Evaluation of CAEL-101 and Plasma Cell Dyscrasia Treatment Efficacy and Safety in Treatment-Naïve Mayo Stage IIIa AL Amyloidosis Patients

The primary objectives of this Phase 3, double-blind, multicenter study are to evaluate the efficacy and safety of **CAEL-101** in combination with treatment for plasma cell dyscrasia (PCD) compared to placebo and PCD treatment in patients with Mayo stage IIIa **AL amyloidosis** who are treatment-naïve. Specifically, the study aims to determine if CAEL-101 improves overall survival and/or decreases the frequency of cardiovascular hospitalizations. Additionally, the study will assess the safety and tolerability of CAEL-101 in this patient population. These objectives are clinically relevant as they address critical outcomes such as survival and cardiovascular health in a population with limited treatment options.

The secondary objectives include: - Determining if CAEL-101 and PCD treatment improve survival post-initiation of study treatment compared to PCD and placebo. - Evaluating if CAEL-101 and PCD treatment decrease cardiovascular-related hospitalizations compared to PCD and placebo. - Assessing improvement in cardiomyopathy as measured by NTproBNP. - Evaluating quality of life as measured by the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS). - Assessing cardiac improvement as measured by global longitudinal strain (GLS%). - Evaluating functional improvement as measured by the distance walked in the six-minute walk test (6MWT). - Assessing quality of life as measured by the Short Form 36 Health Survey Physical Component Score (SF-36v2® PCS).

The clinical trial involves a total of **198 participants** diagnosed with **stage IIIa cardiac AL amyloidosis**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on specific inclusion criteria, such as having a histopathological diagnosis of amyloidosis and measurable hematologic disease. The trial population is treatment-naïve, meaning they have not received prior treatment for their condition. Lifestyle considerations, such as diet and physical activity, are not specified. The study does not exclude vulnerable populations, indicating a broad inclusion of individuals who meet the medical criteria. The primary objective is to assess the efficacy and safety of CAEL-101 in combination with treatment for plasma cell dyscrasia, compared to a placebo, in improving overall survival and reducing cardiovascular hospitalizations.

The clinical trial is a **Phase 3**, double-blind, multicenter study designed to evaluate the efficacy and safety of **CAEL-101** in combination with plasma cell dyscrasia treatment compared to placebo in patients with **stage IIIa cardiac AL amyloidosis**. The trial employs a randomized, controlled design to ensure the reliability of the results. The estimated duration of the trial is from March 2021 to August 2027, with participant involvement expected to last until the end of the study or until early termination criteria are met.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as measurable hematologic disease and cardiac involvement. Following successful screening, participants will be randomized to receive either the investigational product or placebo. The trial includes regular follow-up visits to monitor safety and efficacy, with assessments of vital signs, laboratory tests, and electrocardiograms. The primary endpoints focus on time to all-cause mortality and the frequency of cardiovascular hospitalizations, while secondary endpoints include changes in clinical parameters over a 50-week period.

The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial aims to provide comprehensive data on the potential benefits and risks of CAEL-101 in this patient population, contributing valuable insights into the management of AL amyloidosis.

The clinical trial involves the administration of **CAEL-101**, an experimental medication, which is a **solution for infusion**. The active substance in CAEL-101 is **anselamimab**, a protein classified under "Protein - Other". The pharmaceutical form is specifically designed for intravenous use. The dosage is measured in **mg/m² (milligram(s)/sq. meter)**, although the exact dosing schedule and maximum daily dose are not specified in the provided data. The treatment period is set to a maximum of 9999 days, indicating a long-term administration plan. CAEL-101 is designated as an orphan drug, highlighting its use in treating rare conditions, specifically in patients with Mayo Stage IIIa AL amyloidosis who are treatment-naïve.

In addition to CAEL-101, the trial includes the use of **Sodium Chloride**, which serves as a non-experimental treatment. This isotonic solution, containing **potassium chloride Ph. Eur.** and **sodium chloride Ph. Eur.**, is also administered intravenously. The pharmaceutical form is identified as **PHF00169MIG**, and it is commonly referred to by its sponsor product code, **0.9% NaCl**. The isotonic solution is used as a standard-of-care therapy and may act as a placebo in the trial. The maximum treatment period for Sodium Chloride is similarly set to 9999 days, aligning with the long-term nature of the study. The administration of both CAEL-101 and Sodium Chloride is monitored to ensure participant compliance and safety throughout the trial duration.

The efficacy of the investigational product CAEL-101 in combination with plasma cell dyscrasia treatment will be assessed in a Phase 3, double-blind, multicenter clinical trial involving patients with Mayo stage IIIa AL **amyloidosis**. The primary efficacy endpoints include a hierarchical combination of time to all-cause mortality (ACM) and the frequency of cardiovascular hospitalizations (CVH). Secondary efficacy endpoints will evaluate time to ACM and frequency of CVH during the Primary Evaluation Treatment Period (PETP), as well as changes from baseline to Week 50 in several parameters: Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS), N-terminal pro b-type natriuretic peptide (NTproBNP), global longitudinal strain percentage (GLS%), six-minute walk test (6MWT), and the Short Form-36 version 2 Physical Component Summary (SF-36v2 PCS).

Data collection will occur at specified timepoints, with changes from baseline being a key measure of efficacy. The trial will utilize validated scales and laboratory tests to ensure accurate and reliable data collection. The analysis will focus on comparing the investigational product with placebo, both in combination with standard plasma cell dyscrasia treatment, to determine the impact on overall survival and cardiovascular outcomes in the specified patient population.