A Phase 1/2 Study of VX-522 in Subjects with Cystic Fibrosis

Prior treatment

• An acute upper or lower respiratory tract infection, pulmonary exacerbation (PEx), or changes in therapy (including antibiotics) for pulmonary disease within 28 days before the first dose of VX-522.
• Blood donation (of approximately 1 pint [500 mL] or more) within 56 days before the first dose of VX-522 or IVA.
• Arterial oxygen saturation on room air <94% at screening or use of supplemental oxygen within 28 days before the first dose of VX-522

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 drugs (or other drugs administered during the study) to the subject.
• A screen positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or antibodies against human immunodeficiency virus 1 or 2 (HIV-1 and HIV-2 Abs).
• Active COVID-19 infection based on testing on Day 1.
• Lung infection with organisms associated with a more rapid decline in pulmonary status.
• Alcohol or drug abuse in the past year, including, but not limited to, abuse of cannabis (or cannabinoid-containing products), cocaine, and opiates (as deemed by the investigator and according to the Diagnostic and Statistical Manual of Mental Health Disorders, Fifth Edition [DSM-5] diagnostic criteria20, 2120, 21). Non-abusive use of cannabinoids is permitted, other than by the inhaled route.

Lab values

• Any clinically significant laboratory abnormalities that would interfere with the study assessments or pose an undue risk for the subject.
• Any of the following abnormal laboratory values at screening: Hemoglobin <10 g/dL, Total bilirubin ≥2 × ULN, AST, ALT, GGT, or ALP ≥3 × ULN

Other

• Abnormal renal function, defined as glomerular filtration rate ≤50 mL/min/1.73 m2
• For female subjects: Pregnant or breast-feeding. Females of childbearing potential (Section 11.5.8) must have a negative pregnancy test at the Screening Visit and before the first dose of VX-522 or IVA as described in Section 11.5.2. For male subjects: Male subjects with a female partner who is pregnant, nursing, or planning to become pregnant during the study or within 180 days after the last dose of VX- 522 or IVA.
• Standard 12 lead ECG median of triplicate demonstrating QTcF >450 msec at screening.

• Subject will sign and date an informed consent form.
• Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
• Subjects (male and female) between the ages of 18 and 65 years, inclusive.
• Body mass index (BMI) of <30.0 kg/m2 and a total body weight >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.
• CFTR mutations on both alleles that are not responsive to CFTR modulator therapy. A list of eligible CFTR mutations is included in Table 15-1. Genotype should be confirmed at the Screening Visit. 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.
• Stable CF disease, as judged by the investigator, and forced expiratory volume in 1 second (FEV1) value, percent of predicted mean for age, sex, and height (equations of the Global Lung Function Initiative [GLI])18 in the following range at Screening: a. SAD: ≥40% b. MAD: ≥50% to ≤90%
• On stable CF treatment regimen for 28 days prior to dosing and willing to remain on a stable CF treatment regimen (other than study drug) through completion of study participation.
• Bronchoscopy substudy (MAD): Platelet count and prothrombin time test international normalized ratio (INR) within the normal range.