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PROTEON THERAPEUTICS INC filed this Form S-1/A on 10/07/2014
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The study will follow each patient for a maximum of 12 months. If the results of the first Phase 3 trial are sufficiently compelling, we intend to meet with the FDA to discuss the possibility of submitting a BLA, supported by the single Phase 3 trial in which the single Phase 3 trial would form the primary basis of the demonstration of safety and efficacy, and the Phase 2 trial, including non-prespecified analyses, would provide supportive information. We may decide to submit a BLA to the FDA prior to completing the second Phase 3 trial.

Preclinical Development

        We have conducted an extensive preclinical program to evaluate the safety and tolerability of single doses of PRT-201 administered locally in animal models of AVF and AVG placement, by percutaneous and endovascular injection in animal models of peripheral artery disease, or PAD, as well as intravenously. We have conducted preclinical studies in multiple species at doses up to 50 milligrams of PRT-201, which is over 1500 times higher than the dose we intend to study in our planned Phase 3 clinical trials. We observed no systemic activity or toxicity for PRT-201 in any of our preclinical studies. We observed no toxicity in any of the doses that we subsequently studied or plan to study 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 we intend to study in our planned Phase 3 clinical trials). 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 AVF studies in rabbits at doses up to 10 milligrams and in all the AVG studies in dogs and pigs at doses up to 20 milligrams (the highest doses tested).

        In our preclinical studies, we observed dose-dependent activity of PRT-201 on elastin removal as studies have established a correlation with a reduction in neointimal hyperplasia.

Other Programs, Indications and Trials

    Other AVF Trials

    European clinical program

        We are currently evaluating our clinical program to support filing in Europe. We may, based on additional data including the data from our Phase 3 clinical trials in the United States and if sufficient funds become available, choose to conduct a clinical trial of PRT-201 in Europe. Prior to initiating a European clinical trial, we plan to formally seek guidance from the European Medicines Agency, or EMA, regarding their requirements for regulatory approval.

    Brachiocephalic AVF

        We believe that our Phase 2 clinical data supports further development of PRT-201 in brachiocephalic AVF placement. We may, based on additional data including the data from our Phase 3 clinical trials and if sufficient funds become available, study the effects of a 30 microgram dose of PRT-201 versus placebo on brachiocephalic AVFs. Prior to initiation of this trial, we expect to seek guidance from the FDA regarding trial design.

    Arteriovenous Grafts

        An arteriovenous graft, or AVG, is a surgical procedure in which a surgeon places a synthetic tube to connect a vein and an artery. We submitted an IND for PRT-201 as a treatment for patients undergoing AVG placement on April 30, 2008. We conducted a Phase 1/2 randomized, double-blind, placebo-controlled, dose-escalation trial in 89 patients undergoing placement of an AVG. Patients were treated with placebo or eight different doses of PRT-201 ranging from 10 micrograms to 9 milligrams at the time of AVG placement and were followed for up to one year. Those patients who had not lost secondary patency were subsequently enrolled in a registry to obtain additional follow-up information on the AVG.