Nesolicaftor (PTI-428)

Nesolicaftor (PTI-428) is an investigational oral medication being developed by Proteostasis Therapeutics to treat cystic fibrosis (CF).

How does nesolicaftor work?

CF patients have mutations in a gene that provides instructions to make a protein known as the cystic fibrosis transmembrane conductance regulator (CFTR), causing it to misfold. More than 1,700 mutations have been identified that can cause CF.

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

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

Nesolicaftor has been shown to work in CF caused by a variety of different mutations, 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.

Preclinical studies on human bronchial epithelial cells revealed that nesolicaftor can nearly double the total amount of functional CFTR protein being produced.

Nesolicaftor in clinical trials

A three-part Phase 1/2 trial (NCT02718495) investigating the safety and tolerability of nesolicaftor 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 nesolicaftor, 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 nesolicaftor or a placebo for 28 days.

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

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

During these 28 days, patients appeared to tolerate nesolicaftor well, with no serious side effects. Nesolicaftor 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 also conducted a Phase 2 trial (NCT03591094) to investigate the safety, tolerability, and pharmacokinetics (how the treatment moves in the body) of nesolicaftor in patients on Symdeko (tezacaftor/ivacaftor) therapy. The study tested 40 participants who were homozygous for (had two copies of) the F508del mutation. The participants were randomized with half receiving nesolicaftor and half receiving placebo. The study concluded in February 2019 but no results have yet been released.

Nesolicaftor has also been used in combination with two other Proteostasis treatments, a CFTR corrector called posenacaftor (PTI-801) and a CFTR potentiator called dirocaftor (PTI-808). The triple combination was tested as part of a Phase 1/2 clinical trial (NCT03500263). A total of 31 CF patients with two copies of the F508del mutation were recruited and randomly assigned to receive a placebo, or the triple combination for 14 days.

The results showed that after 14 days, the group receiving the triple combination with high-dose posenacaftor experienced a significant 5% increase above baseline values in the percent predicted forced expiratory volume (ppFEV) in one second, a measure of lung function. The chloride ions in the sweat of these patients were reduced by 19 mmol/L compared to baseline or 24 mmol/L compared to the placebo group.

In another Phase 1/2 trial (NCT03251092), Proteostasis recruited 28 patients with two copies of the F508del mutation and 40 participants with one copy of the mutation. Participants were randomized and received a combination of dirocaftor and posenacaftor, with or without nesolicaftor, or a placebo, over a four-week treatment period.

Preliminary results showed that in the group with two copies of the F508del mutation and receiving the triple treatment, ppFEV1 scores were improved by 8 percentage points and sweat chloride levels were reduced by 29 mmol/L compared to the placebo group at day 28.

Participants with one copy of the F508del mutation had much more variable results; ppFEV1 increased by 20 percentage points in some, while it decreased by 13 percentage points in others. Sweat chloride was also variable with the concentrations falling as much as 79 mmol/L in some participants while increasing by 12 mmol/L in others.

Proteostasis plans to initiate two more Phase 3 clinical trials in 2020. One trial, called MORE, will follow up on the success of the triple treatment combination in CF patients with two copies of the F508del mutation, and the other trial, called CHOICES, will focus more on a personalized medicine approach.

The MORE trial will aim to recruit a larger pool of participants to confirm the previous results of combining dirocaftor, nesolicaftor, and posenacaftor.

In CHOICES, stem cells will be taken from individual participants and used to create organoids, small organ-specific tissues. Different treatment combinations will then be tested on the organoids, with their responses helping to determine the treatments to be tested in the patients.

Other information

Nesolicaftor was granted the designations of breakthrough therapy and orphan drug by the U.S. Food and Drug Administration in March 2018.

The agency has also granted fast track designation for the nesolicaftor, posenacaftor, and dirocaftor triple combination therapy.


Last updated: Jan. 22, 2020


Cystic Fibrosis News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.