WS06-1 Initial results evaluating combinations of the novel CFTR corrector PTI-801, potentiator PTI-808, and amplifier PTI-428 in cystic fibrosis subjects

Abstract

Objectives: To determine the safety, tolerability, PK and effect of co‐administration of the novel CFTR modulators PTI‐801, PTI‐808 and PTI‐428, based on initial results from ongoing studies. Background: Currently‐approved CFTR modulator therapies have variable clinical efficacy leaving room for additional clinical benefit. PTI‐801 and PTI‐808 represent a novel CFTR corrector and potentiator, respectively. PTI‐428, a CFTR amplifier, selectively increases the amount of immature CFTR protein and provides additional substrate for correctors and potentiators to act upon. In vitro, in human bronchial epithelial cells from F508del homozygous donors, the combination of PTI‐801 + PTI‐808 increased CFTR chloride transport activity by 170 and 193%, compared to that of lumacaftor + ivacaftor and tezacaftor + ivacaftor, respectively, suggesting a superior in vitro response to currently approved modulator combinations. In vitro, with the addition of PTI‐428 to a background of PTI‐801 + PTI‐808, CFTR chloride transport activity approached that of wild type CTFR. Methods: Dose combinations of PTI‐801 + PTI‐808 or PTI‐801 + PTI‐808 + PTI‐428 are being evaluated in randomized, double blinded, placebo‐controlled clinical studies in subjects with CF, age ≥18 years, with FEV1 40–90% of predicted. Primary objectives are safety and tolerability, secondary objectives are PK and change in FEV1. Exploratory objectives include changes in sweat chloride. Results: Initial data suggest a generally well‐tolerated safety profile and clinical benefit with the combination PTI‐801 + PTI‐808. An absolute change in percent predicted FEV1 of 6.6 percentage points was observed following a treatment period of 14 days in the preliminary analysis, and a reduction in sweat chloride of 13 mM was observed at day 14. Additional data from approximately 30 subjects are expected in advance of the 2019 ECFS Conference. Conclusions: PTI‐801, PTI‐808 and PTI‐428 represent novel CFTR modulators in clinical development.