Evaluation of Long-Term Safety and Efficacy of SAR447537 in Adults with Alpha-1 Antitrypsin Deficiency Emphysema

The primary objective of this study is to evaluate the long-term **safety** and tolerability of SAR447537 in adults with Alpha-1 Antitrypsin Deficiency (AATD) emphysema. This is clinically relevant as it aims to ensure that the treatment is safe for prolonged use, which is crucial for managing a chronic condition like AATD emphysema.

Secondary objectives include:

• To evaluate the change in lung density by quantitative computerized tomography (CT), which is important for assessing the impact of the treatment on lung structure.
• To assess serum pharmacokinetics (PK) of SAR447537 and functional AAT (fAAT), providing insights into the drug's absorption, distribution, metabolism, and excretion, as well as its functional efficacy.
• To assess the immunogenicity of SAR447537, which is essential for understanding the potential for immune response against the treatment.

The clinical trial involves a total of **100 participants** diagnosed with **Alpha-1 Antitrypsin Deficiency (AATD) Emphysema**. The study population comprises both **males and females** aged between **18 to 80 years**, inclusive, at the time of screening. Participants were selected based on their diagnosis of AATD and evidence of emphysema secondary to this condition. All participants have a **forced expiratory volume in one second (FEV1)** of at least 30% predicted at screening and a post-bronchodilator FEV1/FVC ratio of less than 0.7. Importantly, all individuals are current non-smokers. The trial includes a vulnerable population, ensuring a comprehensive evaluation of the long-term safety and tolerability of SAR447537. Lifestyle considerations such as smoking status are significant, as only non-smokers are included in the study. The selection criteria ensure a focused examination of the target demographic affected by AATD emphysema.

The clinical trial is designed to evaluate the long-term safety and clinical efficacy of **SAR447537** in adults diagnosed with **Alpha-1 Antitrypsin Deficiency (AATD) Emphysema**. This is a Phase 2, single-arm, open-label extension study. The investigational product, INBRX-101, is a concentrate for solution for infusion, administered intravenously. The trial is expected to commence recruitment on September 28, 2024, and conclude by November 29, 2028. Participants will be involved in the study for a maximum treatment period of 36 months.

Participants eligible for inclusion are males or females aged 18 to 80 years, with a confirmed diagnosis of AATD and evidence of emphysema secondary to AATD. They must have a forced expiratory volume in one second (FEV1) of at least 30% predicted at screening and a post-bronchodilator FEV1/forced vital capacity (FVC) ratio of less than 0.7. Current non-smoking status is also required. The primary endpoint is the incidence of all treatment-emergent adverse events (TEAEs), including those of grade 3 or higher, serious adverse events (SAEs), and adverse events of special interest (AESIs) that may lead to discontinuation from the investigational product.

The study will include several visits, starting with a screening visit to confirm eligibility based on the inclusion criteria. Follow-up visits will be scheduled to monitor the safety and efficacy of the treatment, assess lung density changes via quantitative CT, and evaluate the pharmacokinetic profile of SAR447537. The end-of-study visit will conclude the participant's involvement, ensuring all safety assessments are completed. Participants may be withdrawn from the study if they experience significant adverse events or if they no longer meet the study criteria. The trial aims to provide comprehensive data on the long-term use of SAR447537 in managing AATD emphysema.

The clinical trial involves the administration of **INBRX-101**, a concentrate for solution for infusion, with a concentration of 50 mg/ml. The active substance in this experimental medication is the **human alpha-1-proteinase inhibitor immunoglobulin G fusion protein, recombinant**. This pharmaceutical form is a solution for infusion, designed for intravenous administration. The dosing regimen specifies a maximum daily dose of 120 mg/kg, with the treatment period extending up to 36 weeks. The medication is provided by INHIBRX, INC., and is identified by the sponsor product code SAR447537. The trial aims to evaluate the long-term safety and clinical efficacy of this treatment in adults with Alpha-1 Antitrypsin Deficiency (AATD) emphysema.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus remains solely on the administration of the experimental drug, INBRX-101. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is structured as a Phase 2, single-arm, open-label extension study, emphasizing the assessment of long-term safety and tolerability of the investigational product.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint focuses on the safety profile, specifically the incidences of all treatment-emergent adverse events (TEAEs), TEAEs of Grade 3 or higher, serious adverse events (SAEs), and adverse events of special interest (AESIs), including infusion-related reactions, that lead to discontinuation of the investigational product, SAR447537. Secondary endpoints include the annual rate of change in lung density, assessed by serial quantitative CT at total lung capacity, from baseline to the end of treatment. Additionally, the serum pharmacokinetic (PK) profile of SAR447537 and functional alpha-1-antitrypsin (fAAT) will be evaluated. Population PK modeling will be conducted to assess the impact of physiologically relevant participant characteristics and disease on the PK of SAR447537. The incidence of anti-drug antibodies (ADAs) and neutralizing anti-drug antibodies (NAbs) against SAR447537 will also be measured.