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--= Overview =
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++==== Overview ====
++
  Proteon Therapeutics is a late-stage biopharmaceutical company focused on the development of novel, first-in-class pharmaceuticals to address the needs of patients with renal and vascular disease. The company's product candidate, vonapanitase, is a recombinant human elastase that Proteon Therapeutics is developing to improve vascular access outcomes in patients with chronic kidney disease, or CKD, undergoing or planning for hemodialysis, a lifesaving treatment that cannot be conducted without a functioning vascular access. The company believe data from its completed Phase 2 and Phase 3 clinical trials of vonapanitase support that a one-time, local application of investigational vonapanitase during surgical creation of a radiocephalic fistula for hemodialysis may improve fistula use for hemodialysis and secondary patency (time to fistula abandonment), thereby improving patient outcomes and reducing the burden on patients and the healthcare system.
  Arteriovenous fistulas are the gold standard of vascular access for hemodialysis, given they are associated with fewer complications and reduced rates of hospitalization as compared to other forms of vascular access. The company estimate there are approximately 130,000 fistulas created in the United States annually, a procedure in which a surgeon transects a vein and sutures it to the side of a nearby artery, typically in the arm. Radiocephalic fistulas created in the forearm are the preferred form of arteriovenous fistula because they preserve the maximum number of future sites for vascular accesses (i.e., the potential use of other vascular access sites further up in the arm) and are associated with the lowest rate of serious complications such as steal syndrome (hand ischemia).
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  The company believe that, if its ongoing Phase 3 clinical trial is successful and vonapanitase is approved, vonapanitase will potentially become the standard of care for patients with CKD undergoing surgical creation of a radiocephalic fistula. The company retain worldwide commercial rights to vonapanitase. If approved by regulatory authorities, the company intend to commercialize this product in the United States itself  with a specialty sales force, focused primarily on vascular surgeons. The company also intend to seek one or more collaborators to commercialize the product in additional markets, including Europe and China. The company's patents include claims covering formulations, methods of manufacturing and use of elastases, providing protection in the United States into 2030 and European Union through 2028, with potential extension into 2033 in the United States and in the European Union.
--= Strengths =
++==== Strengths ====
  The company believe its company and vonapanitase possess the following attributes that increase the likelihood that the company will be successful in developing and commercializing vonapanitase:
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  * Substantial and readily-addressable market opportunity. If vonapanitase is approved, the company intend to commercialize this product in the United States itself  with a specialty sales force, focused primarily on vascular surgeons. The company also intend to seek one or more collaborators to commercialize the product in markets outside of the United States, including Europe and China. In the United Sates, the company estimate a sales force of approximately 75-100 representatives will enable it to call on the approximately 1,300 hospitals that account for more than 90% of the fistula surgical creations performed annually. The company believe vonapanitase will be supported by key stakeholders, including referring nephrologists, patient advocacy groups, large dialysis organizations and payors. The company also believe that, if its ongoing Phase 3 clinical trial is successful and vonapanitase is approved, it will potentially become the standard of care for patients with CKD undergoing surgical creation of a radiocephalic fistula by increasing the use of fistulas for hemodialysis and reducing the rate of fistula abandonment and, in doing so, reduce the overall burden on patients and the healthcare system. The company also believe vonapanitase will be reimbursed adequately by Medicare, Medicaid and other public and commercial payors. Costs related to fistula surgical creation, which is typically performed in the hospital outpatient setting, are not included in the End Stage Renal Disease, or ESRD bundle, the single bundled payment from Medicare for a number of the costs of hemodialysis treatments, medications, labs and supplies for patients with end-stage renal disease. Vascular access failure results in substantially higher healthcare costs. A recent study indicated that the total cost to Medicare for managing hemodialysis vascular access was more than $2.8 billion in 2013, which excludes costs of managing vascular access in predialysis patients and dialysis patients covered by Medicare Advantage HMOs or other non-Medicare payers as well as patient co-pays and deductibles. It was also reported that fistulas that fail to become usable resulted in incremental costs to Medicare of up to $24,000 in the first year and $11,000 in the second year following fistula creation.
