A Study of VX-121 Combination Therapy in Participants With Cystic Fibrosis (CF) Who Are Homozygous for F508del, Heterozygous for F508del and a Gating (F/G) or Residual Function (F/RF) Mutation, or Have At Least 1 Other Triple Combination Responsive (TCR) CFTR Mutation and No F508del Mutation

• VX-121/TEZ/D-IVA (Drug), also known as VX-121/VX-661/CTP-656, VX-121/VX-661/VX-561, VX-121/tezacaftor/deutivacaftor: Fixed-dose combination tablets for oral administration.
• ELX/TEZ/IVA (Drug), also known as VX-445/VX-661/VX-770, elexacaftor/tezacaftor/ivacaftor: Fixed-dose combination tablets for oral administration.
• IVA (Drug), also known as VX-770, ivacaftor: Tablet for oral administration.
• Placebo (matched to VX-121/TEZ/D-IVA) (Drug): Placebo matched to VX-121/TEZ/D-IVA for oral administration.
• Placebo (matched to ELX/TEZ/IVA) (Drug): Placebo matched to ELX/TEZ/IVA for oral administration.
• Placebo (matched to IVA) (Drug): Placebo matched to IVA for oral administration.

Primary outcomes

• Absolute Change in Percent Predicted Forced Expiratory Volume in 1second (ppFEV1) [From Baseline Through Week 24]: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

Secondary outcomes

• Absolute Change in Sweat Chloride (SwCl) [From Baseline Through Week 24]: Sweat samples were collected using an approved collection device.
• Percentage of Participants With SwCl <60 Millimole Per Liter (mmol/L) (Pooled With Data From Study VX20-121-102) [From Baseline Through Week 24]: Sweat samples were collected using an approved collection device.
• Percentage of Participants With SwCl <30 mmol/L (Pooled With Data From Study VX20-121-102) [From Baseline Through Week 24]: Sweat samples were collected using an approved collection device.

Sex: All, ages: 12 Years to any

Key Inclusion Criteria:

* Participant has one of the following genotypes:

  * Homozygous for F508del;
  * Heterozygous for F508del and a gating (F/G) mutation;
  * Heterozygous for F508del and a residual function (F/RF) mutation;
  * At least 1 other TCR CFTR gene mutation identified as responsive to ELX/TEZ/IVA and no F508del mutation
* Forced expiratory volume in 1 second (FEV1) value >=40% and <=90% of predicted mean for age, sex, and height for participants currently receiving CFTR protein modulator therapy; FEV1 >=40% and <=80% for participants not currently receiving CFTR protein modulator therapy

Key Exclusion Criteria:

* History of solid organ or hematological transplantation
* Hepatic cirrhosis with portal hypertension, moderate hepatic impairment (Child Pugh Score 7 to 9), or severe hepatic impairment (Child Pugh Score 10 to 15)
* Lung infection with organisms associated with a more rapid decline in pulmonary status
* Pregnant or breast-feeding females

Other protocol defined Inclusion/Exclusion criteria may apply.

Participant flow

Outcome results

• Absolute Change in Percent Predicted Forced Expiratory Volume in 1second (ppFEV1) (Primary), Least squares mean, percentage points: ELX/TEZ/IVA 0.0 (-0.5 to 0.5); VX-121/TEZ/D-IVA 0.2 (-0.3 to 0.7) (p < 0.0001)
• Absolute Change in Sweat Chloride (SwCl) (Secondary), Least squares mean, millimole per liter (mmol/L): ELX/TEZ/IVA -2.3 (-3.6 to -0.9); VX-121/TEZ/D-IVA -5.1 (-6.4 to -3.7) (p =0.0034)
• Percentage of Participants With SwCl <60 Millimole Per Liter (mmol/L) (Pooled With Data From Study VX20-121-102) (Secondary), Number, percentage of participants: ELX/TEZ/IVA 76.6; VX-121/TEZ/D-IVA 85.8 (p < 0.0001)
• Percentage of Participants With SwCl <30 mmol/L (Pooled With Data From Study VX20-121-102) (Secondary), Number, percentage of participants: ELX/TEZ/IVA 22.5; VX-121/TEZ/D-IVA 30.5 (p < 0.0001)

Adverse events

Time frame: Day 1 up to Safety follow-up (up to 56 weeks)

Serious adverse events by term

Other adverse events by term

70 more sites not listed.

• Results publication: Keating C, Yonker LM, Vermeulen F, Prais D, Linnemann RW, Trimble A, Kotsimbos T, Mermis J, Braun AT, O'Carroll M, Sutharsan S, Ramsey B, Mall MA, Taylor-Cousar JL, McKone EF, Tullis E, Floreth T, Michelson P, Sosnay PR, Nair N, Zahigian R, Martin H, Ahluwalia N, Lam A, Horsley A; VX20-121-102 Study Group; VX20-121-103 Study Group. Vanzacaftor-tezacaftor-deutivacaftor versus elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): results from two randomised, active-controlled, phase 3 trials. Lancet Respir Med. 2025 Mar;13(3):256-271. doi: 10.1016/S2213-2600(24)00411-9. Epub 2025 Jan 2. PMID 39756424
• Results publication: Heneghan M, Southern KW, Murphy J, Sinha IP, Nevitt SJ. Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). Cochrane Database Syst Rev. 2023 Nov 20;11(11):CD010966. doi: 10.1002/14651858.CD010966.pub4. PMID 37983082

• Study Protocol (PDF, 2021-08-19)
• Statistical Analysis Plan (PDF, 2023-09-19)