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With Positive Trial Data, Vertex to Seek Approval for CF Drug in New Genetically Defined Population

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Based on promising results from a late-stage trial, Vertex Pharmaceuticals is hoping to expand the indication of its cystic fibrosis drug Kalydeco (ivacaftor) in other genetically defined patient populations.

The company this week released preliminary data from a Phase III crossover study investigating Kalydeco monotherapy in approximately 40 patients ages six years and older with at least one copy of a non-G551D gating mutation. The study met its primary endpoint and demonstrated that Kalydeco significantly improved lung function compared to placebo in CF patients with a gating mutation other than G551D.

Patients in the trial received Kalydeco or placebo for eight weeks, followed by a four-week washout period. After this, those in the Kalydeco arm were switched to placebo, and those in the placebo group received Kalydeco for eight weeks. At 20 weeks, researchers assessed how Kalydeco impacted the patients' ability to exhale compared to placebo – measured as absolute change from baseline in percent predicted FEV1. After the crossover period, all patients received Kalydeco from week 20 to week 36.

"In this study, the mean absolute treatment difference in percent predicted FEV1 between treatment with [Kalydeco] and placebo was 10.7 percent and the mean relative treatment difference in percent predicted FEV1 was 14.2 percent through the eight-week treatment period," Vertex said in a statement. "The mean absolute and relative percent predicted FEV1 improvements during [Kalydeco] treatment (within-group) were 7.5 percent and 10.8 percent, respectively." All the results were statistically significant, the company said.

Additionally, Kalydeco significantly improved weight gain and showed better patient reported quality of life based on the Cystic Fibrosis Questionnaire Revised. Vertex will present full data from this Phase III trial in the second half of this year.

Around the same time, based on the success of this trial, Vertex plans to submit a supplemental New Drug Application in the US and a Marketing Authorization Application variation in Europe "for the use of [Kalydeco] monotherapy in people with CF ages six and older who have at least one non-G551D CFTR gating mutation," the company said in a statement.

The US Food and Drug Administration approved Kalydeco in early 2012 for CF patients six and older who have at least one copy of the G551D mutation in the CFTR gene. The drug received approval from European regulators later that same year (PGx Reporter 8/1/2012).

Vertex estimates that approximately 2,000 people have at least one copy of G551D, a so-called gating mutation in the CFTR gene. Mutations in the CFTR gene result in defective or missing proteins that cause CF, a disease that is characterized by a buildup of sticky mucus that becomes infected and hinders breathing.

CFTR encodes the chloride channel that transports ions across cellular membranes. When a person has a copy of the G551D gating mutation, it hinders this channel's ability to use ATP to transport ions. Kalydeco is a CFTR "potentiator," in that it helps keep the protein channels open.

There are more than 1,800 mutations in CFTR that researchers have found to be involved in CF. According to Vertex, approximately 400 CF patients six years and older have at least one gating mutation other than G551D.

Beyond this study involving non-G551D gating mutations, Vertex is looking to expand the indication of Kalydeco as a single agent in CF patients six years and older with at least one copy of the R117H mutation; and in children between ages two to five with gating mutations, including G551D mutations.

Data from the R117H mutation study is slated for release later this year, and Vertex plans to file an sNDA in this patient subset early next year. Approximately 3 percent of CF patients harbor R117H mutations, according to a Vertex spokesperson.

A 24-week study of Kalydeco involving two-to-five year olds with CF and gating mutations is slated for completion in mid-2014. Around 1 percent of CF patients in this age group have a gating mutation.

The Vertex spokesperson also noted that up to 10 percent of CF patients have a "residual function" mutation, and the company is in the midst of a Phase II proof-of-concept trial studying the impact of Kalydeco in this patient subset.

"Taken together with the 2,000 eligible patients who have the G551D mutation and the 400 eligible patients who have another gating mutation, this represents between 10-15 percent of people with CF worldwide, who we believe may be able to be treated with [Kalydeco] monotherapy," the Vertex spokesperson said.

Vertex is also investigating Kalydeco as a combination treatment for CF in several trials.

With a $75 million investment from the Cystic Fibrosis Foundation, Vertex is studying Kalydeco in combination with VX-809 in cystic fibrosis patients with the F508del mutation in two Phase III trials initiated earlier this year. VX-809, dubbed a CFTR "corrector," helps CFTR proteins reach the cell surface (PGx Reporter 5/23/2012).

In earlier Phase II trials, the combination of VX-809 and Kalydeco significantly improved lung function in those with two copies of the F508del mutation. The FDA has awarded Breakthrough Therapy Designation to the Kalydeco/VX-809 regimen, which will likely help speed up the development of the treatment. The company is planning to submit an NDA for the combination drug in this patient subset with the FDA next year.

In the Phase III studies, TRAFFIC and TRANSPORT, researchers are enrolling a total of 1,000 patients ages 12 and older with two copies of the F508del mutation. Study participants will be randomized to three arms: two arms will be the combination regimen providing VX-809 at different doses and a third placebo arm. The primary endpoint will look at lung function in each arm through 24 weeks of treatment.

Vertex is also studying Kalydeco/VX-809 in children between ages six to 11 who have two copies of the F508del mutation, as well as in people with one copy of the mutation.

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