Tezacaftor and Ivacaftor

SYMDEKO is indicated for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence [see Clinical Pharmacology (12.1) and Clinical Studies (14) ] . If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use. SYMDEKO is a combination of tezacaftor and ivacaftor, indicated for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence. ( 12.1 , 14 ) If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use. ( 1 )

Tablets: Tezacaftor 50 mg/ivacaftor 75 mg fixed-dose combination tablets co-packaged with ivacaftor 75 mg tablets Tezacaftor 50 mg/ivacaftor 75 mg tablets are white, oblong-shaped, and debossed with "V50" on one side and plain on the other. Ivacaftor 75 mg tablets are light blue, oblong-shaped, and printed with "V 75" in black ink on one side and plain on the other. Tablets: Tezacaftor 100 mg/ivacaftor 150 mg fixed-dose combination tablets co-packaged with ivacaftor 150 mg tablets Tezacaftor 100 mg/ivacaftor 150 mg tablets are yellow, oblong-shaped, and debossed with "V100" on one side and plain on the other. Ivacaftor 150 mg tablets are light blue, oblong-shaped, and printed with "V 150" in black ink on one side and plain on the other. Tablets: tezacaftor 50 mg/ivacaftor 75 mg fixed-dose combination tablets co-packaged with ivacaftor 75 mg tablets. ( 3 ) Tablets: tezacaftor 100 mg/ivacaftor 150 mg fixed-dose combination tablets co-packaged with ivacaftor 150 mg tablets. ( 3 )

None. None. ( 4 )

Elevated transaminases (ALT or AST): Transaminases (ALT and AST) should be assessed prior to initiating SYMDEKO, every 3 months during the first year of treatment, and annually thereafter. In patients with a history of transaminase elevations, more frequent monitoring should be considered. Dosing should be interrupted in patients with significant elevations of transaminases, e.g., patients with ALT or AST >5 × upper limit of normal (ULN), or ALT or AST >3 × ULN with bilirubin >2 × ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming treatment. ( 5.1 , 6 ) Hypersensitivity reactions: Anaphylaxis has been reported with SYMDEKO in the postmarketing setting. Initiate appropriate therapy in the event of a hypersensitivity reaction. ( 5.2 ) Intracranial hypertension : Intracranial hypertension (IH) has been reported in the postmarketing setting with the use of drugs containing the same or similar active ingredients as SYMDEKO. If an unusual headache or visual disturbances occur during treatment, and IH is suspected, interrupt SYMDEKO and refer for prompt medical evaluation. ( 5.3 ) Neuropsychiatric events, including suicidal thoughts and behaviors : Serious neuropsychiatric events, including symptoms of anxiety, depression, suicidal ideation and behavior, and sleep disturbances, have been reported in the postmarketing setting for SYMDEKO or drugs containing the same or similar active ingredients. Monitor patients closely for new or worsening symptoms. Consider the risks and benefits for the individual patient to determine if therapy with SYMDEKO should be interrupted at the occurrence of neuropsychiatric symptoms. ( 5.4 ) Use with CYP3A inducers: Concomitant use with strong CYP3A inducers (e.g., rifampin, St. John's wort) substantially decrease exposure of ivacaftor and may decrease the exposure of tezacaftor, which may reduce therapeutic effectiveness. Therefore, co-administration is not recommended. ( 5.5 , 7.1 , 12.3 ) Cataracts: Non-congenital lens opacities/cataracts have been reported in pediatric patients treated with SYMDEKO. Baseline and follow-up examinations are recommended in pediatric patients initiating SYMDEKO treatment. ( 5.6 , 8.4 )

5.1 Transaminase (AST/ALT) Elevations Elevated transaminases have been observed in patients with CF treated with SYMDEKO, as well as with ivacaftor monotherapy. Assessments of transaminases (ALT and AST) are recommended for all patients prior to initiating SYMDEKO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations more frequent monitoring should be considered. In the event of significant elevations of transaminases, e.g., patients with ALT or AST >5 × upper limit of normal (ULN), or ALT or AST >3 × ULN with bilirubin >2 × ULN, dosing should be interrupted and laboratory tests closely followed until the abnormalities resolve. Following the resolution of transaminase elevations consider the benefits and risks of resuming treatment [see Adverse Reactions (6) ] .

5.2 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including cases of anaphylaxis, have been reported in the postmarketing setting [see Adverse Reactions (6.2) ] . If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue SYMDEKO and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with SYMDEKO.

