29 July 2021 - - US-based Vertex Pharmaceuticals Inc. (NASDAQ: VRTX) will initiate a Phase 3 development program for the new once-daily investigational triple combination of VX-121/tezacaftor/VX-561 (deutivacaftor) in the second half of 2021, the company said.

The combination of VX-121/tezacaftor/VX-561 was first identified as having potential for increased efficacy based on its ability to drive higher levels of chloride transport compared to Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor) in human bronchial epithelial cells in vitro.

The combination of VX-121/tezacaftor/VX-561 was evaluated in a Phase 2 study in people with cystic fibrosis ages 18 and older with one F508del mutation and one minimal function mutation and in people with CF ages 18 and older with two F508del mutations.

The regimen was generally well-tolerated, and the study met the primary efficacy endpoint of absolute change from baseline in ppFEV1 and all secondary efficacy endpoints including absolute change from baseline in sweat chloride concentration in both patient populations.

Taken together, these data suggest the triple combination holds the potential to restore cystic fibrosis transmembrane conductance regulator function in people with CF to even higher levels than seen with other Vertex CFTR modulators and thereby provide enhanced clinical benefit.

VX-561 was also evaluated in a dose-ranging monotherapy study. Complete data from the Phase 2 clinical study of VX-121/tezacaftor/VX-561 and the VX-561 Phase 2 monotherapy study will be presented at a later date.

The Phase 3 program consists of two randomized, double-blind, active-controlled 48-week trials, which will evaluate the safety and efficacy of VX-121 (20 mg)/tezacaftor (100 mg)/VX-561 (250 mg) in comparison to TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor).

The first study will enroll approximately 350 people with CF ages 12 years and older with one F508del mutation and one minimal function mutation.

The second study will enroll approximately 450 people with CF ages 12 years and older with two F508del mutations or one F508del mutation and a second mutation responsive to CFTR modulators. The primary endpoint in both studies is the absolute change from baseline in ppFEV1, which will be analyzed for non-inferiority to TRIKAFTA.

Both studies will also assess absolute change from baseline in ppFEV1 and sweat chloride for superiority to Trikafta.

In people with certain types of mutations in the CFTR gene, the CFTR protein is not processed and cannot move through the cell normally.

This results in little to no protein at the cell surface. VX-121 and tezacaftor are designed to increase the amount of mature protein at the cell surface by targeting the processing and trafficking defect of the CFTR protein.

VX-561 (deutivacaftor) is an investigational potentiator designed to keep CFTR proteins at the cell surface open longer to improve the flow of salt and water across the cell membrane, which helps hydrate and clear mucus from the airways.

The VX-121/tezacaftor/VX-561 program was granted Fast Track and Orphan Drug Designations from the US Food and Drug Administration for the treatment of cystic fibrosis.

Trikafta is a prescription medicine used for the treatment of cystic fibrosis in patients aged six years and older who have at least one copy of the F508del mutation in the cystic fibrosis transmembrane conductance regulator gene or another mutation that is responsive to treatment with Trikafta.