  * Experienced team. The company's executive management team has extensive experience in the renal and vascular disease fields through their substantial involvement in companies such as Abbott, AMAG, GelTex, Genzyme, Glaxo and Merck. The company's Chief Executive Officer and Chief Medical Officer were senior executives at GelTex, a biopharmaceutical company, where they played leading roles in the development and commercialization of Renagel, a treatment for hemodialysis patients that led to Genzyme's acquisition of GelTex for more than $1 billion. The company's Senior Vice President of Commercial was a senior executive at AMAG Pharmaceuticals, a biopharmaceutical company, where he played a leading role in the commercialization of Feraheme for iron-deficiency anemia in adults with CKD.
--= Strategy =
++==== Strategy ====
  The company's strategy is to develop and commercialize vonapanitase for patients suffering from renal and vascular diseases, beginning with patients with CKD undergoing surgical creation of a radiocephalic fistula. Key elements of its strategy include its plans to:
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  * Pursue indications for vonapanitase in peripheral artery disease. In addition to vascular access indications, Proteon Therapeutics is investigating vonapanitase as a treatment for patients with symptomatic peripheral artery disease, or PAD. In 2016, the company initiated a Phase 1, multicenter, dose-escalation trial designed to evaluate the safety and technical feasibility of a single administration of vonapanitase as an adjunct to angioplasty for patients with PAD below the knee. The company expect to complete the enrollment and treatment of 24 patients in this study before the end of 2018. The company may, if sufficient funds become available, increase enrollment in the Phase 1 trial evaluating vonapanitase below the knee and/or begin patient enrollment in a Phase 1, multicenter, dose-escalation trial evaluating vonapanitase as a monotherapy for PAD above the knee.
  * In-license or acquire additional product opportunities. The company plan to search for additional product opportunities that could be marketed and sold by the specialty sales force required to successfully launch vonapanitase in the United States if it is approved for marketing by the FDA.
--= Background on Hemodialysis =
++==== Background on Hemodialysis ====
  Healthy kidneys serve many functions, including eliminating metabolic waste products and excess water, helping to control blood pressure, and keeping electrolytes such as sodium and potassium in balance. Patients with CKD have lost kidney function, most commonly due to diabetes or hypertension. Kidney disease is progressive and once a patient has reached end-stage CKD, the kidneys are no longer able to perform their normal functions. At this point, some form of renal replacement therapy is required, such as hemodialysis, in which blood is processed by a hemodialysis machine; peritoneal dialysis, a process using a cavity in the abdomen called the peritoneum as a membrane across which fluids are exchanged from the blood; or kidney transplant.
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  The least desirable type of vascular access is a catheter, a plastic tube that is placed directly through the skin into a vein, typically via an incision in the neck enabling placement of the catheter into a large vein that leads directly to the heart. The catheter connects the patient's vasculature to the hemodialysis machine. Because the catheter penetrates the skin continuously, it is subject to a high risk of infection and increased mortality. One of the primary goals of hemodialysis care is to keep patients off catheters. However, in the United States approximately 80% of patients initiate hemodialysis through a catheter until a fistula or graft is ready to be used, and are dialyzed through a catheter when the fistula or graft does not become usable for hemodialysis or must be abandoned and a new one has to be created. Approximately 12% of hemodialysis patients in the United States dialyze with a permanent catheter, compared to 10-28% of patients in the major European countries and approximately 10% and 2% of patients in China and Japan, based on published data.
--= Established Medical Need =
++==== Established Medical Need ====
  The need to improve vascular access outcomes is well established in the hemodialysis community. The health-related and economic costs of creating vascular accesses and addressing access dysfunction and associated complications have led to a global effort to address the problem. Over the last twenty years, the NKF has established guidelines in an effort to increase the use of fistulas while reducing the rate of complications, mostly through the identification and promulgation of best practices. The National Institutes of Health, or NIH, joined the effort in 2000 with the creation of a multi-center consortium of medical centers, the Dialysis Access Clinical Trials Consortium, to coordinate the testing of new treatments designed to improve fistula and graft outcomes. The intensity of these efforts increased markedly in 2004, when the Centers for Medicare and Medicaid Services, or CMS, reacting to health and economic data, announced the “Fistula First” initiative to increase the use of fistulas while reducing complications. According to Fistula First, fistulas should be considered for every patient needing hemodialysis because, compared to other forms of vascular access, fistulas last longer, require fewer surgical and endovascular interventions, are associated with lower rates of infection, hospitalization and death, and are less costly. As a result of these efforts, fistula use has approximately doubled since 2004 to 68% of United States hemodialysis patients.