5.3 Intracranial Hypertension Cases of intracranial hypertension (IH) have been reported in the postmarketing setting with the use of drugs containing the same or similar active ingredients as SYMDEKO [see Adverse Reactions (6.2) ] . Clinical manifestations of IH include headache, blurred vision, diplopia, and potential vision loss; papilledema can be found on fundoscopy. If an unusual headache or visual disturbances occur during treatment, and IH is suspected, interrupt SYMDEKO and refer for prompt medical evaluation. Consider the benefits and risks for the individual patient to determine whether to resume treatment with SYMDEKO. Patients should be monitored until IH resolution and for recurrence. Patients with elevated vitamin A levels may be at increased risk.

5.4 Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors Serious neuropsychiatric events, including symptoms of anxiety, depression, suicidal ideation and behavior, and sleep disturbances, have been reported in the postmarketing setting in patients taking SYMDEKO or drugs containing the same or similar active ingredients [see Adverse Reactions (6.2) ] . The events were reported in adult and pediatric patients with and without a previous history of neuropsychiatric symptoms. Symptoms may occur within the first three months of treatment initiation. Assess patients for baseline neuropsychiatric symptoms and monitor for new or worsening symptoms of anxiety, depression, suicidal ideation or behavior, or sleep disturbances. Consider the benefits and risks for the individual patient to determine if therapy with SYMDEKO should be interrupted at the occurrence of neuropsychiatric symptoms and whether to resume therapy with symptom improvement.

5.5 Concomitant Use with CYP3A Inducers Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of CYP3A inducers, which may reduce the therapeutic effectiveness of SYMDEKO. Therefore, co-administration with strong CYP3A inducers is not recommended [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) , and Patient Counseling Information (17) ] .

5.6 Cataracts Cases of non-congenital lens opacities have been reported in pediatric patients treated with SYMDEKO, as well as with ivacaftor monotherapy. Although other risk factors were present in some cases (such as corticosteroid use, exposure to radiation), a possible risk attributable to treatment with SYMDEKO cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with SYMDEKO [see Use in Specific Populations (8.4) and Patient Counseling Information (17) ] .

The following adverse reactions are discussed in greater detail in other sections of the label: Transaminase Elevations [see Warnings and Precautions (5.1) ] Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.2) ] Intracranial Hypertension [see Warnings and Precautions (5.3) ] Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.4) ] Cataracts [see Warnings and Precautions (5.6) ] The most common adverse drug reactions to SYMDEKO (occurring in ≥3% of patients) were headache, nausea, sinus congestion, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The overall safety profile of SYMDEKO is based on data from 1001 patients in three double-blind, placebo-controlled, clinical trials: two parallel-group trials of 12 and 24-week duration and one cross-over design trial of 8 weeks duration. Eligible patients were also able to participate in an open-label extension safety study (up to 96 weeks of SYMDEKO). In the three placebo-controlled trials (Trials 1, 2, and 3), a total of 496 patients with CF aged 12 years and older received at least one dose of SYMDEKO. The proportion of patients who discontinued study drug prematurely due to adverse reactions was 1.6% for SYMDEKO-treated patients and 2.0% for placebo-treated patients. Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in SYMDEKO-treated patients compared to placebo included distal intestinal obstruction syndrome, 3 (0.6%) SYMDEKO-treated patients vs. 0 placebo. There were no deaths in the placebo-controlled trials, and one death in the open-label extension study due to respiratory failure and influenza infection in a patient who had discontinued SYMDEKO seven weeks prior. The safety profile of SYMDEKO was generally similar across all subgroups of patients, including analysis by age, sex, baseline percent predicted FEV 1 (ppFEV 1 ), and geographic regions. Table 5 shows adverse reactions occurring in ≥3% of SYMDEKO-treated patients that also occurred at a higher rate than in the placebo-treated patients in the 12- and 24-week placebo-controlled, parallel-group trials (Trials 1 and 3). Table 5: Incidence of Adverse Drug Reactions in ≥3% of SYMDEKO-Treated Patients and Greater than Placebo Adverse Reactions (Preferred Term) SYMDEKO N=334 n (%) Placebo N=343 n (%) Headache 49 (15) 44 (13) Nausea 29 (9) 24 (7) Sinus congestion 13 (4) 6 (2) Dizziness 12 (4) 8 (2) The safety data from the following trials are similar to that observed in Trials 1 and 3: an 8-week randomized, double-blind, placebo-controlled crossover study in 244 patients with CF aged 12 years and older who were heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor (Trial 2). a 24-week open-label study in 70 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 second mutation predicted to be responsive to tezacaftor/ivacaftor (Trial 4). Laboratory Abnormalities Transaminase elevations During the placebo-controlled trials in patients aged 12 years and older, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × the upper limit of normal (ULN) was similar between SYMDEKO-treated patients and placebo-treated patients; 0.2%, 1.0%, and 3.4% in SYMDEKO-treated patients, and 0.4%, 1.0%, and 3.4% in placebo-treated patients. One patient (0.2%) on SYMDEKO and 2 patients (0.4%) on placebo permanently discontinued treatment for elevated transaminases. No SYMDEKO-treated patients experienced a transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN. During the 24-week, open-label study in patients aged 6 to less than 12 years (Trial 4), the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × ULN were 1.4%, 4.3%, and 10.0%, respectively. No SYMDEKO-treated patients experienced a transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN or discontinued SYMDEKO treatment due to transaminase elevations.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of SYMDEKO or drugs containing the same or similar active ingredients as SYMDEKO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders : anaphylaxis Skin : rash Nervous System Disorders : intracranial hypertension Psychiatric Disorders : anxiety, depression, suicidal ideation and behavior, insomnia

