Trikafta Elexacaftor, Tezacaftor, and Ivacaftor Kit — NDC 51167-331-01 (Billing 51167-0331-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Elexacaftor and tezacaftor bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of select mutant forms of CFTR (including F508del-CFTR) to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface. The combined effect of elexacaftor, tezacaftor and ivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increased CFTR activity as measured both by CFTR-mediated chloride transport in vitro and by sweat chloride in patients with CF.

CFTR Chloride Transport Assay in Fischer Rat Thyroid Cells Expressing Mutant CFTR Protein Effects of elexacaftor/tezacaftor/ivacaftor on chloride transport for mutant CFTR proteins was determined in Ussing chamber electrophysiology studies using a panel of Fischer Rat Thyroid (FRT) cell lines stably expressing individual mutant CFTR protein. Elexacaftor/tezacaftor/ivacaftor increased chloride transport in FRT cells expressing CFTR variants, as identified in Table 6. The threshold that the treatment-induced increase in chloride transport must exceed for the mutant CFTR protein to be considered responsive is ≥10% of normal over baseline.

This threshold was used because it is expected to predict clinical benefit. For individual variants, the magnitude of the net change over baseline in CFTR-mediated chloride transport in vitro is not correlated with the magnitude of clinical response. CFTR Chloride Transport Assay in Human Bronchial Epithelial Cells Expressing Mutant CFTR Protein Homozygous and heterozygous N1303K -Human Bronchial Epithelial (HBE) cells showed greater chloride transport in the presence of elexacaftor/tezacaftor/ivacaftor than F508del/F508del -HBE cells treated with tezacaftor/ivacaftor (which has shown clinical benefit in people homozygous for F508del) .

Patient Selection Select adult and pediatric patients 2 years of age and older for the treatment of CF with TRIKAFTA based on a clinical diagnosis of CF and the presence of at least one variant in the CFTR gene that is either responsive based on clinical and/or in vitro data or results in production of CFTR protein [see Indications and Usage (1) ] . TRIKAFTA should only be used in patients with a clinical diagnosis of CF. The presence of eligible CFTR variant(s) should not be the sole determinant for using TRIKAFTA.

Table 6 lists CFTR variants responsive to TRIKAFTA based on clinical and/or in vitro data in FRT or HBE cells [see Clinical Studies (14) ] . Table 6: List of CFTR Gene Variants Responsive to TRIKAFTA The list of responsive CFTR variants is non-exhaustive. There may be protein-producing CFTR variants not listed that respond to treatment with TRIKAFTA.

Variants responsive to TRIKAFTA based on clinical data Clinical data obtained from Trials 1, 2, and 5. 2789+5G→A D1152H This variant is also predicted to be responsive by FRT assay. L206W R1066H S945L 3272-26A→G F508del L997F R117C T338I 3849+10kbC→T G85E M1101K R347H V232D A455E L1077P P5L R347P Variants responsive to TRIKAFTA based on in vitro data The N1303K variant is predicted to be responsive by HBE assay.

All other variants predicted to be responsive with in vitro data are supported by FRT assay. 1140-1151dup E264V H620P N396Y S1251N 1461insGAT E282D H620Q N418S S1255P 1507_1515del9 E292K H939R N900K S13F 2055del9 E384K H939R;H949L P1013H S13P 2183A→G E403D H954P P1013L S158N 2851A/G E474K I1023R P1021L S182R 293A→G E527G I1027T P1021T S18I 3007del6 E56K I105N P111L S18N 3132T→G E588V I1139V P1372T S308P 3141del9 E60K I1203V P140S S341P 3143del9 E822K I1234L P205S S364P 314del9 E92K I1234V del6aa P439S S434P 3331del6 F1016S I125T P499A S492F 3410T→C F1052V I1269N P574H S50P 3523A→G F1074L I1366N P67L S519G 3601A→C F1078S I1366T P750L S531P 3761T→G F1099L I148L P798S S549I 3791… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Elexacaftor and tezacaftor bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of select mutant forms of CFTR (including F508del-CFTR) to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface. The combined effect of elexacaftor, tezacaftor and ivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increased CFTR activity as measured both by CFTR-mediated chloride transport in vitro and by sweat chloride in patients with CF.

