Overview
This is a Phase 1/2, open-label, multi-center, dose escalation (Part 1), dose expansion (Part 2), and single repeat dose (Part 3) study to evaluate the safety, tolerability, efficacy, and PK/PD parameters of TSRA-196 in adults with the PiZZ genotype who have lung and/or liver disease associated with severe alpha-1 antitrypsin deficiency (AATD)
Eligibility
Inclusion Criteria:
* Males or females who are 18 to 70 years of age, inclusive, at the time of signing the informed consent
* Body mass index of 18 to 37 kg/m2, inclusive
* Confirmed diagnosis of AATD and PiZZ genotype
* At least one previous measure of blood total AAT level \<11 µmol/L
* Nonsmoker for at least 6 months before screening and must remain nonsmoking for the entire study duration
* Either AAT treatment-naïve or washed out of all investigational or approved treatments that modify AAT levels for 5 half-lives or at least 4 weeks, whichever is longer, before TSRA-196 administration
Parts 1A and 2A (AATD lung disease with no or minimal liver fibrosis)
* Clinically significant lung disease, defined as 1) evidence of emphysema or bronchiectasis by computed tomography or 2) DLCO \<70% of the predicted value or 3) ppFEV1 \<80%
* ppFEV1 ≥35%
* METAVIR fibrosis score F0 or F1 confirmed by liver biopsy at screening, or a liver stiffness measure by FibroScan ≤7 kPa at screening
* FIB-4 index score ≤3.25 at screening
* ALT and/or AST \7 and ≤15 kPa at screening
* ALT and/or AST \<2 x ULN at screening
Exclusion Criteria:
* Presence of genetic variation in SERPINA1 gene that may disrupt the function of TSRA-196, determined by screening genotyping
* History of liver disease unrelated to AATD, or history of or clinical signs of cirrhosis
* Significant lung disease not attributable to manifestations of AATD, as determined by the investigator
* History of one or more hospitalizations due to severe exacerbation of underlying lung disease during the year before screening or received IV antibiotics for treatment of a pulmonary infection within 6 months before screening
* Unstable AATD-related COPD, as determined by the investigator, or severe bronchiectasis
* Lung volume reduction surgery within 1 year before screening or plan to receive lung volume reduction surgery during the study period
* Documented chronic need for positive airway pressure therapy beyond nocturnal use
* Seropositive for human immunodeficiency virus (HIV) (HIV-1 or HIV-2)
* Seropositive for hepatitis B (hepatitis B surface antigen \[HBsAg\] or hepatitis B core antibody \[HBcAb\] positive) with detectable HBV DNA
* Hepatitis C virus (HCV) RNA positive at screening (Parts 1A and 2A), or HCV RNA positive and/or HCV antibody positive at screening (Parts 1B and 2B)
* Has received an organ transplant or is on a waiting list for an organ transplant
* Prior treatment with gene therapy using viral vectors or intended to permanently change the patient's DNA
* Any investigational products within 30 days before dosing or plan to take an investigational product before the end of study
