BOSTON, Mass. — Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced positive results from its once-daily vanzacaftor/tezacaftor/deutivacaftor (the “vanza triple”) program, the most comprehensive Phase 3 pivotal program ever conducted by Vertex for the treatment of cystic fibrosis (CF), a progressive, multi-organ disease caused by dysfunction of the CFTR protein. The Phase 3 program included two randomized, double-blind, active-controlled, 52-week trials, SKYLINE 102 and SKYLINE 103, evaluating the efficacy of vanzacaftor (20 mg)/tezacaftor (100 mg)/deutivacaftor (250 mg) 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 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.
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, M.D., 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.”
“I have been working as a pediatric pulmonologist for more than four decades and have seen first-hand the dramatic impact of CFTR modulators on people with CF, transforming CF from a life-shortening disease to today, where we see the potential for halting the disease before it starts. These results were particularly striking in the pediatric study where 95% of children achieved a SwCl level below 60 mmol/L, the diagnostic cut-off for a positive test for CF, and more than 50% of children achieved a SwCl level below carrier levels where they may see no symptoms of disease at all,” said Bonnie Ramsey, M.D., 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.”
Efficacy Results
In both active-controlled trials SKYLINE 102 and SKYLINE 103 in people with CF ages 12 years and older, the primary endpoint of absolute change from baseline in ppFEV1 through week 24 was met. All patients received TRIKAFTA during a 4-week run-in prior to randomization, and baseline values were measured at the end of the TRIKAFTA run-in. The vanza triple was shown to be non-inferior to TRIKAFTA (SKYLINE 102: LS mean difference of 0.2; 95% CI: -0.7, 1.1; 1-sided P<0.0001 and SKYLINE 103: LS mean difference of 0.2; 95% CI: -0.5, 0.9; 1-sided P<0.0001).
For the first key secondary endpoint, in the trial of people with CF heterozygous for F508del and a minimal function mutation (F/MF) (SKYLINE 102), the absolute mean change from baseline in SwCl through week 24 was ‑7.5 mmol/L for those taking the vanza triple, compared to +0.9 mmol/L for those taking TRIKAFTA, demonstrating a statistically significant and clinically meaningful improvement in CFTR function (LS mean difference of -8.4; 95% CI: -10.5, -6.3; P<0.0001). In the trial of people with CF with other mutations responsive to triple combination CFTRm (SKYLINE 103), the absolute mean change from baseline in SwCl through week 24 was ‑5.1 mmol/L for those taking the vanza triple, compared to -2.3 mmol/L for those taking TRIKAFTA, again demonstrating statistically significant and clinically meaningful improvement in CFTR function (LS mean difference of -2.8; 95% CI: -4.7, -0.9; P=0.0034).
For the second and third key secondary endpoints based on the pooled analysis across SKYLINE 102 and SKYLINE 103, following treatment with the vanza triple, 86% of people with CF across both trials had a SwCl level below the diagnostic threshold of 60 mmol/L through 24 weeks, compared to 77% of people treated with TRIKAFTA (odds ratio 2.21; 95% CI: 1.55, 3.15; P<0.0001). Following treatment with the vanza triple, 31% of people across both trials had a SwCl level below carrier level of 30 mmol/L through 24 weeks, compared to 23% of people treated with TRIKAFTA (odds ratio 2.87; 95% CI: 2.00, 4.12; P<0.0001). Consequently, in these combined trials, there was about a two-times greater likelihood in the odds of achieving a SwCl level below 60 mmol/L for those treated with the vanza triple compared to TRIKAFTA and about a three-times greater likelihood in the odds of achieving a SwCl level below 30 mmol/L for those treated with the vanza triple compared to TRIKAFTA.
In the single-arm, open-label study in children 6 to 11 years old with CF and at least one mutation responsive to triple combination CFTRm (RIDGELINE 105), the vanza triple demonstrated safety, the primary endpoint. Secondary endpoints included evaluation of absolute change in SwCl from baseline through week 24, absolute change in ppFEV1 from baseline through week 24, the proportion of children with SwCl levels of <60 mmol/L through week 24, and the proportion of children with SwCl <30 mmol/L through week 24, among other endpoints. Prior to receiving the vanza triple, all children were on TRIKAFTA for at least 4 weeks, and the baseline values were measured at the end of the 4-week run-in. Children with CF in the study maintained their baseline level of lung function (ppFEV1 of 99.7) with an absolute LS mean change from baseline through week 24 of 0.0 (95% CI: ‑2.0, 1.9) and had an absolute mean change in sweat chloride of -8.6 mmol/L (95% CI: -11.0, -6.3) from baseline levels of 40.4 mmol/L while on TRIKAFTA.
Following treatment with the vanza triple, 95% of children in the study had a SwCl level below 60 mmol/L through 24 weeks (95% CI: 87%, 99%) and 53% of children had a SwCl level below 30 mmol/L (95% CI: 41%, 64%).
