October - American Pharmacist Month

Value of Medical Innovation

Proteon Therapeutics - Vonapanitase: A potenial for AVF Hemodialysis Patients

Written by: Shruti Desai (@shrutidesai99)

Proteon (NASDAQ: PRTO) is a biopharmaceutical company developing a therapy for patients with hemodialysis. Proteon has leading drug candidate in pipeline, VONAPANITASE (PRT-201). It is a therapeutic drug that inhibits the obstruction of the surgical AVF.

ACCESS POINTS FOR HEMODIALYSIS

Long term hemodialysis requires permanent access point to bloodstream.

Vascular access points: Arteriovascular fistula (AVF) and Arteriovascular graft (AVG)

Proteon R&D Presentation

WHAT IS AVF?

Arteriovenous Fistulas, a surgical procedure, are connections between blood vein to artery to increase the blood flow. This procedure allows an easy access to filter blood during hemodialysis. However, this surgical attachment causes injury to the vessel and causing narrowing of the vessel (patency loss) which reduces the flow of blood and also creates new vessels and also prevent hemodialysis. Typically, patency loss can occur in half of the patients within one year of surgical AVF. It is important to reduce/reverse AVF loss. Patency loss requires angioplasty and missing hemodialysis appointments. 

WHAT IS PAD? (Secondary Indication)

Peripheral Artery Disease is a disease in which plaque builds up in the arteries causing occlusion and harder for blood to flow smoothly. Plaque can be a combination of cholesterol, fat, fibrous tissue, and other substances. Eventually, the plaque gets harder that narrows the vessels and decrease blood flow, decrease oxygen and increase pressure in arteries and/or veins.

MARKET POTENTIAL

Recent data suggests there are 20 million adults in the U.S. with some level of kidney dysfunction (also known as Chronic Kidney Disease). This disease may eventually lead to dialysis stage (also known as ESRD), which is stage 5 of CKD. Dialysis is needed when kidneys do not function (GFR <15). According to statistical data, about 600,000 adults are on dialysis. In 2012, Medicare (Part A and B) spent $44.6 million on CKD, and $28.6 million on ESRD, only. By 2050, there will be about 1.5 billion people in worldwide with CKD, and prevalence of ESRD will increase in parallel.

CURRENT TREATMENT FOR AVF

Current treatment for AVF are nonpharmacologic or invasive procedures such as forced saline flush, surgical thrombectomy, and exchange of catheter over guidewire.

VONAPANITASE (PRT-201)

Proteon Therapeutics’ Vonapanitase (PRT-201) is a recombinant human chymotrypsin-like elastase family member 1. It is administered to the surface of artery and vein

• Elastin fibrin thought to attract proliferating cells
• Inhibits cells from migrating to inner vessels and hindering the blockage of the vessel
• Prevents artery from narrowing and obstruction of the blood flow

A multicenter, randomized, double-blind, placebo-controlled phase 1 and 2 clinical trial was completed in 2013. The trial evaluated the use of vonapanitase in patients undergoing arteriovenous graft (AVG). This is an alternative surgical procedure in patients who do not qualify for AVF. The results of the trial indicated statistically insignificant trend for AVG survival. Later, phase 2 trial was completed evaluating safety and efficacy of vonapanitase in single application administered immediately after radiocephalic or brachiocephalic AVF. This trial compared vonapanitase to placebo. Results suggest statistical significant improvement in AVF maturation at 12 weeks and “rate of corrective procedures over more than three years of follow-up. “

DRUG SAFETY

Drug side effects that were noted in trials were procedural pain, postprocedural edema, peripheral edema, sepsis, and hypoesthesia. The adverse effects of vonapanitase were consistent with CKD patients and medical events

PHASE 1 AND 2 TRIAL

“Application of human type I pancreatic elastase (PRT-201) to the venous anastomosis of arteriovenous grafts in patients with chronic kidney disease

• Primary focus was safety and efficacy of the investigational drug and increase blood flow rate by increasing vein diameter. This study enrolled 89 patients. As per statistical analysis of the trial, comparing high with placebo group, the result of increasing vein diameter is statistically significant with p-value of 0.06. However, not significant with low and medium groups.
• Results indicated that Intraoperative vein diameter increased by 5% (p=0.14) in placebo group compared to vonapanitase which increased diameter by 13% (p=0.01), 15% (p=0.07), and 12% (p<0.001), low, medium, and high groups, respectively. Low group received 0.01 and 0.03mg, medium group received 0.1, 0.3, 1.0mg and high group received 3.0, 6.0, and 9.0mg

