PTI-801 is being developed by Proteostasis Therapeutics as a possible treatment of cystic fibrosis, a genetic disease caused by mutations in the CFTR gene.

How PTI-801 works

The CFTR gene encodes for a protein that is involved in the normal transport of water and charged ions, such as chloride, across cell membranes, allowing the formation of a thin mucus that is necessary to protect and lubricate internal organs and tissues.

Mutations in the CFTR gene cause the production of a defective and misfolded CFTR protein, and impairs the flow of ions in and out of cells, ultimately leading to a thick and sticky mucus that builds in the lungs, pancreas, and other organs.

PTI-801 is a CFTR corrector, meaning that it helps to overcome the defects that result in the production of misfolded CFTR protein, so the protein takes a proper and functional shape. This allows for protein’s increased transport to the cell membrane, where it functions as a chloride channel and helps maintain the right balance of fluid — water and salts — in vital organs.

PTI-801 in clinical trials

PTI-801 is now being evaluated in the second part a Phase 1/2 clinical trial (NCT03140527), involving adults with cystic fibrosis on stable treatment with Orkambi, a CF therapy approved by the U.S. Food and Drug Administration (FDA). The first part concerned ascending oral doses in healthy volunteers, and favorably evaluated PTI-801’s safety, tolerability, drug-drug interactions, and pharmacokinetics (movement in the body).

In the second part, the study’s primary objectives again involved treatment safety, tolerability and pharmacokinetics, with exploratory endpoints that include changes in sweat chloride, body mass index (BMI), and percent predicted FEV1 (ppFEV1) a measure of lung function being analyzed to determine safety.

Patients are randomized to receive once a day for 14 days either a placebo or PTI-801 at one of three escalating capsule doses: 100 mg, 200 mg, and 400 mg.

Results from 48 of 49 patients who finished treatment (at a data cutoff point) found that those on the highest dose, 400 mg, showed significant improvements in both sweat chloride and BMI. At the 200 mg dose, improvements were found to be significant only for the sweat chloride. Treatment with PTI-801 also showed improvements in lung function (as measured by ppFEV1) across all dose levels, although it did not reach statistical significance.

PTI-801 was generally well-tolerated, with only mild or moderate adverse effects like symptom worsening, seen in 10 percent of participants.

The study continues to recruit CF patients across the U.S. and in Canada, Germany, and Denmark, who will be treated for two weeks with 400 mg of PTI-801. Final results are expected in the fall 2018.

A Phase 1 trial (NCT03500263), currently recruiting CF patients at a single site in the U.K., is evaluating the safety and early efficacy of PTI-808 in combination with PTI-801, PTI-428, or placebo. PTI-428 and PTI-808 are also being developed by Proteostasis to possibly treat the disease.

This study’s main goal is to test the safety, tolerability, and efficacy of the triple combination therapy, a potential amplifier, corrector, and potentiator of the CFTR gene. Researchers will also evaluate improvements in patients’ lung function.

The trial, which is expected to concluded in September 2018, was endorsed by the Cystic Fibrosis Foundation’s Therapeutics Development Network (TDN).

Other details

The FDA granted fast-track designation to Proteostasis’  triple combination (PTI-801, PTI-428 and PTI-808) in April 2018.


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