Icenticaftor Effective in CF Patients With Certain Mutations, Phase 1/2 Trial Shows

Experimental therapy icenticaftor (QBW251) was able to improve lung function in cystic fibrosis (CF) patients carrying class 3 and 4 mutations in the CFTR gene, results from a Phase 1/2 trial show.

It also appeared to be safe and well tolerated when given to both healthy volunteers and CF patients, according to the trial findings, reported in the study, “Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251),” and published in the Journal of Cystic Fibrosis.

CF occurs when mutations in the CFTR gene cause the CFTR protein encoded by this gene to either malfunction or cease to be produced. This protein normally acts as a gate for chloride ions, regulating their passage in and out of cells, which is needed to maintain healthy fluid transport.

When CFTR is either absent or dysfunctional, a thick and sticky mucus is produced. Over time, this mucus can damage several organs, including the lungs, pancreas, digestive tract, and reproductive system, leading to the typical symptoms of CF.

CFTR mutations are grouped into six classes, depending on the effects they have on the CFTR protein itself. In patients carrying class 3 mutations, the CFTR protein is made and transported to the cell membrane, but fails to open. Conversely, in those carrying class 4 mutations, a misshapen CFTR protein again reaches the cell membrane, but only allows a small number of chloride ions to pass through.

Icenticaftor is an oral CFTR potentiator that is being developed by Novartis for the treatment of CF. The medication works by keeping the CFTR protein open long enough to allow a healthy flow of chloride ions to pass through. Due to this mechanism of action, icenticaftor may be particularly helpful in treating CF patients harboring class 3 and 4 mutations.

Icenticaftor’s safety, tolerability, pharmacokinetics (how a medication is processed in the body), and preliminary pharmacodynamics (a therapy’s effects on the body) were investigated in a randomized, proof-of-concept Phase 1/2 trial (NCT02190604), which enrolled healthy volunteers and CF patients.

The study was divided into three parts. The first two portions of the study focused on assessing the safety and tolerability of single and multiple ascending doses (SAD and MAD, respectively) of icenticaftor to determine the tolerable dose, which would then be used in part three, the multi-dose efficacy part of the study in CF patients.

The main goal of the first and second parts of the study was to determine the number of healthy volunteers experiencing adverse events, or undesirable side effects. Objectives of the third part included assessing changes in the lung clearance index (LCI) — a measure of lung function — and the incidence and severity of adverse events among CF patients.

Other study outcomes included assessing changes in forced expiratory volume in one second (FEV1, a measure of lung function) and the amount of chloride found in sweat, a measure of CFTR activity.

Patients and healthy volunteers participating in the trial were randomly assigned to receive either icenticaftor or a matched placebo for a period of 14 days.

Healthy volunteers tolerated icenticaftor at all doses in the SAD (10 mg to 1,000 mg) and MAD (150 mg once daily to 750 mg twice daily) portions of the study. Headaches (14% of participants) and dizziness (8%) were the most commonly reported adverse events in the SAD portion, while headaches (20%), flatulence (15%), cough (13%), and dizziness (8%) were those most frequently observed in the MAD portion, across all doses tested.

In part three, CF patients were divided into three groups based on dose and type of mutation they carried: all harboring class 3 and 4 mutations received icenticaftor at a dose of 150 and 450 mg twice daily; while those who had two copies of the F508del mutation — the most common mutation found in CF — received the therapy at a dose of 450 mg twice daily.

When given to patients, icenticaftor was also found to be safe and well tolerated across all doses tested. The therapy did not cause any unexpected side effects, deaths, or premature discontinuations.

At the 450 mg dose, patients with class 3 and 4 mutations experienced several improvements in lung function, compared with a placebo. Average LCI dropped by 1.13 points, FEV1 increased by 6.46%, and sweat chloride decreased by 8.36 mmol/L.

Furthermore, these patients experienced “clinically meaningful” quality-of-life improvements related to respiratory function, as measured by the Cystic Fibrosis Questionnaire Revised.

However, investigators did not observe any significant changes in patients carrying two copies of the F508del mutation and testing in that group was stopped at an interim analysis.

“Icenticaftor was safe and well-tolerated in healthy volunteers and CF patients and demonstrated clinically meaningful changes in lung function and sweat chloride level in CF patients with Class III and IV CFTR mutations,” the investigators wrote.

They noted, however, that additional studies enrolling a larger number of patients carrying other mutations are needed to confirm these findings.