independent of the manufacturer, then the activities fall outside the FDA restrictions on promotion to which the manufacturer is subject.

 

The FDA considers several factors in determining whether an educational event or activity is independent from the substantive influence of the product manufacturer and therefore non-promotional, including, but not limited to, the following:

 

 

Axogen seeks to ensure that the activities it supports pursuant to educational grants program are in accordance with these criteria for independent educational activities. However, Axogen cannot provide assurance that the FDA or other government authorities would view the programs supported as being independent.

 

Fraud, Abuse and False Claims

 

Axogen is directly and indirectly subject to various federal and state laws governing relationships with healthcare providers and pertaining to healthcare fraud and abuse, including anti-kickback laws. In particular, the U.S. Anti-Kickback Statute prohibits persons from knowingly and willfully soliciting, offering, receiving or providing remuneration, directly or indirectly, in exchange for or to induce either the referral of an individual, or the furnishing, arranging for or recommending a good or service for which payment may be made in whole or part under federal healthcare programs, such as the Medicare and Medicaid programs. Penalties for violations include criminal penalties and civil sanctions such as fines, imprisonment and possible exclusion from Medicare, Medicaid and other federal healthcare programs. The Anti-Kickback Statute is broad and prohibits many arrangements and practices that are lawful in businesses outside of the healthcare industry. In implementing the statute, the Office of Inspector General of the U.S. Department of Health and Human Services (“OIG”) has issued a series of regulations, known as “safe harbors.” These safe harbors set forth provisions that, if all their applicable requirements are met, will assure healthcare providers and other parties that they will not be prosecuted under the Anti-Kickback Statute for activities that fit within a safe harbor. The failure of a transaction or arrangement to fit precisely within one or more safe harbors does not necessarily mean that it is illegal or that prosecution will be pursued. However, conduct and business arrangements that do not fully satisfy each applicable element of a safe harbor may result in increased scrutiny by government enforcement authorities, such as the OIG, and are at risk activities unless a favorable advisory opinion is obtained from the OIG.

 

The Federal False Claims Act (“FCA”) imposes civil liability on any person or entity that submits, or causes the submission of, a false or fraudulent claim to the U.S. government. Damages under the FCA can be significant and consist of the imposition of fines and penalties. The FCA also allows a private individual or entity with knowledge of past or present fraud against the federal government to sue on behalf of the government to recover the civil penalties and treble damages. The DOJ has previously alleged that the marketing and promotional practices of pharmaceutical and medical device manufacturers included the off-label promotion of products or the payment of prohibited kickbacks to doctors violated the FCA resulting in the submission of improper claims to federal and state healthcare entitlement programs such as Medicaid. In certain cases, manufacturers have entered into criminal and civil settlements with the federal government under which they entered into plea agreements, paid substantial monetary amounts and entered into corporate integrity agreements that require, among other things, substantial reporting and remedial actions going forward.

 

AdvaMed is one of the primary voluntary U.S. trade associations for medical device manufacturers. This association has established guidelines and protocols for medical device manufacturers in their relationships with healthcare professionals on matters including research and development, product training and education, grants and charitable contributions, support of third party educational conferences, and consulting arrangements. Adoption of the AdvaMed Code by a medical device manufacturer is voluntary, and while the OIG and other federal and state healthcare regulatory agencies encourage its adoption and may look to the AdvaMed Code, they do not view adoption of the AdvaMed Code as proof of compliance with applicable laws. Axogen has incorporated the principles of the AdvaMed Code in its standard operating procedures, sales force training programs, and relationships with doctors. Key to the underlying principles of the AdvaMed Code is the need to focus the relationships between manufacturers and healthcare professionals on matters of training, education and scientific research, and limit payments between manufacturers and healthcare professionals to fair market value for legitimate services provided and payment of modest meal, travel and other expenses for a healthcare professional under limited circumstances. Axogen has incorporated these principles into its relationships with healthcare professionals under its consulting agreements, payment of travel and lodging expenses, research and educational grant procedures and sponsorship of third party conferences. In addition, Axogen has conducted and will continue to conduct training sessions on these principles.  Finally, the Sunshine act, as defined below, imposes additional  reporting and disclosure requirements on Axogen for any “transfer of value” made or distributed to physicians and teaching hospitals, as well as reporting of certain physician ownership interests.  Axogen cannot provide any assurance that regulatory or enforcement authorities will view its relationships with physicians or policies as being in compliance with applicable regulations and laws.

 

Regulation Outside of the United States

 

Distribution and sales of medical products outside of the U.S. are subject to foreign governmental regulations that vary substantially from country to country. The time required to obtain certification or approval by a foreign country may be longer or shorter than that required for FDA clearance or approval and the requirements may be different.

 

There are restrictions under U.S. law on the export from the U.S. of medical devices and biological product that cannot be legally distributed in the U.S. If a Class I or Class II device does not have 510(k) clearance and the manufacturer reasonably believes that the device could obtain 510(k) clearance in the U.S., then the device can be exported to a foreign country for commercial marketing without the submission of any type of export request or prior FDA approval if (i) the device is not sold or offered for sale in the U.S., (ii) is labeled for export only and (iii) satisfies certain criteria relating primarily to specifications of the foreign purchaser and compliance with the laws of the country to which it is being exported, known as Importing Country Criteria. An unapproved Class III device can be exported if it (i) complies with the criteria discussed above for devices that could obtain 510(k) clearance, (ii) meets certain other quality and labeling requirements, and (iii) has a valid marketing authorization from one of a list of countries listed in the FD&C Act. If an unapproved Class III device does not have a valid marketing authorization from one of the listed countries, an export permit from the FDA is required in order to export it. An unapproved biological product can be exported without submitting an export request to FDA if the product has received a marketing authorization in one of a list of countries listed in the FD&C Act and it meets applicable requirements of the FD&C Act and the laws of the country to which it is exported.  An investigational biological product may also be exported under an IND if a listed investigator is in a foreign country and certain requirements specified in FDA’s regulations are met.  Axogen currently believes it complies with applicable regulations when exporting its products and Axogen intends to continue such compliance in the event there are any regulatory changes regarding its products in the United States.

 

The primary regulatory body in Europe is the E.U. which has adopted numerous directives and promulgated voluntary standards regulating the design, manufacture and labeling of, and clinical trials and adverse event reporting for, medical devices. Devices that comply with the requirements of a relevant directive will be entitled to bear CE marking, indicating that the device conforms to the essential requirements of the applicable directives and, accordingly, can be commercially distributed throughout the member states of the E.U. and other countries that comply with these directives. The method for assessing conformity varies depending on the type and class of the device, but normally involves an assessment by the manufacturer and a third-party assessment by a notified body, an independent and neutral institution appointed by a country to conduct the conformity assessment. This third-party assessment may consist of an audit of the manufacturer’s quality system and specific testing of the manufacturer’s device. Such an assessment is required for a manufacturer to commercially distribute the product throughout these countries.  In the second quarter of 2014, Axogen’s Quality System became registered to ISO 13485 for Receipt, Handling, Storage and Distribution of Medical Devices related to nerve repair.

 

Cook Biotech is responsible for all regulatory filings for the Axoguard® Connector and Protector products including international registrations. Axogen works with Cook Biotech by providing the countries for Cook to register or get approval for these Axoguard® products. Cook Biotech prepares the product filing documentation and submits this documentation to the Ministry of Health (“MOH”) for the country. Each country or region has its own regulations and the documentation required for submission varies. It typically takes less than nine months from the initiation of the project to obtain clearance in a given country or region. To date, the Axoguard® Connector and Protector product lines were registered in May 2013 in Canada for distribution and in April 2013 the product lines were awarded the CE Mark allowing distribution into the E.U. and other countries that accept the CE Mark.  However, Cook Biotech is currently renewing the Axoguard® products CE Mark and until such renewal, Axogen is able to sell only those Axoguard® products that are currently in inventory in the E.U., which inventory may not be sufficient to satisfy all product sales prior to obtaining the renewal.    

 

The British and E.U. negotiators have reached a draft agreement concerning the UK’s transition from its current E.U. membership which ends on December 31, 2020.  During such time, E.U. Law will remain applicable thus the placement on the market of medical devices may continue uninterrupted on both sides of the English Channel and the notified body certificates will remain valid.    Axogen registers its human tissue products in each individual E.U. country

and each distributor in the UK has import authority for Axogen’s human tissue product.  In the event of a no deal or deal Brexit, it is expected that a licensed UK establishments that import or export tissues or cells will need written agreements with the relevant E.U. licensed establishments to continue importing and exporting with the E.U.  As Axogen ships directly to the UK from the U.S., we would expect no delay in shipment of human tissue products into the UK.  Further, the RANGER® clinical trial being performed at select hospitals in the UK would not be affected by Brexit as long as the products come directly from the U.S.

 

Tissue products are not currently regulated under the CE Mark

 

Axogen is responsible for all regulatory filings for Avance® Nerve Graft and Avive® Soft Tissue Membrane including international registrations.  To obtain approvals Axogen will prepare the product filing documentation and submit this documentation to the Ministry of Health (“MOH”) for a country.

 

Although some standards of harmonization exist, each country in which Axogen conducts business has its own specific regulatory requirements. Axogen procures and processes its tissue for the Avance® Nerve Graft and Avive® Soft Tissue Membrane in the U.S., and markets the Avance® Nerve Graft in Canada, United Kingdom, and certain other countries under compliance with the individual country regulations.  These requirements are dynamic in nature and, as such, are continually changing. New regulations may be promulgated at any time and with limited notice. Axogen will review the regulations at the time of submission of the product dossier for regulatory review. This review involves reviewing the appropriate MOH regulations, discussion with in-country distributors and use of consultants. It typically takes less than nine months from the initiation of the product to develop a product dossier (specific for that country), submission of the documentation and MOH review of the product filing. While Axogen believes that it is in compliance with all existing pertinent international and domestic laws and regulations, there can be no assurance that changes in governmental administrations and regulations will not negatively impact Axogen’s operations.  Avive® Soft Tissue Membrane is currently available in the U.S. and has received regulatory registration allowing for distribution in both Canada and Austria. 

 

The FDA and international regulatory bodies conduct periodic compliance inspections of Axogen’s U.S. processing facilities. Axogen’s operations are registered with CBER, as a tissue establishment. Axogen is also accredited by the AATB and is licensed in the states of Florida, New York, California, Maryland, Delaware, Oregon and Illinois. Axogen believes that worldwide regulation of tissue products is likely to intensify as the international regulatory community focuses on the growing demand for these implant products and the attendant safety and efficacy issues of recipients. Changes in governing laws and regulations could have a material adverse effect on Axogen’s financial condition and results of operations. Axogen management further believes that it can help to mitigate this exposure by continuing to work closely with government and industry regulators.

 

Environmental

 

Axogen’s products, as well as the chemicals used in processing, are handled and disposed of in accordance with country-specific, federal, state and local environmental regulations. Since 2007, Axogen has used outside third parties to perform all biohazard waste disposal.

 

Axogen contracts with independent, third parties to perform sterilization of its allografts. In view of the engagement of a third party to perform irradiation services, the requirements for compliance with radiation hazardous waste do not apply, and therefore Axogen does not anticipate that this engagement will have any material adverse effect upon its capital expenditures, results of operations or financial condition. However, Axogen is responsible for assuring that the service is being performed in accordance with applicable regulations. Although Axogen believes it is in compliance with all applicable environmental regulations, the failure to fully comply with any such regulations could result in the imposition of penalties, fines and/or sanctions which could have a material adverse effect on Axogen’s business.

 

Corporate History

 

On September 30, 2011, Axogen Corporation (“AC”), a Delaware corporation, completed its business combination with LecTec Corporation (“LecTec”), a Minnesota corporation, in accordance with the terms of an Agreement and Plan of Merger, dated as of May 31, 2011, by and among LecTec, Nerve Merger Sub Corp., a subsidiary of LecTec (“Merger Sub”), and AC, which the parties amended on August 9, 2011 and September 30, 2011 (as amended, the “Merger Agreement”). Pursuant to the Merger Agreement, Merger Sub merged with and into AC, with AC continuing after the merger as the surviving corporation and a wholly owned subsidiary of LecTec (the “Merger”). Immediately following the Merger, LecTec changed its name to Axogen, Inc. In October 2011, Axogen Inc. moved its corporate headquarter facilities (principal executive office) from Texarkana, Texas to Alachua, Florida.

 

LecTec was organized in 1977 as a Minnesota corporation and went public in December 1986.  Prior to the Merger, LecTec was an intellectual property licensing and holding company. LecTec held multiple domestic and international patents based on its original hydrogel patch technology and filed patent applications on a hand sanitizer patch. LecTec also had a licensing agreement with Novartis Consumer Health, Inc.  LecTec took legal action to protect its IP and settled all of its litigation prior to the Merger and Axogen, subsequent to the Merger, continued to hold LecTec IP until it expired.

