Study of VX-121 in Healthy Subjects and in Subjects With Cystic Fibrosis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate safety and tolerability of VX-121 in healthy subjects and in subjects with cystic fibrosis (CF).

Official Title
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A Phase 1/2 Study of VX-121 in Healthy Subjects and in Subjects With Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Placebo (matched to VX-121 suspension)
* Drug: VX-121 (Suspension)
* Drug: TEZ/IVA
* Drug: IVA
* Drug: Placebo (matched to TEZ/IVA)
* Drug: Placebo (matched to IVA)
* Drug: VX-121 (Tablet)
* Drug: Placebo (matched to VX-121 tablet)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Part A, B, and C: Healthy Volunteers 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 Part D: Subjects with CF Heterozygous for F508del and an MF mutation (F/MF) FEV1 value ≥40% and ≤90% of predicted mean for age, sex, and height Body weight ≥35 kg Key Exclusion Criteria: Part A, B and C: Healthy Volunteers Any condition possibly affecting drug absorption History of febrile illness or other acute illness within 5 days before the first study drug dose Part D: Subjects with CF History of clinically significant cirrhosis with or without portal hypertension History of solid organ or hematological transplantation Lung infection with organisms associated with a more rapid decline in pulmonary status 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: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Part A: Pooled Placebo (Cohorts A1-5; Except A3)<br>Participants received single dose of placebo matched to VX-121. | Drug: Placebo (matched to VX-121 suspension)<br>* Placebo matched to VX-121 suspension for oral administration.<br>|
| Experimental: Part A: VX-121 (Cohort A1)<br>Participants received single dose of VX-121 10 milligrams (mg). | Drug: VX-121 (Suspension)<br>* Suspension for oral administration.<br>|
| Experimental: Part A: VX-121 (Cohort A2)<br>Participants received single dose of VX-121 20 mg. | Drug: VX-121 (Suspension)<br>* Suspension for oral administration.<br>|
| Experimental: Part A: VX-121 (Cohort A3)<br>Participants received single dose of VX-121 5 mg or matched placebo without milk, followed by open label VX-121 5 mg with milk. | Drug: Placebo (matched to VX-121 suspension)<br>* Placebo matched to VX-121 suspension for oral administration.<br>Drug: VX-121 (Suspension)<br>* Suspension for oral administration.<br>|
| Experimental: Part A: VX-121 (Cohort A4)<br>Participants received single dose of VX-121 40 mg. | Drug: VX-121 (Suspension)<br>* Suspension for oral administration.<br>|
| Experimental: Part A: VX-121 (Cohort A5)<br>Participants received single dose of VX-121 60 mg. | Drug: VX-121 (Suspension)<br>* Suspension for oral administration.<br>|
| Experimental: Part A: VX-121 (Cohort A9)<br>Participants received single dose of VX-121 10 mg suspension on Day 1, VX-121 10 mg tablet on Day 9, followed by VX-121 10 mg tablet with milk on Day 17. | Drug: VX-121 (Suspension)<br>* Suspension for oral administration.<br>Drug: VX-121 (Tablet)<br>* Tablet for oral administration.<br>|
| Placebo Comparator: Part B: Pooled Placebo (Cohorts B1-4)<br>Participants received placebo matched to VX-121 for 10 days. | Drug: Placebo (matched to VX-121 suspension)<br>* Placebo matched to VX-121 suspension for oral administration.<br>|
| Experimental: Part B: VX-121 (Cohort B1)<br>Participants received VX-121 10 mg once daily (qd) for 10 days. | Drug: VX-121 (Suspension)<br>* Suspension for oral administration.<br>|
| Experimental: Part B: VX-121 (Cohort B2)<br>Participants received VX-121 20 mg qd for 10 days. | Drug: VX-121 (Suspension)<br>* Suspension for oral administration.<br>|
| Experimental: Part B: VX-121 (Cohort B3)<br>Participants received VX-121 40 mg qd for 10 days. | Drug: VX-121 (Suspension)<br>* Suspension for oral administration.<br>|
| Experimental: Part B: VX-121 (Cohort B4)<br>Participants received VX-121 60 mg qd for 10 days. | Drug: VX-121 (Suspension)<br>* Suspension for oral administration.<br>|
| Placebo Comparator: Part C: Pooled Placebo (Cohorts C1-3)<br>Participants received placebo matched to VX-121/TEZ/IVA for 14 days. | Drug: Placebo (matched to VX-121 suspension)<br>* Placebo matched to VX-121 suspension for oral administration.<br>Drug: Placebo (matched to TEZ/IVA)<br>* Placebo matched to TEZ/IVA for oral administration.<br>Drug: Placebo (matched to IVA)<br>* Placebo matched to IVA for oral administration.<br>|
