Evaluation of the Efficacy and Safety of VX-864 in Subjects With the PiZZ Genotype

Phase 1

• Conditions: Alpha 1 antitrypsin deficiency in Subjects With the PiZZ Genotype; MedDRA version: 23.1Level: PTClassification code 10083869Term: Alpha-1 antitrypsin deficiencySystem Organ Class: 10010331 - Congenital, familial and genetic disorders; Therapeutic area: Body processes [G] - Genetic Phenomena [G05]

• Registration Number: EUCTR2019-004881-16-IE
• Lead Sponsor: Vertex Pharmaceuticals Incorporated

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-07-09
• Last Update Posted: 7 June 2021

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

1. Subject will sign and date an informed consent form (ICF).
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions,
laboratory tests, contraceptive guidelines, and other study procedures.
3. Subjects will be 18 through 80 years of age, inclusive, at the time of signing of the ICF.
4. All female subjects must have a negative pregnancy test at screening (serum test). Premenopausal female subjects of child-bearing potential must also have a negative pregnancy test on Day 1 (urine test) and must not be breastfeeding or planning to become pregnant during the study or within 90 days after the last study drug dose.
5. Body mass index (BMI) of 18.0 to 35.0 kg/m2, inclusive.
6. Subjects must have a PiZZ genotype confirmed at screening.
NOTE: PiZZ genotype must be tested at the central laboratory. Historical genotype results can be used to determine eligibility if they were obtained as part of a different Vertex study. In addition, if the screening PiZZ genotype result is not received before randomization, a previous non-Vertex PiZZ genotype laboratory report (approved by the medical monitor or designee) may be used to establish provisional eligibility. Subjects who have been randomized and whose screening genotype subsequently does not confirm study eligibility must be discontinued from the study.
7. Plasma antigenic AAT level <8 ìM during screening.
NOTE: For subjects who have been on augmentation therapy at any time, results used to
confirm eligibility must be drawn >42 days after the last dose of augmentation therapy.
Antigenic AAT levels must be obtained from the central laboratory and results confirmed
before randomization.
8. Willing to remain off of augmentation therapy from >42 days before antigenic AAT levels
are obtained for eligibility through the last Safety Follow-Up Visit.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 30
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 10

Exclusion Criteria

1. History or presence of any illness or clinical condition that, in the opinion of the investigator, might affect the subject's safety or compliance or confound the results of the study or pose an additional risk in administering study drug(s) to the subject. This includes, but is not limited to, the following:
• Solid organ, lung, or hematological transplantation or is currently on a transplant list
• Subjects who have undergone gastrectomy or other gastrointestinal tract surgery, except appendectomy, cholecystectomy, and hemorrhoid surgery.
• Cancer, except for basal cell skin cancer, Stage 0 cervical carcinoma in situ, and Stage 0 melanoma (regardless of recurrence), or adequately treated squamous cell skin cancer and Stage 1 melanoma (with no recurrence during the last 5 years)
2. History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year before screening, defined as more than 14 drinks/week for females or 21 drinks/week for males
3. Illegal drug use within 1 year before screening as deemed by the investigator, including but not limited to cocaine, heroin, and other opioids.
4. Ongoing or prior participation in a study of an investigational treatment within 28 days or
5 terminal half-lives (whichever is longer) before screening.
5. History of use of gene therapy or RNAi therapy at any time previously.
6. Use of oral corticosteroids (at any dose) for a duration of greater than 3 months at any time
within the 3 months before screening.
7. A post-bronchodilator forced expiratory volume in 1 second (FEV1) value <30% of predicted mean for age, sex, and height (equations of the Global Lung Function Initiative [GLI]) during screening. Post-bronchodilator spirometry measurements must meet American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria for acceptability and repeatability.
8. All clinically important pulmonary disease other than AATD-related pulmonary disease, including but not limited to interstitial lung disease, cystic fibrosis, pulmonary hypertension with or without cor pulmonale, history of pulmonary embolism, or malignant lung cancer.
9. Unstable AATD-related COPD as deemed by the investigator.
10. Documented chronic need for positive airway pressure therapy beyond nocturnal use.
11. Documented medical history or diagnosis of clinically evident liver disease including but not limited to a prior diagnosis of hepatitis of any etiology, cirrhosis, portal hypertension, or confirmed or suspected esophageal varices.
12. Any of the following abnormal laboratory values at screening:
. Platelet count <150 ~ 109/L.
. Albumin .3.5 g/dL
. International normalized ratio .1.2
. Hemoglobin <10 g/dL
. Total bilirubin > upper limit of normal (ULN)
. Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase
(GGT), or alkaline phosphatase (ALP) >2 ~ ULN
. Estimated glomerular filtration rate (eGFR) .30 mL/min/1.73 m2
13. Risk factors for Torsade de Pointes or concomitant medications that prolong the QT/QTc interval or any history of unstable cardiac disorder that, in the opinion of the investigator, might put the subject at risk or may confound the results of the study.
14. Any clinically significant ECG abnormality or median QTcF of triplicate standard 12-lead ECGs >450 msec at screening.
15. History of Gilbert's Syndrome.
16. Positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) RNA, or HIV-1
and HI

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified