PURPOSE: Many PAH Trials have short-term Placebo-Controlled phases between 12-16 weeks, followed by long-term open extensions. Risk of disease progression has been associated with certain thresholds of response across several trials. We evaluated patients achieving 16 week 6MWD response thresholds (absolute walk >400 m and ∆ walk > 40m change from BL) in the phase 3 double-blind, placebo-controlled trial (PHIRST-1) to see if they retained a response above the thresholds at 52 weeks in the long-term extension study (PHIRST-2).
METHODS: There were 154 patients who received the approved tadalafil 40 mg dose across both studies for whom 6MWD were available at 16 and 52 weeks after starting drug. Of these, 79 began receiving the 40 mg dose during PHIRST-1, and 75 began receiving the 40 mg dose during PHIRST-2 (having received placebo during PHIRST-1).
RESULTS: In the initial study, 52% of the 154 patients achieved a 6MWD >400 meters and 38% achieved a >40 m change from BL at week 16. This response was maintained in 85% and 79% in patients achieving >400 at 16 weeks (n=66), and >40m change from BL (n=48), respectively.
CONCLUSION: During the PHIRST-2 extension study, 6MWD milestones achieved with tadalafil 40 mg at 16 weeks were maintained at 52 weeks in greater than 75% of the patients. Successful outcomes at 52 weeks were largely predicted by responses at 16 weeks, with few 52 week late responders that had not achieved response by 16 weeks.
CLINICAL IMPLICATIONS: The sustained improvement in 6MWD seen in patients on tadalafil 40 mg QD over the 52 week treatment period is consistent with the improvements in 6MWD achieved at 16-weeks, suggesting durable clinical benefit for tadalafil in PAH treatment. The 16 week time point therefore is a reasonable assessment milestone to predict therapy in responders.
DISCLOSURE: Jeremy Feldman, Consultant fee, speaker bureau, advisory committee, etc. Dr. Feldman is a consultant/advisory board member/speaker for United Therapeutics, Gilead and Encysive and an investigator in sponsored studies for United Therapeutics, Actelion Gilead and Pfizer.Dr. Arneson and Dr. Wade are paid employees of United Therapeutics; No Product/Research Disclosure Information