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Vertex Gets FDA Advisory Committee Nod for Kalydeco in CF Patients with R117H Mutation

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Originally published Oct. 24.

NEW YORK (GenomeWeb) – The US Food and Drug Administration's Pulmonary Allergy Advisory Committee voted 13 to 2 in favor of approving Vertex Pharmaceuticals' Kalydeco (ivacaftor) as a treatment for cystic fibrosis in patients six or older who harbor the R117H mutation in the CFTR gene.

Kalydeco is already approved in the US for CF patients six and older who have the G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene. In Canada the drug is available for patients with these markers and the G970R mutation. The drug is not effective in CF patients who are homozygous for the F508del mutation, however.

The drug's currently approved indications enable it to be prescribed to more than 2,600 CF patients with these so-called gating mutations in North America, Europe, and Australia. In order to respond to Kalydeco, patients must carry a mutation that results in an abnormal ion channel but one that still resides in the epithelial cell membrane.

“Other CF patient populations either do not or would not be predicted to benefit from ivacaftor because the causative mutations disrupt transcription of the gene or translation of the CFTR protein to the extent that the ion channel is either absent or is prematurely degraded and, therefore not transported to the epithelial membrane where it normally resides,” The FDA explained in briefing documents to the advisory committee.

While the R117H residual function mutation falls in another category of CFTR mutations than Kalydeco's currently approved targets, it also results in a disrupted ion channel, but one that is still present in the epithelial cell membrane. Therefore, this suggests that patients with this mutation could benefit from Kalydeco. Patients with R117H comprise 3 percent of the CF population – approximately 500 CF patients in the US, Vertex estimated.

The agency had held several meetings with Vertex to discuss its clinical program for Kalydeco in the R117H mutated CF population. In March this year, the company shared summary data from Study 110, which the agency determined didn't meet its primary endpoint. Subsequently, the company considered pursuing an indication in adult CF patients, but in the end chose to pursue approval for CF patients with the R117H mutation who are six years or older.

The supplementary NDA that the advisory committee discussed included data from Study 110, which failed to show absolute change in percent FEV1 from baseline through a 24-week treatment period. However, “it is notable that all patients demonstrated a significant (about 35-40 percent from baseline) reduction in sweat chloride, a pharmacodynamic endpoint reflective of CFTR ion channel activity,” the FDA said in review documents to the advisory committee.

Additionally, the “adult subpopulation appeared to demonstrate a positive response to ivacaftor treatment, reflected by both a 5 percent increase in FEV1 and an improvement over placebo (12 points) in respiratory symptoms as measured by the CFQ-R respiratory domain patient reported outcome measure,” the FDA said.

Data from another trial, Study 112, which enrolled patients 18 years or older from Study 110 after a washout period, yielded statistically significant response as measured in terms of the absolute change in percent predicted FEV1 in those who received placebo then Kalydeco and those who received Kalydeco followed by Kalydeco.

Although most advisory committee members supported approval of the drug in this patient subset, their opinion was more nuanced when voting just on whether the efficacy data of Kalydeco supported the indication of CF patients 6 years or older with R117H mutations. On this question, nine panel members voted in favor and six voted against.

According to Vertex, the agency is slated to decide on the market approval for Kalydeco in this new patient subgroup by Dec. 30. The agency isn't required to decide in line with its advisory committee members, but historically has followed their advice.

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