CFTR Chloride Transport Assay in Fischer Rat Thyroid Cells Expressing Mutant CFTR Protein Effects of elexacaftor/tezacaftor/ivacaftor on chloride transport for mutant CFTR proteins was determined in Ussing chamber electrophysiology studies using a panel of Fischer Rat Thyroid (FRT) cell lines stably expressing individual mutant CFTR protein. Elexacaftor/tezacaftor/ivacaftor increased chloride transport in FRT cells expressing CFTR variants, as identified in Table 6. The threshold that the treatment-induced increase in chloride transport must exceed for the mutant CFTR protein to be considered responsive is ≥10% of normal over baseline.

This threshold was used because it is expected to predict clinical benefit. For individual variants, the magnitude of the net change over baseline in CFTR-mediated chloride transport in vitro is not correlated with the magnitude of clinical response. CFTR Chloride Transport Assay in Human Bronchial Epithelial Cells Expressing Mutant CFTR Protein Homozygous and heterozygous N1303K -Human Bronchial Epithelial (HBE) cells showed greater chloride transport in the presence of elexacaftor/tezacaftor/ivacaftor than F508del/F508del -HBE cells treated with tezacaftor/ivacaftor (which has shown clinical benefit in people homozygous for F508del) .

Patient Selection Select adult and pediatric patients 2 years of age and older for the treatment of CF with TRIKAFTA based on a clinical diagnosis of CF and the presence of at least one variant in the CFTR gene that is either responsive based on clinical and/or in vitro data or results in production of CFTR protein [see Indications and Usage (1) ] . TRIKAFTA should only be used in patients with a clinical diagnosis of CF. The presence of eligible CFTR variant(s) should not be the sole determinant for using TRIKAFTA.

Table 6 lists CFTR variants responsive to TRIKAFTA based on clinical and/or in vitro data in FRT or HBE cells [see Clinical Studies (14) ] . Table 6: List of CFTR Gene Variants Responsive to TRIKAFTA The list of responsive CFTR variants is non-exhaustive. There may be protein-producing CFTR variants not listed that respond to treatment with TRIKAFTA.

Variants responsive to TRIKAFTA based on clinical data Clinical data obtained from Trials 1, 2, and 5. 2789+5G→A D1152H This variant is also predicted to be responsive by FRT assay. L206W R1066H S945L 3272-26A→G F508del L997F R117C T338I 3849+10kbC→T G85E M1101K R347H V232D A455E L1077P P5L R347P Variants responsive to TRIKAFTA based on in vitro data The N1303K variant is predicted to be responsive by HBE assay.

All other variants predicted to be responsive with in vitro data are supported by FRT assay. 1140-1151dup E264V H620P N396Y S1251N 1461insGAT E282D H620Q N418S S1255P 1507_1515del9 E292K H939R N900K S13F 2055del9 E384K H939R;H949L P1013H S13P 2183A→G E403D H954P P1013L S158N 2851A/G E474K I1023R P1021L S182R 293A→G E527G I1027T P1021T S18I 3007del6 E56K I105N P111L S18N 3132T→G E588V I1139V P1372T S308P 3141del9 E60K I1203V P140S S341P 3143del9 E822K I1234L P205S S364P 314del9 E92K I1234V del6aa P439S S434P 3331del6 F1016S I125T P499A S492F 3410T→C F1052V I1269N P574H S50P 3523A→G F1074L I1366N P67L S519G 3601A→C F1078S I1366T P750L S531P 3761T→G F1099L I148L P798S S549I 3791C/T F1107L I148N P988R S5… [Excerpted — this section continues on DailyMed.]