 

Our website address is http://www.Axogeninc.com.  We have included our website address as an inactive textual reference only.  We make available, free of charge through our website, our annual reports on Form 10-K, our quarterly reports on Form 10-Q, our current reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act as soon as reasonably practicable after we electronically file such material, or furnish it to the SEC.  We also similarly make available, free of charge on our website, the reports filed with the SEC by our executive officers, directors and 10% stockholders pursuant to Section 16 under the Exchange Act as soon as reasonably practicable after copies of those filings are provided to us by those persons.  We are not including the information contained at http://www.Axogeninc.com, or at any other website.

 

Employees 

 

At December 31, 2018,  Axogen had 297 total employees, including 19 part-time employees and 278 full-time employees.  Of the full-time employees, 27 employees work in administration, information technology and finance, 54 employees work in manufacturing and quality control, 39 employees work in research and development and regulatory and 158 employees work in sales and marketing.  As of the date of this annual report on Form 10-K Axogen has not had a work stoppage and no employees are represented by a labor union.  Axogen believes its relationship with its employees is satisfactory.

 

Executive Officers of the Registrant 

 

The following table lists the names and positions of the individuals who are, as of February 28, 2019, executive officers of Axogen:

 

 

Biographical information for each of our executive officers is included below.

 

Karen Zaderej, Chairman, Chief Executive Officer and President (Age 57)

 

Ms. Zaderej has served as Axogen’s President, Chief Executive Officer, a member of our board of directors (the “Board of Directors”) since September 2011 and became the Chairman of our Board of Directors in May 2018. She has served as the Chief Executive Officer of Axogen, and a member of Axogen’s board of directors since May 2010. Ms. Zaderej joined Axogen in May 2006 and served as Vice President of Marketing and Sales from May 2006 to October 2007 and as Chief Operating Officer from October 2007 to May 2010. From October 2004 to May 2006, Ms. Zaderej worked for Zaderej Medical Consulting, a consulting firm she founded, which assisted medical device companies in building and executing successful commercialization plans. From 1987 to 2004, Ms. Zaderej worked at Ethicon, Inc., a Johnson & Johnson company, where she held senior positions in marketing, business development, and research & development, as well as ran a manufacturing business. Ms. Zaderej is a Director of Viveve Medical, Inc., a public women's intimate health company and SEBio, a non-profit supporting the life science industry in the southeastern United States.  Ms. Zaderej has a MBA from the Kellogg Graduate School of Business and a BS in Chemical Engineering from Purdue University.

 

Peter Mariani, Chief Financial Officer (Age 55)

 

Mr. Mariani, has been Axogen’s Chief Financial Officer since March of 2016.  Prior to joining Axogen, he served as Chief Financial Officer of Lensar, Inc, a privately held laser refractive cataract surgery company, from July 2014 through January 2016, which was sold in December 2015.  From June 2011 to June 2014 Mr. Mariani served as Chief Financial Officer of Hansen Medical, a publicly traded medical device company developing robotic solutions for intravascular procedures.  From 2007 through 2010 Mr. Mariani served as Chief Financial Officer for two privately held companies: Harlan Laboratories (2007 – 2009); and BMW Constructors (2009 – 2010).  From 1994 through 2006 Mr. Mariani served in various senior financial roles with Guidant Corporation, a publicly traded leader in the development and sale of medical devices for the treatment of cardiovascular disease.  Mr. Mariani began his career with Guidant Corporation as Director of Corporate Financial Reporting where he supported the initial public offering of Guidant Corporation and ultimately served as Vice President, Controller and Chief Accounting Officer.  Mr. Mariani’s experience at Guidant Corporation included two years as Director of Financial Reporting, Guidant Vascular Intervention in Santa Clara, California, and four years in Tokyo, Japan, mostly as Vice President Finance and Administration where he helped to facilitate the conversion and scale of the Japan business from a distributor network to a direct sales and marketing organization.  Following the 2006 sale of Guidant Corporation to Boston Scientific Corporation, Mr. Mariani co-led the initial integration of the two companies.  From 1987 to 1994, Mr. Mariani worked with Ernst and Young,

LLP, where he served a diverse client base as a Certified Public Accountant.  Mr. Mariani received a Bachelor of Science Degree in Accounting from Indiana University.

 

Gregory G. Freitag, JD, CPA, General Counsel and Director (Age 57)

 

Mr. Freitag, JD, CPA, has been Axogen’s General Counsel and a member of our Board of Directors since September 2011.  He was Axogen’s Chief Financial Officer from September 2011 to May 2014 and August 2015 to March 2016, and its Senior Vice President Business Development from May 2014 to October 2018. He was Chief Executive Officer, Chief Financial Officer and a board member of LecTec Corporation, an IP licensing and holding company that merged with Axogen in September 2011, from June 2010 through September 2011.  From May 2009 to the present, Mr. Freitag has been a principal of FreiMc, LLC, a healthcare and life science consulting and advisory firm he founded that provides strategic guidance and business development advisory services. Prior to founding FreiMc, LLC, Mr. Freitag was a Director of Business Development at Pfizer Health Solutions, a former subsidiary of Pfizer, Inc., from January 2006 to May 2009. From July 2005 to January 2006, Mr. Freitag worked for Guidant Corporation in its business development group. Prior to Guidant Corporation, Mr. Freitag was the Chief Executive Officer of HTS Biosystems, a biotechnology tools start-up company, from March 2000 until its sale in early 2005. Mr. Freitag was the Chief Operating Officer, Chief Financial Officer and General Counsel of Quantech, Ltd., a public point of care diagnostic company, from December 1995 to March 2000. Prior to that time, Mr. Freitag practiced corporate law in Minneapolis, Minnesota. Mr. Freitag is also a director of the Foundation Board of Fairview Health Services, a health care system in Minnesota, and PDS Biotechnology Corporation, a private, clinical stage biopharmaceutical company developing immunotherapies for cancer and other disease areas such as infectious disease.  Mr. Freitag holds a JD from the University of Chicago and a BA Economics & Business and Law & Society from Macalester College, Minnesota.

 

Eric A. Sandberg, Chief Commercial Officer (Age 54)

 

Mr. Sandberg has served as Axogen’s Chief Commercial Officer since January 2019.  From 2016 until joining Axogen, he served as the Chief Executive Officer of Visura Technologies, Inc., a cardiologist-founded medical device company.  From 2016 until 2018, Mr. Sandberg served as the Chief Business Officer of Rhythm Therapeutics, Inc., an electrophysiologist-founded preclinical biotechnology company.  From 2014 until 2016, he served as the President and Chief Executive Officer of Tangent Medical Technologies, Inc., a medical device company.  Mr. Sandberg also served as Senior Vice President, Sales at CardioDx, Inc., a molecular diagnostics company, from 2008 until 2013.  Prior to joining CardioDx, Inc., Mr. Sandberg worked at Russell Reynolds Associates and held leadership positions across sales, marketing, corporate accounts, and business development at Guidant Corporation and Boston Scientific.  Mr. Sandberg currently serves as an observer on the Board of Directors of Visura Technologies, Inc.  Mr. Sandberg earned an MBA from Harvard Business School and a Bachelor of Science degree in mechanical engineering from Bradley University in Peoria, IL.

 

Mark Friedman, Ph.D., Vice President of Regulatory Affairs and Quality Assurance(Age 61)

 

Dr. Friedman has served as Axogen’s Vice President of Regulatory Affairs and Quality Assurance since November 2011. He has also served as Axogen’s Director of Quality Assurance and Regulatory Affairs from September 2006 to June 2011. Prior to joining Axogen, Dr. Friedman held several regulatory and quality leadership positions at Enable Medical Corporation, a medical device company, including Director of Quality Assurance from 1997 to 1998 and Vice President of Quality and Regulatory from 1998 to 2001 and from 2004 to 2005. Dr. Friedman also worked for AtriCure, Inc., a company that develops, manufactures and sells surgical ablation systems to treat atrial fibrillation, as Vice President of Quality and Regulatory from 2001 to 2004 and as Vice President of Operations in 2004. AtriCure acquired Enable Medical in 2005. Dr. Friedman has over 25 years of experience in developing and directing regulatory strategy and quality systems for medical products, including 15 years with start-up medical product firms. Dr. Friedman has a Ph.D. in Chemistry specializing in protein biochemistry from the University of Cincinnati. Dr. Friedman sits on various agency committees for the Alliance of Regenerative Medicine, Medical Device Manufacturer’s Association and American Association of Tissue Banks, working on improving regulatory laws and standards for regenerative products and medical devices.

 

David Hansen, Vice President of Finance and Treasurer (Age 58)

 

Mr. Hansen has served as Axogen’s Vice President of Finance and Treasurer since June 2017.  Mr. Hansen previously served as Chief Accounting Officer of Axogen from December 2015 to May 2017, and as Corporate Controller of Axogen from June 2006 to November 2015. Mr. Hansen was Vice President of Finance—Corporate Controller and Treasurer of Perma-Fix Environmental Services, Inc., a publicly-traded environmental services company, and held other corporate and regional accounting positions at Perma-Fix Environmental Services from 1995 to 2005. Mr. Hansen was also the Vice President - Finance at Kraft Foodservice, Inc., Ocala, Florida from 1994 to 1995 and held other accounting and procurement positions at Kraft Foodservice, Inc. from 1985 to 1994. Mr. Hansen has over 20 years of experience in senior financial positions at both publicly traded and private companies. Mr. Hansen holds a BBA degree in Accounting from the University of Oklahoma.

 

Maria Martinez, Chief Human Resources Officer (Age 50)

 

Ms. Martinez has served as Axogen’s Chief Human Resources Officer since October 2018.  From January 2018 until joining Axogen as Chief Human Resources Officer, Ms. Martinez provided consulting services related to human resources through her consulting firm MDM Consulting Services, LLC. Prior to founding MDM , she was Chief Human Resources Officer at HSNi, a $3.5B interactive multichannel retailer overseeing nearly seven thousand employees in nine locations.  Ms. Martinez joined HSNi in July 2010 and served as SVP Talent Management until she assumed the role of Chief Human Resources Officer.  Prior to joining HSNi, Ms. Martinez was Vice President of Human Resources with Laser Spine Institute, LLC., a minimally invasive spine surgery company, having started with them in 2008.  From 2007 to 2008,  she worked at Bausch + Lomb, Inc. where she served as Director, Human Resources US Pharmaceuticals and, from 2005 to 2007,  Ms. Martinez was Sr. Director, Human Resources Corporate with Darden Restaurants, Inc.  Prior to 2005, Ms. Martinez held positions related to the field of human resources.

 

Ms. Martinez has a  Master of Science in  Industrial/Organizational Psychology from the Florida Institute of Technology, Melbourne, FL and a Bachelor of Science in Psychology; Bachelor of Arts in French, Minor in Italian from the University of South Florida, Tampa, FL.

 

 

Isabelle Billet, Chief Strategy and Business Development Officer (Age 57)

 

Ms. Billet has served as Axogen’s Chief Strategy and Business Development Officer since October 2018.  From July 2013 until joining Axogen as Chief Strategy and Business Development Officer,  Ms. Billet worked for IBHC Advisors LLC, a consulting firm she founded which assisted medical device companies in their organic and inorganic growth strategies and supported private equity firms on their investment strategy and due diligence.  From 2010 to 2013, Ms. Billet worked at Cardinal Health, Inc where she served as Senior Vice President of Marketing and Innovation for the Medical segment focusing on their private brand portfolio development. From 2005 to 2010, she was Vice President Marketing and New Business Development for C.R. Bard Medical division. She worked for Johnson and Johnson from 1992 to 2005, splitting her tenure between Advanced Sterilization Products and Ethicon, Inc in positions of increasing responsibilities in marketing and new business development in France, Europe and US. Ms. Billet spent the first 7 years of her career as the head pharmacist and material manager for a private hospital in France.  Ms. Billet is a member of the Clinical Innovations Board of Directors, a medical device company exclusively focused in Labor and Delivery and Neonates Intensive Care. She has an MBA from EM Lyon Business School, France and Cranfield School of Management, UK and a Doctorate in Pharmacy from Montpellier University in France.

 

Erick DeVinney, Vice President of Clinical and Translational Sciences (Age 44)

 

Mr. DeVinney has served as Axogen’s Vice President of Clinical and Translational Sciences since January 2014. From April 2007 until January 2014, Mr. DeVinney was the Director of Clinical and Translational Sciences for Axogen. Erick has over 14 years of experience in the successful planning and management of clinical development.  Prior to joining Axogen Mr. DeVinney served as Manager of Clinical Operations for Angiotech Pharmaceuticals from 2005 to 2007 and Clinical Program Lead for Pharmaceutical Research Associates International from 2001 to 2005.  Mr. DeVinney has been involved in the successful submission of numerous 510(k), IDE and NDA applications.  He has a BS in Chemistry from Virginia Commonwealth University.

 

Mike Donovan, Vice President of Operations (Age 54)

 

Mr. Donovan has served as Axogen’s Vice President of Operations since September 2015. Prior to September 2015, Mr. Donovan was Axogen’s Director of Operations from January 2011 until September 2015. From 1988 to 2010, Mr. Donovan held positions at Zimmer Holdings in manufacturing, continuous improvement, quality assurance and sterilization including Director of Manufacturing from 2002 to 2010. Mr. Donovan has a BS in Chemical Engineering and an MBA from the University of Akron.

