Study of VX-809 in Cystic Fibrosis Subjects With the ∆F508-CFTR Gene Mutation

This was a Phase 2, randomized, double-blind, placebo-controlled, multiple-dose study of orally-administered VX-809 in participants with CF who are homozygous for the specific CFTR mutation known as ∆F508 or F508del. Enrollment was planned for 90 participants at approximately 20 centers. Participants were planned to be randomized in a 4:1 ratio to receive 1 of 4 doses of VX-809 or placebo once a day for 28 days in a parallel design. Participants were outpatients during the study, except for overnight stays on Day 1 and 28.

• VX-809 (Drug): Capsules
• Placebo (Drug): Placebo matched to VX-809 capsules.

Primary outcomes

• Safety and Tolerability Based on Adverse Events (AEs) [Up to 14 days after last dose (last dose = Day 28)]: AE: any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as Non-serious AEs. Serious adverse event (SAE) (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Number of participants with AEs and SAEs are reported. An AE that started at or after initial dosing of study drug, or increased in severity after initial dosing of study drug visit is considered treatment-emergent.

Secondary outcomes

• Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Day 28 [Baseline, Day 28]: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
• Change From Baseline in Percent Predicted FEV1 at Day 28 [Baseline, Day 28]: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Predicted FEV1 (for age, gender, and height) was calculated using the Knudson method.
• Change From Baseline in Forced Vital Capacity (FVC) at Day 28 [Baseline, Day 28]: FVC is the volume of air that can be forcibly exhaled from the lungs after taking the deepest breath possible.
• Change From Baseline in Forced Expiratory Flow Over the Middle Half of the FVC (FEF25-75) at Day 28 [Baseline, Day 28]: FEF25-75 is total volume of air exhaled from the lungs over the middle half of the FVC test, expressed as liters per second (L/sec).
• Change From Baseline in Sweat Chloride at Day 28 [Baseline, Day 28]: Sweat samples were collected using an approved Macroduct (Wescor) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride.
• Change From Baseline in Nasal Potential Difference (NPD) of Zero Chloride Plus Isoproterenol Response at Day 28 [Baseline, Day 28]: Nasal potential difference (NPD) provides a direct and sensitive evaluation of sodium and chloride transport in secretory epithelial cells via assessment of transepithelial bioelectric properties. NPD under conditions of zero chloride concentration perfusion solution in the presence of isoproterenol is reported. NPDs were performed according to Cystic Fibrosis Foundation Therapeutics Development Network (CFFT TDN) Standard Operating Procedure (SOP) 528.00 "Standardization of Measurement of Nasal Membrane Transepithelial Potential Difference (NPD) - electronic data capture (EDC) and Perfusion or Perfusion-Free Probe".
• Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Domain Scores at Day 28 [Baseline, Day 28]: The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. CFQ-R domains include: Body, Digestion, Eat, Emotion, Health Perceptions, Physical, Respiratory, Role, Social, Treatment Burden, Vitality, and Weight. Individual domain score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
• Maximum Plasma Concentration (Cmax) of VX-809 [Day 1 (pre dose, 0.75, 1.5, 3, 4, 6, 9, 12, and 24 hours post-dose), Day 28 (pre dose, 0.75, 1.5, 3, 4, 6, 9, 12, 24, and 30-60 hours post dose)]: Only participants who received VX-809 were analyzed for this outcome measure.
• Area Under the Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24) of VX-809 [Day 1 (pre dose, 0.75, 1.5, 3, 4, 6, 9, 12, and 24 hours post-dose), Day 28 (pre dose, 0.75, 1.5, 3, 4, 6, 9, 12, and 24 hours post dose)]: Only participants who received VX-809 were analyzed for this outcome measure.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Confirmed diagnosis of CF with ∆F508-CFTR mutation in both alleles
* Forced expiratory volume in 1 second (FEV1) greater than or equal to (>=) 40 percent (%) of predicted normal for age, gender, and height
* Weight >=40 kilograms (kg) and body mass index greater than or equal to 18.5 kilogram per square meter (kg/m\^2)
* Screening laboratory values, tests, and physical examination within acceptable ranges
* Negative pregnancy test (for women of child-bearing potential)
* Able and willing to follow contraceptive requirements
* Willing to remain on a stable medication regimen for the duration of study participation

Exclusion Criteria:

* History of any illness, or any ongoing acute illness, that could impact the safety of the study participant or may confound results of study
* Pulmonary exacerbation or changes in therapy for pulmonary disease within 14 days before receiving the first dose of study drug
* Impaired hepatic or renal function
* History of organ or hematological transplant

