Vertex Pharmaceuticals Inc. is ending a phase III study testing VX-661 with the company's already-approved Kalydeco (ivacaftor) in a hard-to-treat subgroup of cystic fibrosis patients (CF) after learning that the combination failed to deliver a pre-specified improvement in lung function.

Despite progress on a broader phase III program in CF expected to underpin filing of an FDA new drug application for the combo in the second half of 2017, Vertex shares (NASDAQ:VRTX) fell $2.48 to close at $100 on Tuesday.

The trial to be wound down tested VX-661, a corrector of the CF transmembrane regulator (CFTR) trafficking defect, with ivacaftor, a CFTR stimulator, in about 150 people with one copy of the F508del mutation and one copy of a mutation that results in minimal CFTR protein function (F508del het/min). While no safety concerns were identified — good news for the program overall — a planned interim futility analysis at the conclusion of the first of the study's two parts led members of an independent data safety monitoring board to recommend stopping the trial.

Vertex did not outline the criteria it had established for determining futility of the study, though Jeff Chodakewitz, the company's chief medical officer, did speak to it briefly during a recent earnings call. "There's a certain tension as you make a decision based on partial information," he said. "We want to try, if the drug is not benefiting patients, to stop the trial. Conversely, there is uncertainty and we also want to be careful about not missing a positive result. Therefore, there always is a certain overlap. And what we tend to do is then say it's clearly not working. We stop."

Patients from the first part of the study who enrolled in the long-term extension study — part two — will be transitioned off the combination.

If not two, then three

Following the futility decision on Tuesday, Chodakewitz said the results "suggest that a triple combination regimen may provide this group of people with CF the best chance at obtaining a meaningful benefit," referring to the company's plans to begin the first study of a next-generation corrector together with VX-661 and ivacaftor in F508del het/min patients later this year. The decision will follow the arrival of data from ongoing phase I studies of the triplet in healthy volunteers. Neither Chodakewitz nor Vertex CEO and President Jeff Leiden were available for comment on Tuesday.

Analysts universally said the doublet's failure to help F508del het/min patients was no big surprise in light of low odds for its success and, like Vertex, looked to the triplet as a potential ticket to better results for those patients. "We believe adding a second corrector is the critical part of improving efficacy, as they have shown 100 percent to 200 percent better data in assays," wrote RBC Capital Markets analyst Michael Yee.

Vertex has yet to say which of two next-gen CFTR correctors in its pipeline that it will include in a phase II study of triplet, VX-152 or VX-440. But in vitro data the company has published in the past has shown enhanced CFTR function in cells with triple combination therapy vs. Orkambi.

Both of the next-gen correctors are designed to further improve processing and trafficking of the CFTR protein to the surface of human bronchial epithelial cells, beyond that observed with a single corrector combined with ivacaftor, which may enable increased CFTR chloride transport, a measure of the function of the CFTR protein at the cell surface.

More studies underway

Despite the setback in F508del het/min CF patients, Vertex is moving ahead with tests of the combo in other subgroups. It completed enrollment for a 500-patient phase III study in people with two copies of the F508del mutation, a group for which it expects an ivacaftor + VX-661 combo may have an improved benefit-risk profile compared to Orkambi. Results from the trial, which will study 24 weeks of treatment with the combination, are expected in the first half of 2017. (See BioWorld Today, March 7, 2016, and April 29, 2016.)

In September, the company expects to complete enrollment in a 200-patient phase III study in people with one F508del mutation and one residual function mutation. The crossover study includes two eight-week dosing periods, separated by an eight-week washout period. In addition to the combination arm, it also includes ivacaftor monotherapy and placebo arms. Data from the study are expected in the first half of 2017.

"This is important as it could convert patients from old Orkambi (ivacaftor + lumacaftor) into new '661 doublet due to better tolerability and safety as well as bring back patients into the market who had previously discontinued Orkambi," wrote Yee.

By late 2016 or early 2017, enrollment is also expected to be complete for a study designed to evaluate VX-661 in combination with ivacaftor in people with gating mutations that have been shown to be responsive to ivacaftor alone. The hypothesis there is that the combo may provide enhanced clinical benefits over ivacaftor monotherapy. The study is expected to enroll approximately 200 patients and is evaluating eight weeks of treatment with VX-661 in combination with ivacaftor.

Vertex has patents in the U.S. and European Union covering the composition of matter of VX-661 that expire in 2027 and 2028, respectively, subject to potential extensions.