PHASE 2 TRIAL

• Primary focus was to evaluate the safety and efficacy of vonapanitase in patients with CKD undergoing surgical creation of an AVF (radiocephalic or brachiocephalic) for hemodialysis”
• Enrolled 151 patients. It was a multicenter, randomized, double-blind, placebo-controlled clinical study. Placebo, 10 and 30mcg (1:1:1) randomization. Follow up at weeks 2,6,12 and then every 3 months. Primary endpoint of the study was to demonstrate a trend of prolonged primary patency. Secondary endpoint of the study was to unassisted maturation at 12 weeks, secondary patency, and AVF usability.
• As per results and statistical analysis of primary endpoint, trend towards prolonging primary unassisted patency over three years of follow-up was statistically significant

o   Primary patency (maintaining AVF access for sufficient blood flow and hemodialysis) is when partial or complete blockage of vein occur which leads to less to no blood flow and inhibiting hemodialysis. The only way to fix this occlusion is invasive procedure (surgery), but it has poor durability meaning veins can potentially block in future.

As per results and statistical analysis of secondary endpoint, improvement in secondary patency, AVF maturation at 12weeks and in rate of corrective procedure over three years of follow-up were all statistically significant

o   Secondary patency (AKA AVF survival). Secondary patency loss is when procedure is done to restore AVF post primary patency loss. If a patient had secondary patency loss, then that patient can no longer fix the initial AVF. The patient either have to get a new AVF or AVG. This procedure cannot be done immediately, therefore in mean while patient undergo temporary catheter for hemodialysis.

META-ANALYSIS

“Recombinant Human Elastase Treatment of Cephalic Veins”

Goal of this study was a safety of vonapanitase and if it is applied to outflow vein during the AVF surgery could improve longevity of AVF surgery. The primary focus of the study was to investigate the pharmacology of the effective vonapanitase doses (3mcg-33mcg) on elastin of human cephalic vein. (Elastin contents are measured by desmosin content, which is protein cross linked to elastin using radioimmunoassay). As per results and statistical analysis, Mean desmosin content of vein treated with various concentrations of vonapanitase, which showed that the higher the concentration of vonapanitase, the greater the reduction of desmosin with p-value of <0.05, and p-value of <0.001 when compared to placebo. In conclusion, vonapanitase targets elastin in elastic fibers and reduces desmosin within 1-4 hours post administration

PERSONAL OPINION

My personal view on the drug is that vonapanitase has shown promising results in terms of increasing diameter of veins, prolonging primary patency, and reduction of desmosin. Additionally, vonapanitase has no other medication to compete against or to compare. It has shown significant results post single administration of the drug.

NEAR TERM CATALYST AND PRICE TARGET

Proteon is currently conducting Phase 3 (PATENCY-1 trial and PATENCY-2 trial).

PATENCY

• Randomized, double blind, placebo controlled
• 300 patients in the US with 12 month followup
• Vonapanitase 30mcg versus placebo (2:1)
• Primary and Secondary endpoints being same as Phase 2 which was statistically significant.

In my opinion, Phase 3 PATENCY 1 trial should meet its primary endpoint since 3x improvement was observed in Phase 2 in radiocephalic AVFs and Phase 3 trial requires 2x improvement for p=0.0001. The PATENCY-1 should be fully enrolled in October 2015 with top line data in December 2016. In addition, PATENCY-2 should be fully enrolled in Q1 2017 with topline data in 2H 2018. As of May 9^th, 2016, Proteon Therapeutics has cash, cash equivalent ad available-for-sale investments totaled $59.4 million. According to CEO, cash is enough to fund operation until 1Q 2017.

With current market valuation and recent biotech selloff, this creates good opportunity for investor to go long PRTO with my price target of $10.53 (conservative DCF model)

REFERENCES:

• Dwivedi, A.J. et al. Application of human type I pancreatic elastase (PRT-201) to the venous anastomosis of arteriovenous grafts in patients with chronic kindey disease. J Vasc Access 2014;15 (5): 376-384
• Burke, S.K. et al. Vonapanitase (PRT-302, Recombinant Human Type 1Panreatic elastase. for improved arteriovenous fistula outcomes- Long Term Results
• Wong et al., Recombinant Human Elastase Treatment of Cephalic Veins. Cardiovasc Pharm Open Access 2016, 5:2
• Clinical Trials | Clinical Development | Proteon Therapeutics. (n.d.). Retrieved from http://www.proteontherapeutics.com/clinical-development/clinical-trials.php
• National Kidney Foundation