Patients with Cystic Fibrosis with at Least One F508del Mutation

The safety profile of TRIKAFTA in patients with CF with at least one F508del mutation is based on data from 510 patients aged 12 years and older in two double-blind, controlled trials of 24 weeks and 4 weeks treatment duration (Trials 1 and 2, respectively). Eligible patients were also able to participate in an open-label extension safety study (up to 96 weeks of TRIKAFTA). In the two controlled trials, a total of 257 patients aged 12 years and older received at least one dose of TRIKAFTA.

In Trial 1, the proportion of patients who discontinued study drug prematurely due to adverse events was 1% for TRIKAFTA-treated patients and 0% for placebo-treated patients.

In Trial 1, serious adverse reactions that occurred more frequently in TRIKAFTA-treated patients compared to placebo were rash (1% vs <1%) and influenza (1% vs 0%). There were no deaths.

Table 4 shows adverse reactions occurring in ≥5% of TRIKAFTA-treated patients and higher than placebo by ≥1% in the 24-week, placebo-controlled, parallel-group trial (Trial 1).

Additional adverse reactions that occurred in TRIKAFTA-treated patients at a frequency of 2% to <5% and higher than placebo by ≥1% include the following: flatulence, abdominal distension, conjunctivitis, pharyngitis, respiratory tract infection, tonsillitis, urinary tract infection, c-reactive protein increased, hypoglycemia, dizziness, dysmenorrhea, acne, eczema and pruritus.

In addition, the following clinical trials have also been conducted [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3) and Clinical Studies (14)]:

• a 24-week, open-label trial in 66 patients with CF aged 6 to less than 12 years who were either homozygous for the F508del mutation or heterozygous for the F508del mutation, and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor (Trial 3).
• a 24-week, open-label trial in 75 patients with CF aged 2 to less than 6 years. Patients who had at least one F508del mutation or a mutation known to be responsive to TRIKAFTA were eligible for the study (Trial 4).

The safety profile for the CF patients enrolled in Trials 2, 3, and 4 was consistent to that observed in Trial 1.

Patients with Cystic Fibrosis with at Least One Qualifying Non-F508del Mutation

The safety of TRIKAFTA in patients with CF with at least one non-F508del mutation is based on data from 307 patients aged 6 years and older with at least one qualifying non-F508del CFTR mutation that was TRIKAFTA-responsive. Trial 5 was a randomized, double blind, placebo-controlled trial for a 24-week treatment duration in which 205 patients received at least one dose of TRIKAFTA. Eligible patients were also able to participate in an open-label extension safety study.

In Trial 5, the proportion of patients who discontinued study drug prematurely due to adverse reactions was 2% for TRIKAFTA-treated patients and 0% for placebo-treated patients.

Table 5 shows adverse reactions occurring in ≥5% of TRIKAFTA-treated patients and higher than placebo by ≥1% in the 24-week, placebo-controlled, parallel-group trial (Trial 5).

Specific Adverse Reactions

Liver Function Test Elevations

In Trial 1, the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 × ULN was 1%, 2%, and 8% in TRIKAFTA-treated patients and 1%, 1%, and 5% in placebo-treated patients. The incidence of adverse reactions of transaminase elevations (AST and/or ALT) was 11% in TRIKAFTA-treated patients and 4% in placebo-treated patients.

In Trial 1, the incidence of maximum total bilirubin elevation >2 × ULN was 4% in TRIKAFTA-treated patients and <1% in placebo-treated patients. Maximum indirect and direct bilirubin elevations >1.5 × ULN occurred in 11% and 3% of TRIKAFTA-treated patients, respectively. No TRIKAFTA-treated patients developed maximum direct bilirubin elevation >2 × ULN.

During Trial 3, in patients aged 6 to less than 12 years, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × ULN were 0%, 1.5%, and 10.6%, respectively. No TRIKAFTA-treated patients had transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN or discontinued treatment due to transaminase elevations.

During Trial 4 in patients aged 2 to less than 6 years, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × ULN were 1.3%, 2.7%, and 8.0%, respectively. No TRIKAFTA-treated patients had transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN. One patient required treatment interruption during Trial 4 and later discontinued TRIKAFTA during the open label extension due to transaminase elevations.

