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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 F508 delta, a class 2 or protein-processing mutation.

The potential treatment is currently in Phase 1 clinical trials, in both healthy volunteers and patients, to assess its safety and tolerability.

How PTI-808 works

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 a 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 F508 delta. 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.

PTI-808 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, PTI-428 and PTI-801, PTI-808 restores CFTR function to almost normal levels.

PTI-808 in clinical trials

Proteostasis announced the completion of the first half of a Phase 1 clinical trial (NCT03251092) testing PTI-808 in 48 healthy volunteers. Participants received up to 300 mg of PTI-808 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 ongoing in CF patients with F508 delta mutations who are treated with PTI-808 in combination with PTI-428 and PTI-801, 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.

Patients are receiving either placebo, or PTI-808 daily for seven days followed by PTI-808 plus PTI-428 and PTI-801 daily for 14 days. The concentration of the treatments in the blood is then assessed. Sweat salt concentration is also being measured, along with changes in a nasal biomarker.

Another Phase 1 clinical trial (NCT03140527) is currently recruiting healthy volunteers and adult CF patients with F508 delta mutations in the U.S., Canada, and Europe to assess the safety, tolerability, pharmacokinetics, food effect, and drug-drug interactions of PTI-801.

The trial aims to enroll 125 people, randomized to one of four treatment groups and being conducted in two parts — one involving 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, PTI-801, or PTI-801 in combination with PTI-808. 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 PTI-801 plus PTI-808.

A randomized, double-blind, placebo-controlled Phase 1 trial (NCT03500263) is recruiting 32 CF patients, at one site in Belfast and one in Manchester, to be treated with PTI-808 in combination with PTI-801 and PTI-428, or placebo.

Patients will receive one dose per day of either placebo, PTI-808, or some combination of PTI-428, PTI-801, and PTI-808 for seven days, with a follow-up visit at 14 days. Treatment safety and tolerability will be 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 will be assessed by measuring their forced expiratory volume in one second (FEV1), a measure of lung function where patients breath into a

, a device that measures the volume of air exhaled.

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