 

Angelo G. Scopelianos, Ph.D., Vice President of Research and Development (64)

 

Dr. Scopelianos has served as Axogen’s Vice President of Research and Development since September 2018.  From 2012 until joining Axogen, Dr. Scopelianos was an independent consultant specializing in medical devices. He began consulting after his retirement from a 24-year tenure at Johnson & Johnson (J&J). Angelo began at J&J in 1988 as section manager of R&D and held the escalating positions of manager of R&D, director of R&D, vice president of R&D and finally from October 2010 to September 2012 senior vice president of R&D. He joined J&J after research leadership positions at EI Dupont de Nemours in Wilmington, Delaware, and Pennwalt Corporation. Angelo received his doctorate degree in organic chemistry from Pennsylvania State University, following completion of a Bachelor of Science degree from the State University of New York—Oneonta. He holds over 35 U.S. patents and numerous international patents, and his awards include the Outstanding Science Alumni Award by Penn State University; the Scientific Leadership Award in Biomaterials Science awarded by a consortium of NJ research universities:  Rutgers University, Princeton University and NJ Institute of Technology; the Johnson & Johnson Philip B. Hofmann Award for technical achievements in scientific research; and an Honorary Doctor of Science Degree bestowed by the State University of New York.

 

ITEM 1A.  RISK FACTORS

 

Axogen’s business involves a number of risks, some of which are beyond its control.  The risk and uncertainties described below are not the only ones the Company faces.  Set forth below is a discussion of the risks and uncertainties that management believes to be material to Axogen.

 

Risks Related To The Company

 

Axogen has not experienced positive cash flow from its operations, and the ability to achieve positive cash flow from operations will depend on increasing revenue from distribution of its products, which may not be achievable.

 

Axogen has historically operated with negative cash flow from its operations. As of December 31, 2018, Axogen had an accumulated deficit of approximately $151 million. If  revenue does not increase as anticipated, then it will continue to experience negative cash flows and adverse operating conditions. Axogen’s continuing capital needs and other factors could cause the Company to raise additional funds through public or private equity offerings, debt financings or from other sources. The sale of additional equity may result in dilution to Axogen’s shareholders. There is no assurance that Axogen will be able to secure funding on terms acceptable to it, or at all.

 

Axogen’s revenue growth depends on its ability to expand its sales force, increase distribution and sales to existing customers and develop new customers, and there can be no assurance that these efforts will result in significant increases in sales.

 

Axogen is in the process of investing in its distribution and sales channels composed of a combination of its direct sales force and independent agencies/distributors to allow it to increase distribution and sales to existing customers and reach new customers. There can be no assurance that these efforts will be successful in expanding Axogen’s revenue. Axogen currently distributes tissue and sells products directly through its sales force and indirectly through agency relationships. Axogen is engaged in an initiative to build and further expand sales and marketing capabilities. The incurrence of these expenses impacts Axogen’s operating results, and there can be no assurance of their effectiveness. If Axogen is unable to develop its sales force, increase sales to existing customers and attract new customers, it may not be able to grow revenue or maintain its current level of revenue generation.

 

Axogen’s revenue depends primarily on four products.

 

Substantially all of Axogen’s revenue is currently derived from only four products, Avance® Nerve Graft, Avive® Soft Tissue Membrane, Axoguard® Nerve Protector and Axoguard® Nerve Connector, for the treatment of peripheral nerve damage. Of these four products, the Avance® Nerve Graft represents approximately half of the Company’s total revenues.  Any disruption in Axogen’s ability to generate revenue from the distribution of tissue and sale of products will have a material adverse impact on Axogen’s business, results of operations, financial condition and growth prospects.

 

The Axoguard® products are only available through an exclusive distribution agreement with Cook Biotech. The agreement was amended February 26, 2018 to run through June 30, 2027.  However, there are conditions for continuation of the agreement, including payment terms and minimum purchase requirements, that if breached could result in an earlier termination of the agreement; except that through mutual agreement the parties have not established such minimums and to date have not enforced such minimum purchase provision. Additionally, in the event that Axogen and Cook Biotech were to fail to reach an agreement as to minimum purchase quantities, Cook Biotech could terminate the agreement if it was deemed that Axogen had failed to generate commercially reasonable sales of Axoguard® as measured by sales similar to a competitive product at the same stage in its commercial launch as verified by a mutually acceptable third party. Although there are products that Axogen believes it could develop or obtain that would replace the Axoguard® products obtained through the agreement with Cook Biotech, the loss of the ability to sell the Axoguard® products could have a material adverse effect on Axogen’s business until other replacement products are available.

 

Axogen’s success will be dependent on continued acceptance of its products by the medical community.

 

Continued market acceptance of Axogen’s products will depend on its ability to demonstrate that its products are an attractive alternative to existing nerve reconstruction treatment options and provide appropriate solutions for nerve repair. Its ability to do so will depend on surgeons’ evaluations of clinical safety, efficacy, ease of use, reliability, and cost-effectiveness of Axogen’s nerve repair products. For example, although Axogen’s Avance® Nerve Graft follows stringent safety standards, including sterilization by gamma irradiation, Axogen believes that a small portion of the medical community has lingering concerns over the risk of disease transmission through the use of allografts in general. Furthermore, Axogen believes that even if its products receive general acceptance within the medical community, acceptance and clinical recommendations by influential surgeons will be important to the commercial success of Axogen’s products.

 

Negative publicity concerning methods of donating human tissue and screening of donated tissue, in the industry in which Axogen operates, may reduce demand for its products and negatively impact the supply of available donor tissue.

 

Axogen is highly dependent on its ability to recover human peripheral nerve tissue from tissue donors for its Avance® Nerve Graft product and acquire birth tissue for its Avive® Soft Tissue Membrane. The availability of acceptable donors is relatively limited, and this availability is impacted by regulatory changes, general public opinion of the donation process and Axogen’s reputation for its handling of the donation process. Media reports or other negative publicity concerning both improper methods of tissue recovery from donors and disease transmission from donated tissue, including bones and tendons, may limit widespread acceptance of Axogen’s Avance® Nerve Graft and Avive® Soft Tissue Membrane. Unfavorable reports of improper or illegal tissue recovery practices, both in the U.S. and internationally, as well as incidents of improperly processed tissue leading to transmission of disease, may broadly affect the rate of future tissue donation and market acceptance of allograft technologies and donated tissue use. Potential patients may not be able to distinguish Axogen products, technologies, and tissue recovery and processing procedures from others engaged in tissue recovery. In addition, unfavorable reports could make families of potential donors or donors themselves from whom Axogen is required to obtain consent before processing tissue reluctant to agree to donate tissue to for-profit tissue processors. Any disruption in the supply could have negative consequences for Axogen’s revenue, operating results and continued operations.

 

Axogen is highly dependent on the continued availability of its facilities and could be harmed if the facilities are unavailable for any prolonged period of time.

 

Any failure in the physical infrastructure of Axogen’s facilities, including the facility it licenses from CTS, could lead to significant costs and disruptions that could reduce its revenues and harm its business reputation and financial results. Any natural or man-made event that impacts Axogen’s ability to utilize its facilities could have a significant impact on its operating results, reputation and ability to continue operations. This includes termination of the CTS Agreement which is subject to earlier termination by either party at any time for cause (subject to the non-terminating party’s right to cure, in certain circumstances), or without cause by Axogen upon 6 months prior notice wherebysuch notice cannot be provided until March 1, 2021. Axogen believes it can find and make operational a new licensed facility in less than six months, if required.  In addition, Axogen acquired property which is located near the CTS facility and it is expected that renovations will be completed by the termination date of the CTS Agreement to provide a new processing facility that can be included in our BLA for the Avance® Nerve Graft. However, the regulatory process for approval of facilities whether licensed or owned is time-consuming and unpredictable.   Axogen’s ability to license, renovate, rebuild or find acceptable service facilities takes a considerable amount of time and expense and could cause a significant disruption in service to its customers if it were to lose the availability of its production or distribution facilities.  Although Axogen has business interruption insurance which would, in instances other than service agreement termination, cover certain costs, it may not cover all costs nor help to regain Axogen’s standing in the market.

 

Axogen must maintain high quality processing of its products.

 

Axogen’s Avance® Nerve Graft is processed through its Avance® Process which requires careful calibration and precise, high-quality processing and manufacturing. Its Avive® Soft Tissue Membrane is also human tissue that requires skill in its processing.  Achieving precision and quality control requires skill and diligence by its personnel. If it fails to achieve and maintain these high levels of quality control and processing standards, including avoidance of processing errors, defects or product failures, Axogen could experience recalls or withdrawals of its product, delays in delivery, cost overruns or other problems that would adversely affect its business. Axogen reported two (2) biological deviations in 2018 for quality system issues related to human tissue distribution (no patient safety issues were involved) and corrective action was taken without a material adverse consequence to Axogen.  Axogen cannot completely eliminate the risk of errors, defects or failures. In addition, Axogen may experience difficulties in scaling-up processing of its Avance® and Avive® products, including problems related to yields, quality control and assurance, tissue availability, adequacy of control policies and procedures, and lack of skilled personnel. If Axogen is unable to process and produce its human tissue products on a timely basis, at acceptable quality and costs, and in sufficient quantities, or if it experiences unanticipated technological problems or delays in production, its business would be adversely affected.

 

Delays, interruptions or the cessation of production by Axogen’s third party suppliers of important materials or delays in qualifying new materials, may prevent or delay Axogen’s ability to manufacture or process the final products.

 

Most of the raw materials used in the process for Avance® Nerve Graft and Avive® Soft Tissue Membrane are available from more than one supplier. However, one of the chemicals Axogen used in the processing of Avance® Nerve Graft, Triton X-200, is no longer manufactured by the original single source provider. Axogen developed and outsourced  an identical chemical replacement for Triton X-200 and validated Avance® Nerve Graft processing using that replacement. The FDA was notified of this change in August of 2018 with an IND Amendment and Axogen has transitioned to using the new supplier.  In addition, some of the test results, packaging and reagents/chemicals Axogen uses in its manufacturing process are also obtained from single suppliers. Axogen does not have written contracts with any of its single source suppliers, and at any time they could stop supplying Axogen’s orders. FDA review of a new supplier may be required if these materials become unavailable from Axogen’s current suppliers. Although there may be other suppliers that have equivalent materials that would be available to Axogen, FDA review of any alternate suppliers, if required, could take several months or years to obtain, if able to be obtained at all. Any delay, interruption or cessation of production by Axogen’s third party suppliers of important materials, or any delay in qualifying new materials, if necessary, would prevent or delay Axogen’s ability to manufacture products. In addition, an uncorrected impurity, a supplier’s variation in a raw material or testing, either unknown to Axogen or incompatible with its manufacturing process, or any other problem with Axogen’s materials, testing or components, would prevent or delay its ability to

process tissue. These delays may limit Axogen’s ability to meet demand for its products and delay its clinical trial, which would have a material adverse impact on its business, results of operations and financial condition.

 

The failure of third parties to perform many necessary services for the commercialization of Avance® Nerve Graft and Avive® Soft Tissue Membrane, including services related to recovery/acquisition, distribution and transportation, would impair Axogen’s ability to meet commercial demand.

 

Axogen relies upon third parties for certain recovery/acquisition, distribution and transportation services for its Avance® Nerve Graft and Avive® Soft Tissue Membrane. In accordance with product specifications, third parties ship Avance® Nerve Graft in specially validated shipping containers at frozen temperatures. If any of the third parties that Axogen relies upon in its recovery/acquisition, distribution or transportation process fail to comply with applicable laws and regulations, fail to meet expected deadlines, or otherwise do not carry out their contractual duties to Axogen, or encounter physical damage or natural disaster at their facilities, Axogen’s ability to deliver product to meet commercial demand may be significantly impaired.

 

Axogen is dependent on its relationships with independent agencies to generate revenue.

 

Axogen derives material revenues through its relationships with independent agencies. If certain agency relationships were terminated for any reason, it could materially and adversely affect Axogen’s ability to generate revenues and profits.   If Axogen required additional agencies it may not be able to find additional agencies who will agree to market and distribute Axogen’s products on commercially reasonable terms, if at all. If Axogen is unable to establish new agency relationships or renew certain current distribution agreements on commercially acceptable terms, its operating results could suffer.

 

Loss of key members of management, who it needs to succeed, could adversely affect its business.

 

Axogen’s future success depends on the continued efforts of the members of its senior management team. Competition for experienced management personnel in the healthcare industry is intense. If one or more of Axogen’s senior executives or other key personnel are unable or unwilling to continue in their present positions, or if Axogen is unable to attract and retain high quality senior executives or key personnel in the future, its business may be adversely affected. 

 

 

Axogen’s operating results will be harmed if it is unable to effectively manage and sustain its future growth or scale its operations.

 

There can be no assurance that Axogen will be able to manage its future growth efficiently or profitably. Its business is unproven on a large scale and actual revenue and operating margins, or revenue and margin growth, may be less than expected. If Axogen is unable to scale its production capabilities efficiently or maintain pricing without significant discounting, it may fail to achieve expected operating margins, which would have a material and adverse effect on its operating results. Growth may also stress Axogen’s ability to adequately manage its operations, quality of products, safety and regulatory compliance. If growth significantly decreases it will negatively impact Axogen’s cash reserves, and it may be required to obtain additional financing, which may increase indebtedness or result in dilution to shareholders. Further, there can be no assurance that Axogen would be able to obtain additional financing on acceptable terms if all at.

