Phase 2 Randomized Double‑Blind Study of VX-828/Deutivacaftor With and Without Tezacaftor in Adults with Cystic Fibrosis

The primary objective is to assess the safety and tolerability of VX‑828 combined with deutivacaftor, with or without tezacaftor, and to determine the efficacy of these regimens in adult subjects with cystic fibrosis; establishing an acceptable safety profile and clinically meaningful therapeutic benefit is essential for further development of these CFTR modulators.

Secondary objectives focus on the pharmacokinetics of the investigational agents, specifically characterizing plasma exposure, metabolism, and elimination of VX‑828, tezacaftor, and deutivacaftor (and their metabolites) when administered as the triple combination, and evaluating the pharmacokinetic parameters of VX‑828 and deutivacaftor (and metabolites) when given without tezacaftor.

Seventy‑two participants diagnosed with cystic fibrosis were enrolled, comprising both male and female patients drawn from the predefined pediatric age categories indicated by study codes 3 and 4. Eligibility required a body weight of at least 35 kg and the ability to provide a valid sweat sample with a chloride concentration ≥30 mmol/L (sweat chloride). Confirmation of CF was based on investigator‑determined diagnosis and an eligible CFTR genotype, specifically heterozygosity for the F508del mutation with a second minimal‑function allele for parts 1 and 2, or homozygosity for F508del for parts 3 and 4, as assessed by genotype testing. Pulmonary function criteria mandated a FEV1 of ≥40 % of the predicted value, measured according to ATS/ERS standards. Participants were required to have stable disease and to remain on a consistent CF treatment regimen throughout the trial, which evaluated the safety and efficacy of the combination therapy VX-828/TEZ/D IVA. The cohort was selected by applying these inclusion parameters to individuals screened at the study sites.

The study is a Phase 2, multicenter, sweat chloride–based, randomized, double‑blind, controlled trial evaluating the safety, tolerability and efficacy of VX‑828 in combination with deutivacaftor, with and without tezacaftor, in adults with cystic fibrosis. Eligible participants undergo a screening visit to confirm weight ≥35 kg, a valid sweat‑chloride measurement (≥30 mmol/L), confirmed CFTR genotype (heterozygous F508del/minimal function or homozygous F508del), and a baseline forced expiratory volume in 1 second (FEV1) ≥40 % predicted. After randomization, subjects receive either the investigational regimen, a comparator (e.g., ivacaftor 150 mg), or matching placebos for a 28‑day treatment period. Follow‑up visits are scheduled on Day 7, Day 14, and Day 28 to assess adverse events, laboratory parameters, ECGs, vital signs, sweat‑chloride change, pharmacokinetics, percent predicted FEV1, and CFQ‑R respiratory domain score. The end‑of‑study visit occurs at Day 28 to finalize data collection. Participant involvement therefore spans approximately four weeks from first dose to final assessment. Early termination may occur for failure to meet inclusion criteria, emergence of serious adverse events, non‑adherence to the study regimen, or investigator decision based on safety concerns. The overall trial timeline extends from the anticipated start of recruitment on 15 December 2026 to study completion by 1 November 2027.

The investigational agent VX‑828 is supplied as an oral tablet containing 20 mg of the active substance. The tablet is administered once daily by mouth. Dosing is recorded in the study diary and adherence is monitored by pill count at each site visit.

A second strength of the investigational VX‑828 tablet contains 5 mg of the active substance. This formulation is also taken orally once daily. Compliance is assessed using the same diary and pill‑count procedures as for the 20 mg tablet.

VX‑561 is provided as a film‑coated tablet delivering 250 mg of deutivacaftor per dose. The tablet is taken orally once daily. Participants’ adherence is monitored through electronic dosing logs and reconciliation of returned tablets.

The test product VX‑661 50 mg tablet contains tezacaftor at a dose of 100 mg per administration. It is administered orally once daily. Dosing compliance is evaluated by review of study diaries and pill‑count verification.

The comparator VX‑445/VX‑661/VX‑770 fixed‑dose combination tablet comprises tezacaftor, elexacaftor, and ivacaftor in a total dose of 450 mg. The film‑coated tablet is taken orally once daily and is designated as an orphan drug. Compliance monitoring follows the standard protocol of diary entries and tablet return counts.

Kalydeco 150 mg film‑coated tablets contain ivacaftor and are administered orally once daily as an active comparator. Adherence is tracked using participant dosing records and reconciliation of unused tablets.

The comparator VX‑121/VX‑661/VX‑561 film‑coated tablet combines tezacaftor, deutivacaftor, and vanzacaftor for a total dose of 125 mg. The product is taken orally once daily and is also classified as an orphan drug. Monitoring of compliance is performed with electronic diaries and pill‑count procedures.

Placebo tablets matching the VX‑828 formulation are administered orally once daily. The placebo is indistinguishable in appearance from the active tablet and compliance is assessed by the same methods as active products.

Placebo tablets matching the VX‑561 film‑coated tablet are taken orally once daily. Blinding is maintained by identical packaging, and adherence is monitored through diary entries and tablet counts.

Placebo tablets corresponding to the VX‑661 formulation are administered orally once daily. Compliance monitoring mirrors that of the active tezacaftor tablet.

Placebo tablets matching the VX‑121/VX‑661/VX‑561 combination are taken orally once daily. Participant compliance is evaluated using electronic dosing logs and reconciliation of returned placebo tablets.

Efficacy will be evaluated using the absolute change from baseline in sweat chloride concentrations measured through Day 28 as the primary endpoint. Secondary efficacy endpoints include the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) and the absolute change from baseline in the Cystic Fibrosis Questionnaire Revised (CFQ‑R) respiratory domain score, both assessed at Day 28.

Baseline values for each parameter will be obtained prior to the first dose. Follow‑up assessments will be performed on Day 28, coinciding with the end of the treatment period. Changes from baseline will be calculated for each participant, and comparative analyses between treatment groups will be conducted using appropriate statistical methods to determine the magnitude and significance of the observed effects.