FDA Advisory Panel Questions Clinical Meaningfulness of Vertex’s Cystic Fibrosis Drug Combo

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FDA concludes Orkambi demonstrates a clinical benefit over placebo, but questions the magnitude of the improvement.


On May 12, 2015, FDA voted 12–1 in favor of approval of Vertex’s Orkambi for the treatment of cystic fibrosis, despite some doubts about the drug combination’s overall efficacy compared with existing treatments. The panel unanimously supported the safety of Orkambi.

FDA determined in a briefing that while there was a statistically meaningful benefit to Vertex’s combination therapy of lumacaftor and ivacaftor (Orkambi) for the treatment of cystic fibrosis (CF) in patients age 12 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the agency questioned the clinical meaningfulness of the proposed combination. Lung function with Orkambi was shown to improve by a range of 2­–3%, which is considered statistically significant when compared with placebo. FDA noted in the briefing that the superiority of the combination regimen vs. ivacaftor (branded as Kalydeco) alone “could not be established for any of the endpoints.” Comparative efficacy data comparing Kalydeco and Orkambi could be collected post-approval if necessary, the panelists determined.

Vertex also did not test lumacaftor as a monotherapy, leading some to question whether lumacaftor had any added benefit at all. Vertex said the reason for not testing lumacaftor alone was because it was "unlikely to reveal significant benefit," as prior studies indicated there was no clinical benefit seen in this arm after 16 weeks and because there was a "low response in vitro to lumacaftor alone in airway epithelial cells from patients homozygous for the F508del-CFTR mutation."


Despite the issues raised by FDA, the advisory panel backed the release of Orkambi. Some of the panelists argued that while it was unclear if the patients with the F508del mutation would have a similar response to Kalydeco as a monotherapy, 12 panelists voted in favor of approval, with just one “no” vote. FDA will make a final decision on Orkambi by July 5, 2015.

Nearly half of CF patients have the F508del mutation. Kalydeco alone is indicated in the United States for those who have the G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene. In 2014, Kalydeco accounted for $464 million, or 80%, of Vertex's total revenue of $580 million. In anticipation of Orkambi’s approval, Vertex plans to erect a more than $30-million-dollar continuous manufacturing plant to support the production of lumacaftor and ivacaftor.

Source: FDA