Promising early stage clinical trial results for three next-generation CFTR modulator therapies that target the underlying defect in cystic fibrosis were announced today. The findings are the first to demonstrate the potential of next-generation modulators to treat the underlying cause of CF in people with a single F508del CFTR mutation. The therapies included in the studies combine tezacaftor, ivacaftor, and a next-generation modulator.

The studies, led by Vertex Pharmaceuticals Inc., highlight the potential of next-generation combination therapies to be significantly more effective than current FDA-approved modulators and to also benefit more people with CF than ever before. Data from the trials, along with results from another study expected to begin later this year, will help Vertex decide which next-generation modulator candidate or candidates to move forward into Phase 3 studies in early 2018.

The two Phase 2 studies and one Phase 1 study examined the safety and effectiveness of three different compounds -- VX-440, VX-152, and VX-659 -- in combination with ivacaftor and tezacaftor (VX-661) in individuals with one F508del CFTR mutation and one minimal function mutation. (“Minimal function” refers to mutations that do not make meaningful CFTR protein. These mutations include nonsense mutations, also known as “stop” or “x” mutations.) Participants in the trials showed striking improvements in lung function, comparable to ivacaftor (Kalydeco®) in the original G551D trials. They also experienced improvements in their sweat chloride, and the triple combination was generally well tolerated by patients in the studies.

Data also showed significant improvement in lung function in participants with two copies of the F508del mutation when VX-440 and VX-152 were added to tezacaftor and ivacaftor, compared to treatment with only tezacaftor and ivacaftor.

“We have been working for many years to develop therapies that could benefit people with CF who have a single F508del mutation, and the results announced by Vertex today are a significant step toward that goal,” said Michael Boyle, M.D., senior vice president for therapeutics development for the Cystic Fibrosis Foundation. “This is an exciting moment for the CF community, and we are pleased to play a role supporting the upcoming studies through our clinical trials network and look forward to this next stage which we hope will confirm these very promising results.”

He continued, “Clinical trials play a critical role in continuing to advance these therapies, and we commend all of the participants who volunteer, without whom new advances, such as the ones announced today, simply wouldn't occur.” 

Cystic Fibrosis Foundation Therapeutics Inc., the CF Foundation's nonprofit drug discovery and development affiliate, provided $150 million in research funding to Vertex to support its pursuit of treatments that address the underlying defect in CF, including $75 million to develop next-generation candidates currently in clinical development.

“Today's announcement brings us even closer to reaching our mission, and our community should feel great pride in the tremendous role they have played in achieving this milestone. The dreams of the parents who first started the CF Foundation more than 60 years ago are being realized step by step, and we are inspired to continue our work until all people with CF have the chance they deserve for longer, healthier lives,” said Preston W. Campbell, III, M.D., president and CEO of the Cystic Fibrosis Foundation. “We are grateful to the many people with CF and their families who participated in these clinical studies, as well as to the Vertex team. Based on these results we have more hope than ever that disease-modifying combination treatments will benefit more than 90 percent of the CF community. We will not rest until 100 percent of our population has the cure they need.”

Summary of Results:

• In the Phase 2 clinical trial of VX-440 in combination with ivacaftor and tezacaftor (VX-661), the 18 participants in the study with a single F508del mutation who received the 600 mg dose of VX-440 had a 12 percent increase in lung function, substantial improvement in their quality of life, and a decrease in sweat chloride of 33.1 after four weeks of treatment. The 20 participants in the study with two copies of the F508del mutation who received the 600 mg dose of VX-440 had a 9.5 percent increase in lung function and a decrease in sweat chloride of 31.3 after four weeks of treatment.
• In the Phase 2 clinical trial of VX-152 in combination with ivacaftor and tezacaftor (VX-661), the 10 participants in the study with a single F508del mutation who received the 200 mg dose of VX-152 had a 9.7 percent increase in lung function and a decrease in sweat chloride of 14.1 after two weeks of treatment. The 10 participants in the study who have two copies of the F508del mutation who received the 200 mg dose of VX-152 had a 7.3 percent increase in lung function and a decrease in sweat chloride of 20.9 after two weeks of treatment.
• In the Phase 1 clinical trial of VX-659 in combination with ivacaftor and tezacaftor (VX-661), participants in the study with a single F508del mutation who received the 120 mg dose of VX-659 had a 9.6 percent increase in lung function and decrease in sweat chloride of 41.6 after two weeks of treatment.

For additional information regarding the results of these clinical trials, including the safety and efficacy outcomes, please see the Vertex press release.