SYMDEKO Tezacaftor and Ivacaftor Kit — NDC 51167-113-01 (Billing 51167-0113-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Tezacaftor facilitates the cellular processing and trafficking of select mutant forms of CFTR (including F508del-CFTR) to increase the amount of mature CFTR protein delivered 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. For ivacaftor to function CFTR protein must be present at the cell surface.

Ivacaftor can potentiate the CFTR protein delivered to the cell surface by tezacaftor, leading to a further enhancement of chloride transport than either agent alone. The combined effect of tezacaftor and ivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increases in chloride transport. CFTR Chloride Transport Assay in Fischer Rat Thyroid (FRT) cells expressing mutant CFTR The chloride transport response of mutant CFTR protein to tezacaftor/ivacaftor was determined in Ussing chamber electrophysiology studies using a panel of FRT cell lines transfected with individual CFTR mutations.

Tezacaftor/ivacaftor increased chloride transport in FRT cells expressing CFTR mutations that result in CFTR protein being delivered to the cell surface. The in vitro chloride transport response threshold was designated as a net increase of at least 10% of normal over baseline because it is predictive or reasonably expected to predict clinical benefit. For individual mutations, the magnitude of the net change over baseline in CFTR-mediated chloride transport in vitro is not correlated with the magnitude of clinical response.

Note that splice site mutations cannot be studied in the FRT assay. Table 6 lists responsive CFTR mutations based on (1) a clinical FEV 1 response and/or (2) in vitro data in FRT cells, indicating that tezacaftor/ivacaftor increases chloride transport to at least 10% of normal over baseline. CFTR gene mutations that are not responsive to ivacaftor alone are not expected to respond to SYMDEKO except for F508del homozygotes.

Table 6: List of CFTR Gene Mutations that Produce CFTR Protein and are Responsive to SYMDEKO 546insCTA E92K G576A L346P R117G S589N 711+3A→G Clinical data for these mutations in Clinical Studies [see Clinical Studies (14.1 and 14.2) ] . E116K G576A;R668C Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele. L967S R117H S737F 2789+5G→A E193K G622D L997F R117L S912L 3272-26A→G E403D G970D L1324P R117P S945L 3849+10kbC→T E588V G1069R L1335P R170H S977F A120T E822K G1244E L1480P R258G S1159F A234D E831X G1249R M152V R334L S1159P A349V F191V G1349D M265R R334Q S1251N A455E F311del H939R M952I R347H S1255P A554E F311L H1054D M952T R347L T338I A1006E F508C H1375P P5L R347P T1036N A1067T F508C;S1251N I148T P67L R352Q T1053I D110E F508del A patient must have two copies of the F508del mutation or at least one copy of a responsive mutation presented in Table 6 to be indicated.

I175V P205S R352W V201M D110H F575Y I336K Q98R R553Q V232D D192G F1016S I601F Q237E R668C V562I D443Y F1052V I618T Q237H R751L V754M D443Y;G576A;R668C F1074L I807M Q359R R792G V1153E D579G F1099L I980K Q1291R R933G V1240G D614G G126D I1027T R31L R1066H V1293G D836Y G178E I1139V R74Q R1070Q W1282R D924N G178R I1269N R74W R1070W Y109N D979V G194R I1366N R74W;D1270N R1162L Y161S D1152H G194V K1060T R74W;V201M R1283M Y1014C D1270N G314E L15P R74W;V201M;D1270N R1283S Y1032C E56K G551D L206W R75Q S549N E60K G551S L320V R117C S549R

12.2Pharmacodynamics Effects on Sweat Chloride In Trial 1 (patients aged 12 years and older who were homozygous for the F508del mutation), the treatment difference between SYMDEKO and placebo in mean absolute change from baseline in sweat chloride through Week 24 was -10.1 mmol/L (95% CI: -11.4, -8.8). In Trial 2 (patients aged 12 years and older who were heterozygous for the F508del mutation… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Tezacaftor facilitates the cellular processing and trafficking of select mutant forms of CFTR (including F508del-CFTR) to increase the amount of mature CFTR protein delivered 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. For ivacaftor to function CFTR protein must be present at the cell surface.