12.3Pharmacokinetics The pharmacokinetics of elexacaftor, tezacaftor and ivacaftor are similar between healthy adult subjects and patients with CF. The pharmacokinetic parameters for elexacaftor, tezacaftor and ivacaftor in patients with CF aged 12 years and older are shown in Table 7. Table 7: Pharmacokinetic Parameters of TRIKAFTA Components Elexacaftor Tezacaftor Ivacaftor AUC ss : area under the concentration versus time curve at steady state; SD: Standard Deviation; C max : maximum observed concentration; T max : time of maximum concentration; AUC: area under the concentration versus time curve.

General Information AUC ss (SD), mcg∙h/mL Based on elexacaftor 200 mg and tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours at steady state in patients with CF aged 12 years and older. 162 (47.5) AUC 0-24h . 89.3 (23.2) 11.7 (4.01) AUC 0-12h .

C max (SD), mcg/mL 9.2 (2.1) 7.7 (1.7) 1.2 (0.3) Time to Steady State, days Within 7 days Within 8 days Within 3-5 days Accumulation Ratio 2.2 2.07

2.4Absorption Absolute Bioavailability 80% Not determined Not determined Median T max (range), hours 6 (4 to 12) 3 (2 to 4) 4 (3 to 6) Effect of Food AUC increases 1.9- to 2.5-fold (moderate-fat meal) No clinically significant effect Exposure increases 2.5- to 4-fold Distribution Mean (SD) Apparent Volume of Distribution, L Elexacaftor, tezacaftor and ivacaftor do not partition preferentially into human red blood cells. 53.7 (17.7) 82.0 (22.3) 293 (89.8) Protein Binding Elexacaftor and tezacaftor bind primarily to albumin.

Ivacaftor primarily bind to albumin, alpha 1-acid glycoprotein and human gamma-globulin. >99% approximately 99% approximately 99% Elimination Mean (SD) Effective Half-Life, hours Mean (SD) terminal half-lives of elexacaftor, tezacaftor and ivacaftor are approximately 24.7 (4.87) hours, 60.3 (15.7) hours and 13.1 (2.98) hours, respectively. 27.4 (9.31) 25.1 (4.93) 15.0 (3.92) Mean (SD) Apparent Clearance, L/hours 1.18 (0.29) 0.79 (0.10) 10.2 (3.13) Metabolism Primary Pathway CYP3A4/5 CYP3A4/5 CYP3A4/5 Active Metabolites M23-ELX M1-TEZ M1-IVA Metabolite Potency Relative to Parent Similar Similar approximately 1/6 th of parent Excretion Following radiolabeled doses.

Primary Pathway Feces: 87.3% (primarily as metabolites) Urine: 0.23% Feces: 72% (unchanged or as M2-TEZ) Urine: 14% (0.79% unchanged) Feces: 87.8% Urine: 6.6% Specific Populations Pediatric Patients 2 to Less Than 12 Years of Age Elexacaftor, tezacaftor and ivacaftor exposures observed in patients aged 2 to less than 12 years as determined using population PK analysis are presented by age group and dose administered in Table 8. Elexacaftor, tezacaftor and ivacaftor exposures in this patient population are within the range observed in patients aged 12 years and older.