In Trial 5, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × ULN were 2.0%, 2.0%, and 6.3%, respectively, and led to treatment discontinuation in 0.5% and treatment interruptions in 1.5% of TRIKAFTA-treated patients. There were no transaminase elevations >3 × ULN in placebo-treated patients.

Rash

In Trial 1, the overall incidence of rash was 10% in TRIKAFTA-treated and 5% in placebo-treated patients (see Table 4). The incidence of rash was higher in female TRIKAFTA-treated patients (16%) than in male TRIKAFTA-treated patients (5%).

In Trial 5, the overall incidence of rash was 23% in TRIKAFTA-treated and 2% in placebo-treated patients (see Table 5). The incidence of rash was higher in female TRIKAFTA-treated patients (27%) than in male TRIKAFTA-treated patients (20%).

A role of hormonal contraceptives in the occurrence of rash cannot be excluded [see Drug Interactions (7.3)].

Increased Creatine Phosphokinase

In Trial 1, the incidence of maximum creatine phosphokinase elevation >5 × ULN was 10% in TRIKAFTA-treated and 5% in placebo-treated patients. Among the TRIKAFTA-treated patients with creatine phosphokinase elevation >5 × ULN, 14% (3/21) required treatment interruption and none discontinued treatment.

In Trial 5, the incidence of maximum creatine phosphokinase elevation >5 × ULN was 5.4% (11/205) in TRIKAFTA-treated patients and 1% (1/102) in placebo-treated patients. The incidence of maximum creatine phosphokinase elevation >10 × ULN was 2.4% (5/205) in TRIKAFTA-treated patients and 1% (1/102) in placebo-treated patients. There were no interruptions or discontinuations among the TRIKAFTA-treated patients with creatine phosphokinase elevation >5 × ULN. Among the TRIKAFTA-treated patients with creatine phosphokinase elevation > 10 × ULN, two patients, who had exercised within the preceding 72 hours, developed rhabdomyolysis without evidence of renal involvement resulting in treatment interruption in 1 patient.

Increased Blood Pressure

In Trial 1, the maximum increase from baseline in mean systolic and diastolic blood pressure was 3.5 mmHg and 1.9 mmHg, respectively for TRIKAFTA-treated patients (baseline: 113 mmHg systolic and 69 mmHg diastolic) and 0.9 mmHg and 0.5 mmHg, respectively for placebo-treated patients (baseline: 114 mmHg systolic and 70 mmHg diastolic).

The proportion of patients who had systolic blood pressure >140 mmHg and 10 mmHg increase from baseline on at least two occasions was 4% in TRIKAFTA-treated patients and 1% in placebo-treated patients. The proportion of patients who had diastolic blood pressure >90 mmHg and 5 mmHg increase from baseline on at least two occasions was 1% in TRIKAFTA-treated patients and 2% in placebo-treated patients.

With the exception of sex differences in rash, the safety profile of TRIKAFTA was generally similar across all subgroups of patients, including analysis by age, sex, baseline percent predicted FEV1 (ppFEV1) and geographic regions.

Hepatobiliary: liver injury, fatal liver failure, liver transplantation

Immune System Disorders: anaphylaxis, angioedema

Strong CYP3A Inducers

Concomitant use of TRIKAFTA with strong CYP3A inducers is not recommended. Elexacaftor, tezacaftor and ivacaftor are substrates of CYP3A (ivacaftor is a sensitive substrate of CYP3A). Concomitant use of CYP3A inducers may result in reduced exposures and thus reduced TRIKAFTA efficacy [see Warnings and Precautions (5.3)]. Concomitant use of ivacaftor with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor area under the curve (AUC) by 89%. Elexacaftor and tezacaftor exposures are expected to decrease during concomitant use with strong CYP3A inducers [see Clinical Pharmacology (12.3)].

Examples of strong CYP3A inducers include:

• rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin and St. John's wort (Hypericum perforatum)

Strong or Moderate CYP3A Inhibitors

The dosage of TRIKAFTA should be reduced when used concomitantly with strong CYP3A inhibitors [see Dosage and Administration (2.4) and Warnings and Precautions (5.4)]. Concomitant use with itraconazole, a strong CYP3A inhibitor, increased elexacaftor AUC by 2.8-fold and tezacaftor AUC by 4.0- to 4.5-fold. When used concomitantly with itraconazole and ketoconazole, ivacaftor AUC increased by 15.6-fold and 8.5-fold, respectively [see Clinical Pharmacology (12.3)].

