Two of Proteostasis’ Three Cystic Fibrosis Therapies Are in Clinical Trials, and the Third Is Heading for Trials

Two of the three therapies that Proteostasis Therapeutics has developed to correct the underlying problem in cystic fibrosis are going through clinical trials and a third is heading for trials, the company reports.

That underlying problem is a mutation in a gene known as the cystic fibrosis transmembrane conductance regulator, or CFTR. It produces the faulty version of the CFTR protein that is associated with the disease.

Proteostasis’ therapies are PTI-428, which is a CFTR amplifier; PTI-801, a new-generation CFTR corrector; and PTI-808, a CFTR potentiator. An amplifier increases the amount of an immature form of CFTR protein, so there is more material for other agents to act on. A corrector addresses problems in the protein. And a potentiator improves the performance of another therapy.

The three therapies are designed to improve the activity of cells with a mutated CFTR gene and restore the cells’ normal transport of chloride. The transport malfunction leads to mucus glands producing thick, sticky mucus that interferes with breathing and digestion.

“This is a very exciting time for the CF community, with the potential of next-generation CFTR modulator therapies and combinations just beginning to emerge,” Dr. Po-Shun Lee, executive vice president of Proteostasis, said in a press release.

“We believe that PTI-428, PTI-801 and PTI-808 have the potential to play a pivotal role in emerging next-generation therapies” as stand-alone treatments, in combinations with each other, or as add-ons to standard-of-care therapies, Lee added.

A Phase 1/2 study (NCT02718495) is assessing PTI-428’s safety, stability, and ability to function in the body as a therapy. The 19 patients in the ongoing study have received PTI-428 alone or in combination with Vertex’s Orkambi (lumacaftor/ivacaftor) in a seven-day-on, seven-day-off regimen.

The Phase 1 part of the trial demonstrated that PTI-428 is safe and well-tolerated. All patients’ lung function remained stable, and adverse events were mild or moderate. The trial also showed that PTI-4228 did not significantly interfere with Orkambi’s activity.

Although the Phase 1 component of the study was not designed to assess PTI-428’s effectiveness, those who received PTI-428 plus Orkambi improved their scores on a measure of lung function called forced expiratory volume in one second. The scores were not significantly different from those observed in placebo-treated patients, however.

The Phase 1 results were good enough for Proteostatis to start the Phase 2 component, which will look at the effectiveness of a combination of PTI-428 and Orkambi. This stage will involve patients receiving Orkambi and either PTI-428 or a placebo for 28 days,

Proteostasis is in the process of enrolling patients in the Phase 2 segment. It expects to release preliminary Phase 2 results in the fourth quarter of 2017.

The company is planning another Phase 1/2 study — this one for its CFTR corrector PTI-801 — by the end of 2017. This trial has been endorsed by the Cystic Fibrosis Foundation Therapeutics Development Network Protocol Review Committee and the European Cystic Fibrosis Society Clinical Trial Network.

“We continue to make meaningful progress with all three components of our proprietary triple combination,” said Meenu Chhabra, Proteostasis’ president and CEO. “With the support of U.S. and E.U. patient advocacy groups,” she said, the company plans to enroll patients for the PTI-801 trials at 40 sites in the United States, Canada and Europe.

The U.S. Food and Drug Administration has approved the company’s investigational new drug application for the third therapy in its pipeline, PTI-808. That prompted Proteostasis to start a Phase 1 trial of its safety and pharmacokinetics in healthy volunteers.

If PTI-428 and PTI-801 prove effective, the company will start a trial that evaluates combinations of all three agents by the end of 2017. That study will cover CF patients with the F508del mutation of the CFTR gene who are not receiving Orkambi.