A Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis

Study Overview
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Brief Summary
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This is a first-in-human and proof-of-concept study of VX-445. The study includes 6 parts. Parts A, B, and C were conducted in healthy subjects. Parts D, E, and F were conducted in subjects with Cystic Fibrosis (CF) who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F/F genotype), or who are heterozygous for the F508del mutation and a minimal function (MF) CFTR mutation not likely to respond to TEZ, IVA, or TEZ/IVA (F/MF genotypes).

Official Title
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A Phase 1/2 Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: IVA
* Drug: TEZ/IVA
* Drug: VX-445
* Drug: Matched Placebo
* Drug: TEZ
* Drug: VX-561
* Drug: VX-445


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Parts A, B, and C: Female subjects must be of non-childbearing potential. Between the ages of 18 and 55 years, inclusive. Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, and a total body weight >50 kg Parts D, E, and F: Body weight ≥35 kg. Subjects must have an eligible CFTR genotype: Parts D and F: Heterozygous for F508del and an MF mutation (F/MF) Part E: Homozygous for F508del (F/F) FEV1 value ≥40% and ≤90% of predicted mean for age, sex, and height. Key Exclusion Criteria: Parts A, B, and C: Any condition possibly affecting drug absorption. History of febrile illness within 14 days before the first study drug dose. Glucose-6-phosphate dehydrogenase (G6PD) deficiency. Parts D, E, and F: History of clinically significant cirrhosis with or without portal hypertension. Glucose-6-phosphate dehydrogenase (G6PD) deficiency. Lung infection with organisms associated with a more rapid decline in pulmonary status. History of solid organ or hematological transplantation. Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Part A: Pooled Placebo (Except Cohort A7)<br>Participants without CF who received single dose of placebo matched to VX-445 in Cohort A1 to A5. | Drug: Matched Placebo<br>* Matched placebo.<br>|
| Experimental: Part A: VX-445 (Except Cohort A7)<br>Participants without CF who received single ascending dose of VX-445 tablet starting from 20 milligrams (mg) to 360 mg in Cohort A1 to A5. | Drug: VX-445<br>* VX-445 tablet for oral administration.<br>* Other names: elexacaftor;|
| Experimental: Part A: VX-445 (Cohort A7)<br>Participants without CF who received single dose of VX-445 100 mg tablet on Day 1 in fasted state and on Day 7 in fed state, followed by VX-445 20 mg intravenous (IV) injection on Day 13 in fed state in Cohort A7. | Drug: VX-445<br>* VX-445 tablet for oral administration.<br>* Other names: elexacaftor;Drug: VX-445<br>* VX-445 IV injection<br>* Other names: elexacaftor;|
| Placebo Comparator: Part B: Pooled Placebo (Cohort B1 to B4)<br>Participants without CF who received multiple doses of placebo matched to VX-445 once daily (qd) for 10 days in Cohort B1 to B4. | Drug: Matched Placebo<br>* Matched placebo.<br>|
| Experimental: Part B: VX-445 (Cohort B1 to B4)<br>Participants without CF who received VX-445 tablet qd for 10 days in Cohort B1 (60 mg), B2 (120 mg), B3 (240 mg) and B4 (340 mg). | Drug: VX-445<br>* VX-445 tablet for oral administration.<br>* Other names: elexacaftor;|
| Placebo Comparator: Part C: Pooled Placebo (Cohort C1 to C3)<br>Participants without CF who received placebo matched to VX-445/TEZ/IVA triple combination (TC) qd in the morning and placebo matched to IVA in the evening for 14 days. | Drug: Matched Placebo<br>* Matched placebo.<br>|
| Experimental: Part C: VX-445/TEZ/IVA TC (Cohort C1 to C3)<br>Participants without CF who received VX-445 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C1; VX-445 280 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C2 and VX-445 100 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C3 for 14 days. | Drug: IVA<br>* IVA tablet for oral administration<br>* Other names: ivacaftor;Drug: TEZ/IVA<br>* TEZ/IVA fixed-dose combination for oral administration.<br>* Other names: tezacaftor/ivacaftor;Drug: VX-445<br>* VX-445 tablet for oral administration.<br>* Other names: elexacaftor;|
| Placebo Comparator: Part D: Placebo<br>Participants with CF, F/MF genotype who received placebo matched to VX-445/TEZ/IVA TC qd in the morning and placebo matched to IVA qd in the evening for 4 weeks in the TC treatment period. | Drug: Matched Placebo<br>* Matched placebo.<br>|
| Experimental: Part D: VX-445/TEZ/IVA TC - Low Dose<br>Participants with CF, F/MF genotype who received VX-445 50 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period. | Drug: IVA<br>* IVA tablet for oral administration<br>* Other names: ivacaftor;Drug: TEZ/IVA<br>* TEZ/IVA fixed-dose combination for oral administration.<br>* Other names: tezacaftor/ivacaftor;Drug: VX-445<br>* VX-445 tablet for oral administration.<br>* Other names: elexacaftor;|
| Experimental: Part D: VX-445/TEZ/IVA TC - Medium Dose<br>Participants with CF, F/MF genotype who received VX-445 100 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period. | Drug: IVA<br>* IVA tablet for oral administration<br>* Other names: ivacaftor;Drug: TEZ/IVA<br>* TEZ/IVA fixed-dose combination for oral administration.<br>* Other names: tezacaftor/ivacaftor;Drug: VX-445<br>* VX-445 tablet for oral administration.<br>* Other names: elexacaftor;|
