Dirocaftor (PTI-808) is an experimental therapy being developed by Proteostasis Therapeutics to treat the most common type of cystic fibrosis (CF) caused by the mutation F508del, a class 2 or protein-processing mutation.

The potential treatment is currently in Phase 3 clinical trials to assess its safety and efficacy in combination with posenacaftor (PTI-801) and nesolicaftor (PTI-428).

How does dirocaftor work?

Cystic fibrosis is a heritable disorder caused by mutations in the CFTR gene, which encodes for an ion transport protein that controls the salt and fluid balance in cells. The CFTR protein is a membrane protein that provides a tube or channel that directs ions in and out of the cell.

Mutations in the CFTR gene result in the disruption of the normal traffic of salts and fluids in cells, which causes the buildup of thick mucus in the lungs, pancreas, and other organs and tissues. This mucus in the lungs interferes with breathing and can make patients more susceptible to infections.

The most common CFTR mutation is F508del. It results in the production of a CFTR protein that cannot fold properly. This causes the channel to be partially folded on itself, like a tube that is pinched in the middle, meaning that ions cannot move through the channel easily.

Dirocaftor is a CFTR potentiator — it enhances the function of the CFTR protein by holding the channel open so that chloride ions can move through the channel in spite of the mutation. Pre-clinical studies have shown that when combined with two other experimental Proteostasis treatments, nesolicaftor and posenacaftor, dirocaftor restores CFTR function to almost normal levels.

Dirocaftor in clinical trials

Proteostasis announced the completion of the first half of a Phase 1 clinical trial (NCT03251092) testing dirocaftor in 48 healthy volunteers in 2017. Participants received up to 300 mg of dirocaftor once a day. The results showed that the treatment was well-tolerated. One participant experienced a severe adverse event, but this was due to a pre-existing condition. All other adverse events reported were of mild or moderate severity.

The trial is continuing as a Phase 2 trial in CF patients with F508del mutations who are treated with dirocaftor in combination with nesolicaftor and posenacaftor, or given a placebo. This part of the study is focused on the treatments’ pharmacokinetics, or how quickly they reach the bloodstream and how long it takes for them to be metabolized.

Preliminary results showed that 68 patients received either placebo or dirocaftor daily for seven days followed by dirocaftor plus nesolicaftor and posenacaftor daily for 14 days. Twenty-eight of the patients were homozygous (had 2 copies) of the F508del mutation and the other 40 were heterozygous (only 1 copy) of the gene. The homozygous treatment group improved their percentage predicted forced expiratory volume in one second (ppFEV1) by 8 points and reduced their sweat chloride by 29 mmol/L compared to the placebo group. The heterozygous group was much more variable in their treatment effects, with some patients experiencing improvements in ppFEV1 and sweat chloride concentrations while other patient’s values got worse.

Another Phase 1/2 clinical trial (NCT03140527) is currently recruiting adult CF patients with F508del mutations in the U.S. and Canada to assess the safety, tolerability, pharmacokinetics, food effect, and drug-drug interactions of posenacaftor.

The trial aims to enroll 180 people, randomized to one of multiple treatment cohorts and being conducted in two parts — one involving healthy volunteers and other patients. In the part involving patients, the first three groups will consist of patients who have been stably treated with Orkambi (ivacaftor/lumacaftor) for a minimum of three months. They will receive either placebo, posenacaftor, or posenacaftor in combination with dirocaftor. A final patient group, those not currently using a CFTR modulator therapy (within 30 days of study’s start), will also be randomized to treatment with either placebo or posenacaftor plus dirocaftor. The study shows an estimated completion date of December 2019 but no results have been released as of January 21, 2020.

A randomized, double-blind, placebo-controlled Phase 1/2 trial (NCT03500263) recruited 31 CF patients who were treated with dirocaftor in combination with posenacaftor and nesolicaftor , or placebo.

Patients received one dose per day of either placebo, dirocaftor, or some combination of nesolicaftor, posenacaftor, and dirocaftor for seven days, with a follow-up visit at 14 days. Treatment safety and tolerability were assessed by the number and type of adverse events, as well as clinical laboratory tests, electrocardiography (ECG), physical examinations, and vital signs. Participants’ breathing capacity was also assessed by measuring their ppFEV1, a measure of lung function where patients breathe into a spirometer, a device that measures the volume of air exhaled.

The 31 patients recruited all had 2 copies of the F508del mutation (homozygous) and results showed an increase of 5% in ppFEV1 after 14 days for the treatment group, when compared to baseline. The treatment group also reduced their sweat chloride concentrations by 19 mmol compared to baseline and 24 mmol compared to the placebo group.

Proteostasis announced plans to start two new clinical trials in 2020 to further investigate the triple combination of posenacaftor, dirocaftor, and nesolicaftor for CF patients. The first trial, Modulator Options to RestorE CFTR study (MORE), will use the treatment combination in a larger set of homozygous patients in order to get enough data to support approval.

The second study, nicknamed CHOICES (Crossover trial based on Human Organoid Individual response in CF – Efficacy Study), will utilize organoids to test the effectiveness of treatment combinations before administering the treatments to patients. Organoids are small organs created from individual patient’s stem cells. If the organoids respond positively to the medications, then the treatments will be administered to patients, hopefully leading to more successful outcomes.


Last updated: Jan. 21, 2020


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