Ivacaftor can potentiate the CFTR protein delivered to the cell surface by tezacaftor, leading to a further enhancement of chloride transport than either agent alone. The combined effect of tezacaftor and ivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increases in chloride transport. CFTR Chloride Transport Assay in Fischer Rat Thyroid (FRT) cells expressing mutant CFTR The chloride transport response of mutant CFTR protein to tezacaftor/ivacaftor was determined in Ussing chamber electrophysiology studies using a panel of FRT cell lines transfected with individual CFTR mutations.

Tezacaftor/ivacaftor increased chloride transport in FRT cells expressing CFTR mutations that result in CFTR protein being delivered to the cell surface. The in vitro chloride transport response threshold was designated as a net increase of at least 10% of normal over baseline because it is predictive or reasonably expected to predict clinical benefit. For individual mutations, the magnitude of the net change over baseline in CFTR-mediated chloride transport in vitro is not correlated with the magnitude of clinical response.

Note that splice site mutations cannot be studied in the FRT assay. Table 6 lists responsive CFTR mutations based on (1) a clinical FEV 1 response and/or (2) in vitro data in FRT cells, indicating that tezacaftor/ivacaftor increases chloride transport to at least 10% of normal over baseline. CFTR gene mutations that are not responsive to ivacaftor alone are not expected to respond to SYMDEKO except for F508del homozygotes.

Table 6: List of CFTR Gene Mutations that Produce CFTR Protein and are Responsive to SYMDEKO 546insCTA E92K G576A L346P R117G S589N 711+3A→G Clinical data for these mutations in Clinical Studies [see Clinical Studies (14.1 and 14.2) ] . E116K G576A;R668C Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele. L967S R117H S737F 2789+5G→A E193K G622D L997F R117L S912L 3272-26A→G E403D G970D L1324P R117P S945L 3849+10kbC→T E588V G1069R L1335P R170H S977F A120T E822K G1244E L1480P R258G S1159F A234D E831X G1249R M152V R334L S1159P A349V F191V G1349D M265R R334Q S1251N A455E F311del H939R M952I R347H S1255P A554E F311L H1054D M952T R347L T338I A1006E F508C H1375P P5L R347P T1036N A1067T F508C;S1251N I148T P67L R352Q T1053I D110E F508del A patient must have two copies of the F508del mutation or at least one copy of a responsive mutation presented in Table 6 to be indicated.

I175V P205S R352W V201M D110H F575Y I336K Q98R R553Q V232D D192G F1016S I601F Q237E R668C V562I D443Y F1052V I618T Q237H R751L V754M D443Y;G576A;R668C F1074L I807M Q359R R792G V1153E D579G F1099L I980K Q1291R R933G V1240G D614G G126D I1027T R31L R1066H V1293G D836Y G178E I1139V R74Q R1070Q W1282R D924N G178R I1269N R74W R1070W Y109N D979V G194R I1366N R74W;D1270N R1162L Y161S D1152H G194V K1060T R74W;V201M R1283M Y1014C D1270N G314E L15P R74W;V201M;D1270N R1283S Y1032C E56K G551D L206W R75Q S549N E60K G551S L320V R117C S549R

12.3Pharmacokinetics The pharmacokinetics of tezacaftor and ivacaftor are similar between healthy adult volunteers and patients with CF. Following once-daily dosing of tezacaftor and twice-daily dosing of ivacaftor in patients with CF, plasma concentrations of tezacaftor and ivacaftor reach steady-state within 8 days and within 3 to 5 days, respectively, after starting treatment. At steady-state, the accumulation ratio is approximately 1.5 for tezacaftor and 2.2 for ivacaftor.

Exposures of tezacaftor (administered alone or in combination with ivacaftor) increase in an approximately dose-proportional manner with increasing doses from 10 mg to 300 mg once daily. Key pharmacokinetic parameters for tezacaftor and ivacaftor at steady state are shown in Table 7. Table 7: Mean (SD) Pharmacokinetic Parameters of Tezacaftor and Ivacaftor at Steady State in Patients with CF Drug C max (mcg/mL) Effective t ½ (h) AUC 0-24h or AUC 0-12h (mcg∙h/mL) AUC 0-24h for tezacaftor and AUC 0-12h for ivacaftor Tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours Tezacaftor 5.95 (1.50) 15.0 (3.44) 84.5 (27.8) Ivacaftor 1.17 (0.424) 13.7 (6.06) 11.3 (4.60) Absorption After a single dose in healthy subjects in the fed state, tezacaftor was absorbed with a median (range) time to maximum concentration (t max ) of approximately 4 hours (2 to 6 hours).

