Proteostasis Therapeutics, Inc. announced positive topline results from the company's global, multicenter, randomized, placebo-controlled, 28-day, Phase 2 study evaluating its proprietary cystic fibrosis transmembrane conductance regulator (CFTR) modulator combinations in F508del homozygous and heterozygous CF subjects 18 years of age and older. The trial is designed to assess the efficacy, safety and tolerability of PTI's once-daily proprietary combinations, 300 mg of dirocaftor (PTI-808) and 600 mg of posenacaftor (PTI-801), with or without 10 mg of nesolicaftor (PTI-428), or placebo, over a four week treatment period. A total of 28 F508del homozygous and 40 F508del heterozygous subjects were enrolled into the doublet, triplet or placebo arms. The compounds were generally well tolerated and the majority of reported adverse events were mild to moderate in severity. Most subjects enrolled in the Phase 2 study carried a high disease burden, with over 80% of subjects trying and failing to enroll into trials of currently approved modulators due to ineligibility. Homozygous subjects receiving the triple combination experienced a mean absolute improvement in ppFEV1 of 8% points over pooled placebo at day 28 (p = 0.01, 95% CI 3, 12; n=11). Improvements in lung function were the highest in high disease burden subgroups, predefined as subjects with ppFEV1 <70 at baseline (+10 ppFEV1, n=9), subjects with at least 2 pulmonary exacerbations within 12 months prior to study (+12 ppFEV1, n=5) and poor responders to prior CFTR modulators (+12 ppFEV1, n=7). Sweat chloride concentration in homozygous subjects receiving dirocaftor, posenacaftor and nesolicaftor demonstrated a mean improvement of -29 mmol/L at day 28 (p < 0.0005, 95% CI -42, -16; n=11) compared to pooled placebo. In the homozygous population, the magnitude of the improvements in the ppFEV1 and sweat chloride concentration at day 28 with the dirocaftor, posenacaftor and nesolicaftor were higher than those observed in subjects receiving the double combination of dirocaftor and posenacaftor. These observations highlight the contribution of nesolicaftor to the overall efficacy of the triple combination. In PTI's first clinical study with F508del heterozygous population, 40 subjects with at least 26 different genotypes were enrolled. As expected, given the mechanism of action of CFTR modulators, a broad range of ppFEV1 and sweat chloride responses were observed in these subjects. For those on active treatment, ppFEV1 responses ranged from -13 to +20 and sweat chloride concentration responses ranged from +12 mmol/L to -79 mmol/L. Changes in sweat chloride concentration were statistically significant (p<0.01). Responder rate, defined as ppFEV1 improvement of 5% points or more, was three times as high in subjects who received active vs. placebo. Mean changes in ppFEV1 were not statistically significant in the heterozygous population. Based on these results, the Company is planning to launch a global, Phase 3, randomized, placebo-controlled, MORE trial (Modulator Options to RestorE CFTR study) in CF subjects with the common F508del homozygous mutation, beginning in 2020. The MORE trial complements the CHOICES trial (Crossover trial based on Human Organoid Individual response in CF - Efficacy Study), which is designed to evaluate the translation of organoid ex-vivo response to potential clinical benefit in patients with rare mutations. CHOICES, which is also expected to initiate in 2020, will be the first ever personalized medicine-based study in CF.