Orkambi lumacaftor and ivacaftor 100 mg; 125 mg Granule, 56-count — NDC 51167-900-01 (Billing 51167-0900-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. The F508del mutation results in protein misfolding, causing a defect in cellular processing and trafficking that targets the protein for degradation and therefore reduces the quantity of CFTR at the cell surface. The small amount of F508del-CFTR that reaches the cell surface is less stable and has low channel-open probability (defective gating activity) compared to wild-type CFTR protein.

Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. In vitro studies have demonstrated that both lumacaftor and ivacaftor act directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport.

In vitro responses do not necessarily correspond to in vivo pharmacodynamic response or clinical benefit.

12.2Pharmacodynamics Sweat Chloride Evaluation Changes in sweat chloride in response to relevant doses of lumacaftor alone or in combination with ivacaftor were evaluated in a double-blind, placebo-controlled, Phase 2 clinical trial in patients with CF aged 18 years and older either homozygous or heterozygous for the F508del mutation. In that trial, 10 patients (homozygous for F508del ) completed dosing with lumacaftor alone 400 mg q12h for 28 days followed by the addition of ivacaftor 250 mg q12h for an additional 28 days and 25 patients (homozygous or heterozygous for F508del ) completed dosing with placebo.

The treatment difference between lumacaftor 400 mg q12h alone and placebo evaluated as mean change in sweat chloride from baseline to Day 28 compared to placebo was -8.2 mmol/L (95% CI: -14, -2). The treatment difference between the combination of lumacaftor 400 mg/ivacaftor 250 mg q12h and placebo evaluated as mean change in sweat chloride from baseline to Day 56 compared to placebo was -11 mmol/L (95% CI: -18, -4). Changes in sweat chloride in response to lumacaftor/ivacaftor were also evaluated in a 24-week, open-label, clinical trial (Trial 3) in 58 patients with CF, aged 6 through 11 years (homozygous for F508del ) who received lumacaftor 200 mg/ivacaftor 250 mg q12h for 24 weeks.

Patients treated with lumacaftor/ivacaftor had a reduction in sweat chloride at Day 15 that was sustained through Week 24. The within-group LS mean absolute change from baseline in sweat chloride was -20.4 mmol/L at Day 15 and -24.8 mmol/L at Week 24. In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response.

The within-group LS mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was 21.3 mmol/L. Changes in sweat chloride in response to lumacaftor/ivacaftor were also evaluated in a 24-week, open-label, clinical trial (Trial 6) in 60 patients with CF, aged 2 through 5 years (homozygous for F508del ) who received either lumacaftor 100 mg/ivacaftor 125 mg every 12 hours or lumacaftor 150 mg/ivacaftor 188 mg every 12 hours for 24 weeks. Treatment with lumacaftor/ivacaftor demonstrated a reduction in sweat chloride at Week 4 that was sustained through Week 24.

The mean absolute change from baseline in sweat chloride was –31.7 mmol/L (95% CI: -35.7, -27.6) at Week 24. In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response. The mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was an increase of 33.0 mmol/L (95% CI: 28.9, 37.1; P <0.0001).

Changes in… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. The F508del mutation results in protein misfolding, causing a defect in cellular processing and trafficking that targets the protein for degradation and therefore reduces the quantity of CFTR at the cell surface. The small amount of F508del-CFTR that reaches the cell surface is less stable and has low channel-open probability (defective gating activity) compared to wild-type CFTR protein.

Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. In vitro studies have demonstrated that both lumacaftor and ivacaftor act directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport.

In vitro responses do not necessarily correspond to in vivo pharmacodynamic response or clinical benefit.

12.3Pharmacokinetics The exposure (AUC) of lumacaftor is approximately 2-fold higher in healthy adult volunteers compared to exposure in patients with CF. The exposure of ivacaftor is similar between healthy adult volunteers and patients with CF. After twice daily dosing, steady-state plasma concentrations of lumacaftor and ivacaftor in healthy subjects were generally reached after approximately 7 days of treatment, with an accumulation ratio of approximately 1.9 for lumacaftor.

