PTI-808 and PTI-801 Combo Improves Lung Function in CF Patients, Phase 1 Data Show

Treatment with a combo of Proteostasis Therapeutics’ investigational CFTR modulator therapies — PTI-808, a  potentiator, plus PTI-801, a corrector — can promote significant improvements in lung function and reduction of sweat chloride in patients with cystic fibrosis (CF), Phase 1 data show.

So far in the Phase 1 trial (NCT03140527), 21 patients carrying two copies of the F508del mutation in the CFTR gene — known to cause CF — were randomized and treated with either a placebo or a doublet combination of 100 mg, 200 mg, or 300 mg of PTI-801 plus 50 mg, 100 mg, or 300 mg of PTI-808.

The collected data revealed that after seven and 14 days of treatment with the combo therapy, patients experienced dose-dependent improvements in lung function. In particular, patients treated with the highest doses of both therapies (300 mg each) showed increases from the start of the study in predicted forced expiratory volume in one second (ppFEV₁) of 6.3% on day seven and 5.9% on day 14 of treatment. When compared with placebo, this group showed increases in ppFEV₁ of 8.3% on day seven and 6.6% on day 14.

“The current improvement in ppFEV₁ for standard of care doublets is on average 3%-4% in the F508del homozygous patient population,” Damian Downey, MD, clinical senior lecturer in respiratory medicine at Queen’s University Belfast, said in a press release. “At least a 6% improvement in ppFEV₁, as observed in this study, exceeds efficacy seen with current dual CFTR modulator therapy and is starting to approach the efficacy of experimental triple combinations in this population.”

The combo treatment also reduced sweat chloride levels, which are a clinical sign of CF. In patients receiving the highest doses of both therapies (300 mg each), a reduction of approximately 13 mmol/L was seen on days seven and 14.

The analysis also confirmed that a once-a-day dosing regimen is sufficient to achieve effective activity of both PTI-801 and PTI-808.

During the trial, the combo regimen was demonstrated to be safe and well-tolerated, with no reported pulmonary exacerbations during the treatment or follow-up period.

This Phase 1 trial is still ongoing, and results from the group of patients who are being treated with 400 mg of PTI-801 plus 300 mg of PTI-808 are expected to be announced within the first quarter of 2019.

“These data are the first results seen using an entirely new CF doublet, compare favorably to standard of care, and demonstrate the potential of next-generation CFTR modulators to further improve outcomes in this disease,” said Carsten Schwarz, MD, head of the Adult Cystic Fibrosis Centre, Lung-Transplantation Program, and Endoscopy Unit of the Department of Pediatric Pneumology and Immunology, Charité, Berlin University Medical Center.

“I look forward to results from the fourth dosing cohort and to understanding the potential of another novel combination, PTI-801, PTI-808 and PTI-428,” he said.

Proteostasis is also exploring the effects of combining PTI-808 and PTI-801 with its investigational CFTR protein amplifier, PTI-428, in another Phase 1 trial (NCT03500263). The trial was endorsed by the Cystic Fibrosis Foundation’s Therapeutics Development Network.

The company has completed enrollment of the first group of patients who are receiving the initial dose of the triple combo therapeutic regimen. Preliminary data is expected to be released in the fourth quarter of 2018, with complete data expected during the first quarter of 2019.

In April, the U.S. Food and Drug Administration granted fast track designation to the triple combo treatment program.

In addition to these ongoing trials, Proteostasis is assessing the efficacy and safety of PTI-801 and PTI-428 in CF patients undergoing treatment with Vertex’s CFTR modulator Symdeko (tezacaftor/ivacaftor). Data from these studies are expected in the first quarter of 2019.

These studies, together with previous clinical trials, are expected to provide valuable information to support the design of a Phase 3 program that will further evaluate Proteostasis’ product candidates either in combination or as add-ons to currently available therapies.

The Phase 3 studies are anticipated to be launched within the next 12-18 months, the company announced.

“We’ve taken a significant step forward in demonstrating the potential value of our proprietary combinations with this doublet data, and as our data package builds out across both doublet and triplet programs, we remain committed to bringing more choices in CFTR modulator combinations to the CF community,” said Meenu Chhabra, president and CEO of Proteostasis.

“As part of our evaluation of these next steps, we will expand our exploration of partnering opportunities across our product portfolio and in various geographies, with the goal of bringing the resources and expertise to bear on a platform with transformative potential in cystic fibrosis,” Chhabra added.