 

There may be significant fluctuations in Axogen’s operating results.

 

Significant quarterly fluctuations in Axogen’s results of operations may be caused by, among other factors, its volume of revenues, seasonal changes in nerve repair activity, timing of sales force expansion and general economic conditions. There can be no assurance that the level of revenues and profits, if any, achieved by Axogen in any particular fiscal period, will not be significantly lower than in other comparable fiscal periods. Axogen’s expense levels are based, in part, on its expectations as to future revenues. As a result, if future revenues are below expectations, net income or loss may be disproportionately affected by a reduction in revenues, as any corresponding reduction in expenses may not be proportionate to the reduction in revenues.

 

Axogen’s revenues depend upon prompt and adequate reimbursement from public and private insurers and national health systems.

 

Political, economic and regulatory influences are subjecting the healthcare industry in the U.S. to fundamental change. The ability of a hospital or an ambulatory surgery center (“ASC”) to pay fees for Axogen’s products depends in part on the availability of adequate coverage and reimbursement from third-party payors for either our products specifically, the procedures associated with the use of our products, or both. Providers that purchase our products generally rely on third-party payors to reimburse all or part of the costs and fees associated with the procedures performed with our products or the products themselves. Adequate coverage and reimbursement from third-party payors, including governmental payors, such as Medicare and Medicaid, therefore, is important for obtaining product acceptance and widespread adoption in the marketplace.

When our products (Avance® Nerve Graft, Axoguard® Connector, Axoguard® Protector, Avive® Soft Tissue Membrane) are used in the operating room of a hospital, they are commonly treated as general supplies utilized in surgery and the cost is included in payment to the facility for the procedure. When Avance® Nerve Graft and Axoguard® Connector are used in an outpatient setting where the nerve repair is the primary reason for the procedure, facilities may use a Category I CPT code to facilitate payment.

In January 2018, the American Medical Association created a Category I CPT code (64912) specific to nerve repair with nerve allograft (Avance® Nerve Graft) and a separate code (+64913) for each additional strand of allograft used in a procedure. Category I CPT codes are used by providers to facilitate payment to the provider (either hospital or ASC) for outpatient procedures. Additionally, Category I CPT codes are used to facilitate payment to the surgeon, for both time spent in outpatient and inpatient procedures. Prior to January 2018, there was no designated Category I CPT code for nerve repair cases that included nerve allograft.  To date, the Company has not been able to determine whether there has been either a positive or negative effect as a result of the availability of the new code.

 

The process for securing coding for a product or procedure is separate from the process of securing coverage and establishing a reimbursement payment rate. In the United States, coverage and reimbursement for medical devices vary among payors. In addition, payors review coverage policies on an ongoing basis and can, without notice, change or deny coverage for these new products and procedures. We estimate that commercial payors covering a significant number of U.S. covered lives have legacy non-coverage policies relating to our Avance® Nerve Graft and our Axoguard® product lines, designating these products investigational or experimental. Some commercial payors do not currently cover or reimburse our products because they have determined insufficient evidence of favorable clinical outcomes is available. Although some consider the Avance® Nerve Graft and our Axoguard® product lines investigational or experimental at this time, these payors may in the future determine sufficient evidence has been developed to cover and reimburse our products and related procedures. We are actively working to reverse these non-coverage decisions but cannot provide assurance that we will be successful in these efforts. If we are not successful in reversing existing non-coverage policies, or if other third-party payors issue similar policies, this could have a material adverse effect on our business and operations. Further, third-party payors who currently cover and reimburse customers for procedures using our products may in the future choose to decrease current levels of reimbursement or eliminate reimbursement altogether, either of which will cause our business to suffer.

 

The amount of reimbursement received by our customers from third-party payors is dependent generally on fee schedules established by these payors for the existing CPT codes. For governmental payors, such as Medicare and Medicaid, the fee schedule amount is determined by statutory and regulatory formulas. For commercial payors, the reimbursement amount generally is dependent upon the specific contract terms between the provider and payor. We cannot provide assurance that government or commercial payors will continue to reimburse for procedures with our products using the existing codes, nor can we provide assurance that the payment rates will be adequate. If providers and physicians are unable to obtain reimbursement for the procedure at cost-effective levels when use of our products is included, this could have a material adverse effect on our business and operations. Hospitals and ASCs may not purchase our products if they do not receive payment sufficient to cover the cost of our products and related procedures. In addition, in the event that the current coding and/or payment methodology for these procedures changes, this could have a material adverse effect on our business and business operations.

 

Axogen may be subject to future product liability litigation which could be expensive and its insurance coverage may not be adequate.

 

Although Axogen is not currently subject to any product liability proceedings and it has no provision for product liability disbursements, it may incur material liabilities relating to product liability claims in the future, including product liability claims arising out of the usage of Axogen products. Although Axogen currently carries product liability insurance in an amount consistent with industry averages, its insurance coverage and any provision it may maintain in the future for product related liabilities may not be adequate and Axogen’s business could suffer material adverse consequences.

 

Technological change could reduce demand for Axogen’s products.

 

The medical technology industry is intensely competitive. Axogen competes with both U.S. and international companies that engage in the development and production of medical technologies and processes including:

 

 

Axogen products compete with autograft, hollow-tube conduits, commercially available wraps and amnion products, as well as with alternative medical procedures. For the foreseeable future, Axogen believes a significant number of surgeons will continue to choose to perform autograft procedures when feasible, despite the necessity of performing a second operation and its drawbacks. In addition, many members of the medical community will continue to prefer the use of hollow-tube conduits due in part to their familiarity with these products and the procedures required for their use. Amnion products are widely available and Axogen may not be able to distinguish the Avive® Soft Tissue Membrane from such other products so as to produce significant revenue from its distribution.  Also, steady improvements have been made in synthetic human tissue substitutes, which could compete with Axogen’s products in the future. Unlike allografts, synthetic tissue technologies are not dependent on the availability of human or animal tissue. Although Axogen’s growth strategy contemplates the introduction of new technologies, the development of these technologies is a complex and uncertain process, requiring a high level of innovation, as well as the ability to accurately predict future technology and market trends. Axogen may not be able to respond effectively to technological changes and emerging industry standards, or to successfully identify, develop or support new technologies or enhancements to existing products in a timely and cost-effective manner, if at all. There can be no assurance that in the future Axogen’s competitors will not develop products that have superior performance or are less expensive relative to Axogen’s products rendering Axogen’s products obsolete or noncompetitive.  In this regard, Integra and Baxter have each announced that they will provide a new product consisting of a hollow tube conduit filled with material which they suggest is superior to their current hollow conduit products.  Due to Axogen’s limited resources, its smaller size and its relatively early stage, Axogen may face competitive challenges from these new products or existing products and barriers that are difficult to overcome and could negatively impact its growth.  Finally, a Chinese company provides a human peripheral nerve allograft in China, however, such product is not sold in markets of interest of Axogen because of Axogen’s IP protection in its identified markets.  

 

Axogen may be unsuccessful in commercializing its products outside the U.S.

 

To date, Axogen has focused its commercialization efforts in the U.S., except for minor revenues in certain countries outside the U.S. Axogen intends to expand distribution and sales in these and other countries outside the U.S. and will need to comply with applicable foreign regulatory requirements, including obtaining the requisite approvals to do so. The regulatory environment for Axogen’s portfolio of products is complex.  Avance® Nerve Graft is distributed in Canada, United Kingdom, and certain other countries.  Distribution in Spain currently allows only for compassionate use and Axogen is proceeding with the regulatory submission process in Germany.  Axogen is not seeking approval for France and Italy at this time. Avive® Soft Tissue Membrane is currently available in the U.S. and select other countries for expansion.  Cook Biotech is currently renewing the Axoguard© product CE Mark and until such renewal Axogen can only sell those Axoguard products that are currently in inventory in the E.U., which inventory may not be sufficient to

satisfy all product sales prior to obtaining the renewal.  In addition, the United Kingdom voted to exit the E.U. (“Brexit”) and Axogen cannot be sure what changes could occur or  the cost of regulatory compliance with both the United Kingdom and E.U.  Until such time as Axogen can obtain, if at all, the necessary registrations and approvals for its products, material expansion beyond the United States will be limited.  Finally, the cost of regulatory compliance for sales outside the U.S. can be significant and time consuming.

 

Additionally, Axogen will need to either enter into distribution agreements with third parties or develop a direct sales force in foreign markets. If it does not obtain adequate levels of reimbursement from third party payers outside of the U.S., it may be unable to develop and grow its revenue internationally. Outside of the U.S., reimbursement systems vary significantly by country. Many ex-U.S. markets have government-managed healthcare systems that govern reimbursement for medical devices, implants and procedures. Additionally, some ex-U.S. reimbursement systems provide for limited payments in a given period and therefore result in extended payment periods. If Axogen is unable to successfully commercialize its products internationally, its long-term growth prospects may be limited.

 

If Axogen does not manage tissue and tissue donation in an effective and efficient manner, it could adversely affect its business.

 

Many factors affect the supply, quantity and timing of donor medical releases, such as effectiveness of donor screening, the effective recovery of tissue, the timely receipt, recording, review and approval of required medical and testing documentation, and employee loss and turnover in Axogen’s and its contractor’s recovery department. Axogen can provide no assurance that tissue recovery or donor medical releases will occur at levels that will maximize processing efficiency and minimize Axogen’s costs.

 

If Axogen does not manage product inventory in an effective and efficient manner, it could adversely affect profitability.

 

Many factors affect the efficient use and planning of product inventory, such as effectiveness of predicting demand, effectiveness of preparing manufacturing to meet demand, efficiently meeting product mix and product demand requirements and product expiration. Axogen may be unable to manage its inventory efficiently, keep inventory within expected budget goals, keep its work-in-process inventory on hand or manage it efficiently, control expired product or keep sufficient product on hand to meet demand. Finally, Axogen can provide no assurance that it can keep inventory costs within its target levels.   Failure to do so may harm long term growth prospects.

 

Axogen’s failure to protect its technology systems and comply with data protection laws and regulations could lead to government enforcement actions and significant penalties against Axogen, and adversely impact Axogen’s operating results.

 

We rely on information technology systems, including technology from third party vendors, to process, transmit and store electronic information in our day-to-day operations. Similar to other companies, the size and complexity of our information technology systems makes them vulnerable to a cyber-attack, malicious intrusion, breakdown, destruction, loss of data privacy, or other significant disruption. Our information systems require an ongoing commitment of resources to maintain, protect and enhance existing systems and develop new systems to keep pace with continuing changes in information processing technology, evolving systems and regulatory standards and the increasing need to protect patient and customer information. Any failure by us to maintain or protect our information technology systems and data integrity, including from cyber-attacks, intrusions or other breaches, could result in the unauthorized access to patient data and personally identifiable information, theft of intellectual property or other misappropriation of assets, or otherwise compromise our confidential or proprietary information and disrupt our operations.

 

In the U.S., federal and state privacy and security laws require certain of our operations to protect the confidentiality of personal information including patient medical records and other health information.  E.U. member states and other foreign jurisdictions, including Switzerland, have adopted data protection laws and regulations which impose significant compliance obligations. Moreover, the collection and use of personal health data in the E.U., which was formerly governed by the provisions of the E.U. Data Protection Directive, was replaced with the European Union General Data Protection Regulation (“GDPR”) in May 2018. The GDPR, which is wide-ranging in scope, imposes several

requirements relating to the consent of the individuals to whom the personal data relates, the information provided to the individuals, the security and confidentiality of the personal data, data breach notification and the use of third party processors in connection with the processing of personal data. The GDPR also imposes strict rules on the transfer of personal data out of the E.U. to the United States, provides an enforcement authority and imposes large penalties for noncompliance, including the potential for fines of up to €20 million or 4% of the annual global revenues of the noncompliant company, whichever is greater. The recent implementation of the GDPR has increased Axogen’s responsibility and liability in relation to personal data that Axogen processes, including in clinical trials, and Axogen may in the future be required to put in place additional mechanisms to ensure compliance with the GDPR, which could divert management's attention and increase Axogen’s cost of doing business. In addition, new regulation or legislative actions regarding data privacy and security (together with applicable industry standards) may increase Axogen’s costs of doing business. In this regard, Axogen expects that there will continue to be new proposed laws, regulations and industry standards relating to privacy and data protection in the United States, the E.U. and other jurisdictions, and Axogen cannot determine the impact such future laws, regulations and standards may have on its business.

 

Axogen’s management has broad discretion in the use of Axogen’s cash and cash equivalents and, despite management’s efforts, cash and cash equivalents may be used in a manner that does not increase the value of shareholders’ investments.