The steady-state exposure of ivacaftor is lower than that of Day 1 due to the CYP3A induction effect of lumacaftor. Table 4: Mean (SD) Pharmacokinetic Parameters of Lumacaftor and Ivacaftor at Steady-State in Subjects with CF Drug C max (μg/mL) t ½ Based on lumacaftor 200 mg q12h/ivacaftor 250 mg q12h studied in healthy subjects. (h) AUC 0-12h (μg∙h/mL) Lumacaftor 400 mg q12h/ Ivacaftor 250 mg q12h Lumacaftor 25.0 (7.96) 25.2 (9.94) 198 (64.8) Ivacaftor 0.602 (0.304) 9.34 (3.81) 3.66 (2.25) Absorption When a single dose of lumacaftor/ivacaftor was administered with fat-containing foods, lumacaftor exposure was approximately 2 times higher and ivacaftor exposure was approximately 3 times higher than when taken in a fasting state.

Following multiple oral dose administration of lumacaftor in combination with ivacaftor, the exposure of lumacaftor generally increased proportional to dose over the range of 200 mg every 24 hours to 400 mg every 12 hours. The median (range) t max of lumacaftor is approximately 4.0 hours (2.0; 9.0) in the fed state. Following multiple oral dose administration of ivacaftor in combination with lumacaftor, the exposure of ivacaftor generally increased with dose from 150 mg every 12 hours to 250 mg every 12 hours.

The median (range) t max of ivacaftor is approximately 4.0 hours (2.0; 6.0) in the fed state. Distribution Lumacaftor is approximately 99% bound to plasma proteins, primarily to albumin. After oral administration of 200 mg every 24 hours for 28 days to patients with CF in a fed state, the mean (±SD) for apparent volumes of distribution was 86.0 (69.8) L.

Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Elimination The half-life of lumacaftor is approximately 26 hours in patients with CF. The typical apparent clearance, CL/F (CV), of lumacaftor was estimated to be

2.38L/hr (29.4%) for patients with CF. The half-life of ivacaftor when given with lumacaftor is approximately 9 hours in healthy subjects. The typical CL/F (CV), of ivacaftor when given in combination with lumacaftor was estimated to be

25.1L/hr (40.5%) for patients with CF. Metabolism Lumacaftor is not extensively metabolized in humans with the majority of lumacaftor excreted unchanged in the feces. In vitro and in vivo data indicate that lumacaftor is mainly metabolized via oxidation and glucuronidation.

Ivacaftor is extensively metabolized in humans. In vitro and in vivo data indicate that ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans.

Excretion Following oral administration of lumacaftor, the majority of lumacaftor (51%) is excreted unchanged in the feces. There was minimal elimination of lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urine with 0.18% as unchanged parent). Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion.

There was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine). Specific Populations Pediatric Patients The following conclusions about exposures between adults and the pediatric population are based on population pharmacokinetics (PK) analyses: Table 5: Mean (SD) Lumacaftor and Ivacaftor Exposure by Age Group Age Group Weight Dose Mean Lumacaftor (SD) The mean lumacaftor (SD) AUC ss is comparable to the mean AUC s… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Sweat Chloride Evaluation Changes in sweat chloride in response to relevant doses of lumacaftor alone or in combination with ivacaftor were evaluated in a double-blind, placebo-controlled, Phase 2 clinical trial in patients with CF aged 18 years and older either homozygous or heterozygous for the F508del mutation. In that trial, 10 patients (homozygous for F508del ) completed dosing with lumacaftor alone 400 mg q12h for 28 days followed by the addition of ivacaftor 250 mg q12h for an additional 28 days and 25 patients (homozygous or heterozygous for F508del ) completed dosing with placebo.

The treatment difference between lumacaftor 400 mg q12h alone and placebo evaluated as mean change in sweat chloride from baseline to Day 28 compared to placebo was -8.2 mmol/L (95% CI: -14, -2). The treatment difference between the combination of lumacaftor 400 mg/ivacaftor 250 mg q12h and placebo evaluated as mean change in sweat chloride from baseline to Day 56 compared to placebo was -11 mmol/L (95% CI: -18, -4). Changes in sweat chloride in response to lumacaftor/ivacaftor were also evaluated in a 24-week, open-label, clinical trial (Trial 3) in 58 patients with CF, aged 6 through 11 years (homozygous for F508del ) who received lumacaftor 200 mg/ivacaftor 250 mg q12h for 24 weeks.

