The FDA approved vanzacaftor/tezacaftor/deutivacaftor (Alyftrek; Vertex Pharmaceuticals) for the treatment of cystic fibrosis (CF) in patients 6 years and older who have at least 1 F508del mutation or another mutation in the CFTR gene that is responsive to Alyftrek. The approval is based on comprehensive phase 3 studies, in which Alyftrek met primary and all key secondary end points compared with elexacaftor/tezacaftor/ivacaftor and ivacaftor (Trikafta; Vertex Pharmaceuticals).1
Alyftrek is a once-daily, next-in-class, triple combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator for the treatment of CF. In people with CF, mutations in the CFTR gene lead to decreased quantity and/or function of the CFTR protein channel at the cell surface. Both vanzacaftor and tezacaftor are correctors designed to increase the amount of CFTR protein at the cell surface by facilitating the processing and trafficking of the CFTR protein, whereas deutivacaftor is a potentiator designed to increase the channel open probability of the CFTR protein delivered to the cell surface to improve the flow of salt and water across the cell membrane.1,2
Two randomized, double-blind, active-controlled, 52-week phase 3 clinical trials, SKYLINE 102 (NCT05033080)3 and SKYLINE 103 (NCT05076149)4, were part of this phase 3 program evaluating Alyftrek, which was referred to as “vanza triple” in the studies.1 The study enrolled patients with CF 12 years and older who have at least 1 F508del mutation or a mutation responsive to triple combination CFTR modulators (CFTRm) to assess the efficacy of Alyftrek (vanzacaftor: 20 mg; tezacaftor: 100 mg; and deutivacaftor: 250 mg) compared with Trikafta.2
About the Trials
SKYLINE 102
- Trial Name: A Phase 3 Study of VX-121 Combination Therapy in Participants With Cystic Fibrosis (CF) Heterozygous for F508del and a Minimal Function Mutation (F/MF)
- ClinicalTrials.gov ID: NCT05033080
- Sponsor: Vertex Pharmaceuticals Incorporated
- Completion Date: November 21, 2023
SKYLINE 103
- Trial Name: A Study of VX-121 Combination Therapy in Participants With Cystic Fibrosis (CF) Who Are Homozygous for F508del, Heterozygous for F508del and a Gating (F/G) or Residual Function (F/RF) Mutation, or Have At Least 1 Other Triple Combination Responsive (TCR) CFTR Mutation and No F508del Mutation
- ClinicalTrials.gov ID: NCT05076149
- Sponsor: Vertex Pharmaceuticals Incorporated
- Completion Date: November 30, 2023
According to results published in February 2024, the primary end point of both trials, which was absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) through week 24, was met and showed that treatment with Alyftrek was non-inferior to treatment with Trikafta. Following a 4-week run-in on Trikafta, baseline measurements of ppFEV1, sweat chloride (SwCl) and other efficacy parameters were obtained, after which patients were randomly assigned to receive either Alyftrek or Trikafta.2-4
Additionally, the key secondary end points in both SKYLINE 102 and SKYLINE 103 were absolute change from baseline in SwCl through week 24 compared with Trikafta; proportion of patients pooled across the 2 trials, with SwCl below 60 mmol/L through week 24 compared with Trikafta; and proportion of patients pooled across the 2 trials, with SwCl below 30 mmol/L through week 24 compared with Trikafta.2-4
Further, head-to-head against Trikafta, on the first key secondary end point, the Alyftrek was superior in reducing SwCl levels in SKYLINE 102 and SKYLINE 103. In addition, the second and third key secondary end points, which were pooled across SKYLINE 102 and SKYLINE 103, Alyftrek also achieved superiority in the proportion of patients below 60 mmol/L (the diagnostic threshold for CF) and below 30 mmol/L (carrier level). The investigators also observed that results from other secondary end points were consistent with results of the primary and key secondary end points, and 52-week results were consistent with those observed at 24 weeks.2
“In phase 3 clinical trials, across a broad range of genotypes, once-daily Alyftrek demonstrated non-inferiority to Trikafta in ppFEV1 response and statistically significant improvement in SwCl, a welcomed advancement for the treatment of CF,” Claire L. Keating, MD, co-director of the Gunnar Esiason Adult Cystic Fibrosis and Lung Program at Columbia University, and investigator in the Alyftrek clinical trial program, said in the news release. “Alyftrek has the potential to improve the care of patients with CF.”1
REFERENCES
1. Businesswire. Vertex Announces US FDA Approval of ALYFTREK™, a Once-Daily Next-in-Class CFTR Modulator for the Treatment of Cystic Fibrosis. News release. December 20, 2024. Accessed December 20, 2024. https://www.businesswire.com/news/home/20241220133127/en/Vertex-Announces-US-FDA-Approval-of-ALYFTREK%E2%84%A2-a-Once-Daily-Next-in-Class-CFTR-Modulator-for-the-Treatment-of-Cystic-Fibrosis
2. Vertex Pharmaceuticals. Vertex Announces Positive Results From Pivotal Trials of Vanzacaftor/Tezacaftor/Deutivacaftor, Next-In-Class Triple Combination Treatment for Cystic Fibrosis. February 5, 2024. Accessed December 20, 2024. https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-positive-results-pivotal-trials
3. A Phase 3 Study of VX-121 Combination Therapy in Participants With Cystic Fibrosis (CF) Heterozygous for F508del and a Minimal Function Mutation (F/MF). ClinicalTrials.gov identifier: NCT05033080. Updated October 3, 2024. Accessed December 20, 2024. https://clinicaltrials.gov/study/NCT05033080#xd_co_f=YjMxMWE5MTQtNzQzNi00MzE3LTk5YTItZjgwZjYxOGE5NWQw~
4. A Study of VX-121 Combination Therapy in Participants With Cystic Fibrosis (CF) Who Are Homozygous for F508del, Heterozygous for F508del and a Gating (F/G) or Residual Function (F/RF) Mutation, or Have At Least 1 Other Triple Combination Responsive (TCR) CFTR Mutation and No F508del Mutation. ClinicalTrials.gov identifier: NCT05076149. Updated June 13, 2024. Accessed December 20, 2024. https://clinicaltrials.gov/study/NCT05076149#xd_co_f=YjMxMWE5MTQtNzQzNi00MzE3LTk5YTItZjgwZjYxOGE5NWQw~