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  The company submitted an investigational new drug application, or IND, for vonapanitase as a treatment for patients undergoing fistula creation on April 30, 2008. The company's initial clinical trial of vonapanitase was a Phase 1/2, randomized, double-blind, placebo-controlled, dose-escalation safety and exploratory efficacy trial in 66 patients undergoing creation of a radiocephalic or brachiocephalic fistula. Patients were treated with vonapanitase at nine dose levels ranging from 3.3 micrograms to 9 milligrams or placebo at the time of fistula creation and were followed for up to one year. This trial did not meet its primary endpoint, an endpoint the company did not pursue in its Phase 2 and Phase 3 trials. However, doses of vonapanitase at 3.3, 10 and 33 micrograms were associated with a trend toward prolonged primary unassisted patency (secondary endpoint p=0.66 in the All Treated population and p=0.15 in the All Treated Minus 3 population), fewer procedures to restore or maintain patency (collected as supportive data) and less hemodynamically significant lumen stenosis (collected as supportive data) compared with placebo treated patients or patients treated with higher vonapanitase doses. Higher doses showed results similar to placebo and no dose met the primary efficacy endpoint with statistical significance. No dose-related increases in adverse events were observed in the trial. Based on the results of this trial, the company selected 10 microgram and 30 microgram doses for further study in the Phase 2 trial.
--= Preclinical Development =
++==== Preclinical Development ====
  Proteon Therapeutics has conducted an extensive preclinical program to evaluate the safety and tolerability of single doses of vonapanitase administered locally in animal models of fistula and arteriovenous graft creation, by percutaneous and endovascular injection in animal models of PAD as well as intravenously. Proteon Therapeutics has conducted preclinical studies in multiple species at doses up to 50 milligrams of vonapanitase, which is over 1,500 times higher than the dose the company used in its Phase 3 clinical trials. The company observed no systemic activity or systemic toxicity for vonapanitase in any of its preclinical studies. The company observed no toxicity in any of the doses that the company subsequently studied or plan to study in its Phase 3 clinical trial in humans. Only local toxicity was observed at surgical sites at high doses (10 and 50 milligrams, which is over 300-1500 times higher than the dose Proteon Therapeutics is studying in its Phase 3 clinical trial). These changes were reversible, with normal wound healing observed at 14 days except at the highest (50 milligrams) dose, in which there were some mild persistent changes in the jugular vein and subcutaneous tissue. Normal wound healing was observed in all the fistula studies in rabbits at doses up to 10 milligrams and in all the arteriovenous graft studies in dogs and pigs at doses up to 20 milligrams (the highest doses tested).
--= Other Programs, Indications and Trials =
++==== Other Programs, Indications and Trials ====
  **Other Fistula Trials**
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  The company believe that vonapanitase may improve the outcomes associated with vein bypass surgery, resulting in prolonged intervention-free patency. During vein bypass surgery, a surgeon places a vein, typically obtained from the patient’s leg, as an alternative conduit for blood to flow around the area of blockage restoring direct flow to the lower leg and foot. The company believe that vonapanitase, administered to the outside of the vein concurrently with the surgery, may improve the outcomes associated with vein bypass surgery, resulting in prolonged intervention-free patency.
--= Manufacturing and Supply =
++==== Manufacturing and Supply ====
  The company depend on third-party contract manufacturers for the production of vonapanitase. The company's API is produced at its contract manufacturer, Lonza LTD, or Lonza, which is required to comply with the FDA’s Current Good Manufacturing Practice, or cGMP, regulations. Vonapanitase finished product is produced at its contract fill/finisher providers, Jubilant HollisterStier and Patheon Manufacturing Services, LLC (formerly DSM Pharmaceuticals, Inc.), which is required to comply with cGMP regulations.
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  In anticipation of a potential BLA submission, the company plan to manufacture a minimum of three batches of API and of drug product as part of process validation and to test these batches for stability with a goal of establishing a commercial shelf-life of at least two years for finished product and a longer expiry for API.
--= Sales and Marketing =
++==== Sales and Marketing ====
  The company's commercialization strategy is to develop vonapanitase into a leading therapy worldwide for the treatment of fistulas in patients with CKD undergoing or planning for hemodialysis and to improve vascular access outcomes in patients with other vascular diseases. If the PATENCY-2 trial is successful, the company expect to be able to submit a BLA in 2019.
