July 2015 | Iúil 2015

CF Drug Combination Shows Benefits in Phase III Clinical Trial for Phe508del Homozygotes

Tue, 28 July 15 18:54

Two multi-centred international clinical trials involving patients and clinicians at St Vincent’s University Hospital have demonstrated the benefits of a cystic fibrosis trans-membrane conductance regulator (CFTR) corrector (lumacaftor) and a CFTR potentiator (ivacaftor) combination in patients with cystic fibrosis who are homozygous for a common gene mutation, Phe508del.  The study, published recently in the New England Journal of Medicine, provides an important evidence base for the treatment of this patient population.  Ireland has the highest prevalence of cystic fibrosis in the world and 56% of those with the condition have this particular allele.

Study author, Dr Edward McKone, Consultant Respiratory Physician at St Vincent’s University Hospital and UCD Senior Lecturer at the UCD School of Medicine noted:

“For decades our treatment options have been focused on the complications of cystic fibrosis rather than the cause of the disease. This trial has identified a novel drug combination that targets the cause of CF in the most common genetic subgroup of CF in Ireland. Although the effects on lung function were modest, there was a significant improvement in the number of infections that CF patients suffer from, which is an important outcome measure and one that is likely to directly benefit patients.”

About Cystic Fibrosis

Cystic fibrosis is a life-limiting autosomal recessive disease caused by defective or deficient cystic fibrosis trans-membrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation worldwide with approximately 45% of patients with cystic fibrosis homozygous for this allele.  Ireland has the highest incidence of cystic fibrosis in the world and the prevalence of this mutation in the Irish population is 56%[1].

The Phe508del mutation causes a processing defect that severely reduces the trans-membrane conductor regulator protein at the epithelial membrane and disrupts the ion channel opening for those CFTR proteins that reach the cell surface.  Therapeutic strategies for cystic fibrosis include the provision of a CFTR corrector agent and potentiator therapy which aim to address the underlying cellular processing defect and chloride channel function respectively. 

Clinical Trial

The international consortium involving patients and clinicians at St Vincent’s University Hospital have undertaken two major clinical trials evaluating the efficacy of a CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) combination in patients over 12 years of age who had cystic fibrosis and who were homozygous for this mutation.

The study, published recently in the New England Journal of Medicine, comprised two phase three randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1 ) at week 24.  A total of 1,108 patients were randomised to the treatment options.

In both studies, there were significant improvements in the primary end point in both lumacaftor–ivacaftor dose groups.  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 ((P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor–ivacaftor groups than in the placebo group.  The rate of events leading to hospitalization or the use of intravenous antibiotics was also lower in the drug combination treatment groups.  The incidence of adverse events was generally similar in the lumacaftor–ivacaftor and placebo groups.  The rate of discontinuation due to an adverse event was 4.2% for the treatment versus 1.6% for the placebo control.

This data shows that lumacaftor in combination with ivacaftor provided benefits for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation.

More Information

Published Article:

Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous forPhe508del CFTR. Wainwright et al, N Engl J Med 2015 Jul 16 ; 373 (3) : 220-31 [more]

Dr Ed McKone’s research profile [more]

St Vincent’s University Hospital Respiratory Group [more]

Cystic Fibrosis Registry of Ireland [more]

Cystic Fibrosis Ireland [more]



[1] Cystic Fibrosis Registry of Ireland, 2013 Annual Report.