Participant flow

Outcome results

• Safety and Tolerability Based on Adverse Events (AEs) (Primary), Number, participants: Placebo 17; VX-809, 25 mg 16; VX-809, 50 mg 15; VX-809, 100 mg 16; VX-809, 200 mg 18
• Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Day 28 (Secondary), Least squares mean, liters: Placebo 0.029 (-0.0823 to 0.1398); VX-809, 25 mg -0.049 (-0.1578 to 0.0588); VX-809, 50 mg -0.031 (-0.1401 to 0.0787); VX-809, 100 mg 0.015 (-0.0972 to 0.1263); VX-809, 200 mg -0.009 (-0.1146 to 0.0970)
• Change From Baseline in Percent Predicted FEV1 at Day 28 (Secondary), Least squares mean, Percent predicted of FEV1: Placebo 0.285 (-2.8268 to 3.3973); VX-809, 25 mg -1.637 (-4.6836 to 1.4089); VX-809, 50 mg -0.375 (-3.4540 to 2.7046); VX-809, 100 mg 0.168 (-2.9653 to 3.3011); VX-809, 200 mg -0.165 (-3.1346 to 2.8044)
• Change From Baseline in Forced Vital Capacity (FVC) at Day 28 (Secondary), Mean, liters: Placebo 0.085 +/- 0.2857; VX-809, 25 mg -0.055 +/- 0.2331; VX-809, 50 mg -0.020 +/- 0.3494; VX-809, 100 mg -0.004 +/- 0.1916; VX-809, 200 mg -0.023 +/- 0.3668
• Change From Baseline in Forced Expiratory Flow Over the Middle Half of the FVC (FEF25-75) at Day 28 (Secondary), Mean, liters per second (L/sec): Placebo -0.030 +/- 0.1730; VX-809, 25 mg -0.011 +/- 0.3231; VX-809, 50 mg -0.029 +/- 0.4373; VX-809, 100 mg 0.045 +/- 0.2702; VX-809, 200 mg -0.052 +/- 0.3558
• Change From Baseline in Sweat Chloride at Day 28 (Secondary), Least squares mean, millimole per liter (mmol/L): Placebo 0.84 (-3.493 to 5.166); VX-809, 25 mg 0.93 (-3.308 to 5.173); VX-809, 50 mg -3.77 (-7.966 to 0.416); VX-809, 100 mg -5.29 (-9.618 to -0.963); VX-809, 200 mg -7.38 (-11.590 to -3.166)
• Change From Baseline in Nasal Potential Difference (NPD) of Zero Chloride Plus Isoproterenol Response at Day 28 (Secondary), Least squares mean, millivolts (mV): Placebo -1.017 (-3.2979 to 1.2637); VX-809, 25 mg 0.832 (-1.1302 to 2.7943); VX-809, 50 mg 0.142 (-2.0369 to 2.3208); VX-809, 100 mg 1.382 (-0.9853 to 3.7491); VX-809, 200 mg 1.583 (-0.6952 to 3.8612)
• Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Domain Scores at Day 28 (Secondary), Least squares mean, units on a scale: Placebo -1.341 (-6.4183 to 3.7370); VX-809, 25 mg -0.206 (-5.2276 to 4.8151); VX-809, 50 mg -1.626 (-6.6796 to 3.4276); VX-809, 100 mg 2.611 (-2.5525 to 7.7746); VX-809, 200 mg 0.058 (-4.8954 to 5.0123)
• Maximum Plasma Concentration (Cmax) of VX-809 (Secondary), Mean, nanogram per milliliter (ng/mL): VX-809, 25 mg 760 +/- 280; VX-809, 50 mg 1850 +/- 697; VX-809, 100 mg 2930 +/- 916; VX-809, 200 mg 6410 +/- 2550
• Area Under the Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24) of VX-809 (Secondary), Mean, hour*nanogram per milliliter (hr*ng/mL): VX-809, 25 mg 7190 +/- 2190; VX-809, 50 mg 16600 +/- 6290; VX-809, 100 mg 29000 +/- 11400; VX-809, 200 mg 59500 +/- 26400

Adverse events

Time frame: Up to 14 days after last dose (last dose = Day 28)

Serious adverse events by term

Other adverse events by term

85 more terms not shown.

• 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
• Results publication: 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. 2020 Dec 17;12(12):CD010966. doi: 10.1002/14651858.CD010966.pub3. PMID 33331662
• Results publication: Clancy JP, Rowe SM, Accurso FJ, Aitken ML, Amin RS, Ashlock MA, Ballmann M, Boyle MP, Bronsveld I, Campbell PW, De Boeck K, Donaldson SH, Dorkin HL, Dunitz JM, Durie PR, Jain M, Leonard A, McCoy KS, Moss RB, Pilewski JM, Rosenbluth DB, Rubenstein RC, Schechter MS, Botfield M, Ordonez CL, Spencer-Green GT, Vernillet L, Wisseh S, Yen K, Konstan MW. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax. 2012 Jan;67(1):12-8. doi: 10.1136/thoraxjnl-2011-200393. Epub 2011 Aug 8. PMID 21825083

• Medical Monitor, Study director, Vertex Pharmaceuticals Incorporated