Novel Triple Combination Therapy for Cystic Fibrosis Submitted for FDA Review

A New Drug Application (NDA) for the investigational therapy elexacaftor (VX-445), for use in combination with tezacaftor and ivacaftor in the treatment of cystic fibrosis, has been submitted to the FDA by Vertex Pharmaceuticals. 

Elexacaftor and tezacaftor facilitate the cellular processing and trafficking of normal and select mutant forms of cystic fibrosis transmembrane conductance regulator (including F508del-CFTR) to increase the amount of mature CFTR protein delivered to the cell surface. The combination therapy was examined in two placebo controlled, phase 3 studies in patients aged ≥12 years.

The 4-week study randomized 107 patients with two F508del mutations to receive elexacaftor, tezacaftor, and ivacaftor or tezacaftor, ivacaftor and placebo. Results showed a mean absolute improvement in percent predicted forced expiratory volume in one second (ppFEV1) of 10.0 percentage points from baseline to week 4, in the combination group compared with the control group (P <.0001). 

The 24-week study, which included patients with one F508del mutation and one minimal function mutation, compared the fixed-dose combination therapy to placebo. Results showed that treatment with the combination therapy led to a mean absolute improvement in ppFEV1 of 13.8 percentage points compared with placebo (P <.0001) at week 4; this improvement in ppFEV1 was maintained through 24 weeks of treatment. 

An additional study examining the combination therapy in patients aged 6 to 11 years that are homozygous or heterozygous for F508del mutation is currently in the recruitment stages.

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The elexacaftor, tezacaftor and ivacaftor treatment regimen was previously granted Breakthrough Therapy designation. The NDA includes a request for Priority Review, which if granted, would shorten the review time to 8 months. 

“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,” said Reshma Kewalramani, MD, and CMO of Vertex. 

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