 

Axogen’s management has broad discretion in the use of Axogen’s cash and cash equivalents, and investors must rely on the judgment of management regarding the use of such cash and cash equivalents. Management may invest Axogen’s cash and cash equivalents in short-term or long-term, investment-grade, interest-bearing securities. These investments may not yield favorable returns to shareholders. If Axogen does not invest or apply its cash and cash equivalents in ways that enhance shareholder value, Axogen may fail to achieve expected financial results, which could cause its stock price to decline.

 

Axogen incurs costs as a result of operating as a public company, and its management is required to devote substantial time to compliance initiatives.

 

As a public company, Axogen incurs legal, accounting and other expenses to comply with relevant securities laws and regulations, including, without limitation, the requirement of establishment and maintenance of effective disclosure and financial controls and corporate governance practices. Axogen’s management devotes substantial time and financial resources to these compliance initiatives. Failure to comply with public company requirements could have a material adverse effect on Axogen’s business.  In addition, activity by shareholders or others that bring into question aspects of Axogen’s business or financial reporting, whether based on facts or baseless and contrived for individual economic gain, can have a negative impact on the price of Axogen’s stock and can result in substantial time and financial resources being expended to address the situation. 

 

Our business and stock price may be adversely affected if our internal controls are not effective.

 

Section 404 of the Sarbanes-Oxley Act of 2002 requires that public companies conduct a comprehensive evaluation of their internal control over financial reporting. To comply with this statute, each year we are required to document and test our internal control over financial reporting and our management is required to assess and issue a report concerning it.

 

In our annual report on Form 10-K for the year ended December 31, 2016, we reported material weaknesses in our internal control as of December 31, 2016 relating to the design and operation of key controls around the calculations of significant judgment and estimates and quarterly cycle count procedures related to consigned inventories. These control deficiencies did not result in any changes of prior period financial statements or previously released financial results.    We believe we took appropriate actions to remediate the control deficiencies we identified in these instances.

 

Although we have taken actions to correct the control deficiencies we identified and to strengthen our internal control over financial reporting, we cannot assure you that we will not discover other material weaknesses in the future or that no material weakness will result from any difficulties, errors, delays or disruptions while we implement and transition to new internal systems. The existence of one or more material weaknesses could result in errors in our

financial statements, and substantial costs and resources may be required to rectify these or other internal control deficiencies. If we cannot produce reliable financial reports, investors could lose confidence in our reported financial information, the market price of our common stock could decline significantly, we may be unable to obtain additional financing to operate and expand our business and our business and financial condition could be harmed.

 

Our business and financial performance could be adversely affected, directly or indirectly, by disasters, by terrorist activities or by international hostilities.

 

Neither the occurrence nor the potential impact of disasters (such as hurricanes and other natural disasters), terrorist activities and international hostilities can be predicted. However, these occurrences could impact Axogen directly as a result of damage to our facilities or by preventing us from conducting our business in the ordinary course, or indirectly as a result of their impact on our customers, suppliers or other counterparties. We could also suffer adverse consequences to the extent that disasters, terrorist activities or international hostilities affect the financial markets or the economy in general or in any particular region.

 

Axogen’s ability to mitigate the adverse consequences of such occurrences is in part dependent on the quality of our resiliency planning, and our ability, if any, to anticipate the nature of any such event that occurs. The adverse impact of disasters or terrorist activities or international hostilities also could be increased to the extent that there is a lack of preparedness on the part of national or regional emergency responders or on the part of other organizations and businesses that we deal with, particularly those that we depend upon but have no control over.

 

Risks Related to the Regulatory Environment in which Axogen Operates

 

Axogen’s business is subject to continuing regulatory compliance by the FDA and other authorities which is costly and could result in negative effects on its business.

 

Axogen is subject to extensive regulation by foreign and domestic government entities, including compliance with regulations governing appropriate relationships with healthcare professionals, such as physicians, hospitals and those to whom and through whom we may market our products.  We are subject to various federal, state and territorial laws in the United States and other jurisdictions in which we conduct business. These include, for example, anti-kickback laws, false claims laws, health care fraud laws, and anti-bribery laws such as the United States Foreign Corrupt Practices Act. Violations of these laws can be punishable by criminal and/or civil sanctions, including, in some instances, fines, imprisonment and, within the United States, exclusion from participation in government healthcare programs, including Medicare, Medicaid and Veterans Administration health programs. These laws are administered by, among others, the U.S. Department of Justice (“DOJ”), the Office of Inspector General of the Department of Health and Human Services, state attorneys general, and their respective counterparts in the applicable foreign jurisdictions in which we conduct business. Many of these agencies have increased their enforcement activities with respect to medical device manufacturers in recent years. There can also be changes to the regulations by foreign and domestic government entities that require Axogen to update or upgrade business processes or to perform additional validation activities for product or processes.  Compliance with such changes can be costly to implement or result in non-compliance, thus restricting the ability to distribute tissue or sell products that could have a material adverse effect.

 

Our products are also subject to regulation by the FDA in the U.S. The FDA regulates the development, clinical testing, marketing, distribution, manufacturing, labeling, and promotion of biological products, such as that of Axogen’s Avance® Nerve Graft product. The FDA requires the approval of a biological product, like Avance® Nerve Graft, through a BLA prior to marketing. Although Avance® Nerve Graft product has not yet been approved by FDA through a BLA, FDA is permitting the product to be distributed, subject to FDA enforcement discretion, provided that  Axogen: (1)  transitions to compliance with section 501(a)(2)(B) of the FD&C Act, the cGMP regulations in 21 CFR Parts 210 and 211 and the applicable regulations and standards in 21 CFR Parts 600-610 prior to initiation of a phase 3 clinical trial designed to demonstrate the safety, purity, and potency of Avance®    Nerve Graft; (2) conducts a phase 3 clinical trial to demonstrate safety, purity and potency of Avance® Nerve Graft under an SPA; (3) continues to comply with the requirements of 21 CFR Part 1271; and (4) exercises due diligence in executing the transition plan.  See “Business — Government Regulations — U.S. Government Regulation Review.” 

 

Avive® Soft Tissue Membrane is processed and distributed in accordance with FDA requirements for Human Cellular and Tissue-based Products (HCT/P) under 21 CFR Part 1271 regulations and U.S. State regulations. The FDA also regulates medical devices, for example the Axoguard® products, and requires them to be cleared through the 510(k) premarket notification process prior to marketing. The FDA’s premarket review process for new and modified existing devices that precedes product marketing can be time consuming and expensive. Some of the future products and enhancements to such products that Axogen expects to develop and market may require marketing clearance or approval from the FDA.

 

There can be no assurance, however, that clearance or approval will be granted with respect to any of Axogen’s device products or enhancements of marketed products or that Axogen’s Avance® Nerve Graft will meet FDA’s requirements for continued marketing and transition to a BLA or ultimately an approved BLA.  FDA review of Axogen’s devices or biological products may encounter significant delays during FDA’s premarket review process that would adversely affect Axogen’s ability to market its products or enhancements. In addition, there can be no assurance that Axogen products, including the Avance® Nerve Graft, or enhancements will not be subject to a lengthy and expensive approval process with the FDA.

 

It is possible that if regulatory clearances or approvals to market a product are obtained from the FDA, the clearances or approvals may contain limitations on the indicated uses of such product and other uses may be prohibited. Product approvals by the FDA can also be withdrawn due to failure to comply with regulatory standards or the occurrence of unforeseen problems following initial approval. Furthermore, the FDA could limit or prevent the distribution of Axogen products and the FDA has the power to require the recall of such products. FDA regulations depend heavily on administrative interpretation, and there can be no assurance that future interpretations made by the FDA or other regulatory bodies will not adversely affect Axogen’s operations. Axogen, and its facilities, may be inspected by the FDA from time to time to determine whether it is in compliance with various regulations relating to specifications, development, documentation, validation, testing, quality control and product labeling. A determination that Axogen is in violation of such regulations could lead to imposition of civil penalties, including fines, product recalls or product seizures and, in certain cases, criminal sanctions.

 

The use, misuse or off-label use of Axogen’s products may harm its reputation or the image of its products in the marketplace, or result in injuries that lead to product liability suits, which could be costly to Axogen’s business or result in FDA sanctions if the company is deemed to have engaged in off-label promotion. Axogen is seeking a biologics license through the BLA process for specific uses of Avance® Nerve Graft under specific circumstances. Its promotional materials and training methods must comply with FDA requirements and other applicable laws and regulations, including the prohibition against off-label promotion. Axogen’s promotion of the Axoguard® products, which are regulated as medical devices, also must comply with FDA’s requirements and must only use labeling that is consistent with the specific indication(s) for use included in the FDA substantial equivalence order that results in marketing the devices. Avive® Soft Tissue Membrane is processed and distributed in accordance with FDA requirements for (HCT/P) under 21 CFR Part 1271 regulations and is to be dispensed only by or on the order of a licensed physician and is contraindicated for use in any patient in whom soft tissue implants are contraindicated.  The FDA does not restrict or regulate a physician’s use of a medical product within the practice of medicine, and Axogen cannot prevent a physician from using its products for an off-label use. However, the FD&C Act and the FDA’s regulations restrict the kind of promotional communications that may be made about Axogen’s products and if the FDA determines that Axogen’s promotional or training materials constitute the unlawful promotion of an off-label use, it could request that Axogen modify its training or promotional materials and/or subject the Company to regulatory or enforcement actions, including the issuance of an untitled letter, a warning letter, civil money penalties, seizure, injunction or criminal fines and penalties. Other federal, state or foreign governmental authorities might also take action if they consider Axogen promotion or training materials to constitute promotion of an uncleared or unapproved use, which could result in significant fines or penalties under other statutory authorities, such as laws prohibiting false claims for reimbursement, or exclusion from participation in federal health programs. In that event, Axogen’s reputation could be damaged and the use of its products in the marketplace could be impaired.

 

In addition, there may be increased risk of injury if physicians or others attempt to use Axogen products off-label. Furthermore, the use of Axogen’s product for indications other than those for which its products have been approved, cleared or licensed by the FDA may not effectively treat the conditions not referenced in product indications, which

could harm Axogen’s reputation in the marketplace among physicians and patients. Physicians may also misuse Axogen’s product or use improper techniques if they are not adequately trained in the particular use, potentially leading to injury and an increased risk of product liability. Product liability claims are expensive to defend and could divert management’s attention from its primary business and result in substantial damage awards against Axogen. Any of these events could harm Axogen’s business, results of operations and financial condition.

 

Axogen’s Avance® Nerve Graft product is currently allowed to be distributed pursuant to a transition plan with the FDA and a change in position by the FDA regarding its use of enforcement discretion to permit the sale of Avance® Nerve Graft would have a material adverse effect on Axogen.

 

The FDA considers Axogen’s Avance® Nerve Graft product to be a biological product, subject to BLA approval requirements. Although the Avance® Nerve Graft product has not yet been approved by FDA through a BLA, Axogen’s Avance® Nerve Graft product is currently distributed under the controls applicable to a HCT/P pursuant to Section 361 of the Public Health Service Act and 21 CFR Part 1271 of FDA’s regulations, subject to FDA’s enforcement discretion and Axogen’s compliance with a transition plan established by the FDA.  See “Business — Government Regulations — U.S. Government Regulation Review.”  Axogen has continued to communicate with the  CBER since the acceptance of the transition plan on clinical trial design, preclinical studies, Chemistry, Manufacturing, and Controls (“CMC”) for Avance® Nerve Graft, and other issues related to the effective IND.  Subject to the FDA’s enforcement discretion, Axogen can commercially distribute Avance® Nerve Graft  until the FDA makes a final determination on an Avance® Nerve Graft BLA submission, assuming Axogen remains in compliance with the transition plan and exercises due diligence in executing the transition plan. In the event that the FDA becomes dissatisfied with Axogen’s progress or actions with respect to the transition plan or the FDA changes its position for any reason regarding its use of enforcement discretion to permit Axogen to distribute Avance® Nerve Graft product in accordance with the transition plan, Axogen would no longer be able to distribute Avance® Nerve Graft, which would have a material adverse effect on Axogen’s operations and financial viability. In addition, if Axogen does not meet the conditions of the transition plan, or fails to comply with applicable regulatory requirements, the FDA could impose civil penalties, including fines, product seizures, injunctions or product recalls and, in certain cases, criminal sanctions.  These consequences also would have a material adverse effect on Axogen’s operations and financial viability.

 

Axogen’s business is subject to continuing compliance to standards by various accreditation and registration bodies which is costly and loss of accreditation or registration could result in negative effects on its business.

 

Axogen is subject to accreditation such as that by the AATB and as a Verified-Accredited Wholesale Distributor by National Association of Boards of Pharmacy.  Axogen has registration requirements such as that with ISO 13485 registration bodies.  These accreditations and regulations can affect distribution and sale of Axogen products on a state-by-state basis, within the United States and also affects distribution and sale of Axogen products outside of the United States. The loss of accreditation or registration could keep Axogen from selling and distributing its products which may have negative effects on its business.   

 

Axogen’s Axoguard® and Avive® products are subject to FDA and other regulatory requirements.

