A Phase 1, First-in-human Study of VX-433

A Phase 1, First-in-human Study Evaluating the Safety, Tolerability, and Pharmacokinetics of VX-433 and Its Effects on the Pharmacokinetics of Midazolam and Bupropion

The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of VX-433 following single and multiple ascending doses, as well as to assess the effect of VX-433 on the PK of midazolam, bupropion, and hydroxybupropion.

Study Overview

• Status: Not yet recruiting
• Conditions: Narcolepsy Type 1 (NT1)
• Intervention / Treatment: Drug: Placebo; Drug: Midazolam; Drug: VX-433; Drug: Bupropion

Detailed Description

The study is being conducted in healthy participants to evaluate the safety, tolerability, and PK of VX-433 (Parts A and B), as well as potential drug-drug interaction (DDI) between VX-433 and midazolam or bupropion (Part C).

Note: This clinical trial information was submitted voluntarily under the applicable law and, therefore, certain submission deadlines may not apply. (That is, clinical trial information for this applicable clinical trial was submitted under section 402(j)(4)(A) of the Public Health Service Act and 42 CFR 11.60 and is not subject to the deadlines established by sections 402(j)(2) and (3) of the Public Health Service Act or 42 CFR 11.24 and 11.44.).

• Study Type: Interventional
• Enrollment (Estimated): 118
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Medical Information; Phone Number: 617-341-6777; Email: medicalinfo@vrtx.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Key Inclusion Criteria:

• Body mass index (BMI) of 18.0 to 30.0 kilogram per meter square (kg/m2), inclusive
• A total body weight of more than (>) 50 kg
• Nonsmoker or ex-smoker for at least 3 months before screening with current nonsmoking status confirmed by urine or blood cotinine at screening

Key Exclusion Criteria:

• History of febrile illness or other acute illness that has not fully resolved within 14 days before the first dose of study drug
• Any condition possibly affecting drug absorption
• For female participants: of childbearing potential, pregnant, breastfeeding, or planning to become pregnant or donate ova during the study or within 90 days after last dose of study drug

Other protocol defined Inclusion/Exclusion criteria will apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: Single Ascending Dose (SAD); Participants will be randomized to receive a single dose of VX-433.	Drug: VX-433; Suspension for Oral Administration
Placebo Comparator: Part A: Placebo; Participants will be randomized to receive placebo matched to VX-433.	Drug: Placebo; Suspension for Oral Administration
Experimental: Part B: Multiple Ascending Dose (MAD); Participants will be randomized to receive multiple doses of VX-433.	Drug: VX-433; Suspension for Oral Administration
Placebo Comparator: Part B: Placebo; Participants will be randomized to receive placebo matched to VX-433.	Drug: Placebo; Suspension for Oral Administration
Experimental: Part C: Drug Drug Interaction; Participants will receive a single dose of midazolam and bupropion on Day 1 in Dosing Period 1, followed by VX-433 administration for 17 days (Days 5 through 21) and then midazolam and bupropion on Day 18 in Dosing Period 2. Part C will be open-label.	Drug: Midazolam; Syrup for Oral Administration; Drug: VX-433; Suspension for Oral Administration; Drug: Bupropion; Capsule for Oral Administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Part A: Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	From Day 1 up to Day 6
Part B: Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	From Day 1 up to Day 18
Part C: Maximum Observed Plasma Concentration (Cmax) of Midazolam in the Absence and Presence of VX-433	From Day 1 up to Day 22
Part C: Maximum Observed Plasma Concentration (Cmax) of Bupropion and Hydroxybupropion in the Absence and Presence of VX-433	From Day 1 up to Day 22
Part C: Area Under the Concentration Versus Time Curve (AUC) of Midazolam in the Absence and Presence of VX-433	From Day 1 up to Day 22
Part C: Area Under the Concentration Versus Time Curve (AUC) of Bupropion and Hydroxybupropion in the Absence and Presence of VX-433	From Day 1 up to Day 22

Secondary Outcome Measures

Outcome Measure	Time Frame
Part A: Maximum Observed Plasma Concentration (Cmax) of VX-433	From Day 1 up to Day 6
Part B: Maximum Observed Plasma Concentration (Cmax) of VX-433	From Day 1 up to Day 18
Part A: Area Under the Concentration Versus Time Curve (AUC) of VX-433	From Day 1 up to Day 6
Part B: Area Under the Concentration Versus Time Curve (AUC) of VX-433	From Day 1 up to Day 18
Part A: Time Required for Plasma Concentration of VX-433 to Reduce to Half (t1/2)	From Day 1 up to Day 6
Part B: Time Required for Plasma Concentration of VX-433 to Reduce to Half (t1/2)	From Day 1 up to Day 18
Part A: Renal Clearance (CLr) of VX-433	From Day 1 up to Day 2
Part B: Renal Clearance (CLr) of VX-433	From Day 1 up to Day 11
Part A: Amount of VX-433 excreted in Urine	From Day 1 up to Day 2
Part B: Amount of VX-433 excreted in Urine	From Day 1 up to Day 11
Part C: Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	From Day 1 up to Day 29

Collaborators and Investigators

• Sponsor: Vertex Pharmaceuticals Incorporated

Study record dates

Study Major Dates

• Study Start (Estimated): May 12, 2026
• Primary Completion (Estimated): March 5, 2027
• Study Completion (Estimated): March 5, 2027

Study Registration Dates

• First Submitted: May 6, 2026
• First Submitted That Met QC Criteria: May 6, 2026
• First Posted (Actual): May 13, 2026

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 6, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzazepines; Benzodiazepines; Ketones; Propiophenones; Midazolam; Bupropion
• Other Study ID Numbers: VX25-433-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Details on Vertex data sharing criteria and process for requesting access can be found at: https://www.vrtx.com/our-science/clinical-trials-data-sharing/

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No