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PROTEON THERAPEUTICS INC filed this Form S-1 on 09/16/2014
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    Phase 1/2 AVF Clinical Trial

        We submitted an investigational new drug application, IND, for PRT-201 as a treatment for patients undergoing AVF placement on April 30, 2008. Our initial clinical trial of PRT-201 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 AVF. Patients were treated with PRT-201 at nine dose levels ranging from 3.3 micrograms to 9 milligrams or placebo at the time of AVF placement and were followed for up to one year. This trial did not meet its primary endpoint, an endpoint we did not pursue in our Phase 2 trial. However, consistent with our mechanism of action that involves partial fragmentation of elastin doses of PRT-201 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 AVF lumen stenosis (collected as supportive data) compared with placebo treated patients or patients treated with higher PRT-201 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, we selected 10 microgram and 30 microgram doses for further study in the Phase 2 trial.

    Our Phase 3 Program

        We plan to conduct two randomized, double-blind Phase 3 trials, with staggered start dates, comparing a 30 microgram dose of PRT-201 to placebo. We initiated our first Phase 3 pivotal trial for PRT-201 in patients with CKD undergoing placement of a radiocephalic AVF in the third quarter of 2014. The trials will enroll patients undergoing a surgical procedure to create a radiocephalic AVF. Each Phase 3 trial will enroll approximately 300 patients, for a total of approximately 600 patients, who will be randomized such that twice as many will receive PRT-201 as compared to placebo.

        In April 2013, we held an end of Phase 2 meeting with the FDA, during which we confirmed the following key elements of our Phase 3 development plan: (i) the primary efficacy endpoint in our Phase 3 trials, primary unassisted patency, which is the same as our primary endpoint in our Phase 2 trial and suitable for approval of PRT-201 in the United States; (ii) the secondary efficacy endpoint in our Phase 3 trials, secondary patency, which was a secondary endpoint in our Phase 2 trial, could be acceptable for inclusion in the approved product labeling in the United States if we hit statistical significance on both the primary endpoint and the secondary endpoint, and possibly even if we do not hit statistical significance on the secondary endpoint; (iii) the total number of patients expected to be treated through our Phase 3 trial will provide a sufficient safety database to support a BLA filing; (iv) we do not need to conduct additional preclinical studies prior to conducting its Phase 3 clinical trials or to support a BLA filing; and (v) we have Phase 3-ready drug substance and drug product.

        We began enrolling patients in our first Phase 3 trial in the third quarter of 2014. Each patient will be followed for 12 months. We expect that results will be available in 2017.

        Our Phase 3 trials will be conducted at sites in the United States with the second trial potentially including Canadian sites. In addition to collecting data on the primary and secondary endpoints, the Phase 3 clinical trials will collect information related to the tertiary endpoints of maturation, use for hemodialysis and the rate of procedures to restore or maintain patency. Patients who consent will be enrolled in a patient registry to obtain long-term follow-up efficacy information.

        We have designed each Phase 3 trial to have over 95% power i.e. there is more than a 95% probability that the study will detect observed clinical effects of PRT-201 if the observed effects are true. For the first Phase 3 trial, 300 patients will be randomly allocated by site in a 2:1 ratio to either PRT-201, at 30 micrograms, or to placebo. With the 300 patient sample size (200 PRT-201 and 100 placebo), the study is powered to approximately 96% power to detect an increase in median primary unassisted patency from 5 months to 10 months and 97% power to detect an increase in the proportion of patients with secondary patency at 12 months from 65% to 85%. A 10% drop out rate has been assumed in all of the calculations.