RARE Daily

Vertex Reports Positive Results of Next-In-Class Triple Combo CF Treatment

February 6, 2024

Rare Daily Staff

Vertex Pharmaceuticals reported positive results from its once-daily vanza triple program, the company’s most comprehensive phase 3 pivotal program for the treatment of rare lung disease cystic fibrosis.

Cystic fibrosis (CF) is a rare, progressive, multi-organ disease that affects the lungs, liver, pancreas, GI tract, sinuses, sweat glands and reproductive tract. CF is caused by a defective and/or missing CFTR protein resulting from certain mutations in the CFTR gene. While there are many different types of CFTR mutations that can cause the disease, the vast majority of people with CF have at least one F508del mutation. CFTR mutations lead to CF by causing CFTR protein to be defective or by leading to a shortage or absence of CFTR protein at the cell surface. The defective function and/or absence of CFTR protein results in poor flow of salt and water into and out of the cells in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus, chronic lung infections and progressive lung damage that eventually leads to death for many patients. The median age of death is in the 30s, but with treatment, projected survival is improving.

The phase 3 program included two randomized, double-blind, active-controlled, 52-week trials, SKYLINE 102 and SKYLINE 103, evaluating the efficacy of vanzacaftor/tezacaftor/deutivacaftor  once daily in people with CF ages 12 years and older who have at least one F508del mutation or a mutation responsive to triple combination CFTR modulators (CFTRm), compared to Vertex’s Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor). A third phase 3 single-arm, 24‑week, open-label study, RIDGELINE 105, evaluated the safety and efficacy of the vanza triple in children with CF ages 6 to 11 years with at least one mutation responsive to triple combination CFTRm.

Treatment with the once-daily vanza triple CFTR modulator regimen met all primary and key secondary endpoints in two randomized controlled trials in people with CF ages 12 years and older. Results were more pronounced in the single-arm study in children ages 6 to 11 years, demonstrating the potential that treating early in life may prevent disease development, and Vanza triple was generally well tolerated across all three studies.

In SKYLINE 102 and SKYLINE 103, following a 4-week run-in on Trikafta, baseline measurements of percent predicted forced expiratory volume in 1 second (ppFEV1), sweat chloride (SwCl) and other efficacy parameters were obtained, after which patients were randomized to either the vanza triple or Trikafta. As in the SKYLINE trials, all children in the RIDGELINE 105 study received at least 4 weeks of Trikafta to establish a baseline for ppFEV1, SwCl, and other efficacy parameters prior to receiving vanza triple.

In both SKYLINE 102 and SKYLINE 103, the primary endpoint of absolute change from baseline in ppFEV1 through week 24 was met and showed that treatment with vanza triple was non-inferior to treatment with Trikafta.

The key secondary endpoints in SKYLINE 102 and SKYLINE 103 were absolute change from baseline in SwCl through week 24​ compared to Trikafta; proportion of patients pooled across the two trials, with SwCl below 60 mmol/L through week 24 compared to Trikafta; and proportion of patients pooled across the two trials, with SwCl below 30 mmol/L through week 24 compared to Trikafta.

Head-to-head against Trikafta, on the first key secondary endpoint, the vanza triple was superior in reducing SwCl levels in SKYLINE 102 and SKYLINE 103. In the second and third key secondary endpoints, which were pooled across SKYLINE 102 and SKYLINE 103, the vanza triple achieved superiority in the proportion of patients below 60 mmol/L (the diagnostic threshold for CF) and below 30 mmol/L (carrier level) compared to Trikafta.

The results from other secondary endpoints were consistent with results of the primary and key secondary endpoints. Additionally, the results at 52 weeks were consistent with results at 24 weeks.

The primary endpoint in the RIDGELINE 105 study in children 6 to 11 years old was safety. On the secondary endpoint measuring the absolute change in mean SwCl levels through week 24, the vanza triple reduced SwCl by -8.6 mmol/L compared to a baseline on Trikafta. 95% of children achieved SwCl levels below 60 mmol/L and the majority of children treated with the vanza triple achieved normal levels of CFTR function with SwCl levels below 30 mmol/L.

Treatment with the vanza triple was well tolerated in all three studies, and the safety was similar between the vanza triple and TRIKAFTA treatment groups in SKYLINE 102 and SKYLINE 103. The safety of the vanza triple in children 6 to 11 years old was similar to the safety in people 12 years of age and older.

“We are very pleased with today’s results, which demonstrate the vanza triple is non-inferior to Trikafta in improving lung function and superior to Trikafta in lowering levels of sweat chloride in people living with CF, setting a new standard for the level of CFTR protein function achievable, and raising the very high bar set by Trikafta,” said Carmen Bozic, executive vice president, Global Medicines Development and Medical Affairs, and chief medical officer at Vertex. “We look forward to submitting our application to regulators with the aim of bringing this potential medicine to patients as quickly as possible.”

“These results were particularly striking in the pediatric study,” said Bonnie Ramsey, professor emerita of Pediatrics, University of Washington School of Medicine, senior consultant to the CF Foundation Therapeutics Development Network and co-chair of Vertex’s CFTR Modulator Steering Committee. “The efficacy seen with the vanza triple gives me great hope for CF patients in the future.”

Vertex is on track to make global regulatory submissions by mid-2024 including in the United States and Europe for people with CF ages 6 years and older. The company will use a priority review voucher in the United States. The priority review voucher entitles the holder to designate an NDA for priority review, which provides an expedited six‑month review instead of the standard 10-month review.

The full data set from these studies will be presented at future medical meetings later this year.

Photo: Carmen Bozic, executive vice president, Global Medicines Development and Medical Affairs, and chief medical officer at Vertex

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