Data awaited in Phase 3 trials of new triple-combo CFTR modulator

Studies tested vanzacaftor, tezacaftor and deutivacaftor in adults and children

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Results of three global clinical trials of a new triple-combination CFTR modulator therapy for cystic fibrosis (CF) —  vanzacaftor, tezacaftor and deutivacaftor — are expected shortly, Vertex Pharmaceuticals, the therapy’s developer, announced.

Two of these Phase 3 trials, SKYLINE 103 (NCT05076149) and SKYLINE 102 (NCT05033080), which tested the next-in-class combination therapy in a total of more than 1,000 CF patients, ages 12 and up, are finished.

The third study (NCT05422222) is testing the new the CFTR modulator therapy in about 200 children, ages 1 through 11. While safety, tolerability and efficacy data were evaluated after six or seven months of treatment, the trial is set to end in 2030.

In a business update released ahead of investor meetings, Vertex reported that it expects to share results of its three studies “in early 2024.”

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“2023 was marked by continued strong performance in the cystic fibrosis business and acceleration of our development stage pipeline … We continue to reach more patients than ever before with our CF medicines,” said Reshma Kewalramani, MD, CEO and president of Vertex.

CF is caused by mutations in the CFTR gene, which provides instructions for making a protein of the same name. CFTR modulators are a recently developed class of therapies that help to boost the functionality of this protein in people with certain CF-causing mutations, including F508del, the disease’s most common mutation.

Over the past decade, the introduction of CFTR modulators has radically altered the treatment landscape for many with CF, though a sizable fraction of patients are not eligible for these therapies.

Vertex has been at the forefront of their development, with four therapies widely approved: Kalydeco (ivacaftor), the dual-combination treatments Orkambi (ivacaftor/lumacaftor) and Symdeko (tezacaftor/ivacaftor; sold as Symveki in Europe), and the triple-combination therapy Trikafta (elexacaftor/tezacaftor/ivacaftor; sold as Kaftrio in Europe).

Three company researchers recently were honored for their work in developing these modulator treatments, awarded the 2024 Breakthrough Prize in Life Sciences.

SKYLINE trials comparing new combination treatment with Trikafta

The investigative combination includes tezacaftor (part of Symdeko and Trikafta), alongside two newer modulators: vanzacaftor (also called VX-121) and deutivacaftor (also called VX-561). Data from a Phase 2 trial (NCT03912233) in adults with one F508del and one minimal function mutation indicated the treatment was well tolerated and improved lung function relative to a placebo.

Both SKYLINE trials compared the new triple combination with Trikafta, while the study in children was open label, meaning all were given the investigative treatment.

Vertex also is collaborating with Moderna to develop VX-522, an inhalation therapy for the 5,000 or so CF patients whose underlying mutations lead to no CFTR protein production and aren’t likely to respond to modulator treatment. VX-522, an RNA-based treatment, is designed to promote production of a healthy CFTR protein in patient’s lungs.

The safety, tolerability, and early efficacy of VX-522 are being tested in a Phase 1/2 study called BEACON-CF (NCT05668741) in adult patients. Vertex announced that the study’s 28-week, single-ascending dose portion is complete, and the 12-week multiple-ascending dosing phase has begun.

Vertex also announced epidemiological data updating its estimated number of people living with CF in the U.S., Europe, Australia, and Canada. The new total is about 92,000, rather than the roughly 88,000 patients the company previously estimated.