Patients treated with lumacaftor/ivacaftor had a reduction in sweat chloride at Day 15 that was sustained through Week 24. The within-group LS mean absolute change from baseline in sweat chloride was -20.4 mmol/L at Day 15 and -24.8 mmol/L at Week 24. In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response.

The within-group LS mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was 21.3 mmol/L. Changes in sweat chloride in response to lumacaftor/ivacaftor were also evaluated in a 24-week, open-label, clinical trial (Trial 6) in 60 patients with CF, aged 2 through 5 years (homozygous for F508del ) who received either lumacaftor 100 mg/ivacaftor 125 mg every 12 hours or lumacaftor 150 mg/ivacaftor 188 mg every 12 hours for 24 weeks. Treatment with lumacaftor/ivacaftor demonstrated a reduction in sweat chloride at Week 4 that was sustained through Week 24.

The mean absolute change from baseline in sweat chloride was –31.7 mmol/L (95% CI: -35.7, -27.6) at Week 24. In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response. The mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was an increase of 33.0 mmol/L (95% CI: 28.9, 37.1; P <0.0001).

Changes in sweat chloride in response to lumacaftor/ivacaftor were evaluated in a 24-week, open-label, clinical trial (Trial 7) in 46 patients with CF, aged 1 through 2 years (homozygous for F508del ) who received lumacaftor 75 mg/ivacaftor 94 mg (patient weighing 7 kg to <9 kg at screening), lumacaftor 100 mg/ivacaftor 125 mg (patient weighing 9 kg to <14 kg at screening), lumacaftor 150 mg/ivacaftor 188 mg (patient weighing ≥14 kg at screening), every 12 hours for 24 weeks. Treatment with lumacaftor/ivacaftor demonstrated a reduction in sweat chloride at Week 4 which was sustained through Week 24.

The mean absolute change from baseline in sweat chloride at Week 24 was -29.1 mmol/L (95% CI: -34.8, -23.4). In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response. The mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was 27.3 mmol/L (95% CI: 22.3, 32.3).

There was no direct correlation between decrease in sweat chloride levels and improvement in lung function (ppFEV 1 ). Cardiac Electrophysiology The effect of multiple doses of lumacaftor 600 mg once daily/ivacaftor 250 mg q12h and lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h on QTc interval was evaluated in a randomized, placebo- and active-controlled (4… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES Dose Ranging Dose ranging for the clinical program consisted primarily of one double-blind, placebo-controlled, multiple-cohort trial which included 97 Caucasian patients with CF (homozygous for the F508del mutation) aged 18 years and older with a screening ppFEV 1 ≥40. In the trial, 76 patients (homozygous for the F508del mutation) were randomized to receive lumacaftor alone at once daily doses of 200 mg, 400 mg, or 600 mg or 400 mg q12h for 28 days followed by the addition of ivacaftor 250 mg q12h and 27 patients (homozygous or heterozygous for the F508del mutation) received placebo.

During the initial 28-day lumacaftor monotherapy period, treatment with lumacaftor demonstrated a dose-dependent decrease in ppFEV 1 compared to placebo. Changes from Day 1 at Day 28 in ppFEV 1 compared to placebo were 0.24, -1.4, -2.7, and -4.6 for the 200 mg once daily, 400 mg once daily, 600 mg once daily, and 400 mg q12h lumacaftor doses, respectively. Following the addition of ivacaftor 250 mg q12h, the changes from Day 1 at Day 56 in ppFEV 1 compared to placebo were 3.8, 2.7, 5.6, and 4.2, respectively.

Sweat chloride was also assessed in this trial. Following the initial 28 days of lumacaftor monotherapy, the changes from Day 1 at Day 28 in sweat chloride compared to placebo were -4.9, -8.3, -6.1, and -8.2 mmol/L for the 200 mg once daily, 400 mg once daily, 600 mg once daily, and 400 mg q12h lumacaftor doses, respectively. Following the addition of ivacaftor 250 mg q12h, the changes from Day 1 at Day 56 in sweat chloride compared to placebo were -5.0, -9.8, -9.5, and -11 mmol/L, respectively.

