Kalydeco (Page 6 of 11)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year studies were conducted in CD-1 mice and Sprague-Dawley rats to assess carcinogenic potential of KALYDECO. No evidence of tumorigenicity was observed in mice or rats at ivacaftor oral doses up to 200 mg/kg/day and 50 mg/kg/day, respectively (approximately equal to 1 and 4 times the MRHD based on summed AUCs of ivacaftor and its metabolites).

Ivacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene mutation, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus test.

Ivacaftor impaired fertility and reproductive performance indices in male and female rats at 200 mg/kg/day (yielding exposures approximately 8 and 5 times, respectively, the MRHD based on summed AUCs of ivacaftor and its major metabolites). Increases in prolonged diestrus were observed in females at 200 mg/kg/day. Ivacaftor also increased the number of females with all nonviable embryos and decreased corpora lutea, implantations, and viable embryos in rats at 200 mg/kg/day (approximately 5 times the MRHD based on summed AUCs of ivacaftor and its major metabolites) when dams were dosed prior to and during early pregnancy. These impairments of fertility and reproductive performance in male and female rats at 200 mg/kg/day were attributed to severe toxicity. No effects on male or female fertility and reproductive performance indices were observed at ≤100 mg/kg/day (yielding exposures approximately 6 and 3 times, respectively, the MRHD based on summed AUCs of ivacaftor and its major metabolites).

14 CLINICAL STUDIES

14.1 Trials in Patients with CF who have a G551D Mutation in the CFTR Gene

Dose Ranging:

Dose ranging for the clinical program consisted primarily of one double-blind, placebo-controlled, crossover trial in 39 adult (mean age 31 years) Caucasian patients with CF who had FEV1 ≥40% predicted. Twenty patients with median predicted FEV1 at baseline of 56% (range: 42% to 109%) received KALYDECO 25, 75, 150 mg, or placebo every 12 hours for 14 days and 19 patients with median predicted FEV1 at baseline of 69% (range: 40% to 122%) received KALYDECO 150, 250 mg, or placebo every 12 hours for 28 days. The selection of the 150 mg every 12 hours dose was primarily based on nominal improvements in lung function (pre-dose FEV1 ) and changes in pharmacodynamic parameters (sweat chloride and nasal potential difference). The twice-daily dosing regimen was primarily based on an apparent terminal plasma half-life of approximately 12 hours.

Efficacy:

The efficacy of KALYDECO in patients with CF who have a G551D mutation in the CFTR gene was evaluated in two randomized, double-blind, placebo-controlled clinical trials in 213 clinically stable patients with CF (109 receiving KALYDECO 150 mg twice daily). All eligible patients from these trials were rolled over into an open-label extension study.

Trial 1 evaluated 161 patients with CF who were 12 years of age or older (mean age 26 years) with FEV1 at screening between 40-90% predicted [mean FEV1 64% predicted at baseline (range: 32% to 98%)]. Trial 2 evaluated 52 patients who were 6 to 11 years of age (mean age 9 years) with FEV1 at screening between 40-105% predicted [mean FEV1 84% predicted at baseline (range: 44% to 134%)]. Patients who had persistent Burkholderia cenocepacia, Burkholderia dolosa , or Mycobacterium abscessus isolated from sputum at screening and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the ULN were excluded.

Patients in both trials were randomized 1:1 to receive either 150 mg of KALYDECO or placebo every 12 hours with fat-containing food for 48 weeks in addition to their prescribed CF therapies (e.g., tobramycin, dornase alfa). The use of inhaled hypertonic saline was not permitted.

The primary efficacy endpoint in both studies was improvement in lung function as determined by the mean absolute change from baseline in percent predicted pre-dose FEV1 through 24 weeks of treatment.

In both studies, treatment with KALYDECO resulted in a significant improvement in FEV1 . The treatment difference between KALYDECO and placebo for the mean absolute change in percent predicted FEV1 from baseline through Week 24 was 10.6 percentage points (P <0.0001) in Trial 1 and 12.5 percentage points (P <0.0001) in Trial 2 (Figure 4). These changes persisted through 48 weeks. Improvements in percent predicted FEV1 were observed regardless of age, disease severity, sex, and geographic region.

Figure 4: Mean Absolute Change from Baseline in Percent Predicted FEV1 *
*
Primary endpoint was assessed at the 24-week time point.

Figure 4
(click image for full-size original)

Other efficacy variables included absolute change from baseline in sweat chloride [see Clinical Pharmacology (12.2)], time to first pulmonary exacerbation (Trial 1 only), absolute change from baseline in weight, and improvement from baseline in Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain score, a measure of respiratory symptoms relevant to patients with CF such as cough, sputum production, and difficulty breathing. For the purpose of the study, a pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms. Patients treated with KALYDECO demonstrated statistically significant improvements in risk of pulmonary exacerbations, CF symptoms (in Trial 1 only), and gain in body weight (Table 5). Weight data, when expressed as body mass index normalized for age and sex in patients <20 years of age, were consistent with absolute change from baseline in weight.

Table 5: Effect of KALYDECO on Other Efficacy Endpoints in Trials 1 and 2
Trial 1Trial 2
EndpointTreatment difference *(95% CI)P valueTreatment difference *(95% CI)P value
CI: confidence interval; NA: not analyzed due to low incidence of events.
*
Treatment difference = effect of KALYDECO – effect of Placebo.
Hazard ratio for time to first pulmonary exacerbation.
Mean absolute change from baseline in CFQ-R respiratory domain score (points)
Through Week 248.1(4.7, 11.4)<0.00016.1(-1.4, 13.5)0.1092
Through Week 488.6(5.3, 11.9)<0.00015.1(-1.6, 11.8)0.1354
Relative risk of pulmonary exacerbation
Through Week 240.40 0.0016NANA
Through Week 480.46 0.0012NANA
Mean absolute change from baseline in body weight (kg)
At Week 242.8(1.8, 3.7)<0.00011.9(0.9, 2.9)0.0004
At Week 482.7(1.3, 4.1)0.00012.8(1.3, 4.2)0.0002
Absolute change in sweat chloride (mmol/L)
Through Week 24-48(-51, -45)<0.0001-54(-62, -47)<0.0001
Through Week 48-48(-51, -45)<0.0001-53(-61, -46)<0.0001

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