The Safety and Efficacy of ORKAMBI (lumacaftor-ivacaftor) and the Next Steps In Improving the Drug

The New England Journal of Medicine recently published findings regarding two, multinational, phase 3 studies on the administration of lumacaftor (VX-809) in combination with ivacaftor (VX-770; kayldeco). The study, titled, “Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR,” demonstrated the safety and efficacy in CF patients with two copies of the F508del mutation.

Cystic fibrosis is a complex, multi-organ disease that results from one of nearly 2,000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and are classified into six categories based on their effect on the protein.

The F508del mutation is the most common in those with CF with nearly 50 percent of patients who are homozygous (two copies) and over 90 percent that have at least one copy. The complex, multifaceted F508del mutation causes the CFTR protein to fold improperly, which results in only a fraction of the protein reaching the cell surface. The small amount of protein that does insert into the membrane has increased difficulty in opening and allowing the flow of chloride across the cell.

The high occurrence of the F508del mutation in the CF population makes it an ideal drug target. Vertex Pharmaceuticals has developed an oral drug, orkambi, which is a combination of lumacaftor and ivacaftor. The two drugs work coordinately to alleviate the defect of the mutation in two steps. Lumacaftor functions in the first step as a corrector, interacting with the CFTR protein to allow it to fold properly. This then allows a greater proportion of the protein to insert in the cell membrane. Ivacaftor then works as a potentiator to increase the probability that the CFTR will remain open on the cell surface.

The study published in the New England Journal of Medicine used 1,108 CF patients to test the safety and efficacy of using this drug combination. The study reported “the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0 percentage points,” and the “rate of pulmonary exacerbations was 30 to 39% lower in lumacaftor-ivacaftor groups than in placebo groups.”

The study marks a significant step in the progress of CF care. Orkambi will be the second medication which directly targets the underlying mutation of CF if approved by the FDA in the beginning of July. Despite the proven benefit of the combination drug there is still great improvements that can be made to increase its efficacy.

Pamela Davis in an editorial published in the New England Journal of Medicine draws attention to the lower improvements in the combination therapy noting that, “a critical interaction between ivacaftor and lumacaftor has been reported in two laboratory studies. In cell-culture models that express Phe508del CFTR treated with lumacaftor, prolonged exposure to ivacfaftor interferes with the therapeutic effect of lumacaftor.” She continues highlighting that, “by 6 hours after exposure to the drug combination, 40% less protein escaped from the endoplasmic reticulum in the cultured cells, and there was concomitantly less chloride transport activity than was observed immediately after application of the drug.”

In one of the articles cited by Davis, titled, “Some Gating Potentiators, Including VX-770, Diminish ∆F508-CFTR Functional Expression,” the authors conclude with a comment on the interaction between ivacaftor (VX-770) and the CFTR protein. “Our results suggest that VX-770, as well as most of the available investigational potentiators, impairs the biochemical stability of ∆F508-CFTR and other class II processing mutations.”

These studies bring to light the possibility that a drug interaction may be at play preventing maximal gains in lung improvement. The studies, although insightful to a possible interaction, were conducted in vitro, outside of a living system, and their results require further confirmation.

Although continued work is required to improve drugs directed toward the F508del mutation, Davis optimistically concludes, “This is the beginning of effective therapy for cystic fibrosis associated with the most common mutant form of CFTR. With further drug development to avoid drug–drug interactions, even the challenging Phe508del CFTR mutation will almost surely come under excellent therapeutic control.”