These data supported the evaluation of lumacaftor 400 mg/ivacaftor 250 mg q12h (ORKAMBI) and lumacaftor 600 mg once daily/ivacaftor 250 mg q12h in the confirmatory trials. Confirmatory The efficacy of ORKAMBI in patients with CF who are homozygous for the F508del mutation in the CFTR gene was evaluated in two randomized, double-blind, placebo-controlled, 24-week clinical trials (Trials 1 and 2) in 1108 clinically stable patients with CF of whom 369 patients received ORKAMBI twice daily. Trial 1 evaluated 549 patients with CF who were aged 12 years and older (mean age 25.1 years) with ppFEV 1 at screening between 40-90 [mean ppFEV 1 60.7 at baseline (range: 31.1 to 94.0)].

Trial 2 evaluated 559 patients aged 12 years and older (mean age 25.0 years) with ppFEV 1 at screening between 40-90 [mean ppFEV 1 60.5 at baseline (range: 31.3 to 99.8)]. Patients with a history of colonization with organisms such as Burkholderia cenocepacia , Burkholderia dolosa , or Mycobacterium abscessus , or who had 3 or more abnormal liver function tests (ALT, AST, AP, GGT ≥3 × the ULN or total bilirubin ≥2 × the ULN) were excluded. Patients in both trials were randomized 1:1:1 to receive either ORKAMBI (lumacaftor 400 mg q12h/ivacaftor 250 mg q12h; or lumacaftor 600 mg once daily/ivacaftor 250 mg q12h) or placebo.

Patients took the study drug with fat-containing food for 24 weeks in addition to their prescribed CF therapies (e.g., bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). The primary efficacy endpoint in both trials was change in lung function as determined by absolute change from baseline in ppFEV 1 at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24. In both trials, treatment with ORKAMBI resulted in a statistically significant improvement in ppFEV 1 .

The treatment difference between ORKAMBI and placebo for the mean absolute change in ppFEV 1 from baseline at Week 24 (assessed as the average of the treatment effects at Week 16 and at Week 24) was 2.6 percentage points [95% CI (1.2, 4.0)] in Trial 1 ( P =0.0003) and 3.0 percentage points [95% CI (1.6, 4.4)] in Trial 2 ( P <0.0001). These changes persisted throughout the 24-week treatment period (see Figure 1 ). Improvements in ppFEV 1 were observed regardless of age, disease severity, sex, and geographic region.

Figure 1. Absolute Cha… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with ORKAMBI; however, studies are available for individual components, lumacaftor and ivacaftor, as described below. Lumacaftor A two-year study in Sprague-Dawley rats and a 26-week study in transgenic Tg.rasH2 mice were conducted to assess carcinogenic potential of lumacaftor. No evidence of tumorigenicity was observed in rats at lumacaftor oral doses up to 1000 mg/kg/day (approximately 5 and 13 times the MRHD on a lumacaftor AUC basis in males and females, respectively).

No evidence of tumorigenicity was observed in Tg.rasH2 mice at lumacaftor oral doses up to 1500 and 2000 mg/kg/day in female and male mice, respectively. Lumacaftor 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. Lumacaftor had no effects on fertility and reproductive performance indices in male and female rats at an oral dose of 1000 mg/kg/day (approximately 3 and 8 times, respectively, the MRHD on a lumacaftor AUC basis).

Ivacaftor Two-year studies were conducted in mice and rats to assess carcinogenic potential of ivacaftor. No evidence of tumorigenicity was observed in mice and rats at ivacaftor oral doses up to 200 mg/kg/day and 50 mg/kg/day, respectively (approximately equivalent to 3 and 10 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 an oral dose of 200 mg/kg/day (approximately 15 and 7 times 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 7 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 an oral dose of ≤100 mg/kg/day (approximately 8 and 5 times the MRHD based on summed AUCs of ivacaftor and its metabolites).