Posenacaftor (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 does posenacaftor work?

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 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 thick and sticky mucus that builds in the lungs, pancreas, and other organs.

Posenacaftor 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 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.

Posenacaftor in clinical trials

Posenacaftor is now being evaluated in the second part of 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 posenacaftor ‘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 forced expiratory volume (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 posenacaftor 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 posenacaftor also showed improvements in lung function (as measured by ppFEV1) across all dose levels, although it did not reach statistical significance.

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

The next phases of the study continue to recruit CF patients with the F508del/F508del mutation genotype across the U.S. and in Canada. Patients who have not been on or who are stable on a CFTR modulator for at least 30 days will be randomized to receive either a combination of posenacaftor with dirocaftor (PTI-808) or a placebo for two weeks. Other new patients who are stable on tezacaftor/ivacaftor (Orkambi) will be treated for two weeks with posenacaftor or placebo. The study was estimated to conclude in December 2019 but no results have been released as of January 20, 2020.

A Phase 1 trial (NCT03500263) at a single site in the U.K. evaluated the safety and early efficacy of dirocaftor (PTI-808) in combination with posenacaftor, nesolicaftor (PTI-428), or placebo. Nesolicaftor and dirocaftor are also being developed by Proteostasis to possibly treat the disease.

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

Results of the trial included 31 CF patients with the homozygous F508del/F508del mutation genotype who were randomized to get one of two doses of the triple combination or placebo. Patients first received seven days of dirocaftor or placebo followed by 14 days of the treatment combination with a seven day washout period afterward where patients did not receive any treatment. The treatment combination was given in 2 different doses between cohorts. Both cohorts received 30 mg of nesolicaftor, then one received a low dose (200 mg) of posenacaftor and a high dose (300 mg) of dirocaftor and the other cohort received a high dose (600 mg) of posenacaftor and a mid-dose (150 mg) of dirocaftor. At 14 days, the treatment group showed a 5% improvement in ppFEV1 when compared to baseline. The treatment group also showed a decrease in sweat chloride of 19 millimoles (mmol) compared to baseline and 24 mmol compared to placebo.

To follow-up on the success of this previous study, Proteostasis initiated a Phase 2 study (NCT03251092) to test the triple combination as well as a double combination (posenacaftor and dirocaftor) in 180 patients for 28 days. The trial included 28 participants with homozygous F508del mutations (two copies) as well as 40 heterozygous participants (only one copy).

Results of this study showed that homozygous patients improved more with the triple combination than the double combination. Compared to placebo, homozygous patients receiving the triple combination had an average improvement of 8 points in ppFEV1 and a reduction of 29 mmol in sweat chloride concentrations. Patients with only one copy of the mutant gene (heterozygous) had much more variable results with some patients improving while others worsened on the treatment. All compounds were found to be generally safe and well-tolerated.

Proteostasis has also announced that it will open two new Phase 3 clinical trials in 2020. The first trial, called the MORE trial (Modulator Options to RestorE CFTR study), will further investigate the triple combination of treatments in a larger group of patients with homozygous F508del mutations in the hopes to acquire the necessary data to apply for approval.

The second Phase 3 clinical trial that will begin in 2020 is called the CHOICES trial (Crossover trial based on Human Organoid Individual response in CF – Efficacy Study). The trial will be the first attempt at personalized medicine in CF patients. The study will test if organoids (small organ models created from individual patient’s stem cells) respond to the triple treatment combination. If the organoids respond favorably to treatment, then the patients will be given the treatment as well.

Other details

The FDA granted fast-track designation to Proteostasis’  triple combination (posenacaftor, nesolicaftor, and dirocaftor) in April 2018.


Last updated: Jan. 20, 2020


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