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PROTEON THERAPEUTICS INC filed this Form S-1/A on 10/07/2014
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choice for new hemodialysis patients. A radiocephalic AVF as compared to other forms of vascular access preserves the potential future use of other access further up in the arm, is simpler to create and is less likely to result in serious complications, including heart failure, central stenosis, which is the narrowing of blood vessels in shoulder or chest, and reduced blood flow to the hand. Unfortunately, radiocephalic AVFs suffer from high failure rates, with up to 70% failing within 12 months after their surgical placement. We estimate approximately 40% of all AVF placements are radiocephalic.

        AVF failure can usually be restored via an intervention such as balloon angioplasty, which is dilation of a blood vessel with a balloon, or a surgical revision. However, these procedures are costly, invasive, painful, and associated with a number of complications and often need to be repeated. AVF patients in the United States on average require greater than 1.5 procedures per year. Procedures to restore function typically cost Medicare between $5,000 and $13,000 per procedure. A recent publication indicates that maintaining a radiocephalic AVF can cost on average more than $17,000 in the first year after surgical placement.

PRT-201

        We demonstrated that PRT-201, a recombinant human elastase, generates fragments of elastin, a protein present in blood vessel walls. We believe the fragments of elastin inhibit formation of neointimal hyperplasia, which is the growth of tissue inside vessels that narrows AVFs and reduces blood flow. We believe that a one-time, local application of PRT-201 to the external surface of the vessels during AVF surgical placement can modify the injury response, or scarring, resulting from surgery and thereby reduce the severity of neointimal hyperplasia and AVF failure following surgery. During the AVF placement surgery, the surgeon administers drops of PRT-201 onto the surface of the artery and vein of the AVF for 10 minutes followed by a saline irrigation. We believe that, if our Phase 3 clinical program is successful, PRT-201 will potentially become the standard of care for patients with chronic kidney disease who are undergoing surgical placement of a radiocephalic AVF.

    Phase 2 AVF Trial Results

        In 2013, we completed a multicenter, randomized, double-blind, placebo-controlled Phase 2 trial of PRT-201, which treated 151 patients with chronic kidney disease undergoing surgical creation of a radiocephalic AVF (n=67) or brachiocephalic AVF (n=84), which is performed by suturing the brachial artery to the cephalic vein at the elbow. Of these 151 patients, 51 patients received placebo, 51 patients received a dose of 10 micrograms of PRT-201, and 49 patients received a dose of 30 micrograms of PRT-201. The primary efficacy endpoint was AVF primary unassisted patency, defined as the time from surgical creation of the AVF to occurrence of a thrombosis or an intervention, such as angioplasty to restore or maintain patency, or function. Other efficacy endpoints included unassisted maturation, which is defined as increased vessel diameter and blood flow at the AVF without the need for an intervention such as angioplasty, average rate of procedures to restore or maintain AVF patency, secondary patency, which is defined as abandonment of the AVF and the need for creation of a new vascular access, use for hemodialysis and hemodynamically significant stenosis, or narrowing of blood vessels.

    Primary Endpoint

        Both doses of PRT-201 showed a trend toward efficacy, although neither dose met the primary endpoint with statistical significance. Median patency, the time at which 50% of patients in a group lost primary unassisted patency, was 224 days in the placebo group and greater than 365 days in each of the PRT-201 treatment groups indicating that PRT-201 prolonged primary unassisted patency. The risk of primary unassisted patency loss was reduced by 31% for the 10 microgram dose group and by 33% for the 30 microgram dose group versus placebo.

 

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