#ECFS2018 — Next-Generation CFTR Correctors for Cystic Fibrosis Show Promise in Early Trial Data

#ECFS2018 — Next-Generation CFTR Correctors for Cystic Fibrosis Show Promise in Early Trial Data

Preliminary clinical trial data of three investigational next-generation CFTR correctors, being developed by Vertex Pharmaceuticals, provides the first demonstration of their potential to improve the outcome of cystic fibrosis (CF) patients.

Trial findings were presented today at the 41st European Cystic Fibrosis Society (ECFS) Conference, taking place through June 9 in Belgrade, Serbia. The oral presentation was titled “Preliminary safety and efficacy of triple combination CFTR modulator regimens in cystic fibrosis.”

In three separate clinical trials, the researchers evaluated the safety and effectiveness of VX-440, VX-152, and VX-659 in combination with tezacaftor (VX-661) and Kalydeco (ivacaftor) in adult CF patients.

Participants were carriers of two copies (one from the father and one from the mother) of the F508del mutation of the CFTR gene the most common cause of CF; or one copy of the F508del CFTR mutation plus a minimal function CFTR mutation.

Patients were randomized across the three double-blind clinical trials (NCT02951182, NCT02951195, and NCT03029455) to be treated with one of the new CFTR correctors or placebo plus tezacaftor and Kalydeco. The patients received 600 mg of VX-440, 200 mg of VX-152, or 120 mg of VX-659 every 12 hours. Results from 96 patients were reported.

After four weeks of treatment with VX-440, patients with one F508del copy and a minimal function mutation showed an improvement in percent predicted forced expiratory volume in one second (ppFEV), a measure of lung function, of 10.6 points, compared with placebo.

A similar difference was also observed in patients with two copies of the F508del mutation, who showed an improvement of 9.5 points after four weeks of VX-440 therapy compared with a decrease in ppFEV1 of 2.5 points in the placebo group.

Treatment with the VX-152 triple combination also improved lung function in CF patients. After two weeks of treatment, it improved ppFEV1 by 10.6 points in patients with one copy of F508del and 8.7 points in patients with two copies, compared with placebo.

In addition, two weeks of treatment with VX-659 improved by 10 points the ppFEV1 of patients with one F508del copy or a minimal function mutation. 

All these positive results in lung function were accompanied by a significant reduction in the levels of chloride released in sweat — a hallmark feature of cystic fibrosis.

In general, all triple combinations were well-tolerated with most adverse events reported being mild or moderate in severity. Across all three trials, only three patients discontinued the treatment due to increased liver enzymes, pneumonia, and increased sputum secretion.

“This is the first demonstration of substantial improvements in CF outcomes with next-generation triple combination regimens” in CF patients, the researchers wrote.

These triple combinations are currently being evaluated in Phase 2 and Phase 3 studies that will guide the development of future treatment regimens.

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