 

Axogen’s Axoguard® product line is regulated as a medical device under the FD&C Act and subject to premarket notification and clearance requirements under section 510(k) of the FD&C Act, 21 CFR Part 820 (Quality System Regulation) and other FDA regulations. Axogen distributes for Cook Biotech the Axoguard® product line and Cook Biotech is responsible for the regulatory compliance of the Axoguard® Connector and Protector product lines. Cook Biotech has obtained a 510(k) premarket clearance for Axoguard® Nerve Connector from the FDA for porcine (pig) small intestine submucosa for the repair of peripheral nerve transections where gap closure can be achieved by flexion of the extremity. Cook Biotech has also obtained a 510(k) premarket clearance for Axoguard® Nerve Protector for the repair of peripheral nerve damage in which there is no gap or where a gap closure is achieved by flexion of the extremity.  Axogen is responsible for the regulatory compliance of the Axoguard® Nerve Cap.  Axogen has obtained a 510(k) premarket clearance for Axoguard® Nerve Cap to protect a peripheral nerve end and separate the nerve from the surrounding environment and to prevent or to reduce the development of symptomatic or painful neuroma.  If Axogen or Cook Biotech fails to comply with applicable regulatory requirements, the FDA could deny or withdraw

510(k) clearance for the Axoguard® products, or impose civil penalties, including fines, product seizures or product recalls and, in certain cases, criminal sanctions.

 

Avive® Soft Tissue Membrane is processed and distributed in accordance with U.S. FDA requirements for Human Cellular and Tissue-based Products (361 HCT/P) and as such, complies with 21 CFR Part 1271 regulations, U.S. State regulations and the guidelines of the American Association of Tissue Banks (“AATB”). FDA could determine that Avive® Soft Tissue Membrane should be regulated under Section 351 of the Public Health Service Act and cannot be marketed without a BLA.  If so, FDA could take enforcement action including requiring that AxoGen remove the product from the market until a BLA is approved.  If Axogen fails to comply with applicable regulatory requirements, the FDA could also impose civil penalties, including fines, product seizures or product recalls and, in certain cases, criminal sanctions.

 

Axogen’s Axotouch® and Acroval® products are subject to FDA and other regulatory requirements.

 

Axogen’s Axotouch® and Acroval® products are regulated as medical devices under the FD&C Act and subject to premarket notification and clearance requirements under section 510(k) of the FD&C Act, 21 CFR Part 820 (Quality System Regulation) and other FDA regulations.  If Axogen fails to comply with applicable regulatory requirements, the FDA could deny or withdraw 510(k) clearance for these products, or impose civil penalties, including fines, product seizures or product recalls and, in certain cases, criminal sanctions.

 

Defective Axogen product could lead to recall or other negative business conditions.

 

If Axogen’s products are defective or otherwise pose safety risks, the FDA could require their recall or Axogen may initiate a voluntary recall of its products. The FDA may require recall of a marketed medical device product, such as the Axoguard® products, in the event that it determines the medical device presents a reasonable probability of serious adverse health consequences or death. However, most device recalls do not rise to this level of health significance and result from voluntary action. The FDA has authority to recall biological products when a batch, lot or other quantity of the product presents an imminent or substantial hazard to the public health.  However, in such circumstances, the FDA usually initially requests voluntary recalls of biological products, such as the Avance® Nerve Graft. If a company does not comply with an FDA request for a recall, the FDA can order one under the above-referenced circumstances or take other enforcement actions, such as product seizure. In addition, manufacturers may, on their own initiative, recall a product to remove or correct a deficiency or to remedy a violation of the FD&C Act that may pose a risk to health. A government-mandated, government-requested or voluntary recall could occur as a result of an unacceptable risk to health, reports of safety issues, failures, manufacturing errors, design or labeling defects or other deficiencies and issues. Recalls and other field corrections for any of Axogen’s products would divert managerial and financial resources and have an adverse effect on its business, results of operations and financial condition. A recall could harm Axogen’s reputation with customers and negatively affect its sales. Axogen may initiate recalls involving some of its products in the future that it determines do not require notification of the FDA. If the FDA were to disagree with Axogen’s determinations, it could request that it report those actions as recalls, and take regulatory or enforcement action against Axogen or the product.

 

If Axogen’s products cause or contribute to a death, a serious injury or any adverse reaction involving a communicable disease related to its products, or malfunction in certain ways, it will be subject to reporting regulations, which can result in voluntary corrective actions or agency enforcement actions. See “Business — Regulation — Education Grants, U.S. Anti-kickback, False Claims and Other Healthcare Fraud and Abuse Laws — Pervasive and False Claims.”  If Axogen fails to report these events to the FDA within the required timeframes, or at all, the FDA could take regulatory or enforcement action against Axogen. Any adverse event involving Axogen’s products could result in future voluntary corrective actions, such as recalls or customer notifications, or agency action, such as inspection, mandatory recall or other enforcement action. Any corrective action, whether voluntary or involuntary, as well as Axogen defending itself in a lawsuit, would require the dedication of time and capital, distract management from operating its business, and may harm Axogen’s reputation, business, results of operations and financial condition.

 

Axogen’s operations must comply with FDA and other governmental requirements.

 

Axogen’s operations require it to comply with the FDA’s and other governmental authorities’ laws and regulations regarding the manufacture and production of medical products, which is costly and could subject Axogen to enforcement action. See “Business — Government Regulations — Education Grants, U.S. Anti-kickback, False Claims and Other Healthcare Fraud and Abuse Laws — Fraud, Abuse and False Claims”. Any of these actions could impair Axogen’s ability to produce its products in a cost-effective and timely manner in order to meet customer demands. Axogen may also be required to bear other costs or take other actions that may have an adverse impact on its future revenue and its ability to generate profits. Furthermore, Axogen’s key material suppliers, licensors and or other contractors may not continue to be in compliance with all applicable regulatory requirements, which could result in Axogen’s failure to produce its products on a timely basis and in the required quantities, if at all.

 

Distribution of Axogen human tissue products outside the U.S. are subject to foreign regulatory requirements that vary from country to country. In the European Union (“E.U.”), human tissue regulations, if applicable, differ from one E.U. member state to the next. Because of the absence of a harmonized regulatory framework and the proposed regulation for advanced therapy medicinal products in the E.U., as well as for other countries, the approval process for human derived cell or tissue based medical products may be extensive, lengthy, expensive and unpredictable. Axogen products will be subject to E.U. member states’ regulations that govern the donation, procurement, testing, coding, traceability, processing, preservation, storage, and distribution of human tissues and cells and cellular or tissue-based products. In addition, some E.U. member states have their own tissue banking regulations. The inability to meet foreign regulatory requirements could materially affect Axogen’s future growth and compliance with such requirements could place a significant financial burden on Axogen.

 

In addition, the United Kingdom voted to exit the European Union (“Brexit”) and the timing and scope remain unclear. To date there is no business disruption, but Axogen cannot be sure what changes could occur..  The cost of regulatory compliance with both the United Kingdom and E.U. could be significant and time consuming.

 

Finally, regulations in both the United States and other countries are subject to constant change.  There can be no assurance that Axogen can meet the requirements of future regulations or that compliance with current regulations assures future capability to distribute and sell its products.

 

Clinical trials can be long, expensive and results are ultimately uncertain which could jeopardize Axogen’s ability to obtain regulatory approval and continue to market its Avance® Nerve Graft product.

 

Axogen is required to perform a clinical trial for its Avance® Nerve Graft under FDA’s statutory requirements to obtain approval of a BLA for the product. This trial is expensive, is expected to take several years to execute, and is subject to factors within and outside of Axogen’s control. The outcome of this trial is uncertain.

 

Axogen submitted for RECON an IND for the Avance® Nerve Graft in April 2013 and received FDA approval in March 2015.   The phase 3 clinical trial was initiated in the second quarter of 2015.  The RECON study is designed to assess the outcome of peripheral nerve repair in approximately 170 subjects in up to 20 centers. The study completed initial subject enrollment in January 2019.   No outcome data is available at this time.  As required by the SPA and agreed to by FDA and Axogen, an independent statistical analysis was conducted to determine if greater study enrollment is appropriate to maintain the planned statistical power of the study. Axogen is working with FDA to review the interim analysis findings and obtain agreement on the next study phase.  If additional enrollment results from these discussions an amended IND will be filed.  Any such changes will increase the time and cost of RECON and extend the timeframe for final  determination of Axogen’s BLA submission.  

 

Axogen is working to ensure compliance with the applicable regulations by having ongoing discussions on the transition of the quality system to 21 CFR Parts 210/211 and 600-610 regulations with the FDA. Final determination of regulatory compliance with 21 CFR Parts 210/211 and 600-610 will be made during FDA’s pre-license inspection as part of the BLA review. If the FDA is unable to agree with Axogen, or Axogen is unable to meet the standards required of it by the FDA, regarding preclinical studies, clinical studies and CMC, the approval of Axogen’s BLA would not occur or be delayed.

 

Axogen continues to work diligently with the FDA and, in this context, continues to distribute the Avance® Nerve Graft products.  The FDA will end the period of enforcement discretion upon a final determination of Axogen’s BLA submission or if the FDA finds that Axogen does not meet the conditions for the transition plan or is not exercising due diligence in executing the transition (e.g., not progressing toward study completion or BLA submission in a timely or adequate fashion).  If final action on the BLA is negative or Axogen is found to not meet the conditions for the transition plan or its execution, Axogen will not be able to continue to distribute Avance® Nerve Graft, and Axogen’s business and financial condition will be materially adversely affected.

 

The results of non-clinical studies do not necessarily predict future clinical trial results and predecessor clinical trial results may not be repeated in subsequent clinical trials. Additionally, the FDA may disagree with Axogen’s interpretation of the data from its non-clinical studies and clinical trials and may require the company to pursue additional non-clinical studies or clinical trials, or not approve Axogen’s BLA. If Axogen is unable to demonstrate the safety and efficacy of its product through its clinical trials, it will be unable to obtain regulatory approval to market the Avance® Nerve Graft and will not be able to continue to provide it.

 

Axogen will rely on third parties to conduct its clinical trial and they may not perform as contractually required or expected.

 

Axogen will rely on third parties, such as contract research organizations (“CROs”), medical institutions, clinical investigators and contract laboratories to conduct its clinical trial and certain nonclinical studies. Axogen and its CROs are required to comply with all applicable regulations governing clinical research, including good clinical practice, or GCP. The FDA enforces these regulations through periodic inspections of trial sponsors, principal investigators, CROs and trial sites. If Axogen or its CROs fail to comply with applicable FDA regulations, the data generated in its clinical trials may be deemed unreliable and the FDA may require Axogen to perform additional clinical trials before approving its applications. Axogen cannot be certain that, upon inspection, the FDA and similar foreign regulatory authorities will determine that Axogen’s clinical trial complies or complied with clinical trial regulations, including GCP. In addition, Axogen’s clinical trial must be conducted with product produced under applicable cGMP regulations. Failure to comply with the clinical trial regulations may require Axogen to repeat clinical trials, which would delay the regulatory approval process. If these third parties do not successfully carry out their contractual duties or regulatory obligations or meet expected deadlines, if these third parties need to be replaced, or if the quality or accuracy of the data they obtain is compromised due to the failure to adhere to Axogen’s clinical protocols or regulatory requirements or for other reasons, Axogen’s non-clinical development activities or clinical trials may be extended, delayed, suspended or terminated, and it would not be able to obtain regulatory approval for its products on a timely basis, if at all, and its business, results of operations, financial condition and growth prospects would be adversely affected. Furthermore, Axogen’s third party clinical trial investigators may be delayed in conducting its clinical trials for reasons outside of their control.

 

 

U.S. governmental regulation could restrict the use of Axogen’s Avance® Nerve Graft and Avive® Soft Tissue Membrane product, restrict Axogen’s procurement of tissue or increase costs.

 

In addition to the FDA requirements for biological products, Avance® Nerve Graft will continue to be subject to, as is Avive® Soft Tissue Membrane, various requirements for human tissue under 21 CFR Part 1271 controls. Human tissues intended for transplantation have been regulated by the FDA since 1993. In May 2005, three new comprehensive regulations went into effect that address manufacturing activities associated with HCT/P. The first regulation requires that companies that produce and distribute HCT/Ps register with the FDA. The second regulation provides criteria that must be met for donors to be eligible to donate tissues and is referred to as the “Donor Eligibility” rule. The third regulation governs the processing and distribution of the tissues and is often referred to as the “Current Good Tissue Practices” rule. The Current Good Tissue Practices rule covers all stages of allograft processing, from procurement of tissue to distribution of final allografts. Together, the three basic requirements of 21 CFR Part 1271 are designed to ensure that sound, high quality practices are followed to reduce the risk of tissue contamination and of communicable disease transmission to recipients. These regulations increased regulatory scrutiny within the industry in which Axogen operates and have led to increased enforcement actions, which affects the conduct of its business.  In addition, new guidance was issued by the FDA in late 2017 on Regulatory Considerations for Human Cells, Tissues, and Cellular and

Tissue-Based Products: Minimal Manipulation and Homologous Use and FDA Commissioner Gottlieb has publicly announced that other guidance for cell and gene therapy products are forthcoming.  FDA actions interpreting these guidance will need to be followed closely, and the potential implications on the regulatory status of Avive® and future HCT/P products is being evaluated by the Company.