Table 8: Mean (SD) Elexacaftor, Tezacaftor and Ivacaftor Exposures Observed at Steady State by Age Group and Dose Administered Age Group Dose Elexacaftor AUC 0-24h,ss (µg∙h/mL) Tezacaftor AUC 0-24h,ss (µg∙h/mL) Ivacaftor AUC 0-12h,ss (µg∙h/mL) SD: Standard Deviation; AUC ss : area under the concentration versus time curve at steady state. Patients aged 2 to less than 6 years weighing less than 14 kg (N = 16) elexacaftor 80 mg qd/tezacaftor 40 mg qd/ivacaftor 60 mg qAM and ivacaftor 59.5 mg qPM 128 (24.8) 87.3 (17.3) 11.9 (3.86) Patients aged 2 to less than 6 years weighing 14 kg or more (N = 59) elexacaftor 100 mg qd/tezacaftor 50 mg qd/ivacaftor 75 mg q12h 138 (47.0) 90.2 (27.9) 13.0 (6.11) Patients aged 6 to less than 12 years weighing less than 30 kg (N = 36) elexacaftor 100 mg qd/tezacaftor 50 mg qd/ivacaftor 75 mg q12h 116 (39.4) 67.0 (22.3) 9.78 (4.50) Patients aged 6 to less than 12 years weighing 30 kg or more (N = 30) elexacaftor 200 mg qd/ tezacaftor 100 mg qd/ ivacaftor 150 mg q12h 195 (59.4) 103 (23.7) 17.5 (4.97) Pediatric Patients 12 to Less Than 18 Years of Age The following conclusions about exposures between adults and the pediatric population are based on population pharmacok… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Sweat Chloride Evaluation In Trial 1 (patients with an F508del variant on one allele and a variant on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive ivacaftor and tezacaftor/ivacaftor), a reduction in sweat chloride was observed from baseline at Week 4 and sustained through the 24-week treatment period [see Clinical Studies (14.1) ] . In Trial 2 (patients homozygous for the F508del variant), a reduction in sweat chloride was observed from baseline at Week 4 [see Clinical Studies (14.2) ] .

In Trial 3 (patients aged 6 to less than 12 years who are homozygous for the F508del variant or heterozygous for the F508del variant and a variant on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor), the mean absolute change in sweat chloride from baseline through Week 24 was -60.9 mmol/L (95% CI: -63.7, -58.2). In Trial 4 (patients aged 2 to less than 6 years who had at least one F508del variant or a variant known to be responsive to TRIKAFTA), the mean absolute change in sweat chloride from baseline through Week 24 was -57.9 mmol/L (95% CI: -61.3, -54.6).

In Trial 5 (patients aged 6 years and older with at least one qualifying non- F508del elexacaftor/tezacaftor/ivacaftor-responsive CFTR variant), the mean absolute change in sweat chloride from baseline through Week 24 compared to placebo was -28.3 mmol/L (95% CI: -32.1, -24.5). Cardiac Electrophysiology At doses up to 2 times the maximum recommended dose of elexacaftor and 3 times the maximum recommended dose of tezacaftor and ivacaftor, the QT/QTc interval in healthy subjects was not prolonged to any clinically relevant extent.

14 CLINICAL STUDIES

14.1Clinical Studies in Patients with Cystic Fibrosis with at Least One F508del Variant The efficacy of TRIKAFTA in patients aged 12 years and older with cystic fibrosis (CF) with at least one F508del variant was evaluated in two randomized, double-blind, controlled trials (Trials 1 and 2). Trial 1 (NCT03525444) was a 24-week, randomized, double-blind, placebo-controlled study in patients who had an F508del variant on one allele and a variant on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor.

An interim analysis was planned when at least 140 patients completed Week 4 and at least 100 patients completed Week 12. Trial 2 (NCT03525548) was a 4-week, randomized, double-blind, active-controlled study in patients who are homozygous for the F508del variant. Patients received tezacaftor 100 mg qd/ivacaftor 150 mg q12h during a 4-week, open-label run-in period and were then randomized and dosed to receive TRIKAFTA or tezacaftor 100 mg qd/ivacaftor 150 mg q12h during a 4-week, double-blind treatment period.

Patients in Trials 1 and 2 had a confirmed diagnosis of CF and at least one F508del variant. Patients discontinued any previous CFTR modulator therapies, but continued on their other standard-of-care CF therapies (e.g., bronchodilators, inhaled antibiotics, dornase alfa and hypertonic saline). Patients had a ppFEV 1 at screening between 40-90%.