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  If vonapanitase is approved by the EMA, the company expect to commercialize vonapanitase in Europe with one or more commercial partners. The company also may enter into collaborations for the development and commercialization of vonapanitase in China, Japan and other countries outside of the United States.
--= Intellectual Property =
++==== Intellectual Property ====
  The company strive to protect and enhance the proprietary technology, inventions and improvements that are commercially important to its business, including seeking, maintaining and defending patent rights. The company also rely on know-how that may be important to the development of its business. The company additionally expect to rely on regulatory protection afforded through data exclusivity, market exclusivity and patent term extensions where available.
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  The company plan on pursuing in-licensing opportunities to develop, strengthen and maintain its proprietary position for its products. The company expect to use trademark protection for its products as they are marketed.
--== Patents ==
++**Patents**
  As of December 31, 2017, the company own 37 issued patents and 20 pending patent applications. The patents and applications primarily fall into two families, a first relating to the vonapanitase formulation and its manufacture and use, as well as other formulations of elastases (the “formulation family”), and the second relating to certain therapeutic uses of vonapanitase, and associated systems and kits that include a catheter and are suitable for a subset of those therapeutic uses (the “therapy family”). The formulation family includes two issued United States patents, two issued European patents, additional patents issued in Australia, China, Hong Kong, India, Israel, Japan, Mexico, New Zealand, Russia, South Korea and Taiwan, and patent applications pending in several major jurisdictions worldwide, including Japan, China, South Korea, Brazil, Mexico, Europe and the United States. The expected expiration date for any patents that have issued or may issue from the formulation family is December 4, 2028, exclusive of possible patent term extension available for one patent covering vonapanitase under the Hatch-Waxman Amendments or comparable provisions in other jurisdictions, except in the United States where its two formulation family patents were awarded patent term adjustments of 199 and 668 days, respectively, due to United States Patent and Trademark Office, or USPTO delays taking their expiration dates to June 20, 2029 and October 3, 2030, respectively. The therapy family includes eight issued United States patents, three issued European patents, one issued Canadian patent, one issued Hong Kong patent, and an application pending in the United States. The expected expiration date for any patents that have issued or may issue from the therapy family patents is September 24, 2020, except in the United States where several patents were awarded a patent term adjustment and the expected expiration date of two therapy family patents related to systems and kits including elastase and a catheter is June 30, 2021, exclusive of possible patent term extension.
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  **Assignment of Rights and License Agreement**
  As successor to Proteon Therapeutics, LLC by merger, the company acquired all of the assets of the LLC, including all of the intellectual property rights in a patent family entitled “Local, Transcatheter Delivery of Proteases to Reopen Obstructed Biological Conduits” (the “JHU patent family”). This patent family was originally developed by its founder, Dr. F. Nicholas Franano, at The Johns Hopkins University, or Johns Hopkins, and includes United States patent Nos. 7,063,838; 7,153,505; 7,361,335; 7,632,494; 7,883,699; 8,524,226; 8,562,983; and 8,568,716. Johns Hopkins assigned all of the intellectual property rights to Dr. Franano who in turn assigned the rights to the LLC. Under the terms of the assignment of rights and license agreement with Johns Hopkins, Dr. Franano reimbursed certain costs of Johns Hopkins and agreed to pay the future costs and expenses of patent prosecution and maintenance, as well as any costs related to infringement. In addition, under the agreement, Dr. Franano granted to Johns Hopkins rights to practice under the intellectual property rights for non-profit purposes. The company's rights are further subject to any rights the United States Government may have in inventions that are the subject matter of the acquired patents under the Bayh Dole Act due to its sponsorship of research that led to certain of such inventions. The agreement does not specify a term and does not include any termination provisions. Dr. Franano agreed that upon commercialization of the assigned invention, he would remit to Johns Hopkins 2.5% of any revenues or fees received from certain net sales of any product covered by the JHU patent family. The company assumed, and are the successor to, all of Dr. Franano's payment and other obligations to Johns Hopkins. Seven U.S. patents in the JHU patent family, and their foreign counterparts, described above as the therapy family, relate to certain therapeutic uses of vonapanitase, and the associated systems and kits that include a catheter and are suitable for a subset of those therapeutic uses.
--
--= References =