analysis of the primary endpoint data revealed an uneven distribution in primary unassisted patency loss events due to central stenosis, which occur remote from the site of an AVF.
Central stenoses commonly exist prior to AVF placement and are unmasked following placement of brachiocephalic AVFs, which have higher blood flow than radiocephalic AVFs. These stenoses are unrelated
to treatment with PRT-201. To correct for this uneven distribution, we conducted a non-prespecified analysis of the primary endpoint that excluded patency loss events due to central stenoses. In that
analysis, the risk of primary unassisted patency loss was reduced by 31% for the 10 microgram dose group and by 48% for the 30 microgram dose group versus placebo. The comparison of the 30
microgram dose versus placebo was significant from a statistical point of view.
benefit of PRT-201 on primary unassisted patency was most pronounced in the subset of patients undergoing placement of a radiocephalic AVF. Recent publications indicate that
radiocephalic AVFs suffer from higher rates of patency loss and maturation failure, with up to 70% of AVFs in the wrist being subject to patency loss within 12 months after their surgical
placement. The subset analysis of this endpoint was not prespecified. The risk of primary unassisted patency loss was reduced by 41% for the 10 microgram dose group and by 63% for the 30 microgram
dose group versus placebo. Median
patency was 125 days in the placebo group and 377 days in the 30 microgram group (in some cases the 12 month follow up occured after day 365 due to patient schedules), indicating
an improvement in primary unassisted patency that was significant from a statistical point of view.
In one of our prespecified secondary endpoints, unassisted maturation, which is defined as adequate vessel diameter and blood flow
without the need for an intervention such as angioplasty, PRT-201 showed a significant benefit from a statistical point of view at three months in the 30 microgram dose using the two commonly accepted
measures of maturation, namely, the Robbin criteria and the Kidney Disease Outcomes Quality Initiative, or KDOQI, criteria.
effect of PRT-201 on maturation was more pronounced in the subset of patients who underwent creation of a radiocephalic AVF. For the 30 microgram dose of PRT-201, unassisted
maturation of the radiocephalic AVFs, a prespecified analysis, showed an increase in the percentage of patients with mature AVFs compared with placebo using the Robbin criteria (93% versus 47%) which
is significant from a statistical point of view and a trend toward improvement using the KDOQI criteria (57% versus 24%).
In the trial, patients treated with PRT-201 reported adverse events comparable to placebo. These events were consistent with the
medical events experienced by chronic kidney disease patients undergoing AVF placement surgery. The most common adverse events were AVF incision pain, venous stenosis, AVF thrombosis, steal syndrome
and hypoesthesia. Serious adverse events, or SAEs, reported by the investigator as possibly drug-related occurred in two 10 microgram PRT-201 patients, both AVF thrombosis, and two 30 microgram
patients (one chest pain and one swelling at the surgical incision). There were no SAEs reported by the investigator as possibly drug-related in the placebo group. There was one SAE reported by the
investigator to be drug-related in the 10 microgram PRT-201 group, AVF maturation failure, and there were none in the other treatment groups.
In April 2013, we held an end of Phase 2 meeting with the FDA during which we confirmed elements of our Phase 3
development plan, including the primary endpoint. We plan to perform two Phase 3 trials of PRT-201 using a 30 microgram dose, enrolling patients undergoing surgical placement of a radiocephalic
AVF. In our Phase 2 trial, PRT-201 showed the greatest benefit in radiocephalic AVFs.