Ivacaftor (Kalydeco) in combination with lumacaftor for people with two F508del.

In May 2015 the results of the latest studies into Orkambi, the combination of ivacaftor (Kalydeco) and lumacaftor in people who have two copies (homozygous) of the F508del mutation was published in the prestigious New England Journal of Medicine (NEJM).  Two clinical trials found that the combination of the two drugs produced significant improvements in lung function and weight gain. 

Furthermore this Phase III data showed a 30+% reduction in the number of pulmonary exacerbations (infections & hospitalisations) experienced by trial participants.

These results have been heralded as positive and great news in the quest to produce drugs that tackle the underlying cause of CF. However the improvements this combo produces are not of the same magnitude as those seen in people with a G551D mutation taking Kalydeco alone. 

Accompanying the research paper in the NEJM is an editorial by Pamela B. Davis, MD, PhD, which examines the results in the context of other developments in th treatment and management of cystic fibrosis in recent years. 

“The forced expiratory volume in 1 second (FEV1) increased by only about 3 percentage points, as compared with 11 percentage points with ivacaftor alone in patients with the Gly551Asp mutation …approximately the same relative improvement was seen when inhaled DNase was introduced into the cystic fibrosis treatment armamentarium, and greater improvement, about 10% of baseline FEV1, was seen with inhaled tobramycin,7 although neither drug addresses the basic defect in the protein.” 

The more modest results have largely been attributed to the interaction of the two drugs. While the G551D mutation is predominantly a gating issue, where the release of the CFTR protein from cells is disrupted, F508del mutation has the added problem that the protein are not developing properly within the cell and unable to get to the surface for release. Thus it is considered a traffic and transport problem and a combination of therapies was proposed to tackle the complexity. But getting the balance right, in conjunction with other CF medicines, still appears to be difficult.

Davis hypothesizes that “More effective treatment may require an individualized combination of doses rather than a single, fixed-dose combination.”  


Davis PB, Editorial: Another Beginning for Cystic Fibrosis Therapy, NEJM  May 17, 2015 

Wainwright CD, Elborn JS, et al  Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR  NEJM May 17, 2015