 

Additional regulations or guidance documents may be implemented by the FDA in the future.  These changes may require new documentation requirements, process changes or testing that could increase costs and regulatory burden.  See “Business — Government Regulations.”  These regulations can also increase the cost of tissue recovery activities. Finally, Avance® Nerve Graft and Avive® Soft Tissue Membrane are subject to certain state and local regulations, as well as compliance with the standards of the tissue bank industry’s accrediting organization, the AATB.

 

The procurement and transplantation of allograft nerve tissue is also subject to federal law pursuant to the National Organ Transplant Act (“NOTA”), a criminal statute which prohibits the purchase and sale of human organs used in human transplantation, including nerve and related tissue, for “valuable consideration.” NOTA only permits reasonable payments associated with the removal, transportation, processing, preservation, quality control, implantation and storage of human nerve tissue. Axogen makes payments to certain of its clients and tissue banks for their services related to recovering allograft nerve and umbilical cord tissue on its behalf. If NOTA is interpreted or enforced in a manner which prevents Axogen from receiving payment for services it renders, or which prevents it from paying tissue banks or certain of its clients for the services they render for Axogen, its business could be materially and adversely affected.

 

Axogen has engaged, through its marketing employees, independent sales agents and sales representatives in ongoing efforts designed to educate the medical community as to the benefits of Axogen products, and Axogen intends to continue its educational activities. Although Axogen believes that NOTA permits payments in connection with these educational efforts as reasonable payments associated with the processing, transportation and implantation of Axogen products, payments in connection with such education efforts are not exempt from NOTA’s restrictions and Axogen’s inability to make such payments in connection with its education efforts may prevent it from paying Axogen sales representatives for their education efforts and could adversely affect Axogen’s business and prospects. No federal agency or court has determined whether NOTA is, or will be, applicable to every allograft nerve tissue-based material which Axogen’s processing technologies may generate. Assuming that NOTA applies to Axogen’s processing of allograft nerve and umbilical cord tissue, Axogen believes that it complies with NOTA, but there can be no assurance that more restrictive interpretations of, or amendments to, NOTA will not be adopted in the future, which would call into question one or more aspects of Axogen’s method of operations.

 

Other regulatory entities include state agencies with statutes covering tissue banking. Regulations issued by Florida, New York, California and Maryland, among other states, are particularly relevant to Axogen’s business. Most states do not currently have tissue banking regulations. However, incidents of allograft related issues in the industry may stimulate the development of regulation in other states. It is possible that third parties may make allegations against Axogen or against donor recovery groups or tissue banks about non-compliance with applicable FDA regulations or other relevant statutes or regulations. Allegations like these could cause regulators or other authorities to take investigative or other action, or could cause negative publicity for Axogen’s business and the industry in which it operates.

 

Healthcare policy changes may have a material adverse effect on Axogen.

 

In March 2010, President Obama signed into law the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Affordability Reconciliation Act (the “Act”), which Act substantially changes the way healthcare is financed by both governmental and private insurers, and encourages improvements in the quality of healthcare items and services. While implementation of the Act has been uneven, several provisions significantly impact the biotechnology and medical device industries and could have a material adverse impact on numerous aspects of Axogen’s business.

 

This Act includes, among other things, the following measures:

 

 

There are also a number of states (such as Vermont, Massachusetts, Minnesota) with their own Sunshine Acts that implement the reporting and disclosure requirements on healthcare manufacturers for any “transfer of value” made or distributed to physicians and teaching hospitals, as well as reporting of certain physician ownership interests.

 

In the future, there may continue to be additional proposals relating to the reform of the U.S. healthcare system. Certain of these proposals could limit the prices Axogen is able to charge for its products or the amounts of reimbursement available for its products and could also limit the acceptance and availability of its products. The adoption of some or all of these proposals could have a material adverse effect on Axogen’s business, results of operations and financial condition.

 

Additionally, initiatives sponsored by government agencies, legislative bodies and the private sector in the U.S. and elsewhere to limit the growth of healthcare costs, especially for drugs and biologics, including price regulation and competitive pricing, are ongoing in markets where Axogen does business. Axogen could experience an adverse impact on operating results due to increased pricing pressure in the U.S. and in other markets. Governments, hospitals, pharmacy benefit managers (PBMs) and other third-party payors could reduce the amount of approved reimbursement for Axogen’s products, deny coverage altogether, or impose new requirements on manufacturers to justify their prices. Reductions in reimbursement levels or coverage or other cost-containment measures could unfavorably affect Axogen’s future operating results.

 

Risks Related to Axogen’s Intellectual Property

 

Failure to protect Axogen’s IP rights could result in costly and time-consuming litigation and its loss of any potential competitive advantage.

 

Axogen’s success will depend, to a large extent, on its ability to successfully obtain and maintain patents, prevent misappropriation or infringement of IP, maintain trade secret protection, and conduct operations without violating or infringing on the IP rights of third parties. See “Business — Intellectual Property.” There can be no assurance that Axogen’s patented and patent-pending technologies will provide it with a competitive advantage, that Axogen will be able to develop or acquire additional technology that is patentable, or that third parties will not develop and offer technologies which are similar to Axogen’s. Moreover, Axogen can provide no assurance that confidentiality agreements with its employees, consultants and other parties, trade secrecy agreements or similar agreements intended to protect unpatented technology or prevent unauthorized use, disclosure, or misappropriation will not be breached by those third parties. IP litigation is extremely expensive and time-consuming, and it is often difficult, if not impossible, to predict the outcome of such litigation. A failure by Axogen to protect its IP, or a breach by third parties of agreements aimed at protecting Axogen’s IP, could have a materially adverse effect on its business and operating results and its ability to successfully compete in its industry.

 

Future protection for Axogen’s proprietary rights is uncertain which may impact its ability to successfully compete in its industry.

 

The degree of future protection for Axogen’s proprietary rights is uncertain. Axogen cannot ensure that:

 

 

Axogen’s commercial success depends in part on its ability and the ability of its collaborators and licensors to avoid infringing patents and proprietary rights of third parties which could expose it to litigation or commercially unfavorable licensing arrangements. Third parties may accuse Axogen or collaborators and licensors of employing their proprietary technology in Axogen products, or in the materials or processes used to make Axogen products, without authorization. Any legal action against Axogen collaborators, licensors or it claiming damages and/or seeking to enjoin Axogen’s commercial activities relating to the affected products, materials and processes could, in addition to subjecting Axogen to potential liability for damages, require it or its collaborators and licensors to obtain a license to continue to utilize the affected materials or processes or to manufacture or market the affected products. Axogen cannot predict whether it or its collaborators and licensors would prevail in any of these actions or whether any license required under any of these patents would be made available on commercially reasonable terms, if at all. If Axogen were unable to obtain such a license, it and its collaborators and licensors may be unable to continue to utilize the affected materials or processes, or manufacture or market the affected products, or Axogen may be obligated by a court to pay substantial royalties and/or other damages to the patent holder. Even if Axogen were able to obtain such a license, the terms of such a license could substantially reduce the commercial value of the affected product or products and impair Axogen’s prospects for profitability. Accordingly, Axogen cannot predict whether, or to what extent, the commercial value of the affected product or products or Axogen’s prospects for profitability may be harmed as a result of any of the liabilities discussed above. Furthermore, infringement and other IP claims, with or without merit, can be expensive and time-consuming to litigate and can divert management’s attention from its core business. Axogen and its licensors may be unable to obtain and enforce IP rights to adequately protect its products and related IP.

 

The patent protection for our products may expire before we are able to maximize their commercial value which may subject us to increased competition and reduce or eliminate our opportunity to generate product revenue.

 

The patents for our commercialized products and products in development have varying expiration dates and, when these patents expire, we may be subject to increased competition and we may not be able to recover our development costs. For example, the material U.S. patents covering the formulations used in our Axoguard® product line, which are held by Cook Biotech, have expired.  Expiration of these patents could adversely affect our ability to successfully execute our business strategy to maximize the value of Axoguard® products and could negatively impact our future financial condition and results of operations.

 

Others may claim an ownership interest in Axogen IP which could expose it to litigation and have a significant adverse effect on its prospects.

 

A third party may claim an ownership interest in one or more of Axogen’s patents or other IP. A third party could bring legal actions against Axogen claiming it infringes their patents or proprietary rights, and seek monetary damages

and/or enjoin clinical testing, manufacturing and marketing of the affected product or products. While Axogen believes it owns the right, title and interest in the patents for which it or its licensors have applied and Axogen’s other IP (including that which is licensed from third parties), and is presently unaware of any claims or assertions by third-parties with respect to Axogen’s patents or IP, it cannot guarantee that a third party will not assert a claim or an interest in any of such patents or IP. If Axogen becomes involved in any litigation, it could consume a substantial portion of Axogen’s resources and cause a significant diversion of effort by Axogen’s technical and management personnel regardless of the outcome of the litigation. If any of these actions were successful, in addition to any potential liability for damages, Axogen could be required to obtain a license to continue to manufacture or market the affected product, in which case Axogen may be required to pay substantial royalties or grant cross-licenses to Axogen’s patents. Axogen cannot, however, assure you that any such license will be available on acceptable terms, if at all. Ultimately, Axogen could be prevented from commercializing a product or be forced to cease some aspect of its business operations as a result of claims of patent infringement or violation of other IP rights, which could have a material and adverse effect on Axogen’s business, financial condition, and results of operations. Further, the outcome of IP litigation is subject to uncertainties that cannot be adequately quantified in advance, including the demeanor and credibility of witnesses and the identity of the adverse party. This is especially true in IP cases that may turn on the testimony of experts as to technical facts or the scope or meaning of patent claims upon which experts may reasonably disagree.

 

Axogen depends on maintenance of exclusive licenses.

 

Axogen depends fundamentally on keeping and satisfying the terms of exclusive licenses of its nerve repair technologies from UFRF and UTA. Nonetheless, a disagreement between Axogen and either licensor could have a negative impact on its ability to operate its business effectively. In addition, Axogen could learn that the technologies it has licensed do not perform as purported, are not efficacious, or are not the property of the licensor, any of which would have an immediate and negative impact on Axogen’s business.

 

Axogen trademarks are valuable

 

In the U.S. and other countries, we currently hold trademark registrations and have trademark applications pending, any of which may be the subject of a governmental or third party objection, which could prevent the maintenance or issuance of the same. As our products mature, our reliance on our trademarks to protect our brand and, in part, differentiate us from our competitors increases and as a result, if we are unable to prevent third parties from adopting, registering or using trademarks, including trade dress, that infringe, dilute or otherwise violate our trademark rights, our business could be materially adversely affected.

 

Risks Related to Our Common Stock

An active trading market in our common stock may not be maintained.

The trading market in our common stock has been extremely volatile. The quotation of our common stock on The Nasdaq Capital Market does not assure that a meaningful, consistent and liquid trading market will exist. We cannot predict whether an active market for our common stock will be maintained in the future. An absence of an active trading market could adversely affect our shareholders’ ability to sell our common stock at current market prices in short time periods, or possibly at all. Additionally, market visibility for our common stock may be limited and such lack of visibility may have a depressive effect on the market price for our common stock. As of December 31, 2018, approximately 7.41% of our outstanding shares of common stock was held by our officers, directors, beneficial owners of 5% or more of our securities and their respective affiliates, which adversely affects the liquidity of the trading market for our common stock, in as much as federal securities laws restrict sales of our shares by these shareholders. If our affiliates continue to hold their shares of common stock, there will be limited trading volume in our common stock, which may make it more difficult for investors to sell their shares or increase the volatility of our stock price.

 

The price of Axogen’s common stock could be highly volatile due to a number of factors, which could lead to losses by investors and costly securities litigation.

 

Our common stock is listed on the Nasdaq Capital Market under the symbol “AXGN.”  The stock market in general, and the market for medical technology companies in particular, have experienced extreme volatility that has often been unrelated to the operating performance of particular companies.  The trading price of our common stock has experienced substantial volatility and is likely to continue to be highly volatile in response to a number of factors including, without limitation, the following:

 

 

The stock market is subject to significant price and volume fluctuations. In the past, and several recent situations, following periods of volatility in the market price of a company’s securities, securities class action litigation has been initiated against such company. Axogen has experienced such situation and is subject to a class action.  Litigation initiated against us, including that which we are currently involved, whether or not successful, could result in substantial costs and diversion of our management’s attention and resources, which could harm our business and financial condition.