Examples of strong CYP3A inhibitors include:

• ketoconazole, itraconazole, posaconazole and voriconazole
• telithromycin and clarithromycin

The dosage of TRIKAFTA should be reduced when used concomitantly with moderate CYP3A inhibitors [see Dosage and Administration (2.4) and Warnings and Precautions (5.4)]. Simulations indicated that concomitant use with moderate CYP3A inhibitors may increase elexacaftor and tezacaftor AUC by approximately 1.9- to 2.3-fold and 2.1-fold, respectively. Concomitant use of fluconazole increased ivacaftor AUC by 2.9-fold [see Clinical Pharmacology (12.3)].

Examples of moderate CYP3A inhibitors include:

• fluconazole
• erythromycin

Grapefruit

Concomitant use of TRIKAFTA with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of elexacaftor, tezacaftor and ivacaftor; therefore, food or drink containing grapefruit should be avoided during treatment with TRIKAFTA [see Dosage and Administration (2.4)].

CYP2C9 Substrates

Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during concomitant use of TRIKAFTA with warfarin is recommended. Other medicinal products for which exposure may be increased by TRIKAFTA include glimepiride and glipizide; these medicinal products should be used with caution [see Clinical Pharmacology (12.3)].

Transporters

Concomitant use of ivacaftor or tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin AUC by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor. Administration of TRIKAFTA may increase systemic exposure of medicinal products that are sensitive substrates of P-gp, which may increase or prolong their therapeutic effect and adverse reactions. When used concomitantly with digoxin or other substrates of P-gp with a narrow therapeutic index such as cyclosporine, everolimus, sirolimus and tacrolimus, caution and appropriate monitoring should be used [see Clinical Pharmacology (12.3)].

Elexacaftor and M23-ELX inhibit uptake by OATP1B1 and OATP1B3 in vitro. Concomitant use of TRIKAFTA may increase exposures of medicinal products that are substrates of these transporters, such as statins, glyburide, nateglinide and repaglinide. When used concomitantly with substrates of OATP1B1 or OATP1B3, caution and appropriate monitoring should be used [see Clinical Pharmacology (12.3)]. Bilirubin is an OATP1B1 and OATP1B3 substrate.

Ciprofloxacin

Ciprofloxacin had no clinically relevant effect on the exposure of tezacaftor or ivacaftor and is not expected to affect the exposure of elexacaftor. Therefore, no dose adjustment is necessary during concomitant administration of TRIKAFTA with ciprofloxacin [see Clinical Pharmacology (12.3)].

Hormonal Contraceptives

TRIKAFTA has been studied with ethinyl estradiol/levonorgestrel and was found to have no clinically relevant effect on the exposures of the oral contraceptive. TRIKAFTA is not expected to have an impact on the efficacy of oral contraceptives.

Hormonal contraceptives may play a role in the occurrence of rash and cannot be excluded [see Adverse Reactions (6.1)]. For patients with CF taking hormonal contraceptives who develop rash, consider interrupting TRIKAFTA and hormonal contraceptives. Following the resolution of rash, consider resuming TRIKAFTA without the hormonal contraceptives. If rash does not recur, resumption of hormonal contraceptives can be considered.

Risk Summary

There are limited and incomplete human data from clinical trials on the use of TRIKAFTA or its individual components, elexacaftor, tezacaftor and ivacaftor, in pregnant women to inform a drug-associated risk. Although there are no animal reproduction studies with the concomitant administration of elexacaftor, tezacaftor and ivacaftor, separate reproductive and developmental studies were conducted with each active component of TRIKAFTA in pregnant rats and rabbits.

In animal embryo fetal development (EFD) studies oral administration of elexacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 2 times the exposure at the maximum recommended human dose (MRHD) in rats and 4 times the MRHD in rabbits [based on summed AUCs of elexacaftor and its metabolite (for rat) and AUC of elexacaftor (for rabbit)]. Oral administration of tezacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 3 times the exposure at the MRHD in rats and 0.2 times the MRHD in rabbits (based on summed AUCs of tezacaftor and M1-TEZ). Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 5 and 14 times the exposure at the MRHD, respectively [based on summed AUCs of ivacaftor and its metabolites (for rat) and AUC of ivacaftor (for rabbit)]. No adverse developmental effects were observed after oral administration of elexacaftor, tezacaftor or ivacaftor to pregnant rats from the period of organogenesis through lactation at doses that produced maternal exposures approximately 1 time, approximately 1 time and 3 times the exposures at the MRHD, respectively [based on summed AUCs of parent and metabolite(s)] (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Risk Summary

There is no information regarding the presence of elexacaftor, tezacaftor, or ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production. Elexacaftor, tezacaftor, and ivacaftor are excreted into the milk of lactating rats (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TRIKAFTA and any potential adverse effects on the breastfed child from TRIKAFTA or from the underlying maternal condition.

