#ECFS2018 – Potential CFTR Corrector PTI-801, Plus Orkambi, Seen to Treat CF Patients in Phase 1 Trial

Treatment for 14 days with Proteostasis Therapeutics’ PTI-801 in cystic fibrosis (CF) patients also being treated with Orkambi (lumacaftor/ivacaftor) led to statistically significant improvements in sweat chloride, body mass index, and rescued blood glucose levels in a subgroup of patients with diabetes, Phase 1 trial data show.

PTI-801 is being tested in a 14-day study in adults with CF who have two copies of the F508del mutation in the CFTR gene and are on stable background therapy using Vertex’s CFTR modulator Orkambi.  PTI-801 is a third-generation CFTR corrector.

The trial (NCT03140527), being conducted at 30 sites in the U.S. and Europe, had at data cutoff randomized 49 patients to oral PTI-801 (once daily) at one of three escalating dose levels — 100 mg (14 patients), 200 mg (13 patients), and 400 mg (12 patients)— or to a placebo (10 patients).

Of note, the PTI-801 400 mg dose cohort is looking for additional participants. More information is available here.

The trial’s primary objectives are to assess the therapy’s safety, tolerability, and pharmacokinetics. Parameters like sweat chloride and body mass index (BMI) — exploratory endpoints — and changes in percent predicted FEV1 (ppFEV1, a measure of lung function) will also be analyzed.

Patients with CF-related diabetes (CFRD) — nearly half of the enrolled patients – were also analyzed for changes in blood glucose levels. CFRD is a highly prevalent complication linked to poorer quality of life, weight loss, lung function decline, and greater risk of death.

Results in 48 of the 49 patients showed that PTI-801 was generally well-tolerated, with only mild or moderate adverse effects. The most common was pulmonary exacerbations (10%).

Patients randomized to the therapy’s highest dose, 400 mg, showed significant improvements in both sweat chloride and BMI. At a dose of 200 mg, improvements were found to be significant only for the sweat chloride.

“Sweat chloride is the first diagnostic test to identify CF patients and the reduction of mean SC [sweat chloride] concentration levels to 55 mmol, levels below the CF disease diagnostic criteria, after only two weeks of treatment, is very encouraging and I believe a clear sign of a pharmacological effect of PTI-801,” Manu Jain, MD, a professor of Medicine, Pulmonary and Critical Care at Northwestern Medicine and the study’s lead investigator, said in a press release.

Participants treated with PTI-801 also showed improvements in ppFEV1 across all treatment doses, although the difference didn’t reach statistical significance.

In hyperglycemic CFRD patients, all three doses of PTI-801 were effective in normalizing the glucose levels.

Researchers found no changes in blood glucose in placebo-treated participants and in non-diabetic patients.

“With the addition of PTI-801 to Orkambi, we saw improvements in sweat chloride and weight that, at certain dose levels, reached Kalydeco-like levels and the numerical improvement in FEV₁ suggests PTI-801 could potentially double what Orkambi achieves alone. We believe these results demonstrate our ability to deliver a second potential add-on CFTR therapy to enhance current and future CFTR modulator treatments,” said Meenu Chhabra, president and chief executive officer of Proteostasis.

The company plans to soon start a Phase 2 trial of a once-daily triple regimen: “PTI-428, our novel CFTR amplifier, PTI-808, our potentiator, and PTI-801,” Chhabra added.