Phase III trial of a drug for Cystic Fibrosis

Armanth Marthi, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0SP

Cystic Fibrosis (CF) is the most common fatal genetic disease in Caucasians. It is caused by a mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR) preventing movement of chloride ions to or from epithelial surfaces. In the lungs, this leads to dehydration of apical secretions and symptoms of chronic bacterial infection and inflammation. There are currently 1893 mutations listed in the CFTR mutation database shown to cause the disease, the most common of which is F508 (deletion of phenylalanine at 508), present in 70% of CF sufferers worldwide.

In the NEJM this week, Ramsey et. al. (1) report the results of a Phase 3 randomized, double blind control drug trial in CF sufferers 12 years or older who have the G551D (a glycine to aspartate missense) mutation on at least one CFTR allele. The trial drug, Ivacaftor, is an orally bioavailable potentiator of CFTR channels; increasing the time the activated channels stay open. They showed significant improvement in both primary (an improvement of FEV1 by 10.4% at week 24) and multiple secondary end points (e.g. subject reported respiratory symptoms) in the study population. Progressive loss of lung function and falling FEV1 are associated with increased risk of death in CF and so this measure is a key end-point. The changes reported in this study are additive to changes made by existing therapy as patients in both groups continued their pre-study medications (except hypertonic saline – not regulatory approved in the US). Adverse events were similar in both groups.

This is a considerable step forward in the treatment of cystic fibrosis providing benefits additive to those given by existing therapies, such as nebulised tobramycin for chronic P. aeruginosa infection (improvement from baseline – 12% increase in FEV1 at 20 weeks as compared to placebo). The novel mechanism of action and potentially more compliant oral form of the medication is complementary to current treatments. However, the study is particularly limited by its size (163 subjects in total) and follow-up period as current treatments have greatly slowed the progression of the disease and a longer observation period would be required to assess whether there is sustainable long term benefit.

It is important to consider that this improvement in CFTR function was in individuals with a G551D allele form of the disease, known to manifest as a less severe phenotype and is far less prevalent (3-5%) than the common F508 form. Furthermore, many patients with the same allelic variation at the CFTR locus can have considerably different phenotypes suggesting the role of other genetic and environmental factors. This is hopefully just the beginning of many novel therapies to come.


1. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordoñez C, Elborn JS. A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation. N Engl J Med 2011;365(18):1663-1672.
doi: 10.1056/NEJMoa1105185

Story image from Wikimedia Commons.