Safety and Efficacy of VX-828/Deutivacaftor Combination Therapy With and Without Tezacaftor in Subjects With Cystic Fibrosis

Prior treatment

• Ongoing or prior participation in a study of an investigational treatment with the exception of the following: • For prospective subjects with ongoing or prior participation in an investigational study of a Vertex CFTR modulator, a washout period of 28 days or 5 terminal half-lives (whichever is longer) must elapse before Day 1. • For prospective subjects with ongoing or prior participation in all other interventional studies, a washout period of 28 days or 5 terminal half-lives (whichever is longer) must elapse before screening. The duration of the elapsed time may be longer if required by local regulations. • Ongoing participation in a noninterventional study (including observational studies and studies requiring assessments without administration of study drug or assignment to other interventions) is permitted.
• Use of prohibited medications as defined in Table 9 4, within the specified window before the first dose of study drug.
• For female subjects: Subject is pregnant, nursing, or planning to become pregnant during the study or within 90 days after the last dose of study drug. Female subjects of childbearing potential, as defined in Section 11.5.6.1, must have a negative pregnancy test at screening, Day -28 (as applicable), and Day 1 and be willing to comply with contraceptive requirements (Section 11.5.6.1). For male subjects: Male subjects with a female partner who is pregnant, nursing, or planning to become pregnant during the study or within 90 days after the last dose of study drug. Male subjects must also be willing to comply with contraceptive requirements (Section 11.5.6.1).
• An acute upper or lower respiratory infection, pulmonary exacerbation (PEx), or changes in therapy (including antibiotics) for sinopulmonary disease within 28 days before the first dose of study drug.
• Lung infection with organisms associated with a more rapid decline in pulmonary status (e.g., Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus). For subjects who have had a history of a positive culture, the investigator will apply the following criteria to establish whether the subject is free of infection with such organisms: • The subject has not had a respiratory tract culture positive for these organisms within the 12 months before the date of informed consent. • The subject has had at least 2 respiratory tract cultures negative for such organisms within the 12 months before the date of informed consent, with the first and last of these separated by at least 3 months, and the most recent 1 within the 6 months before the date of informed consent.
• An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of study drug.

Other illness

• History of any illness or any clinical condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject. This includes, but is not limited to, the following: • Liver disease with cirrhosis or portal hypertension. • Solid organ or hematological transplantation. • Alcohol or drug abuse in the past year, including, but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator. • Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical carcinoma in situ (all 3 with no recurrence for the last 5 years).
• History of intolerance to study drug that would pose an additional risk to the subject in the opinion of the investigator (e.g., subjects with a history of liver function test [LFT] elevations requiring treatment interruption or discontinuation, allergy or hypersensitivity to the study drug).

Lab values

• Risk factors for Torsade de Pointes and other ventricular arrhythmias, including but not limited to, history of any of the following: familial long QT syndrome, chronic hypokalemia, heart failure, left ventricular hypertrophy, chronic bradycardia, myocardial infarction, cardiomyopathy, arrhythmia (ventricular or atrial fibrillation), acute neurologic events (subarachnoid hemorrhage, intracranial hemorrhage, cerebrovascular accident, or intracranial trauma), or autonomic neuropathy.
• Any of the following abnormal laboratory values at screening: • Total bilirubin ≥2 × upper limit of normal (ULN) • Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), or alkaline phosphatase (ALP) ≥3 × ULN • Hemoglobin <10 g/dL • Abnormal renal function defined as glomerular filtration rate ≤50 mL/min/1.73 m2 (based on the Modified Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation without the race adjustment).

Other

• Standard 12-lead ECG demonstrating QTcF >450 msec at screening. If QTcF exceeds 450 msec, the ECG will be repeated 2 more times, and the mean of the 3 QTcF values will be used to determine the subject’s eligibility.

• Body weight ≥35 kg
• Subjects must be able to produce a valid (quantity sufficient) sweat sample at screening. If the initial screening collection results in insufficient sweat volume, then the SwCl collection may be repeated once. Subjects must have a SwCl value ≥30 mmol/L at screening.
• Confirmed diagnosis of CF as determined by the investigator.
• Subjects must have an eligible CFTR genotype as noted below. If the screening CFTR genotype result is not received before the first dose of study drug, a previous CFTR genotype laboratory report may be used to establish eligibility. Subjects who have been enrolled and whose screening genotype does not confirm study eligibility must be discontinued from the study (Section 9.9). • Parts 1 and 2: Heterozygous for F508del with a second CFTR allele carrying a minimal function mutation that is not responsive to VNZ/TEZ/D-IVA therapy (Appendix A). • Parts 3 and 4: Homozygous for F508del
• Subjects must have a forced expiratory volume in 1 second (FEV1) ≥40% of predicted normal for age, sex, and height (equations of the Global Lung Function Initiative [GLI])7-10 at the Screening Visit. FEV1 measurements must meet American Thoracic Society/European Respiratory Society criteria11 for acceptability and repeatability.
• Stable CF disease as judged by the investigator.
• Willing to remain on a stable CF treatment regimen (as defined in Section 9.5) through completion of study participation.