Next Steps
Vertex is on track to make global regulatory submissions by mid-2024 including a New Drug Application (NDA) to the Food and Drug Administration and a Marketing Authorization Application with the European Medicines Agency for people with CF ages 6 years and older. The company will use a priority review voucher in the U.S. The priority review voucher entitles the holder to designate an NDA for priority review, which provides an expedited 6‑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.
About the Vanza Triple Phase 3 Program
The Phase 3 program in people with cystic fibrosis ages 12 years and older consisted of two randomized, double-blind, active-controlled 52-week trials, SKYLINE 102 and SKYLINE 103, which evaluated the safety and efficacy of the vanza triple in comparison to TRIKAFTA. SKYLINE 102 randomized and dosed 398 people with CF ages 12 years and older with one F508del mutation and one minimal function mutation (F/MF). SKYLINE 103 randomized and dosed 573 people with CF ages 12 years and older who were homozygous for F508del mutations (F/F), heterozygous for F508del and a gating (F/G) or a residual function mutation (F/RF) or have at least one other mutation responsive to triple combination CFTR modulators and no F508del mutation. All patients received TRIKAFTA during a 4-week run-in prior to randomization, and the baseline values for all endpoints were measured at the end of the TRIKAFTA run-in.
The primary endpoint of both SKYLINE 102 and SKYLINE 103 was the absolute change from baseline in ppFEV1 through week 24, and the primary analysis was non-inferiority of the vanza triple compared to TRIKAFTA. The first key secondary endpoint in SKYLINE 102 and SKYLINE 103 was absolute change from baseline in sweat chloride through week 24 compared to TRIKAFTA; the second key secondary endpoint was the proportion of patients pooled across the two studies, with SwCl below 60 mmol/L through week 24 compared to TRIKAFTA; and the third key secondary endpoint was the proportion of patients pooled across two studies, with SwCl below 30 mmol/L through week 24 compared to TRIKAFTA. All three key secondary endpoints were evaluated in a hierarchical manner and multiplicity controlled for superiority to TRIKAFTA.
A third Phase 3 single-arm, open-label study, RIDGELINE 105, dosed 78 children with CF ages 6 through 11 years and evaluated the pharmacokinetics, safety and tolerability, and efficacy of the vanza triple for 24 weeks, after a baseline established on TRIKAFTA. Children received TRIKAFTA for at least 4 weeks prior to receiving vanza triple, and the baseline values for all endpoints were measured at the end of the TRIKAFTA run-in. The primary endpoint was safety and tolerability. The secondary endpoints were efficacy endpoints and included absolute change in SwCl from baseline through week 24, absolute change in ppFEV1 from baseline through week 24, the proportion of children with SwCl <60 mmol/L through week 24, and the proportion of children with SwCl <30 mmol/L through week 24, among other endpoints.
About vanzacaftor/tezacaftor/deutivacaftor (the “vanza triple”)
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. 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. 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.
Investigational vanzacaftor/tezacaftor/deutivacaftor was granted Fast Track and Orphan Drug Designations from the U.S. Food and Drug Administration for the treatment of cystic fibrosis.
The vanza triple will be subject to a meaningfully lower single-digit royalty obligation, compared to the rate payable on Vertex’s current CF portfolio.
About Cystic Fibrosis
Cystic fibrosis (CF) is a rare, life-shortening genetic disease affecting more than 92,000 people globally. CF is a 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. People with CF must inherit two defective CFTR genes — one from each parent — to have CF, and these mutations can be identified by a genetic test. 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.
Diagnosis of CF is often made by genetic testing and is confirmed by testing sweat chloride (SwCl), which measures CFTR protein dysfunction. The diagnostic threshold for CF is SwCl ≥60 mmol/L, while levels between 30-59 indicate CF is possible and more testing may be needed to make the diagnosis of CF. A SwCl level of <30 mmol/L is seen in people who carry one copy of the CF gene but do not have any manifestation of disease (carriers). Higher levels of SwCl are associated with more severe disease. Restoring CFTR function leads to lower levels of SwCl. SwCl levels below 60 mmol/L are associated with improved outcomes such as better and more stable lung function, fewer pulmonary exacerbations, better quality of life and improved survival. Restoring SwCl levels below 30 mmol/L has long been the ultimate treatment goal for Vertex, as levels below 30 mmol/L are considered normal and are typical of CF carriers who do not have disease.
About Vertex
Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has approved medicines that treat the underlying causes of multiple chronic, life-shortening genetic diseases — cystic fibrosis, sickle cell disease and transfusion-dependent beta thalassemia — and continues to advance clinical and research programs in these diseases. Vertex also has a robust clinical pipeline of investigational therapies across a range of modalities in other serious diseases where it has deep insight into causal human biology, including APOL1-mediated kidney disease, acute and neuropathic pain, type 1 diabetes, myotonic dystrophy type 1 and alpha-1 antitrypsin deficiency.
Vertex was founded in 1989 and has its global headquarters in Boston, with international headquarters in London. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia, Latin America and the Middle East. Vertex is consistently recognized as one of the industry’s top places to work, including 14 consecutive years on Science magazine’s Top Employers list and one of Fortune’s 100 Best Companies to Work For.
Contacts
Investors
[email protected]