Potential for other drugs to affect tezacaftor/ivacaftor CYP3A inhibitors: Reduce SYMDEKO dosage when co-administered with strong (e.g., ketoconazole) or moderate (e.g., fluconazole) CYP3A inhibitors. Avoid food containing grapefruit. ( 2.4 , 7.2 , 12.3 )

7.1 Inducers of CYP3A 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 SYMDEKO efficacy. Co-administration of ivacaftor with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor exposure (area under the curve [AUC]) by 89%. Tezacaftor exposures can also be expected to decrease significantly during co-administration with strong CYP3A inducers. Therefore, co-administration of SYMDEKO with strong CYP3A inducers is not recommended [see Warnings and Precautions (5.5) , Clinical Pharmacology (12.3) , and Patient Counseling Information (17) ] . Examples of strong CYP3A inducers include: rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John's wort (Hypericum perforatum)

7.2 Inhibitors of CYP3A Co-administration with itraconazole, a strong CYP3A inhibitor, increased tezacaftor exposure (AUC) by 4.0-fold and ivacaftor by 15.6-fold. When co-administered with strong CYP3A inhibitors, the dosing regimen of SYMDEKO should be adjusted [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) , and Patient Counseling Information (17) ] . Examples of strong CYP3A inhibitors include: ketoconazole, itraconazole, posaconazole, and voriconazole telithromycin and clarithromycin Co-administration of fluconazole increased ivacaftor exposure (AUC) by 3.0-fold. Simulation suggested co-administration with fluconazole, a moderate CYP3A inhibitor, may increase tezacaftor exposure (AUC) by approximately 2.0-fold. When co-administered with moderate CYP3A inhibitors, the dosing regimen of SYMDEKO should be adjusted [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) , and Patient Counseling Information (17) ] . Examples of moderate CYP3A inhibitors include: fluconazole erythromycin Co-administration of SYMDEKO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of tezacaftor and ivacaftor; therefore, food or drink containing grapefruit should be avoided during treatment with SYMDEKO [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) , and Patient Counseling Information (17) ] .

7.3 Ciprofloxacin Co-administration of SYMDEKO with ciprofloxacin had no significant effect on the exposure of tezacaftor or ivacaftor. Therefore, no dosage adjustment is necessary during concomitant administration of SYMDEKO with ciprofloxacin [see Clinical Pharmacology (12.3) ] . Potential for tezacaftor/ivacaftor to affect other drugs 7.4 CYP3A Substrates Co-administration of SYMDEKO with midazolam (oral), a sensitive CYP3A substrate, did not affect midazolam exposure. No dosage adjustment of CYP3A substrates is required when co-administered with SYMDEKO [see Clinical Pharmacology (12.3) ] . 7.5 CYP2C9 Substrates Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during co-administration of SYMDEKO with warfarin is recommended. Other medicinal products for which exposure may be increased by SYMDEKO include glimepiride and glipizide; these medicinal products should be used with caution [see Clinical Pharmacology (12.3) ] .

7.6 Digoxin and Other P-gp Substrates Co-administration of SYMDEKO with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold consistent with weak inhibition of P-gp by ivacaftor. Administration of SYMDEKO 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) ] .

