Efficacy and Safety Evaluation of ALXN2220 in Adult Patients with Transthyretin Amyloid Cardiomyopathy: A Phase 3 Randomized, Double-blind, Placebo-controlled Study

The primary objective of this study is to evaluate the **efficacy** of ALXN2220 in the treatment of adult participants with Transthyretin Amyloid Cardiomyopathy (ATTR-CM). This will be assessed by comparing the total occurrences of all-cause mortality (ACM) and cardiovascular (CV) clinical events between the ALXN2220 and placebo groups. This objective is clinically relevant as it aims to determine the potential of ALXN2220 to improve survival and reduce CV events in patients with ATTR-CM, a condition associated with significant morbidity and mortality.

Secondary objectives include:

• Assessing the effects of ALXN2220 on symptoms, functionality, and health-related quality of life (QoL) as measured by the change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS).
• Evaluating the effects of ALXN2220 on CV-related mortality.
• Assessing the effects of ALXN2220 on change from baseline in the 6-Minute Walk Test (6MWT).
• Evaluating the efficacy of ALXN2220 in the treatment of ATTR-CM as assessed by the rate of CV clinical events and time to ACM.
• Assessing the safety and tolerability of ALXN2220.
• Evaluating the immunogenicity of ALXN2220.
• Characterizing the pharmacokinetics (PK) of ALXN2220 in participants with ATTR-CM.

The clinical trial involves a total of **654 participants** diagnosed with **Transthyretin Amyloid Cardiomyopathy (ATTR-CM)**. The study population includes both male and female adults aged between 18 and 90 years. Participants were selected based on specific criteria, including a confirmed diagnosis of ATTR-CM with either wild-type or variant TTR genotype, and a history of heart failure. The trial does not include a vulnerable population. Participants are required to have a stable health status, with specific lifestyle considerations such as the use of a loop diuretic for at least 30 days prior to screening. The trial population was selected to ensure a comprehensive assessment of the efficacy of ALXN2220 in treating ATTR-CM, with a focus on evaluating cardiovascular clinical events. Key inclusion criteria include an end-diastolic interventricular septal wall thickness of at least 12 mm and an NT-proBNP level greater than 2000 pg/mL. Participants must also have a life expectancy of at least six months as per the investigator's judgment.

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of ALXN2220 in adult participants with **Transthyretin Amyloid Cardiomyopathy (ATTR-CM)**. The trial aims to assess the difference in the total occurrences of all-cause mortality (ACM) and cardiovascular (CV) clinical events between the ALXN2220 and placebo groups. The study is expected to commence recruitment on April 23, 2024, and conclude by October 31, 2028, with a maximum treatment period of 48 weeks for participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of ATTR-CM, and specific clinical parameters. Following randomization, participants will receive either the investigational product, a **recombinant human anti-ATTR immunoglobulin G1 (IgG1) monoclonal antibody (mAb)**, or a placebo, both administered as a solution for infusion. The trial includes regular follow-up visits to monitor safety, efficacy, and any treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs). The primary endpoint is the total occurrence of ACM and CV clinical events during the blinded treatment period, with secondary endpoints including changes in the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score, time to CV-related mortality, and changes in the 6-minute walk test (6MWT) over 24 months.

The expected length of participant involvement is up to 48 weeks, with conditions for early termination including significant adverse events, withdrawal of consent, or investigator judgment of participant safety. The end-of-study visit will involve a comprehensive assessment of the participant's health status and the collection of final data for analysis. The trial is not categorized as low intervention and is conducted in accordance with regulatory standards for clinical research.

The clinical trial involves the administration of **Recombinant human anti-ATTR immunoglobulin G1 (IgG1) monoclonal antibody (mAb)**, known by the sponsor product code **ALXN2220**. This experimental medication is formulated as a **solution for injection** and is administered via **solution for infusion**. The active substance, **ALXN2220**, is a protein-based therapeutic agent developed by Alexion Pharmaceuticals, Inc. The trial is designed to evaluate the efficacy and safety of ALXN2220 in adult participants with **Transthyretin Amyloid Cardiomyopathy (ATTR-CM)**. The dosing schedule allows for a maximum treatment period of 48 weeks, with specific dosing amounts and frequencies determined by the study protocol. Participant compliance with the dosing regimen is monitored throughout the trial to ensure adherence to the treatment plan.

The study also includes a **placebo** group, which receives the **ALXN2220 Placebo Product**. The placebo is designed to match the experimental medication in appearance and administration route, serving as a control to assess the true efficacy of ALXN2220. The placebo is administered in the same manner as the active treatment, ensuring that any observed effects can be attributed to the active substance rather than the administration process. The use of a placebo control is critical in maintaining the double-blind nature of the study, where neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias in the assessment of clinical outcomes.

The efficacy of ALXN2220 in the treatment of adult participants with **Transthyretin Amyloid Cardiomyopathy (ATTR-CM)** will be assessed by evaluating the difference between the ALXN2220 and placebo groups. The primary endpoint for efficacy evaluation is the total occurrence of all-cause mortality (ACM) and cardiovascular (CV) clinical events during the Blinded Treatment Period. Secondary endpoints include changes from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score to 24 months, time to CV-related mortality, changes from baseline in the 6-Minute Walk Test (6MWT) to 24 months, rate of CV clinical events, time to ACM, and incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Additional assessments will include changes from baseline in physical examination, vital signs, clinical laboratory tests, and 12-lead ECGs, as well as the incidence of anti-drug antibodies (ADA) and neutralizing antibodies (NAb), response categories, and titer. Serum ALXN2220 concentration will also be measured.