Vertex Asks FDA to Approve 1st Triple Combo for CF – Elexacaftor, Tezacaftor and Kalydeco

Vertex Pharmaceuticals is asking the U.S. Food and Drug Administration to approve a first triple combination therapy —  elexacaftor (VX-445) plus tezacaftor, and ivacaftor (Kalydeco) — to treat cystic fibrosis (CF) patients who cannot use its other disease-modifying treatments or don’t benefit as intended.

Triple combinations include “next generation” correctors being developed to treat the estimated 40% of people whose underlying mutations don’t respond or respond well to Kalydeco, Orkambi (lumacaftor/ivacaftor), or Symdeko (tezacaftor/ivacaftor, ivacaftor), the company’s approved CF therapies.

“The submission … is a major step toward our goal of bringing this medicine to the largest remaining group of people with CF that still do not have an approved Vertex medicine, as well as toward providing significantly enhanced benefits to patients with two F508del mutations,” Reshma Kewalramani, MD, executive vice president and chief medical officer at Vertex, said in a press release.

Its New Drug Application also includes a request for a priority review, which, if granted, means the FDA would complete its appraisal and announce a decision in eight months (around March), rather than the usual 12.

Data supporting the application was largely drawn from two Phase 3 clinical trials in CF patients ages 12 or older.

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One trial (NCT03525444) included 403 people with CF caused by one F508del and one minimal function mutation who were treated with either the triple combination or placebo for up to 24 weeks. In the other (NCT03525548), 107 patients with two F508del mutations were treated with either elexacaftor or a placebo in combination with tezacaftor and Kalydeco for four weeks.

Patients given the triple combination therapy in both trials demonstrated significant improvements in lung function, as assessed by percent predicted forced expiratory volume in one second (ppFEV1), each study’s primary endpoint or goal. ppFEV1 increased by an average of 14.3% in the 24-week trial, and by 10% in the four-week trial.

Data also showed improvements in secondary endpoints, including a lower annual rate of pulmonary exacerbations, and reduced levels of chloride in patients’ sweat. The treatment was generally well-tolerated.

“We have relentlessly focused on the progression of VX‑445 (elexacaftor), tezacaftor, and ivacaftor from discovery through clinical development and regulatory submission,” Kewalramani said. “We will continue working with the FDA as they review the NDA, and look forward to the potential of this triple combination regimen becoming a new treatment option for people with CF.”

F508del is the most common mutation found in people with CF. Kalydeco is a potentiator for people with the G551D gating mutation; lumacaftor and tezacaftor are correctors.