#NACFC2018 — Vertex Presents Latest Clinical Data on CFTR Modulators

Vertex Pharmaceuticals’ VX-659 or VX-445 in combination with Kalydeco (ivacaftor) and tezacaftor (VX-661) can improve the lung function of patients with cystic fibrosis (CF) with one or two copies of the CFTR F508del mutation, Phase 2 data shows.

Updated results of the studies were discussed in two oral presentations at the 32^nd North American Cystic Fibrosis Conference held recently in Denver, and were also published in the The New England Journal of Medicine.

The reports are titled “VX-659–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles” and “VX-445–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles.”

The Phase 2 trial (NCT03224351) evaluated the oral VX-659 triple combination in 92 CF patients with two copies of the F508del mutation or one F508del and one minimal function (MF) mutations. In a second Phase 2 trial (NCT03227471), researchers evaluated the effects of combining Vertex’s VX-445 with tezacaftor and Kalydeco in 93 adults with CF also carrying two copies of the F508del mutation or F508del–MF mutations.

In each study, participants were randomly assigned to receive the triple therapy or a placebo, and some patients with two F508del mutations received dual therapy with tezacaftor and Kalydeco for up to 29 days.

The first improvements in lung function, assessed through a change in percent predicted forced expiratory volume in one second (ppFEV₁), were noted after 15 days of treatment with either the VX-659 or VX-445 triple combination. This positive effect was sustained until the end of the four-week trials.

VX-659 triple treatment was shown to improve ppFEV₁ by up to 13.3% in patients with F508del-MF mutations. In patients with two copies of the F508del mutation, who were already taking tezacaftor plus Kalydeco, the addition of VX-659 further increased ppFEV₁ scores by 9.7%. The higher the ppFEV₁ score, the better the patient’s lung function.

Similarly, four weeks of treatment with the triple VX-445 combination proved beneficial for CF patients by increasing ppFEV₁ scores by 13.8% in F508del-MF patients and 11% in  F508del-F508del patients over initial values.

The positive effects of these new approaches also included a significant decrease in sweat chloride levels (high sweat chloride levels are a sign of CF), and an improvement in the Cystic Fibrosis Questionnaire-Revised Respiratory Domain score (CFQ-R RD).

“Since the discovery of CFTR modulators, we have envisioned highly effective CFTR modulation therapy that could modify the progression of the disease for all CF patients,” Steven M. Rowe, MD, co-chair of Vertex’s triple combination steering committee and director of the Cystic Fibrosis Research Center at the University of Alabama at Birmingham, said in a press release.

“These impressive results showing marked improvements in lung function and a substantial reduction in sweat chloride in patients with one or two F508del mutations demonstrate we are an important step closer towards achieving that goal,” he said.

“The results from these two studies are truly exciting because they represent the potential for these regimens to provide significant clinical benefits for even more people with CF,” said Jennifer Taylor-Cousar, MD, also co-chair of Vertex’s triple combination steering committee.

An assessment of cells collected from the airways of CF patients also showed that these triple combo therapies enhanced production of functional CFTR protein, with increased efficiency of chloride transport (the molecular mechanism impaired in CF). These preclinical results provide further support for the therapeutic activity of these investigational treatments.

The combo therapies are now being explored in two Phase 3 clinical programs in the same patient populations: the ECLIPSE program assessing the VX-659/tezacaftor/Kalydeco combo (NCT03447249 and NCT03460990), and the AURORA program for VX-445/tezacaftor/Kalydeco (NCT03525444 and NCT03525548).

At the NACFC event, researchers also presented the latest clinical results on the use of Kalydeco in CF infants between 6 and 12 months old.

The ongoing Phase 3 ARRIVAL trial (NCT02725567) enrolled 17 infants who had CFTR gating mutations — including G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, and G1349D — or the R117H mutation. They were treated with Kalydeco for 24 weeks.

The treatment was generally safe and well-tolerated, with only mild to moderate adverse events reported, in line with the safety profile noted in adult studies.

Kalydeco treatment led to a significant reduction in mean sweat chloride levels from 101.5 mmol/L at the beginning of the study to 43.1 mmol/L, which is below the commonly used threshold of 60 mmol/L to diagnose CF.

Additionally, the toddlers had increases in fecal elastase and reductions in immunoreactive trypsin or trypsinogen, lipase, and amylase enzymes levels, suggesting the treatment offered a pancreatic benefit.

These findings were discussed in the poster presentation, “Ivacaftor Treatment in Patients 6 to < 12 Months Old with a CFTR Gating Mutation: Results of a Phase 3, Two-Part Single Arm Study.”

“The data we are presenting at this year’s Conference reinforce our belief that treating the underlying cause of CF early in life may modify the course of this disease, and demonstrate the rapid progress we are making toward our goal of developing a single medicine that will treat the underlying cause of CF in up to 90% of people with this devastating disease,” said Reshma Kewalramani, MD, executive vice president and chief medical officer at Vertex.

These most recent Phase 3 results are expected to support Vertex’s request for marketing approval of Kalydeco to the U.S. Food and Drug Administration and European Medicines Agency to treat children between the ages of 6 and 12 months later this year.

The ARRIVAL trial is now evaluating the safety and efficacy of Kalydeco in infants younger than 6 months.

Other studies presented at NACFC also provide further insights on the benefits of Vertex’s approved therapy Symdeko (tezacaftor/ivacaftor and ivacaftor).

In two poster presentations (Poster 308 and 309), “Effects of Tezacaftor/Ivacaftor Treatment in Patients with Cystic Fibrosis and F508del/F508del-CFTR: Patient-Reported Outcomes in a Phase 3 Randomized, Controlled Trial” and “Effects of Tezacaftor/Ivacaftor Treatment in Patients Heterozygous for F508del-CFTR and a Residual Function Mutation: Patient-reported Outcomes in a Phase 3 Randomized, Controlled Trial,” researchers reviewed the views of CF patients on the impact of Symdeko during the Phase 3 EVOLVE (NCT02347657) and EXPAND (NCT02392234) studies.

Patient-reported data revealed that treatment with Symdeko could improve the health outcomes of CF patients older than 12 with two copies of the F508del mutation or one F508del plus one residual function (RF) mutation. These included positive changes in respiratory symptoms, as well as in health perceptions, vitality, physical functioning, and treatment burden.

In addition, post-hoc analysis of clinical data from the EVOLVE, EXPAND, and the ongoing EXTEND trials (NCT02565914) further demonstrated that treatment with Symdeko can effectively promote significant improvements in breathing capacity and reduce airway resistance in these patients.

This was reported in the poster, “Retrospective Analysis of Physiological Response Patterns to Tezacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for F508del-CFTR or Heterozygous for F508del-CFTR and a Residual Function Mutation” (Poster 135).

Furthermore, results from two observational studies, one conducted in France and the other in the U.S., provided real-word data demonstrating the safety and effectiveness of Kalydeco in treating CF patients.

Presenting data in pediatric, adolescent, and adult patients, the studies showed the clinical benefits of Kalydeco are consistent with those reported in controlled clinical trials, with improvements seen in lung function, weight, and rate of pulmonary exacerbations.

The data, shown in posters “Real-World Outcomes in Pediatric, Adolescent and Adult Patients Treated with Ivacaftor: 2016 Us Registry Analyses” (Poster 22), and “Clinical Effectiveness from the First Interim Analysis of the Brio Study: an Observational Study of Cystic Fibrosis Patients Treated with Ivacaftor in France” (Poster 34), continue to support the potential of Kalydeco as a disease-modifying therapy for CF.