PTI-428 is an investigational oral medication being developed by Proteostasis Therapeutics for treating cystic fibrosis (CF).

How PTI-428 works

CF patients have mutations in a gene that provides instructions for making a protein known as CFTR, causing it to misfold. There are more than 180 known mutations that can cause CF.

The CFTR protein normally transports water and salts (chloride) in and out of cells, allowing thin, freely flowing mucus to be formed. However, in CF patients, this normal process is disrupted, and instead a thick, sticky mucus is produced that affects the function of the lungs, pancreas, and reproductive system.

PTI-428 is a type of CFTR modulator known as an amplifier, which acts to increase the amount of CFTR proteins a cell makes. There are two other types of CFTR modulators: potentiators, such as Kalydeco (ivacaftor), which help chloride ions flow through the CFTR channel; and correctors, such as lumacaftor and tezacaftor, which help mutated CFTR proteins form the right shape to allow sufficient water and salt transport across cell membranes. 

In contrast to other types of CFTR modulators that are effective only in CF caused by a certain type of mutation known as the F508del mutation, PTI-428 has been shown to work in CF caused by a variety of different mutations.

PTI-428 in clinical trials

Preclinical studies on human bronchial epithelial (HBE) cells revealed that PTI-428 is able to almost double the total amount of functional CFTR protein being produced. PTI-428 was also found to be safe and tolerable when tested in non-human primates.

A three-part clinical trial (NCT02718495) aimed at determining the safety and tolerability of PTI-428 in CF patients with any type of mutation was completed in November 2017.

In the first part of the study, patients received either single ascending doses (SAD) or multiple ascending doses (MAD) of PTI-428, for a total of seven days. Both SAD and MAD regimens were compared with a placebo that was also given for the same duration.

The second part involved CF patients who had been on Orkambi (ivacaftor/lumacaftor) for a minimum of three months. These patients received either PTI-428 or placebo for 28 days.

The third part involved three groups of CF patients. One group was not on Orkambi but had to be eligible for Orkambi treatment; the other had been on regular Kalydeco treatment for a minimum of three months; and the last was comprised of CF patients with intact pancreatic function but not on any regular treatment. Patients in each group were then randomized to receive PTI-428 or a placebo for 28 days.

Initial results found that patients who received 50 mg of PTI-428 as an add-on to their existing Orkambi treatment had improved lung function, compared with those taking Orkambi alone. These lung improvements were observed after two weeks on the treatment and maintained until the 28th day.

During this 28-day period, patients appeared tolerate PTI-428 well, with no serious side effects. PTI-428 was also found to increase CFTR protein levels. However, changes in sweat chloride (an important marker of CF disease severity) did not correlate with lung function improvements.

Proteostasis is also planning a Phase 2 trial to investigate the safety, tolerability, and pharmacokinetics (how the treatment moves in the body) of PTI-428 in patients on Symdeko (tezacaftor/ivacaftor) therapy. The trial protocol has been endorsed by the Cystic Fibrosis Foundation‘s Therapeutic Development Network. The study is expected to begin in the third quarter of 2018.

A Phase 1 trial (NCT03258424) investigating the safety, tolerability, and pharmacokinetics of PTI-428 in CF patients with any mutation who have been taking Kalydeco for a minimum of three months is currently recruiting up 16 participants at two clinical sites in the U.K. Patients will be randomized to receive either PTI-428 or a placebo once a day for two weeks. The trial is expected to end in December 2018.

Further details

In March 2018, PTI-428 was granted breakthrough therapy designation and orphan drug designation by the U.S. Food and Drug Administration.

The FDA has also granted fast track designation for a triple therapy regimen, also developed by Proteostasis Therapeutics, in which PTI-428 is given in combination with a CFTR corrector called PTI-801 and a CFTR potentiator called PT-808.


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