Patients with a history of colonization with organisms associated with a more rapid decline in pulmonary status, including but not limited to Burkholderia cenocepacia , Burkholderia dolosa , or Mycobacterium abscessus , or who had an abnormal liver function test at screening (ALT, AST, ALP, or GGT ≥3 × ULN, or total bilirubin ≥2 × ULN), were excluded from the trials. Patients in Trials 1 and 2 were eligible to roll over into an open-label extension study. Trial 1 Trial 1 evaluated 403 patients (200 TRIKAFTA, 203 placebo) with CF aged 12 years and older (mean age 26.2 years).

The mean ppFEV 1 at baseline was 61.4% (range: 32.3%, 97.1%). The primary endpoint assessed at the time of interim analysis was mean absolute change in ppFEV 1 from baseline at Week 4. The final analysis tested all key secondary endpoints in the 403 patients who completed the 24-week study participation, including absolute change in ppFEV 1 from baseline through Week 24; absolute change in sweat chloride from baseline at Week 4 and through Week 24; number of pulmonary exacerbations 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 at Week 4 and through Week 24.

Of the 403 patients included in the interim analysis, the treatment difference between TRIKAFTA and placebo for the mean absolute change from baseline in ppFEV 1 at Week 4 was 13.8 percentage points (95% CI: 12.1, 15.4; P <0.0001). The treatment difference between TRIKAFTA and placebo for mean absolute change in ppFEV 1 from baseline through Week 24 was 14.3 percentage points (95% CI: 12.7, 15.8; P <0.0001). Mean improvement in ppFEV 1 was observed at the first assessment on Day 15 and sustained through the 24-week treatment period (see Figure 1 ).

Improvements in ppFEV 1 were observed regardless of age, baseline ppFEV 1 , sex and geographic region. See Table 11 for a summary of primary and key secondary outcomes in Trial 1. Table 11: Primary and Key Secondary Efficacy Analyses (Trial 1) Analysis Statistic Treatment Difference Treatment difference provided as the outcome measure for changes in ppFEV 1 , sweat chloride, CFQ-R and BMI; Rate ratio provided as the outcome measure for the number of pulmonary exacerbations. for TRIKAFTA (N=200) vs Placebo (N=203) ppFEV 1 : percent predicted Forced Expiratory Volume in 1 second; CI: Confidence Interval; CFQ-R:… [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 the combination of elexacaftor, tezacaftor and ivacaftor; however, separate studies of elexacaftor, tezacaftor and ivacaftor are described below. Elexacaftor A 6-month study in Tg.rasH2 transgenic mice showed no evidence of tumorigenicity at 50 mg/kg/day dose, the highest dose tested. A two-year study was conducted in rats to assess the carcinogenic potential of elexacaftor.

No evidence of tumorigenicity was observed in rats at elexacaftor oral doses up to 10 mg/kg/day (approximately 2 and 5 times the MRHD based on summed AUCs of elexacaftor and its metabolite in male and female rats, respectively). Elexacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene variant, in vitro mammalian cell micronucleus assay in TK6 cells, and in vivo mouse micronucleus test. Elexacaftor did not cause reproductive system toxicity in male rats at 55 mg/kg/day and female rats at 25 mg/kg/day, equivalent to approximately 6 times and 4 times the MRHD, respectively (based on summed AUCs of elexacaftor and its metabolite).

Elexacaftor did not cause embryonic toxicity at 35 mg/kg/day which was the highest dose tested, equivalent to approximately 7 times the MRHD (based on summed AUCs of elexacaftor and its metabolite). Lower male and female fertility, male copulation and female conception indices were observed in males at 75 mg/kg/day and females at 35 mg/kg/day, equivalent to approximately 6 times and 7 times, respectively, the MRHD (based on summed AUCs of elexacaftor and its metabolite). Tezacaftor A two-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 1 and 2 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 variant, 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-TEZ). 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 7 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 variant, 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 7 and 5 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 5 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… [Excerpted — this section continues on DailyMed.]