Data

Juvenile Animal Toxicity Data

Findings of cataracts were observed in juvenile rats dosed from postnatal Day 7 through 35 with ivacaftor dose levels of 10 mg/kg/day and higher (0.21 times the MRHD based on systemic exposure of ivacaftor and its metabolites). This finding has not been observed in older animals [see Warnings and Precautions (5.5)].

Studies were conducted with tezacaftor in juvenile rats starting at postnatal day (PND) 21 and ranging up to PNDs 35 to 49. Findings of convulsions and death were observed in juvenile rats that received a tezacaftor dose level of 100 mg/kg/day (approximately equivalent to 1.9 times the MRHD based on summed AUCs of tezacaftor and its metabolite, M1-TEZ). A no-effect dose level was identified at 30 mg/kg/day (approximately equivalent to 0.8 times the MRHD based on summed AUCs of tezacaftor and its metabolite, M1-TEZ). Findings were dose related and generally more severe when dosing with tezacaftor was initiated earlier in the postnatal period (PND 7, which would be approximately equivalent to a human neonate). Tezacaftor and its metabolite, M1-TEZ, are substrates for P-glycoprotein. Lower brain levels of P-glycoprotein activity in younger rats resulted in higher brain levels of tezacaftor and M1-TEZ. These findings are not relevant for the indicated pediatric population, 2 years of age and older, for whom levels of P-glycoprotein activity are equivalent to levels observed in adults.

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 mutations, 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 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.

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 patients 2 years of age and older for treatment of CF with TRIKAFTA based on the presence of at least one F508del mutation or another responsive mutation in the CFTR gene (see Table 6) [see Indications and Usage (1)].

Table 6 lists CFTR mutations responsive to TRIKAFTA based on clinical response and/or in vitro data in FRT or HBE cells or based on extrapolation of efficacy.

Sweat Chloride Evaluation

In Trial 1 (patients with an F508del mutation on one allele and a mutation 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 mutation), 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 mutation or heterozygous for the F508del mutation and a mutation 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 mutation or a mutation 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 mutation), 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.

Specific Populations

Drug Interaction Studies

Drug interaction studies were performed with elexacaftor, tezacaftor and/or ivacaftor and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies [see Drug Interactions (7)].

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 mutation, 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 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-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 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 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 toxicity.

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 ppFEV1 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 ppFEV1 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 ppFEV1 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 ppFEV1 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 ppFEV1 from baseline through Week 24 was 14.3 percentage points (95% CI: 12.7, 15.8; P<0.0001). Mean improvement in ppFEV1 was observed at the first assessment on Day 15 and sustained through the 24-week treatment period (see Figure 1). Improvements in ppFEV1 were observed regardless of age, baseline ppFEV1, sex and geographic region. See Table 11 for a summary of primary and key secondary outcomes in Trial 1.

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

Trial 2

Trial 2 evaluated 107 patients with CF aged 12 years and older (mean age 28.4 years). The mean ppFEV1 at baseline, following the 4-week, open-label run-in period with tezacaftor/ivacaftor was 60.9% (range: 35.0%, 89.0%). The primary endpoint was mean absolute change in ppFEV1 from baseline at Week 4 of the double-blind treatment period. The key secondary efficacy endpoints were absolute change in sweat chloride and CFQ-R respiratory domain score from baseline at Week 4. Treatment with TRIKAFTA compared to tezacaftor/ivacaftor resulted in a statistically significant improvement in ppFEV1 of 10.0 percentage points (95% CI: 7.4, 12.6; P<0.0001). Mean improvement in ppFEV1 was observed at the first assessment on Day 15. Improvements in ppFEV1 were observed regardless of age, sex, baseline ppFEV1 and geographic region. See Table 12 for a summary of primary and key secondary outcomes.