Ivacaftor (Kalydeco): A treatment of cystic fibrosis for patients with G551D mutation in the CFTR gene

Cystic fibrosis (CF) is a disorder affecting the lungs and other organs that is caused by mutations in the gene encoding the CFTR protein. CF affects about 30,000 people in the United States and is the most common fatal genetic disease in the Caucasian population. On January 31, 2012, FDA approved ivacaftor (Kalydeco) for the treatment of CF in patients aged 6 years and older who have a G551D mutation in the CFTR gene. It is estimated that about 4% of those with CF, or roughly 1,200 people, have the G551D CFTR mutation. Of note, ivacaftor is not effective in CF patients with the F508 mutation in the CFTR gene, the most common mutation resulting in CF.

Efficacy. Ivacaftor's efficacy was evaluated in two 48-week, placebo-controlled clinical trials involving 213 patients with the G551D mutation. One trial evaluated patients aged 12 years and older, and the other evaluated patients between 6 and 11 years of age. In both studies, ivacaftor 150-mg tablets taken twice daily with fat-containing food (along with their other prescribed CF therapies) resulted in significant and sustained improvement in predicted pre-dose FEV₁ at 24 weeks (mean absolute change from baseline: 10.6 percentage points, P<.0001 in trial 1 and 12.5 percentage points, P<.0001 in trial 2). These changes persisted through 48 weeks and were observed regardless of age, disease severity, sex, and geographic region. Patients treated with ivacaftor also demonstrated significant reductions in the risk of pulmonary exacerbations and CF symptoms (in trial 1 only), and were associated with gain in body weight (2.7–2.8 kg at week 48). Ivacaftor was not found efficacious in CF patients with 2 copies of the F508 mutation in the CFTR gene.

Safety. The most common adverse drug reactions associated with ivacaftor (occurring ≥8% of patients with CF who have a G551D mutation in the CFTR gene) were headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, and dizziness. During 48-week, placebo-controlled clinical trials, the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 times the upper limit of normal (ULN) was 2%, 3%, and 6% in ivacaftor-treated patients and 2%, 2%, and 8% in placebo-treated patients. Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve, and ivacaftor should be interrupted in patients with ALT or AST of greater than 5 times the ULN. Following resolution of transaminase elevations, prescribers should consider the benefits and risks of resuming ivacaftor.