Posenacaftor (PTI-801)

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

How does posenacaftor work?

The CFTR gene provides instructions for making 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 lead to the production of a defective and misfolded CFTR protein, and impairs the flow of ions in and out of cells, ultimately leading to the production of thick, sticky mucus that builds up in the lungs, pancreas, and other organs.

Posenacaftor is a CFTR corrector, meaning that it helps overcome the defects that result in the production of misfolded CFTR protein, so the protein takes on a proper functional shape. This allows for the 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 being evaluated in the second part of a Phase 1/2 clinical trial (NCT03140527), involving adults with CF on stable treatment with Orkambi (lumacaftor-ivacaftor), a CF therapy approved by the U.S. Food and Drug Administration (FDA). The first part concerned ascending oral doses of posenacaftor in healthy volunteers and favorably evaluated the treatment’s safety, tolerability, drug-drug interactions, and pharmacokinetics (movement in the body).

The primary objectives of the second part of the trial, as in the first part, involves safety, tolerability, and pharmacokinetics, with exploratory goals that include changes in sweat chloride, body mass index (BMI), and percent predicted forced expiratory volume (ppFEV1), which is a measure of lung function.

Patients are assigned randomly to receive either a placebo or posenacaftor at one of three escalating doses: 100 mg, 200 mg, and 400 mg once a day for 14 days.

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 this did not reach statistical significance. Posenacaftor was generally well-tolerated, with only mild or moderate adverse side effects such as symptom worsening, which was seen in 10% of participants.

The next phases of the study continue to recruit CF patients with the so-called F508del/F508del 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 and dirocaftor (PTI-808, also developed by Proteostasis Therapeutics) or a placebo for two weeks. Other new patients who are stable on 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 yet.

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

This study’s main goal was to test the safety, tolerability, and effectiveness of the triple combination therapy. Researchers also evaluated improvements in patients’ lung function.

The trial included 31 CF patients with the F508del/F508del genotype who were assigned randomly to receive one of two doses of the triple combination or placebo. Patients first received seven days of dirocaftor or placebo. Then patients who received the placebo in the first week continued on the placebo and those who received dirocaftor were given 14 days of one of two treatment combination,s with a seven day washout period afterward in which patients did not receive any treatment. The treatment combination was given in two doses between groups. Both groups 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 group received a high dose (600 mg) of posenacaftor and a mid-dose (150 mg) of dirocaftor.

At 14 days, the treatment group receiving high dose posenacaftor (600mg) showed a 5% improvement in ppFEV1 when compared to baseline. This treatment group also showed a decrease in sweat chloride of 19 mmol compared to baseline and 24 mmol compared to placebo. When the results were adjusted to not include patients who were predisposed to rapid pulmonary decline, then the high dose treatment group showed a 6% increase in ppFEV1 compared baseline and an 8% increase compared to placebo. The improvement in lung function had not reached a plateau by 14 days, which suggests the need for a longer study to see how much more it could improve.

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 plus dirocaftor) in 180 CF patients for 28 days. The trial included 28 participants with the F508del/F508del genotype as well as 40 participants with just one copy of the F508del mutation. 

The results of that study showed patients with two copies of the mutation (F508del/F508del) improved more with the triple combination than with the double combination. Compared to placebo, patients with the F508del/F508del genotype 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 F508del mutation had much more variable results with some patients improving while others worsened on the treatments. All compounds were found to be generally safe and well-tolerated.

Proteostasis also has announced it will open two new Phase 3 clinical trials in 2020. The first trial, called MORE, will further investigate the triple combination in a larger group of patients with the F508del/F508del genotype in the hopes of acquiring the necessary data to apply for approval to the FDA.

The second Phase 3 clinical trial that will begin in 2020 is called the CHOICES trial. This will be the first attempt at personalized medicine in CF patients. The study will test if organoids (small organ models created from patients’ stem cells) respond to the triple treatment combination. If the organoids respond favorably to treatment, then patients will be given the treatment, too.

Other details

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


Last updated: Jan. 20, 2020


Cystic Fibrosis News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.