| Experimental: Part C: VX-121 (Cohort C1)<br>Participants received VX-121 10 mg qd/TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) for 14 days. | Drug: VX-121 (Suspension)<br>* Suspension for oral administration.<br>Drug: TEZ/IVA<br>* Fixed-dose combination tablet for oral administration.<br>* Other names: tezacaftor/ivacaftor;Drug: IVA<br>* Tablet for oral administration.<br>* Other names: ivacaftor;|
| Experimental: Part C: VX-121 (Cohort C2)<br>Participants received VX-121 20 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 14 days. | Drug: VX-121 (Suspension)<br>* Suspension for oral administration.<br>Drug: TEZ/IVA<br>* Fixed-dose combination tablet for oral administration.<br>* Other names: tezacaftor/ivacaftor;Drug: IVA<br>* Tablet for oral administration.<br>* Other names: ivacaftor;|
| Experimental: Part C: VX-121 (Cohort C3)<br>Participants received VX-121 5 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 14 days. | Drug: VX-121 (Suspension)<br>* Suspension for oral administration.<br>Drug: TEZ/IVA<br>* Fixed-dose combination tablet for oral administration.<br>* Other names: tezacaftor/ivacaftor;Drug: IVA<br>* Tablet for oral administration.<br>* Other names: ivacaftor;|
| Placebo Comparator: Part D: Placebo<br>Participants received placebo matched to VX-121/TEZ/IVA for 4 weeks. | Drug: Placebo (matched to TEZ/IVA)<br>* Placebo matched to TEZ/IVA for oral administration.<br>Drug: Placebo (matched to IVA)<br>* Placebo matched to IVA for oral administration.<br>Drug: Placebo (matched to VX-121 tablet)<br>* Placebo matched to VX-121 tablet for oral administration.<br>|
| Experimental: Part D: VX-121/TEZ/IVA<br>Participants received VX-121 5 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks. | Drug: TEZ/IVA<br>* Fixed-dose combination tablet for oral administration.<br>* Other names: tezacaftor/ivacaftor;Drug: IVA<br>* Tablet for oral administration.<br>* Other names: ivacaftor;Drug: VX-121 (Tablet)<br>* Tablet for oral administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | From Day 1 Through Safety Follow-up (up to Day 15 for Part A [except Cohorts A3 and A9], up to Day 26 for Cohort A3, up to Day 34 for Cohort A9, up to Day 20 for Part B, up to Day 24 for Part C and up to Week 9 for Part D) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Maximum Observed Concentration (Cmax) of VX-121 |  | Cohorts A1-5 (Except A3): Pre-dose up to 240 hours post-dose; Cohorts A3 and A9: Pre-dose up to 168 hours post-dose | 
| Part A: Area Under the Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration (AUC[0-last]) of VX-121 |  | Cohorts A1-5 (Except A3): Pre-dose up to 240 hours post-dose; Cohorts A3 and A9: Pre-dose up to 168 hours post-dose | 
| Part B: Maximum Observed Concentration (Cmax) of VX-121 |  | Day 1, Day 5, and Day 10 | 
| Part B: Area Under the Concentration Versus Time Curve During the Dosing Interval (AUCtau) of VX-121 |  | Day 1, Day 5, and Day 10 | 
| Part B: Observed Pre-dose Plasma Concentration (Ctrough) of VX-121 |  | Pre-dose at Day 5 and Day 10 | 
| Part C: Maximum Observed Concentration (Cmax) of VX-121, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) and, IVA and Its Metabolites (M1-IVA and M6-IVA) |  | Day 1, Day 7, and Day 14 | 
| Part C: Area Under the Concentration Versus Time Curve During a Dosing Interval (AUCtau) of VX-121, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) and IVA and Its Metabolites (M1-IVA and M6-IVA) |  | Day 1, Day 7, and Day 14 | 
| Part C: Pre-dose Plasma Concentration (Ctrough) of VX-121, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) and IVA and Its Metabolites (M1-IVA and M6-IVA) |  | Pre-dose at Day 7 and Day 14 | 
| Part D: Maximum Observed Concentration (Cmax) of VX-121, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) and IVA and Its Metabolites (M1-IVA and M6-IVA) |  | Day 1 and Day 15 | 
| Part D: Area Under the Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration (AUC[0-last]) of VX-121, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) and IVA and Its Metabolites (M1-IVA and M6-IVA) |  | Day 1 and Day 15 | 
| Part D: Pre-dose Plasma Concentration (Ctrough) of VX-121, TEZ and Its Metabolites (M1-TEZ and M2-TEZ) and IVA and Its Metabolites (M1-IVA and M6-IVA) |  | Pre-dose at Day 8, Day 15, and Day 29 | 
| Part D: Absolute Change in Sweat Chloride (SwCl) Concentrations | Sweat samples were collected using an approved collection device. | From Baseline Through Day 29 | 
| 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 |