Phase 2 Double-Blind Study of SAR447537 vs. Plasma-Derived Alpha1-Proteinase Inhibitor in Adults with Alpha-1 Antitrypsin Deficiency Emphysema

The primary objective of this study is to evaluate the **pharmacodynamic** effect on serum trough functional alpha-1 antitrypsin (fAAT) levels at steady-state in participants with Alpha-1 Antitrypsin Deficiency (AATD) emphysema. This assessment will be conducted following a treatment period of up to 32 weeks, comparing the effects of SAR447537 to plasma-derived alpha1-proteinase inhibitor (A1PI) augmentation therapy. This objective is clinically relevant as it aims to determine the efficacy of SAR447537 in maintaining adequate fAAT levels, which is crucial for managing AATD emphysema and potentially improving patient outcomes.

Secondary objectives include:

• Assessing serum **pharmacokinetics** (PK) and **pharmacodynamics** (PD) effects of SAR447537 and A1PI on serum average fAAT levels.
• Evaluating the safety and tolerability of SAR447537 and A1PI.
• Assessing the **immunogenicity** of SAR447537 and A1PI.

The clinical trial involves a total of **60 participants** diagnosed with **Alpha-1 Antitrypsin Deficiency (AATD) Emphysema**. The study population comprises both male and female subjects, aged between 18 and 80 years. Participants were selected based on specific criteria, including a confirmed diagnosis of AATD, evidence of emphysema secondary to AATD, and a forced expiratory volume in one second (FEV1) between 30% and 80% of the predicted value at screening. All participants are current non-smokers. The trial includes a vulnerable population, ensuring careful consideration of ethical standards. The study aims to evaluate the pharmacodynamic effect on serum trough functional AAT levels at steady-state over a treatment period of up to 32 weeks.

The clinical trial is designed as a **randomized**, **double-blind**, active-controlled, parallel-group study to evaluate the pharmacokinetics, pharmacodynamics, immunogenicity, and safety of SAR447537 (INBRX-101) compared to plasma-derived alpha-1-proteinase inhibitor (A1PI) augmentation therapy in adults with **Alpha-1 Antitrypsin Deficiency (AATD) Emphysema**. The trial will span an estimated duration of 32 weeks, with participant involvement expected to last the same period. The primary objective is to assess the pharmacodynamic effect on serum trough functional AAT levels at steady-state. The trial will commence with a screening visit to confirm eligibility based on criteria such as age, diagnosis of AATD, evidence of emphysema, and lung function parameters. Participants will be randomly assigned to receive either SAR447537 or A1PI, with dosing administered via **intravenous** infusion. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and any adverse events, with the primary endpoint being the mean change in average fAAT concentration. Secondary endpoints include changes in serum fAAT concentration, incidence of treatment-emergent adverse events, and the presence of anti-drug antibodies. The end-of-study visit will conclude the trial, assessing the overall outcomes and any long-term effects. Conditions for early termination from the study include significant adverse events or non-compliance with the study protocol. Participants are expected to adhere to the study schedule and procedures to ensure the integrity of the trial data.

The clinical trial involves the administration of **INBRX-101**, a recombinant protein known as **human alpha-1-proteinase inhibitor immunoglobulin G fusion protein**. This investigational product is provided as a **concentrate for solution for infusion** with a concentration of 50 mg/ml. The pharmaceutical form is a **solution for infusion**, and it is administered via the **intravenous** route. The dosing regimen involves a maximum daily dose of 60 mg/kg, with a total treatment period extending up to 32 weeks. The product is manufactured by INHIBRX, INC. and is identified by the sponsor product code SAR447537.

As a comparator treatment, the trial utilizes **Respreeza**, which is a **human alpha1-proteinase inhibitor**. This product is supplied as a **powder and solvent for solution for infusion**, with a dosage strength of 1,000 mg. The pharmaceutical form is also a **solution for infusion**, administered through **infusion**. The dosing schedule mirrors that of the investigational product, with a maximum daily dose of 60 mg and a treatment duration of up to 32 weeks. Respreeza is produced by CSL BEHRING GMBH and is authorized under the marketing authorization number EU/1/15/1006/001.

Additionally, **Sodium Chloride 0.9%** is used as a non-experimental treatment in the study. It serves as a standard diluent or placebo, depending on the specific requirements of the trial protocol. The pharmaceutical form and route of administration for Sodium Chloride 0.9% are not specified in the provided data.

The efficacy of the investigational product SAR447537 (INBRX-101) in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the mean change in average serum trough functional **Alpha-1 Antitrypsin** (fAAT) concentration, as measured by anti-neutrophil elastase capacity (ANEC), from baseline to steady-state (Ctrough,ss) in participants treated with SAR447537 compared to plasma-derived Alpha1-Proteinase Inhibitor (A1PI) augmentation therapy. This endpoint will provide insight into the pharmacodynamic effect of the treatment over a period of up to 32 weeks.

Secondary endpoints include the mean change in serum fAAT concentration from baseline to the average concentration at steady state (Cavg,ss), and the percentage of days with fAAT above the lower limit of the normal range during steady-state dosing. Additionally, the trial will monitor the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and the frequency of anti-drug antibodies (ADA) against SAR447537 and endogenous AAT. Population pharmacokinetic (PK) modeling will also be conducted to assess the impact of physiologically relevant patient characteristics and disease on PK. These endpoints will be measured and analyzed using validated laboratory tests and patient-reported outcomes at specified timepoints throughout the trial duration.