SYMDEKO (Page 6 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with the combination of tezacaftor and ivacaftor, however, separate studies of tezacaftor and ivacaftor are described below.

Tezacaftor

A 2-year study in Sprague-Dawley rats and a 6-month study in Tg.rasH2 transgenic mice were conducted to assess the carcinogenic potential of tezacaftor. No evidence of tumorigenicity from tezacaftor was observed in male and female rats at oral doses up to 50 and 75 mg/kg/day (approximately 2 and 3 times the MRHD based on summed AUCs of tezacaftor and its metabolites in males and females, respectively). No evidence of tumorigenicity was observed in male and female Tg.rasH2 transgenic mice at tezacaftor doses up to 500 mg/kg/day.

Tezacaftor 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.

There were no effects on male or female fertility and early embryonic development in rats at oral tezacaftor doses up to 100 mg/kg/day (approximately 3 times the MRHD based on summed AUC of tezacaftor and M1 metabolite).

Ivacaftor

Two-year studies were conducted in CD-1 mice and Sprague-Dawley rats to assess the carcinogenic potential of ivacaftor. No evidence of tumorigenicity from ivacaftor was observed in mice or rats at oral doses up to 200 mg/kg/day and 50 mg/kg/day, respectively (approximately equivalent to 2 and 9 times the MRHD, respectively, 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 (approximately 9 and 6 times, respectively, the MRHD based on summed AUCs of ivacaftor and its 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 6 times the MRHD based on summed AUCs of ivacaftor and its 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 (approximately 6 and 4 times, respectively, the MRHD based on summed AUCs of ivacaftor and its metabolites).

14 CLINICAL STUDIES

Dose Ranging:

Dose selection for the clinical program primarily consisted of one double-blind, placebo-controlled, multiple-cohort trial which included 176 patients with CF (homozygous for the F508del mutation) 18 years of age and older with a screening ppFEV1≥40. In the study, 34 and 106 patients, respectively, received tezacaftor at once-daily doses of 10 mg, 30 mg, 100 mg, or 150 mg alone or in combination with ivacaftor 150 mg q12h, and 33 patients received placebo. During the 28-day treatment period, dose-dependent increases in mean ppFEV1 change from baseline were observed with tezacaftor in combination with ivacaftor. Tezacaftor/ivacaftor in general had a greater mean treatment effect than tezacaftor alone. No additional benefit was observed at tezacaftor doses greater than 100 mg daily.

Efficacy:

The efficacy of SYMDEKO in patients with CF age 12 years and older was evaluated in three double-blind, placebo-controlled trials (Trials1, 2, and 3).

Trial 1 was a 24-week randomized, double-blind, placebo-controlled, two-arm study in patients with CF who were homozygous for the F508del mutation in the CFTR gene.

Trial 2 was a randomized, double-blind, placebo-controlled, 2-period, 3-treatment, 8-week crossover study in patients with CF who were heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor. Mutations predicted to be responsive were selected for the study based on the clinical phenotype (pancreatic sufficiency), biomarker data (sweat chloride), and in vitro responsiveness to tezacaftor/ivacaftor [see Clinical Studies (14.2)]. Patients were randomized to and received sequences of treatment that included SYMDEKO, ivacaftor, and placebo.

Trial 3 was a 12-week randomized, double-blind, placebo-controlled, two-arm study in patients with CF who were heterozygous for the F508del mutation and a second CFTR mutation predicted to be unresponsive to tezacaftor/ivacaftor. Mutations predicted to be non-responsive were selected for the study based on biologic plausibility (mutation class), clinical phenotype (pancreatic insufficiency), biomarker data (sweat chloride), and in vitro testing to tezacaftor and/or ivacaftor.

Patients in all trials continued on their standard-of-care CF therapies (e.g. , bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline) and were eligible to roll over into a 96-week open-label extension. Patients had a ppFEV1 at screening between 40-90%. Patients with a history of colonization with organisms associated with a more rapid decline in pulmonary status such as Burkholderia cenocepacia , Burkholderia dolosa , or Mycobacterium abscessus , or who had 2 or more abnormal liver function tests at screening (ALT, AST, AP, GGT ≥3 × ULN or total bilirubin ≥2 × ULN) or AST or ALT ≥5 × ULN, were excluded from the trials.

14.1 Trial in Patients with CF Who Were Homozygous for the F508del Mutation in the CFTR Gene (Trial 1)

Trial 1 evaluated 504 patients (248 SYMDEKO, 256 placebo) with CF age 12 years and older (mean age 26.3 years). The mean ppFEV1 at baseline was 60.0% (range: 27.8% to 96.2%). The primary efficacy endpoint was change in lung function as determined by absolute change from baseline in ppFEV1 through Week 24. Treatment with SYMDEKO resulted in a statistically significant improvement in ppFEV1 . The treatment difference between SYMDEKO and placebo for the mean absolute change in ppFEV1 from baseline through Week 24 was 4.0 percentage points (95% CI: 3.1, 4.8; P< 0.0001). These changes persisted throughout the 24-week treatment period (Figure 2). Improvements in ppFEV1 were observed regardless of age, sex, baseline ppFEV1 , colonization with Pseudomonas , concomitant use of standard-of-care medications for CF, and geographic region.

Key secondary efficacy variables included relative change from baseline in ppFEV1 through Week 24; number of pulmonary exacerbations from baseline through Week 24; absolute change in BMI from baseline at Week 24, and absolute change in CFQ-R Respiratory Domain Score (a measure of respiratory symptoms relevant to patients with CF, such as cough, sputum production, and difficulty breathing) from baseline through Week 24. For the purposes of this trial, 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. See Table 11 for a summary of key secondary outcomes in Trial 1.

Table 11: Key Secondary Efficacy Analyses, Full Analysis Set (Trial 1)*
PlaceboN=256SYMDEKON=248
BMI: body mass index; CI: confidence interval; CFQ-R: Cystic Fibrosis Questionnaire-Revised; IVA: ivacaftor; NA: not applicable; ppFEV1 : percent predicted forced expiratory volume in 1 second;
*
A hierarchical testing procedure was performed for primary and secondary endpoints vs placebo; at each step, P ≤0.05 and all previous tests also meeting this level of significance were required for statistical significance.
Indicates statistical significance confirmed in the hierarchical testing procedure. Other efficacy measures considered not statistically significant.
Estimated event rate per year calculated using 48 weeks per year.
Relative change in ppFEV1 from baseline through Week 24 (%)Treatment difference (95% CI)6.8 (5.3, 8.3)
P valueNAP< 0.0001
Number of pulmonary exacerbations from baseline through Week 24Number of events (event rate per year )Rate ratio (95% CI)122 (0.99) 78 (0.64)0.65 (0.48, 0.88)
P valueNAP =0.0054
Absolute change in BMI from baseline at Week 24 (kg/m2)Treatment difference (95% CI)0.06 (-0.08, 0.19)
Absolute change in CFQ-R Respiratory Domain Score from baseline through Week 24 (points)Treatment difference (95% CI)5.1 (3.2, 7.0)

Figure 2: Absolute Change From Baseline in Percent Predicted FEV1 at Each Visit in Trial 1

Figure 2
(click image for full-size original)

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