Rare Daily Staff

Proteostasis Therapeutics reported positive topline results from its global, multicenter, randomized, placebo-controlled, 28-day, phase 2 study evaluating its proprietary cystic fibrosis transmembrane conductance regulator modulator combinations in cystic fibrosis patients 18 years of age and older with the most common mutation F508del.

Cystic fibrosis (CF) is a rare, life-shortening genetic disease. It is caused by mutations in the CFTR gene that lead to a defective or missing cystic fibrosis transmembrane conductance regulator (CFTR) protein. Children must inherit two defective CFTR genes—one from each parent—to have CF. There are approximately 2,000 known mutations in the CFTR gene with the F508del being the most common.

Some of these mutations, which can be determined by a genetic test, lead to CF by creating non-working or too few CFTR proteins at the cell surface. The defective function or absence of CFTR protein results in poor flow of salt and water into and out of the cell in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage in many patients that eventually leads to death. The median age of death is in the early 30s.

Nesolicaftor (PTI-428) is an experimental CFTR amplifier in development for the treatment of CF in patients with at least one F508del mutation in the CFTR gene, as part of PTI’s proprietary triple combination regimen that includes dirocaftor (PTI-808), a novel potentiator, and posencaftor (PTI-801), a third-generation CFTR corrector. Posencaftor has been granted Fast Track designation from the U.S. Food and Drug Administration.  Nesolicaftor has been granted Orphan Drug designation by the FDA and the European Commission, and Breakthrough Therapy designation and Fast Track designation from the FDA.

Proteostasis’ trial is designed to assess the efficacy, safety and tolerability of its 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 more than 80 percent of subjects trying and failing to enroll into trials of currently approved modulators due to ineligibility.

Eleven homozygous subjects receiving the triple combination experienced a mean absolute improvement in ppFEV1 of 8 percentage points over pooled placebo at day 28. Improvements in lung function were the highest in the nine high disease burden patients, two with at least two pulmonary exacerbations within 12 months prior to study and seven poor responders to prior CFTR modulators. Sweat chloride concentration in homozygous subjects receiving dirocaftor, posenacaftor, and nesolicaftor also demonstrated a mean improvement 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 Proteostasis’ 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. Responder rate, defined as ppFEV1 improvement of 5 percentage points or more, was three times as high in subjects who received active versus placebo.  Mean changes in ppFEV1 were not statistically significant in the heterozygous population.

Based on these results, Proteostasis is planning to launch a global, phase 3, randomized, placebo-controlled, MORE trial in CF subjects with the common F508del homozygous mutation, beginning in 2020. The MORE trial complements the CHOICES trial, which is designed to evaluate the translation of organoid ex-vivo response to potential clinical benefit in patients with rare mutations. CHOICES, expected to begin in 2020, will be the first ever personalized medicine-based study in CF. 

“Evidenced by the variability of subject response and tolerability to currently approved CFTR modulators, it remains clear that the CF community is in need of additional CFTR modulator options,” said Jennifer Taylor-Cousar, professor of medicine and pediatrics, and co-director and CF Therapeutics Development Network Center director of the Adult CF Program at National Jewish Health. “The latest data from the dirocaftor, posenacaftor, and nesolicaftor combination suggests that, even in a population with high disease burden and including subjects who were not eligible for studies of currently approved CFTR modulators, this triple combination demonstrated remarkable outcomes across key study endpoints and performed well in the most challenging disease settings, including those subjects with at least two pulmonary exacerbations within 12 months prior to study entry.”

Photo: Jennifer Taylor-Cousar, professor of medicine and pediatrics, and co-director and CF Therapeutics Development Network Center director of the Adult CF Program at National Jewish Health

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