Orkambi: A New Option for a Narrow Band of Cystic Fibrosis Patients


Review the clinical data behind the FDA's approval of the combination drug Orkambi (lumacaftor/ivacaftor) for select patients with cystic fibrosis.

Review the clinical data behind the FDA’s approval of the combination drug Orkambi (lumacaftor/ivacaftor) for select patients with cystic fibrosis.

The FDA approved Orkambi (lumacaftor/ivacaftor) on July 2, 2015. This approval was based on clinical data reviewed at a May 12, 2015 meeting of the FDA Pulmonary-Allergy Drugs Advisory Committee. Panelists reviewed data recommending approval of the combination of lumacaftor and ivacaftor for treatment of cystic fibrosis (CF) in patients aged 12 years and older.

Importantly, per the proposed indication, use is limited to certain patients with CF who are homozygous for a deletion of a specific amino acid from a critical gene called the cystic fibrosis transmembrane conductance regulator (CFTR). The mutation, known as the F508del, is the most common in the CF population. Of the estimated 30,000 patients in the United States with CF, approximately 8500 patients have the requisite genetic characteristic qualifying them for treatment with the proposed new combination.

One component of the new drug, ivacaftor, was previously approved by the FDA in 2012 under the trade name Kalydeco. Ivacaftor acts as a potentiator of CFTR function. The synergistic medication lumacaftor promotes chloride channel function in a different way—by promoting intracellular processing and trafficking of the CFTR protein. In vitro data suggest that the drug may even alter the errant protein to make it look and possibly function more like wild-type CFTR. The extent to which this effect will translate to a clinical benefit, however, is unknown.

According to panelists, common adverse events approximate symptoms that might normally be expected in patients with CF, with the exception of dyspnea, abnormal respiration, flatulence, and rash, all of which were more common in the placebo group than in the treatment group. Conversely, common adverse events relating to pulmonary exacerbations and declines in pulmonary function tests were slightly more common in patients receiving active treatment than in patients receiving placebo.

Serious adverse events were primarily related to pulmonary exacerbations of CF, as would be expected in this patient population. However, encouragingly, severe pulmonary exacerbations occurred at a lower rate in patients receiving combination therapy (13%) than in patients receiving placebo (24%). Other serious adverse events recorded with the combination hemoptysis, distal intestinal obstruction syndrome, and hepatic encephalopathy; each occurring very rarely (<1% of patients).

Over 24 weeks of therapy, discontinuations due to treatment-related adverse events occurred in 3.3% of patients over each of the 2 placebo-controlled trials, and occurred more frequently in the active treatment groups (4.1%) than in the placebo groups (1.6%).

The medications in Orkambi have been studied together in 2 clinical studies of 24 weeks duration each. Studies were similar in design, and both compared the combination drug with placebo. Patients in each trial were randomized in equal proportions to receive placebo, lumacaftor 600 mg daily with ivacaftor 250 mg every 12 hours, or lumacaftor 400 mg daily with ivacaftor 250 mg every 12 hours. In each of the 2 studies, treatment arms included approximately 180 patients. Investigators assessed changes in forced expiratory volume in 1 second (FEV1) as an indicator of drug efficacy.

On this primary end point, investigators observed a 2.7% to 3% increase in FEV1 with both doses of active drug versus placebo, both of which were statistically significant. Because the higher dose did not appear to increase efficacy, investigators opted to seek approval for the lower dose: lumacaftor 400 mg daily/ivacaftor 250 mg twice daily. Investigators also assessed several secondary end points: relative change on pre/post FEV1, change in body mass index, change in the CFQ-R-respiratory domain score, response rates (defined by a 5% or greater increase in pre/post FEV1), and exacerbation rates. Results on these secondary endpoints did not reveal significant improvements with the combination over placebo.

Compared with the already-approved CF drug ivacaftor, clinical results with the lumacaftor/ivacaftor combination were similar to those observed with ivacaftor alone. Even so, a dual mechanism of action that both potentiates the activity of existing CFTR channels and potentially changes the conformation of defective CFTR to more closely approximate the healthy channel is powerful basic scientific evidence to recommend approval.


  • FDA Approval Letter: Orkambi. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/206038Orig1s000ltr.pdf. Accessed July 2, 2015.
  • FDA Briefing Document NDA#206038. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM446193.pdf. Accessed July 2, 2015.

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