Dirocaftor (PTI-808)

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 so-called F508del mutation.

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

How does dirocaftor work?

CF 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 cells.

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 in the body. In the lungs, this mucus interferes with breathing and can make patients more susceptible to infections.

The most common CFTR mutation is F508del, which results in the production of a CFTR protein that cannot fold properly. This causes the CFTR 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 in the CFTR gene. Preclinical studies have shown that when combined with nesolicaftor and posenacaftor, dirocaftor can restore CFTR function to nearly normal levels.

Dirocaftor in clinical trials

Proteostasis announced the completion of the first half of a Phase 1/2 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, with one participant experiencing a severe adverse event, but this was due to a pre-existing condition. All other adverse events reported were mild or moderate in severity.

The Phase 2 portion of the trial is ongoing in CF patients with F508del mutations. Patients are being treated with dirocaftor plus 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.

A total of 68 patients were assigned to receive a daily combination treatment of dirocaftor (300 mg) and posenacaftor (600 mg), with or without nesolicaftor (10 mg), or a placebo, over four weeks. Twenty-eight of the patients had two copies of the F508del mutation (homozygous) and the other 40 had the F508del mutation in one copy of the CFTR gene (heterozygous), while the other copy of the gene was healthy.

Preliminary results showed that in the homozygous treatment group, the percentage predicted forced expiratory volume in one second (ppFEV1) improved by eight percentage points, and the sweat chloride was reduced by 29 mmol/L compared to the placebo group. The treatment effects were much more variable in the heterozygous group with some patients experiencing improvements in ppFEV1 and sweat chloride concentrations while in others these values got worse compared to the placebo at day 28.

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

The trial aims to enroll 180 people, randomized to one of multiple treatment groups and will be conducted in two parts. One part will involve healthy volunteers and the second will involve CF patients.

In the part involving patients, the first three groups will consist of those who have been stably treated with Orkambi (ivacaftor/lumacaftor) for a minimum of three months. They will receive either a placebo, posenacaftor, or posenacaftor in combination with dirocaftor. A final patient group, those not currently using a CFTR modulator therapy (within 30 days of the study’s start), will also be randomized to treatment with either a placebo or posenacaftor plus dirocaftor. The estimated completion date of the study is March 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 a placebo.

Patients received one dose per day of either a placebo or dirocaftor for seven days. Afterward, patients who received dirocaftor were given 30 mg of nesolicaftor and one of two combinations: 200 mg of posenacaftor and 300 mg of dirocaftor, or 600 mg of posenacaftor and 150 mg of dirocaftor for 14 days, with a follow-up visit at the end of those 14 days. After the treatment period, patients had a seven-day washout period where they did not receive any treatment. The treatments’ safety and tolerability were assessed by the number and type of adverse events as well as clinical laboratory tests, electrocardiography, physical examinations, and vital signs. Participants’ breathing capacity was also assessed by measuring their ppFEV1. 

The 31 patients recruited all had two copies of the F508del mutation. The results for the treatment group receiving the high dose (600 mg) of posenacaftor along with the middle dose (150 mg) of dirocaftor showed an increase of five percentage points in ppFEV1 after 14 days when compared to baseline. The sweat chloride concentration of patients in this treatment group was also reduced by 19 mmol compared to baseline and 24 mmol compared to the placebo group.

When the results were adjusted for patients who were predisposed to rapid pulmonary function decline, this treatment group had an even better increase of six percentage points in ppFEV1 compared to baseline and eight percentage points compared to the placebo group. The increase in ppFEV1 had not plateaued during the trial period, which indicated the need for a longer trial to assess the limits of the lung function improvements in these patients.

Proteostasis announced plans to start two new clinical trials in 2020 to further investigate the triple combination of posenacaftor, dirocaftor, and nesolicaftor in CF patients. The first trial, called MORE, will use the treatment combination in a larger set of homozygous patients to get enough data to support the approval of the treatment by the U.S. Food and Drug Administration.

The second study, called CHOICES, will use organoids to test the effectiveness of treatment combinations before administering them to patients. Organoids are small organs created from a 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: Feb. 10, 2020


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