GAITHERSBURG, MD. (FRONTLINE MEDICAL NEWS) – A fixed-dose combination of ivacaftor, already approved for a cystic fibrosis indication, and lumacaftor will likely be the first drug treatment approved for the most common type of cystic fibrosis, based on a Food and Drug Administration advisory panel’s near unanimous support for approval.

At a meeting May 12, the FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 12-1 that the data on the safety and efficacy of the fixed-dose combination of ivacaftor, 250 mg, and lumacaftor, 400 mg, administered twice a day, support approval for treating patients aged 12 years and older with CF who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. About half of patients with CF are F508del homozygous, and if approved, this would be the first treatment that addresses the underlying cause of CF in these patients, according to Vertex Pharmaceuticals, the manufacturer of both drugs.

Lumacaftor “facilitates the processing and trafficking of F508del-CTFR to increase its amount at the cell surface,” while ivacaftor “potentiates the channel-open probability of F508del-CTFR delivered to the cell surface by” lumacaftor, according to Vertex. Ivacaftor ( Kalydeco) is a CFTR potentiator approved in January 2012 for treating patients with the G551D mutation, who represent about 4% of patients with CF – its indications have been expanded since that time to include other CFTR gene mutations.

In two phase III studies, the proposed dose and another fixed-dose combination of the two drugs were compared with placebo for 24 weeks in about 1,100 patients homozygous for the F580del mutation who were aged 12 years and over. At 24 weeks, the absolute change in percent-predicted forced expiratory volume in 1 second (ppFEV1) over placebo, the primary efficacy endpoint, was a mean of 2.6% and 3.0% among those treated with the 400 mg/250 mg fixed dose every 12 hours, which were statistically significant changes. In an extension study, the effect was sustained through 48 weeks. There also were reductions in pulmonary exacerbations, improvements in body mass index, and CFQ-R improvements – secondary endpoints that favored the treatment arms, according to the company.

The most common adverse events were typical for patients with CF and similar between the treatment groups. There was an imbalance in respiratory adverse events affecting those on the drug combination (23% vs. almost 14% among those on placebo), but most occurred early in treatment, were generally mild to moderate, and resolved without stopping treatment. Those on the drug combination also had more liver-related serious adverse events (three cases among those on the proposed dose and none among those on placebo).

At the time the phase III studies were being planned, the FDA and the company agreed that an ivacaftor monotherapy arm was not needed and that demonstration of the combination’s superiority over placebo would be adequate to show efficacy. In the phase III studies, however, the combination effect was smaller than expected, and there was no substantial evidence indicating that the efficacy of the combination was greater than that of ivacaftor alone, an issue raised by the FDA reviewers.

Despite the lack of monotherapy arms and the inability to determine the contribution of the individual components to the treatment effects, the panel agreed that the drug combination had been shown to be efficacious and voted 13-0 that the data supported the safety of treatment. Panelists commented that the risks appeared to be minimal and that patients could be monitored for liver function test abnormalities and respiratory function, which were manageable.

Voting in favor of approval, pediatric pulmonologist Dr. Robert Castile, professor of pediatrics at Ohio State University, Columbus, said he was particularly impressed with the lack of decline in FEV 1 over 48 weeks among those treated with the combination “and probably more impressed over the steady increase in BMI over the same period.” He added that he balanced those benefits with what he considered minimal risks with the drug with appropriate monitoring.

If the FDA grants approval, Vertex plans to market the combination product as Orkambi. The FDA usually follows the recommendations of its advisory panels. Panelists were cleared of conflicts before the meeting.

About 30,000 people in the United States have cystic fibrosis, about half of whom are homozygous for the F508del, the most common CF mutation, according to the FDA.


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