Study of DCR-A1AT in Healthy Adult Volunteers

A1ATD- associated liver disease is a progressive Alpha-1 Antitrypsin-Deficiency Associated Liver Disease condition resulting in liver fibrosis, cirrhosis, and hepatocellular carcinoma. The lack of functional A1AT in individuals with PiZZ genotype, in conjunction with other precipitating factors, can lead to unchecked activity in neutrophil elastases in the alveoli; causing emphysema and chronic obstructive pulmonary disease (COPD). This loss-of-function mechanism can be addressed with intravenous augmentation therapy, which aims to substitute the missing A1AT by infusing alpha1 proteinase inhibitor (A1PI), purified from pooled human plasma.

While augmentation therapy can address the loss of A1AT in the lungs, no treatment exists for the associated liver disease.

Given the severity of the disease, with approximately 10% of affected patients developing liver cirrhosis and a subgroup of those patients in need of liver transplantation, and lack of an effective treatment that addresses the toxic hepatic "gain-of-function" mechanism, there is an urgent unmet medical need to develop a therapy that can help in this particular patient population.

Inclusion criteria

• Male or Female aged 18 to 55 years, inclusive. Female participants must be either surgically sterile or postmenopausal. No women of childbearing potential are eligible for enrollment.
• Overtly Healthy, as determined by the investigator.
• Serum A1AT protein concentration >100 mg/dL
• Adequate forced expiratory volume in one second (FEV1) and adequate FEV1/forced vital capacity (FVC) ratio
• Non-smokers with a <2 pack-year history and smoking cessation for at least 6 months with a negative urinary cotinine test a screening

Exclusion criteria

• Presence of any condition or comorbidities that would interfere with study compliance or data interpretation or potentially affect participant safety
• Clinically significant abnormal laboratory tests
• Received an experimental drug within past 4 months
• Prior to use of RNAi drug or oligonucleotide-based therapy
• Known human immunodeficiency virus (HIV), hepatitis C virus (HCV), or Hepatitis B (HBV)
• Serum creatinine or estimated glomerular filtration rate (eGFR) outside normal reference ranges.