7.7 Hormonal Contraceptives SYMDEKO has been studied with an ethinyl estradiol/norethindrone oral contraceptive and was found to have no significant effect on the exposures of the hormonal contraceptive. SYMDEKO is not expected to modify the efficacy of hormonal contraceptives [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary There are limited and incomplete human data from clinical trials and postmarketing reports on the use of SYMDEKO or its individual components, tezacaftor and ivacaftor, in pregnant women to inform a drug-associated risk. Although there are no animal reproduction studies with the concomitant administration of tezacaftor and ivacaftor, separate reproductive and developmental studies were conducted with tezacaftor and ivacaftor in pregnant rats and rabbits. In animal reproduction studies, oral administration of tezacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse developmental effects at doses that produced maternal exposures up to approximately 3 times the exposure at the maximum recommended human dose (MRHD) in rats and 0.2 times the MRHD in rabbits (based on summed AUCs for tezacaftor and M1 metabolite). Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse developmental effects at doses that produced maternal exposures up to approximately 6 and 16 times the exposure at the MRHD, respectively. No adverse developmental effects were observed after oral administration of either tezacaftor or ivacaftor to pregnant rats from the period of organogenesis through lactation at doses that produced maternal exposures approximately 1 and 4 times the exposures at the MRHD, respectively ( 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 Animal Data Tezacaftor In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation Days 6-17, tezacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 3 times the MRHD (based on summed AUCs for tezacaftor and M1 metabolite at maternal oral doses up to 100 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation Days 7-20, tezacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 0.2 times the MRHD (based on summed AUCs for tezacaftor and M1 metabolite at maternal oral doses up to 25 mg/kg/day). Lower fetal body weights were observed in rabbits at a maternally toxic dose that produced exposures approximately 1 times the MRHD (at a maternal dose of 50 mg/kg/day). In a pre- and postnatal development (PPND) study in pregnant rats dosed from gestation Day 6 through lactation Day 18, tezacaftor had no adverse developmental effects on pups at an exposure of approximately 1 times the MRHD (based on summed AUCs for tezacaftor and M1 metabolite at a maternal dose of 25 mg/kg/day). Decreased fetal body weights and early developmental delays in pinna detachment, eye opening, and righting reflex occurred at a maternally toxic dose (based on maternal weight loss) that produced exposures approximately 2 times the exposure at the MRHD (based on summed AUCs for tezacaftor and M1 metabolite at a maternal oral dose of 50 mg/kg/day). Placental transfer of tezacaftor was observed in pregnant rats. Ivacaftor In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation Days 7-17, ivacaftor was not teratogenic and did not affect fetal survival at exposures up to 6 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at a maternal oral dose of 200 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation Days 7-19, ivacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 16 times the MRHD (on an ivacaftor AUC basis at maternal oral doses up to 100 mg/kg/day). In a PPND study in pregnant rats dosed from gestation Day 7 through lactation Day 20, ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 4 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose that produced exposures 6 times the MRHD. Placental transfer of ivacaftor was observed in pregnant rats and rabbits.

8.2 Lactation Risk Summary There is no information regarding the presence of tezacaftor or ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production. Both 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 SYMDEKO and any potential adverse effects on the breastfed child from SYMDEKO or from the underlying maternal condition. Data Tezacaftor Lacteal excretion of tezacaftor in rats was demonstrated following a single oral dose (30 mg/kg) of 14 C-tezacaftor administered 6 to 10 days postpartum to lactating dams. Exposure of 14 C-tezacaftor in milk was approximately 3 times higher than in plasma (based on AUC 0-72h ). Ivacaftor Lacteal excretion of ivacaftor in rats was demonstrated following a single oral dose (100 mg/kg) of 14 C-ivacaftor administered 9 to 10 days postpartum to lactating dams. Exposure of 14 C-ivacaftor in milk was approximately 1.5 times higher than in plasma (based on AUC 0-24h ).

8.4 Pediatric Use The safety and effectiveness of SYMDEKO for the treatment of CF have been established in pediatric patients aged 6 to less than 18 years who are homozygous for the F508del mutation or who have at least one mutation in the CFTR gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence [see Clinical Pharmacology (12.1) and Clinical Studies (14) ]. Clinical trials included the following patients with CF: 12 to less than 18 years of age who are homozygous for the F508del mutation [see Adverse Reactions (6) and Clinical Studies (14) ] . 12 to less than 18 years of age who are heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor [see Adverse Reactions (6) and Clinical Studies (14) ] . 6 to less than 12 years of age who are either homozygous for the F508del mutation or heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor [see Adverse Reactions (6) and Clinical Pharmacology (12) ]. The effectiveness of SYMDEKO in patients aged 6 to less than 12 years was extrapolated from patients aged 12 years and older with support from population pharmacokinetic analyses showing similar tezacaftor and ivacaftor exposure levels in patients aged 6 to less than 12 years and in patients aged 12 years and older [see Clinical Pharmacology (12.3) ] . Safety of SYMDEKO in this population was derived from a 24-week, open-label, clinical trial in 70 patients aged 6 to less than 12 years (mean age at screening 8.1 years) administered either tezacaftor 50 mg/ivacaftor 75 mg and ivacaftor 75 mg or tezacaftor 100 mg/ivacaftor 150 mg and ivacaftor 150 mg, 12 hours apart (Trial 4). The safety profile for patients in this trial was similar to that observed in Trials 1 and 3 [see Adverse Reactions (6.1) ]. The safety and effectiveness of SYMDEKO in patients with CF younger than 6 years of age have not been studied. 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 (0.25 times the MRHD based on systemic exposure of ivacaftor and its metabolites). This finding has not been observed in older animals. […]

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