| Experimental: Part D: VX-445/TEZ/IVA TC - High Dose<br>Participants with CF, F/MF genotype who received VX-445 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period. | Drug: IVA<br>* IVA tablet for oral administration<br>* Other names: ivacaftor;Drug: TEZ/IVA<br>* TEZ/IVA fixed-dose combination for oral administration.<br>* Other names: tezacaftor/ivacaftor;Drug: VX-445<br>* VX-445 tablet for oral administration.<br>* Other names: elexacaftor;|
| Active Comparator: Part E: TEZ/IVA<br>Following run-in period of 4 weeks with TEZ/IVA, participants with CF, F/F genotype who received TEZ 100 mg qd/IVA 150 mg q12h and placebo matched to VX-445 for 4 weeks in the TC treatment period. | Drug: TEZ/IVA<br>* TEZ/IVA fixed-dose combination for oral administration.<br>* Other names: tezacaftor/ivacaftor;|
| Experimental: Part E: VX-445/TEZ/IVA TC<br>Following run-in period of 4 weeks with TEZ/IVA, participants with CF, F/F genotype who received VX-445 200 mg qd/TEZ 100 mg qd /IVA 150 mg q12h for 4 weeks in the TC treatment period. | Drug: IVA<br>* IVA tablet for oral administration<br>* Other names: ivacaftor;Drug: TEZ/IVA<br>* TEZ/IVA fixed-dose combination for oral administration.<br>* Other names: tezacaftor/ivacaftor;Drug: VX-445<br>* VX-445 tablet for oral administration.<br>* Other names: elexacaftor;|
| Placebo Comparator: Part F: Placebo<br>Participants with CF, F/MF genotype who received placebo matched to VX-445/TEZ/VX-561 for 4 weeks in the TC treatment period. | Drug: Matched Placebo<br>* Matched placebo.<br>|
| Experimental: Part F: VX-445/TEZ/VX-561 TC<br>Participants with CF, F/MF genotype who received VX-445 200 mg qd/TEZ 100 mg qd/VX-561 150 mg qd for 4 weeks in the TC treatment period. | Drug: VX-445<br>* VX-445 tablet for oral administration.<br>* Other names: elexacaftor;Drug: TEZ<br>* Tablet for oral administration.<br>* Other names: tezacaftor;Drug: VX-561<br>* Tablet for oral administration.<br>* Other names: CTP-656;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts A, B and C: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | From first dose of study drug in treatment period up to safety follow-up (up to 28 days) | 
| Parts D, E and F: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | From first dose of study drug in TC treatment period up to 28 days after last dose of study drug (up to 5 weeks) | 
| Part D: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | From Baseline through Day 29 | 
| Part E: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | From Baseline through Day 29 | 
| Part F: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | From Baseline through Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Maximum Observed Concentration (Cmax) of VX-445 |  | Cohort A1-A5: Pre-dose to 96 hours post-dose; Cohort A7: Pre-dose to 120 hours post-dose | 
| Part A: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of VX-445 |  | Cohort A1-5: Pre-dose to 96 hours post-dose; Cohort A7: Pre-dose to 120 hours post-dose | 
| Part B: Maximum Observed Concentration (Cmax) of VX-445 |  | Pre-dose to 96 hours post-dose on Day 1 and Day 10 | 
| Part B: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of VX-445 |  | Pre-dose to 96 hours post-dose on Day 1 and Day 10 | 
| Part B: Observed Pre-dose Plasma Concentration (Ctrough) of VX-445 |  | Pre-dose on Day 10 | 
| Part C: Maximum Observed Concentration (Cmax) of VX-445, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) |  | Pre-dose to 96 hours post-dose on Day 1, Day 7 and Day 14 | 
| Part C: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of VX-445, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) |  | Pre-dose to 96 hours post-dose on Day 1, Day 7 and Day 14 | 
| Part C: Maximum Observed Concentration (Cmax) of IVA and Its Metabolites (M1-IVA and M6-IVA) |  | Pre-dose to 96 hours post-dose on Day 1, Day 7 and Day 14 | 
| Part C: Area Under Plasma Concentration Time Curve From Time of Dosing to Last Measurable Concentration (AUC0-tlast) of IVA and Its Metabolites (M1-IVA and M6-IVA) |  | Pre-dose to 96 hours post-dose on Day 1, Day 7 and Day 14 | 
| Part C: Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) |  | Pre-dose on Day 7 and Day 14 | 
| Part C: Observed Pre-dose Concentration (Ctrough) of IVA and Its Metabolites (M1-IVA and M6-IVA) |  | Pre-dose on Day 7 and Day 14 | 
| Part D: Observed Pre-dose Plasma Concentration (Ctrough) of VX-445, TEZ and Its Metabolite (M1-TEZ), IVA and Its Metabolite (M1-IVA) |  | Pre-dose on Day 15 and Day 29 | 
| Part E: Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ and Its Metabolite (M1-TEZ) and IVA and Its Metabolite (M1-IVA) |  | Pre-dose on Day 15 and Day 29 | 
| Part F: Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ and Its Metabolite (M1-TEZ) and VX-561 |  | Pre-dose on Day 15 and Day 29 | 
| Part D: Absolute Change in Sweat Chloride Concentration | Sweat samples were collected using an approved collection device. | From Baseline through Day 29 | 
| Part E: Absolute Change in Sweat Chloride Concentration | Sweat samples were collected using an approved collection device. | From Baseline through Day 29 | 
| Part F: Absolute Change in Sweat Chloride Concentration | Sweat samples were collected using an approved collection device. | From Baseline through Day 29 | 
| Part D: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | From Baseline through Day 29 | 
| Part E: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | From Baseline through Day 29 | 
| Part F: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | From Baseline through Day 29 | 
| Part D: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. | From Baseline through Day 29 | 
| Part E: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. | From Baseline through Day 29 | 
| Part F: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. | From Baseline through Day 29 |