Ivacaftor for Cystic Fibrosis and the G551D-CFTR Mutation

Clinical Studies

The FDA approved ivacaftor within three months of submission of the new drug application, under the priority review program. The approval was based largely on the results of one proof of concept dose-ranging study conducted in 39 adults and two 48-month clinical studies which enrolled at total of 213 children and adults. Two of the studies have been published in The New England Journal of Medicine.

In 2010, Accurso and colleagues published the results of a randomized, double-blind, cross-over dose-ranging study in 39 adults with CF and at least one G551D-CFTR allele. Twenty subjects were randomized to receive ivacaftor at a dose of 25, 75, or 150 mg or placebo orally every 12 hours for 14 days in the first phase of the study. At day 14, the mean relative change from baseline in the percentage of predicted FEV₁ was 4.9% (95% CI ™2.6, 12.5), 10% (95% CI 4.5, 15.6), and 10.5% (95% CI 3.3, 17.7) in the 25, 75, and 150 mg groups, respectively, with a 0.7% change (95% CI ™8.8, 10.2) in the placebo group. The improvement was statistically significant only in the 75 mg and 150 mg groups (p = 0.002 and p = 0.008 for within-subject comparison with baseline values).

Based on the results of the first phase, another 19 subjects were randomized to an ivacaftor dose of 150 or 250 mg or placebo every 12 hours for 28 days. At completion of the study, the median relative change from baseline in the percentage of predicted FEV₁ was 8.7% (range 2.3–31.3%, p = 0.008) in the 150 mg group, 4.4% (0–18.3%, p = 0.03) in the 250 mg group, and 7.3% (4.2–8.2%, p = 0.13) in the controls. Combined data from the subjects receiving ivacaftor 150 mg every 12 hours revealed a median change in the nasal potential difference in response to an isoproterenol challenge of ™3.5 mV (range ™8.3 to 0.5 mV, p = 0.02 for within-subject comparison), demonstrating a positive effect on nasal electrophysiology. The median change in sweat chloride was ™59.5 mmol/L (range ™66.0 to ™19.0; p = 0.008). Two subjects experienced a serious adverse reaction: a rash in one patient and 5 incidents of elevated blood or urine glucose levels in a patient with underlying diabetes. None of the subjects withdrew from the study. Based on the results of this brief dose-ranging study, the authors concluded that ivacaftor, at a dose of 150 mg every 12 hours, produced significant improvement in CFTR and lung function compared to baseline in patients with the G551D-CFTR mutation.

The following year, Ramsey and colleagues (writing for the VX08–770–102 Study Group) published the first of the 48-month efficacy trials. A total of 161 subjects were enrolled in this phase III randomized, double-blind, placebo-controlled trial. Subjects ranged in age from 12 The following year, Ramsey and colleagues (writing for the VX08–770–102 Study Group) published the first of the 48-month efficacy trials. A total of 161 subjects were enrolled in this phase III randomized, double-blind, placebo-controlled trial. Subjects ranged in age from 12

At 24 weeks, the change from baseline in predicted FEV₁ was significantly greater in the ivacaftor group (10.4 percentage points in the ivacaftor group versus ™0.2 percentage points in the controls, p < 0.0001). The mean increase in FEV₁ was 0.367 L in the treatment group, compared to 0.006 L in the controls (p < 0.001), corresponding to a relative change from baseline of 17.2% with treatment and 0.1% with placebo. For most subjects, treatment effect was evident by the end of the second week. Response to treatment was sustained at week 48, with a change from baseline in predicted FEV₁ 10.5 percentage points greater in the ivacaftor group (p < 0.001).

Sixty-seven percent of the subjects in the treatment group had remained free of pulmonary exacerbations at week 48 compared to 41% of the controls (p = 0.001). There were 99 exacerbations in the placebo group, but only 47 in the treatment group. Hospitalizations were less frequent in the ivacaftor group (21 in 11 patients) compared to the controls (31 in 23 patients). Mean change from baseline in scores for the respiratory domain of the CF Questionnaire-revised instrument was significantly greater in the ivacaftor group (a 5.9 point increase versus a 2.7 point decrease in the controls, p < 0.001). A change of 4 points on this scale is considered the threshold for clinical significance. Weight gain was also significantly greater in the treatment group (mean 3.1 kg versus 0.4 kg in the controls, p < 0.001), with a plateau after 16 weeks.

At week 24, the change from baseline in sweat chloride was ™48.7 mmol/L in the ivacaftor group and – 0.8 mmol/L in the controls (p < 0.001). The mean value for sweat chloride in the ivacaftor group was 47.8 mmol/L, lower than the 60 mmol/L diagnostic threshold for CF. This treatment effect was noted in most subjects by day 15 and was sustained through week 48.

Serious adverse effects were identified in 20 ivacaftor patients (24%) and 33 controls (42%). In addition to pulmonary exacerbations, hemoptysis was reported in four controls and one patient receiving ivacaftor. Hypoglycemia was reported in two subjects in the ivacaftor group, including one subject with diabetes who was receiving insulin. Four subjects in the placebo group and one in the ivacaftor group withdrew from the study because of an adverse effect.

A second randomized, double-blind, placebo-controlled efficacy trial was conducted in 52 children between 6 and 11 years of age (mean 9 years). The results of this trial have not yet been published, but are available in the product prescribing information. Randomization was identical to the previous trial, with ivacaftor administered at a dose of 150 mg every 12 hours. As in the first efficacy trial, at 24 weeks the change from baseline in predicted FEV₁ was significantly greater in the ivacaftor group (12.5 percentage points greater than in the controls, p < 0.0001). This change persisted at 48 weeks. Weight gain was also significantly greater in the treatment group, with a mean absolute change from baseline of 1.9 kg (95% CI 0.9, 2.9) at week 24 and 2.8 kg (95% CI 1.3, 4.2) at week 48 (p = 0.0004 and p = 0.0002, respectively). The results of these trials provided strong support for the approval of ivacaftor in patients with the G551D-CFTR mutation.