Phase 1/2 Open‑Label Multi‑Center Dose‑Escalation and Expansion Study of Intravenous TSRA‑196 in Adults with PiZZ‑Genotype Alpha‑1 Antitrypsin Deficiency‑Related Lung and/or Liver Disease

Alpha-1 Antitrypsin Deficiency associated lung and/or liver disease is the target condition. The primary objective is to assess the safety and tolerability of a single intravenous dose of TSRA‑196 (Part 1), to determine the efficacy of a single dose (Part 2), and to evaluate the efficacy of a second dose (Part 3) in adult participants with the PiZZ genotype. These assessments are intended to establish the therapeutic potential and risk profile of TSRA‑196 for a disease with limited treatment options. Secondary objectives include: - Evaluation of the efficacy of a single dose of TSRA‑196 (Part 1). - Assessment of the incidence of adverse events of special interest (AESIs) after a single dose (Parts 1 & 2). - Monitoring of changes in safety laboratory values, vital signs, and electrocardiogram parameters after a single dose (Parts 1 & 2). - Determination of the pharmacokinetics of TSRA‑196 after single and repeat dosing (Parts 1‑3). - Evaluation of additional efficacy endpoints for both single and second doses (Parts 2 & 3). - Assessment of safety and tolerability of a second dose (Part 3). - Investigation of the effect of TSRA‑196 on lung function and on chronic obstructive pulmonary disease (COPD) exacerbations (Parts 2 & 3).

The trial enrolled 35 adult participants, both male and female, aged 18 to 70 years, who were identified as patients with Alpha-1 Antitrypsin Deficiency and confirmed PiZZ genotype. Eligible individuals required a body mass index between 18 and 37 kg/m² and demonstrated either clinically significant lung disease with minimal liver fibrosis or moderate‑to‑severe liver fibrosis, as determined by biopsy or non‑invasive assessment. Participants were required to be nonsmokers for at least six months prior to screening and to maintain abstinence from smoking throughout the study; alcohol consumption was prohibited for 14 days before and 30 days after dosing, and limited for the study duration. Selection criteria also included a documented blood total AAT level below 11 μmol/L, acceptable laboratory and hematology values, and either being treatment‑naïve for AAT or having completed a washout of prior AAT‑modifying therapies. The cohort comprised vulnerable adults classified as patients, reflecting the target disease population.

The study is an open‑label, multi‑center Phase 1/2 trial evaluating TSRA‑196, an intravenous solution for infusion containing RNAIVT9315 and RNACS24757, in adults with the PiZZ genotype who have lung and/or liver disease associated with Alpha‑1 Antitrypsin Deficiency. The design incorporates dose escalation, dose expansion, and a single repeat‑dose cohort and follows a sequential part structure: Part 1 assesses safety and tolerability after a single dose; Part 2 evaluates efficacy after a single dose; Part 3 examines efficacy after a second dose. Participant involvement extends up to 12 months from the first dosing visit. The visit schedule includes a screening visit for eligibility assessment, a baseline visit on the day of infusion, a dosing visit, and follow‑up assessments at approximately Day 7, Month 1, Month 3, Month 6, and Month 12, concluding with an end‑of‑study visit. Primary endpoints comprise incidence of treatment‑emergent adverse events and the proportion of participants achieving serum total AAT levels at or above the lower limit of normal at specified months. Secondary endpoints include longitudinal AAT concentrations, functional AAT activity, clinical laboratory parameters, pharmacokinetic measures, pulmonary function (post‑bronchodilator ppFEV1), and COPD exacerbation rates. Early termination may occur if a participant experiences a serious adverse event related to the investigational product, fails to meet critical protocol criteria, or withdraws consent. Recruitment is planned to begin on 30 April 2026 and to complete by 31 March 2029.

The investigational product, designated TSRA‑196, is supplied as a solution for infusion intended for intravenous administration. TSRA‑196 contains the active substances RNAIVT9315 and RNACS24757. In Part 1 of the study a single intravenous infusion of TSRA‑196 is administered; Part 3 includes a second infusion administered to participants who receive a repeat dose. The exact dose amount is defined in the protocol but is not disclosed in this summary.

No standard‑of‑care therapy, placebo, or active comparator is administered as part of the trial; participants receive only the investigational product.

Administration of TSRA‑196 is performed under clinical supervision with infusion records maintained to verify dose delivery. Participant compliance is monitored through observation during the infusion, documentation of infusion start and completion times, and assessment of vital signs and laboratory parameters pre‑ and post‑infusion.

Efficacy will be evaluated by measuring serum concentrations of total alpha‑1 antitrypsin (AAT) and functional AAT activity, as well as pulmonary function and clinical outcomes. The primary efficacy parameters include the proportion of participants with serum total AAT levels at or above the lower limit of normal (LLN) at Month 3 and Month 6 following a single dose, and the change from baseline in functional AAT concentrations, determined by an elastase inhibition assay, through Month 12. Additional efficacy assessments comprise the proportion of participants achieving serum total AAT ≥ 11 µM at the same time points, and the longitudinal change in functional AAT after a second dose.

Secondary efficacy endpoints include serial measurements of serum total AAT from baseline through Month 12, with specific evaluations at Month 3, Month 6, and continuous assessment from Month 3 to Month 12. Functional AAT activity will also be assessed at Month 3 and Month 6. Pulmonary efficacy will be monitored by post‑bronchodilator percent predicted forced expiratory volume in one second (ppFEV1) measured at baseline and at scheduled visits up to Month 12. The incidence of chronic obstructive pulmonary disease (COPD) exacerbations will be recorded from baseline over the study duration.

Blood samples for total AAT concentration and functional activity will be collected at screening, pre‑dose, and at each scheduled follow‑up visit (Month 3, Month 6, and Month 12). Serum AAT levels will be quantified using validated immunoassays, while functional activity will be measured with a standardized elastase inhibition assay. Pulmonary function tests, including post‑bronchodilator ppFEV1, will be performed according to accepted spirometry guidelines at baseline and at each follow‑up visit. All efficacy data will be analyzed descriptively, with proportions calculated for participants meeting predefined serum AAT thresholds and changes from baseline summarized using appropriate statistical measures.