 

On January 9, 2019, Plaintiff Neil Einhorn, on behalf of himself and others similarly situated, filed a putative class action complaint alleging violations of the federal securities laws against Axogen, Inc., certain of its directors and officers (“Individual Defendants”), and Axogen’s 2017 Offering Underwriters and 2018 Offering Underwriters (collectively, with the Individual Defendants, the “Defendants”), captioned Einhorn v. Axogen, Inc., et al., No. 8:19-cv-00069 (M.D. Fl.).  Plaintiff asserts that Defendants made false or misleading statements in connection with the Company’s November 2017 registration statement issued regarding its secondary public offering in November 2017 and May 2018 registration statement issued regarding its secondary public offering in May 2018, and during a class period of August 7, 2017 to December 18, 2018.   In particular, Plaintiff asserts that Defendants issued false and misleading statements and failed to disclose to investors: (1) that the Company aggressively increased prices to mask lower sales; (2) that the Company’s pricing alienated customers and threatened the Company’s future growth; (3) that ambulatory surgery centers form a significant part of the market for the Company’s products; (4) that such centers were especially sensitive to price increases; (5) that the Company was dependent on a small number of surgeons whom the Company paid to generate sales; (6) that the Company’s consignment model for inventory was reasonably likely to lead to channel stuffing; (7) that the Company offered purchase incentives to sales representatives to encourage channel stuffing; (8) that the Company’s sales representatives were encouraged to backdate revenue to artificially inflate metrics; (9) that the Company lacked adequate internal controls to prevent such channel stuffing and backdating of revenue; (10) that the Company’s key operating metrics, such as number of active accounts, were overstated; and (11) that, as a result of the foregoing, Defendants’ positive statements about the Company’s business, operations, and prospects, were materially misleading and/or lacked a reasonable basis.  Axogen was served on January 15, 2019.  On February 4, 2019, the court granted the parties’ stipulated motion which provided that Axogen is not required to file a response to the complaint until thirty days after Plaintiff files a consolidated amended complaint, which will not occur until thirty days after the court appoints a lead plaintiff and lead counsel.

 

We do not anticipate paying any cash dividends in the foreseeable future.

 

The operation and expansion of our business will continue to require funding. We  do not anticipate that we will pay any cash dividends on our common stock for the foreseeable future. Any determination to pay dividends in the future will be at the discretion of our Board of Directors and will depend upon results of operations, financial condition, contractual restrictions, restrictions imposed by applicable law and other factors our board of directors deems relevant. Accordingly, if any investor purchases shares of common stock, realization of a gain on such investment will depend on the appreciation of the price of our common stock, which may never occur. Investors seeking cash dividends in the foreseeable future should not purchase our common stock.

 

Anti-takeover provisions in Minnesota law may deter acquisition bids for us that you might consider favorable.

 

We are governed by the provisions of Sections 302A.671, 302A.673 and 302A.675 of the Minnesota Business Corporation Act (the “MBCA”). These provisions may discourage a negotiated acquisition or unsolicited takeover of us and deprive our shareholders of an opportunity to sell their common stock at a premium over the market price.

 

In general, Section 302A.671 of the MBCA provides that a corporation’s shares acquired in a control share acquisition have no voting rights unless voting rights are approved in a prescribed manner. A “control share acquisition” is a direct or indirect acquisition of beneficial ownership of shares that would, when added to all other shares beneficially owned by the acquiring person, entitle the acquiring person to have voting power of 20% or more in the election of directors.

 

In general, Section 302A.673 of the MBCA prohibits a public Minnesota corporation from engaging in a business combination with an interested shareholder for a period of four years after the date of the transaction in which the person

became an interested shareholder, unless the business combination is approved in a prescribed manner. The term “business combination” includes mergers, asset sales and other transactions resulting in a financial benefit to the interested shareholder. An “interested shareholder” is a person who is the beneficial owner, directly or indirectly, of 10% or more of a corporation’s voting stock or who is an affiliate or associate of the corporation, and who, at any time within four years before the date in question, was the beneficial owner, directly or indirectly, of 10% or more of the corporation’s voting stock. Section 302A.673 does not apply if a committee of our Board of Directors consisting of all of its disinterested directors (excluding current and former officers) approves the proposed transaction or the interested shareholder’s acquisition of shares before the interested shareholder becomes an interested shareholder.

 

If a tender offer is made for our common stock, Section 302A.675 of the MBCA precludes the offeror from acquiring additional shares of stock (including in acquisitions pursuant to mergers, consolidations or statutory share exchanges) within two years following the completion of the tender offer, unless shareholders selling their shares in the later acquisition are given the opportunity to sell their shares on terms that are substantially the same as those contained in the earlier tender offer. Section 302A.675 does not apply if a committee of our Board of Directors consisting of all of its disinterested directors (excluding its current and former officers) approves the proposed acquisition before any shares are acquired pursuant to the earlier tender offer.

 

ITEM 1B.  UNRESOLVED STAFF COMMENTS

 

None.

 

ITEM 2.  PROPERTIES 

 

The Company and SNH Medical Office Properties Trust, a Maryland real estate investment trust (“SNH”), are parties to that certain lease dated as of February 6, 2007, as amended, (the “Primary Lease”) pursuant to which the Company leases its approximately nineteen thousand square foot corporate headquarters facility in the Progress Center at 13631 Progress Boulevard, Alachua, Florida 32615 (the “Primary Premises”). The annual cost for the Primary Premises ranges from $353,000 to $363,000 through the end of the term of the lease, which expires on October 31, 2021.  On January 23, 2017 the Company entered into a lease (the “First Expansion Lease”) with SNH for one thousand four hundred square feet at 13709 Progress Boulevard, Alachua, Florida 32615 (the “First Expansion Premises”) adjacent to the Primary Premises.  The Company has entered into the Second Expansion Lease and Third Expansion Lease, as defined below, which relate to properties that are adjacent to the Primary Premises and First Expansion Premises resulting in the Company having approximately eighteen thousand square feet for its corporate headquarters and certain research space in the Progress Center in Alachua, Florida. 

   

On November 19, 2018, the Company entered into a Lease (the “Second Expansion Lease”) with SNH for two thousand eight hundred square feet at 13709 Progress Boulevard, Suites S-160, S-162 and S-164, Alachua, Florida 32615 (the “Second Expansion Premises”). Pursuant to the Second Expansion Lease, the Company is to use the Second Expansion Premises for general office uses. The Second Expansion Lease commenced December 1, 2018 and expires November 30, 2020. The annual cost of the Second Expansion Premises is approximately $45,000 for the first twelve months of the term and $42,000 for the final eleven months. The Company is also obligated to pay for certain taxes, insurance costs and electricity costs incurred by SNH.

 

On November 19, 2018, AC entered into a Lease (the “Third Expansion Lease”) with SNH for two thousand square feet at 13709 Progress Boulevard, Suites S-175, S-177 and S-179, Alachua, Florida 32615 (the “Third Expansion Premises”). Pursuant to the Third Expansion Lease, the Company is to use the Third Expansion Premises for general office and biomedical research uses. The Third Expansion Lease commenced December 1, 2018 and its term expires November 30, 2020.  The annual cost of the Third Expansion Premises is approximately $37,000 for the first twelve months of the term and $35,000 for the final eleven months. The Company is also obligated to pay for certain taxes, insurance costs and electricity costs incurred by SNH.

 

On November 21, 2018, the Company, entered into Commercial Lease Amendment 3 (the “Burleson Amendment”), to the Commercial Lease dated April 21, 2015, as amended, with Ja-Cole L.P. Under the terms of the Burleson Amendment, the Company leased an additional two thousand five hundred square feet of warehouse/office space in

Burleson, Texas (collectively with the space leased under the Commercial Lease with Ja-Cole L.P. prior to the effectiveness of the Burleson Amendment,  the “Burleson Facility”).  The Burleson Facility will now comprise a total of twelve thousand five hundred square feet, all of which, pursuant to the Burleson Amendment, will be leased until December 31, 2021.  The annual rental cost of the entire Burleson Facility is now approximately $113 through December 31, 2020 and $116 for the calendar year 2021. The Burleson Facility houses raw material storage and product distribution while allowing same day order fulfillment for both the east and west coasts of the United States.

 

On October 26, 2018 (the “Ashley Avenue Lease Effective Date”), the Company entered into a Lease (the “Ashley Avenue Lease”) with Ashley Avenue Associates I, LLC., a Delaware limited liability company (“Ashley”), for the lease by the Company of approximately fifteen thousand square feet of office space on the second floor of the building located at 1000 N. Ashley Drive, Tampa, Florida 33602 (the “Ashley Avenue Premises”).  Pursuant to the Ashley Avenue Lease, the Company will use the Ashley Avenue Premises for general office purposes.  The initial term of the Ashley Avenue Lease commenced on December 1, 2018 and expires on November 30, 2020. The Company has an option to terminate the lease after eighteen months by providing Ashley with four months advance written notice.  The rental cost for the Ashley Avenue Premises will be $381,000 for the first twelve month period, and $360,000 for the final eleven month period. The Company will also be obligated to pay for its pro rata share of the building’s property taxes, utilities, administrative costs, common area maintenance and management fees, excluding any capital improvements or any damage due to fire, hurricane or other casualty.

 

On September 20, 2018, the Company entered into an agreement with Heights Union, LLC, a Florida limited liability company (“Heights Union”), for the lease of seventy-five thousand square feet of office space (the “Heights Union Premises”) in a one hundred and fifty thousand square foot office building that Heights Union intends to construct and complete on or before February 15, 2020, on an area of land in Tampa, Florida.  Pursuant to the Heights Union lease, the Company will use the Heights Union Premises for general office, medical laboratory, training and meeting purposes.  The annual costs of the Heights Union Premises ranges from $2.4 million to $3.3 million during the term of the lease.    Axogen believes it can obtain certain economic incentives from state authorities associated with the employment at the facility; such incentives are not expected to be a material offset to the expenses of the project as a whole.

 

On August 6, 2015, Axogen entered into the CTS Agreement with CTS, an FDA registered tissue establishment.  Processing of the Avance® Nerve Graft pursuant to the CTS Agreement began in February 2016.  The CTS Agreement terminates December 31, 2021, subject to earlier termination by either party for cause (subject to the non-terminating party’s right to cure, in certain circumstances), or without cause upon 6  months’ notice whereby notice cannot be provided prior to March 1, 2021.   Under the CTS Agreement, Axogen pays CTS a facility fee for clean room/manufacturing, storage and office space.  CTS also provides services in support of Axogen’s manufacturing such as routine sterilization of daily supplies, providing disposable supplies, microbial services and office support.

 

Effective June 8, 2018, AC entered into an Agreement for Purchase and Sale of Real Property with ARC CRVANOH001, LLC, a Delaware limited liability company (“ARC”), for the acquisition (the “Acquisition”) by AC of certain real property located in Vandalia, Ohio comprised of a 70,000 square foot building on approximately 8.6 acres of land.  AC thereafter transferred its rights and obligations under the Agreement to Axogen Processing Corporation, incorporated for purposes of the Acquisition. On July 31, 2018, Axogen Processing Corporation completed the Acquisition pursuant to the terms of the Agreement for Purchase and Sale of Real Property.

 

In addition, Axogen leases space and maintains records at certain other facilities, including Axogen’s prior corporate headquarters at 1407 South Kings Highway, Texarkana, Texas 75501.

 

The aggregate cost of all of Axogen’s and its subsidiaries’ properties is approximately $1.9 million per year.  Axogen believes that its facilities will be sufficient to operate its business for the next 12 months and that current lease obligations will not change materially.

 

 

 ITEM 3.  LEGAL PROCEEDINGS

 

Except as provided below, Axogen and its subsidiaries do not have any active or pending material legal proceedings:

 

 

 

 

ITEM 4.  MINE SAFETY DISCLOSURES

 

None.

PART II

 

ITEM 5.  MARKET FOR REGISTRANT’S COMMON EQUITY, RELATED SHAREHOLDER MATTERS AND ISSUER PURCHASES OF EQUITY SECURITIES 

 

Axogen’s common stock is traded on the Nasdaq Capital Market under the symbol “AXGN.”  On February 22, 2019, the last reported closing sale price of the Company common stock on the Nasdaq Capital Market was $17.96 per share.

 

Shareholders

 

As of February 22, 2019, the Company had 38,945,029 shares of common stock outstanding, and approximately 254 common shareholders of record, based upon information received from our stock transfer agent.  However, this number does not include beneficial owners whose shares were held of record by nominees or broker dealers.  The Company estimates that there are more than 11,890 individual owners.

 

Stock Performance Graph

 

The following graph compares the cumulative total shareholder return on our common stock for the period from December 31, 2013 to December 31, 2018 with (i) the Nasdaq Stock Market Composite Index; and (ii) the Nasdaq Stock Market Biotechnology Index.  The graph assumes an investment of $100 in our common stock and the respective indices for the period of December 31, 2013 to December 31, 2018.  The comparisons set forth in the graph are provided pursuant to SEC rules and are not intended to forecast or be indicative of the future performance of our common stock or either of the included indices.  The performance graph shall not be deemed incorporated by reference by any general statement incorporating by reference this annual report into any filing under the Securities Act of 1933, as amended, or

the Exchange Act of 1934, as amended, except to the extent we specifically incorporate this information by reference, and shall not otherwise be deemed filed under such acts.

 

 

Purchases of Equity Securities by the Issuer and Affiliated Purchasers

 

We did not repurchase any of our securities in the fourth quarter of 2018.

 

Recent Sales of Unregistered Securities

 

We had no sales of unregistered securities in 2018.

ITEM 6.  SELECTED FINANCIAL DATA

 

The selected financial data set forth below has been derived from our audited financial statements.  This data should be read in conjunction with the financial statements, the notes thereto and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” included elsewhere in this report.   Dollar amounts are in thousands, except per share amounts.