The median (range) t max of ivacaftor was approximately 6 hours (3 to 10 hours) in the fed state. When a single dose of tezacaftor/ivacaftor was administered with fat-containing foods, tezacaftor exposure was similar and ivacaftor exposure was approximately 3 times higher than when taken in a fasting state. Distribution Tezacaftor is approximately 99% bound to plasma proteins, primarily to albumin.

Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. After oral administration of tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours in patients with CF in the fed state, the mean (±SD) for apparent volume of distribution of tezacaftor and ivacaftor was 271 (157) L and 206 (82.9) L, respectively. Neither tezacaftor nor ivacaftor partition preferentially into human red blood cells.

Elimination After oral administration of tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours in patients with CF in the fed state, the mean (±SD) for apparent clearance values of tezacaftor and ivacaftor were 1.31 (0.41) and 15.7 (6.38) L/h, respectively. After steady-state dosing of tezacaftor in combination with ivacaftor in patients with CF, the effective half-lives of tezacaftor and ivacaftor were approximately 15 (3.44) and 13.7 (6.06) hours, respectively. Metabolism Tezacaftor is metabolized extensively in humans.

In vitro data suggested that tezacaftor is metabolized mainly by CYP3A4 and CYP3A5. Following oral administration of a single dose of 100 mg 14 C-tezacaftor to healthy male subjects, M1, M2, and M5 were the three major circulating metabolites of tezacaftor in humans. M1 has the similar potency to that of tezacaftor and is considered pharmacologically active.

M2 is much less pharmacologically active than tezacaftor or M1, and M5 is not considered pharmacologically active. Another minor circulating metabolite, M3, is formed by direct glucuronidation of tezacaftor. Ivacaftor is also metabolized extensively in humans.

In vitro and in vivo data indicate that ivacaftor is metabolized primarily by CYP3A4 and CYP3A5. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active.

M6 is not considered pharmacologically active. Excretion Following oral administration of 14 C-tezacaftor, the majority of the dose (72%) was excreted in the feces (unchanged or as the M2 metabolite) and about 14% was recovered in urine (mostly as M2 metabolite), resulting in a mean overall recovery of 86% up to 21 days after the dose. Less than 1% of the administrated dose… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Effects on Sweat Chloride In Trial 1 (patients aged 12 years and older who were homozygous for the F508del mutation), the treatment difference between SYMDEKO and placebo in mean absolute change from baseline in sweat chloride through Week 24 was -10.1 mmol/L (95% CI: -11.4, -8.8). In Trial 2 (patients aged 12 years and older who were heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor), the treatment difference in mean absolute change from baseline in sweat chloride through Week 8 was -9.5 mmol/L (95% CI: -11.7, -7.3) between SYMDEKO and placebo, and -4.5 mmol/L (95% CI: -6.7, -2.3) between ivacaftor and placebo.

In Trial 4 (patients aged 6 to less than 12 years) a reduction in sweat chloride was observed from baseline through Week 4 and sustained throughout the 24-week treatment period. Mean absolute change in sweat chloride from baseline through Week 24 was -14.5 mmol/L (95% CI: -17.4, -11.6). Cardiac Electrophysiology At a dose 3 times the maximum approved recommended dose, tezacaftor does not prolong the QT interval to any clinically relevant extent.

In a separate study of ivacaftor evaluating doses up to 3 times the maximum approved recommended dose, ivacaftor does not prolong the QT interval to any clinically relevant extent.

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 ppFEV 1 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 aged 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 ppFEV 1 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.

14.1Trial 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 aged 12 years and older (mean age 26.3 years). The mean ppFEV 1 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 ppFEV 1 through Week 24.

Treatment with SYMDEKO resulted in a statistically significant improvement in ppFEV 1 . The treatment difference between SYMDEKO and placebo for the mean absolute change in ppFEV 1 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 1).

Improvements in ppFEV 1 were observed regardless of age, sex, baseline ppFEV 1 , 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 ppFEV 1 through Week 24; number of pulmonary exacerbations from baseline through Week 24;… [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 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).