Safety Dose Finding Study of ADVM-043 Gene Therapy to Treat Alpha-1 Antitrypsin (A1AT) Deficiency

Alpha-1 Antitrypsin (A1AT) is a major inhibitor of serine proteases and plays an important role in the lung as an inhibitor of neutrophil elastase. A1AT deficiency is associated with decreases in plasma A1AT levels and is associated with an increased risk for developing asthma, emphysema/COPD, and bronchiectasis. Much of the lung damage is thought to be caused by proteolytic damage from neutrophil elastase and other proteases.

ADVM-043 is an investigational gene therapy product (serotype AAVrh.10 vector) expressing human A1AT that is intended to deliver a functional gene to the liver of patients with A1AT deficiency. Study ADVM-043-01 will study up to 4 dose levels in up to 20 patients and assess the hypothesis that a single administration of an AAV vector expressing the human M-type A1AT (i.e., ADVM-043) to patients with A1AT deficiency is safe and results in persistent therapeutic levels of A1AT in blood and alveolar epithelial lining fluid (epithelial lining fluid is only to be collected in subjects who are dosed intrapleurally). The primary endpoint is safety, and changes in plasma A1AT levels at multiple time points up to 52 weeks after dosing. A prophylactic tapering corticosteroid regimen will be used to protect against potential vector induced transaminitis. Subjects will be followed for up to 52 weeks after dosing. Safety and efficacy data from the IV cohorts will be considered when determining whether to proceed to intrapleural administration. After completion of this study, subjects will be asked to enroll in a Long Term Follow Up study.

Key Inclusion Criteria:

• Capable of providing informed consent
• Alpha1AT genotype of ZZ or Z Null
• Males and females 18 years and older
• Ongoing treatment with A1AT augmentation is not required, however any subject receiving A1AT augmentation therapy must be willing to washout. Washout is defined as at least 8 weeks between last augmentation therapy and pre-treatment plasma A1AT level
• Willing to remain off PAT for at least 3 months following treatment
• Body mass index 18 to 35 kg/m2
• Fertile men and women of childbearing potential must agree to use barrier contraception for 3 months after treatment

Key Exclusion Criteria:

• FEV1 <35 percent of predicted value at the Screening visit
• Receiving systemic corticosteroids or other immunosuppressive medications
• Immunodeficiency disease or evidence of active infection of any type, including human immunodeficiency virus
• Abnormal liver function tests
• Organ transplant recipient or awaiting transplantation
• Participation in another current or previous gene transfer study
• AAVrh.10 neutralizing antibody titer ≥ 1:5
• Female who is pregnant or lactating
• History of alcohol or drug abuse within the past 5 years
• Any history of allergies that may prohibit study-specific investigations
• Receiving an investigational medicinal product or participating in another investigational study within 3 months prior to consent
• Cigarette smoking, or any other tobacco use, e-cigarettes or other recreational inhalant within 1 year of the Screening Visit