PTI-428 is a cystic fibrosis transmembrane conductance regulator (CFTR) protein modulator, also known as an “amplifier.” The oral treatment, which is being developed by Proteostasis Therapeutics, demonstrated positive effects on CFTR protein activity in preclinical tests when used in combination with existing treatments. Unlike other approved and investigational therapies that address specific CF gene mutations, such as F508del, PTI-428 is being developed to treat multiple CF mutations.

How PTI-428 works

The transport of water and charged ions (e.g., chloride) across cell membranes is regulated through the CFTR protein. The normal function of this protein allows the formation of a thin mucus, which is necessary to protect and lubricate internal organs (like the lungs and pancreas), entire body systems (like the reproductive system), and tissues.

Defective CFTR proteins are produced when a mutation (e.g., F508del) occurs in the gene that encodes the protein. This causes the protein to misfold, resulting in a functional deficiency that affects the chloride ion flux. Instead of thin mucus, a thick, sticky mucus is produced and accumulates in vital organs and body systems.

PTI-428 modulates the CFTR protein. The drug acts as an amplifier, meaning it increases the amount of an immature form of the CFTR protein, providing substrate for other CFTR modulating agents, such as potentiators and correctors, to act upon.

In vitro test results revealed that PTI-428, combined with other therapies, nearly doubled CFTR protein activity.

History of PTI-428

PTI-428’s preclinical tests involved human bronchial epithelial (HBE) cells and multiple doses of the drug in non-humam primates. Their results revealed PTI-428’s potential to increase the CFTR function, nearly doubling the efficacy of other CFTR modulating agents, as well as its safety and tolerability.

The U.S. Food and Drug Administration placed PTI-428 on what is known as its Fast Track designation in February 2016, to speed its clinical development and FDA review as a potential CF treatment.

According to the ClinicalTrials.gov website, there are two Phase 1 studies currently recruiting participants.

The first Phase 1 study (NCT0271845) — which is recruiting CF patients with any mutation — aims to evaluate PTI-428’s safety, tolerability, and pharmacokinetics. The randomized, placebo-controlled study expects to enroll 36 patients and is involving several sites across the U.S. and Ontario, Canada. The study will be divided into two parts, with the first consisting of three single-ascending dose (SAD) groups, in which the CF patients will receive a single dose of PTI-428 or a placebo and be followed for seven days. The second part will consist of three multiple-ascending dose (MAD) groups of either PTI-428 or placebo, with once-a-day treatment given for seven days, and participants followed for 14 days (seven days after treatment’s end).

The second Phase 1 study (NCT02846142) is recruiting female volunteers and aims to assess the safety, tolerability, pharmacokinetics, electrocardiogram (ECG) effects, and drug-drug interaction (DDI) of hormonal contraceptives and PTI-428. The single-center study in Kansas expects to enroll 88 participants. In a first stage, SAD and MAD groups (placebo or PTI-428) will be evaluated. Following the completion of this part, 40 female healthy volunteers will be divided into two DDI treatment groups – one consisting of once daily oral contraceptive (OC) and the other of PTI-428 or placebo in combination with a once daily OC.

Preliminary data from both Phase 1 studies, presented at the 30th Annual North American Cystic Fibrosis Conference in October 2016, revealed that PTI-428’s pharmacokinetic profile is similar for both healthy volunteers and CF patients. PTI-428 was seen to be safe and biologically active after a single 100 mg dose, and a single dose increased by approximately two-fold CFTR protein mRNA expression in healthy volunteers. According to an August 2016 company release, a two-fold increase in CFTR mRNA could translate to a potential doubling of lung function when PTI-428 is used in combination with existing standard-of-care therapies.

Next steps for PTI-428

Proteostasis Therapeutics is developing a triple combination of PTI-428 with other CFTR correctors and potentiators. The results presented at Cystic Fibrosis conference in October revealed greater chloride transport activity in in vitro tests (HBE cells), and, overall, PTI-428’s potential to restore CFTR function in people with CF homozygous and heterozygous of the F508del mutation.

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