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

The primary objectives of this study are to evaluate the efficacy and safety of **CAEL-101** in combination with treatment for plasma cell dyscrasia (PCD) in patients with Mayo stage IIIb **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 compared to PCD treatment and placebo. 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.
• Assessing if CAEL-101 and PCD treatment decrease cardiovascular-related hospitalizations compared to PCD and placebo.
• Evaluating quality of life as measured by the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS).
• Assessing improvement in cardiomyopathy as measured by NT-proBNP levels.
• Evaluating cardiac improvement as measured by global longitudinal strain (GLS%).
• Assessing functional improvement as measured by the distance walked in the six-minute walk test (6MWT).
• Evaluating 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 **69 participants** diagnosed with **Stage IIIb cardiac AL amyloidosis**. The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of AL amyloidosis with cardiac involvement, as defined by the European Modification of the 2004 Standard Mayo Clinic Staging. The trial population is treatment-naïve, with planned first-line treatment for plasma cell dyscrasia involving a cyclophosphamide-bortezomib-dexamethasone (CyBorD)-based regimen. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to contraception requirements if of childbearing potential. The study includes a vulnerable population, ensuring comprehensive safety and tolerability assessments of the investigational treatment. The trial aims to evaluate the impact of CAEL-101 in combination with standard treatment on overall survival and cardiovascular hospitalization frequency in this specific patient group.

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy and safety of CAEL-101 in combination with plasma cell dyscrasia treatment versus placebo in patients with Mayo Stage IIIb **AL amyloidosis**. The trial aims to assess whether CAEL-101 improves overall survival and reduces cardiovascular hospitalizations in treatment-naïve patients. The study is expected to run until September 2027, with recruitment having commenced in April 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as NT-proBNP levels and measurable hematologic disease. Following successful screening, participants will be randomized to receive either CAEL-101 or placebo, both administered via **intravenous use**. The trial includes regular follow-up visits to monitor safety and efficacy, with assessments of vital signs, weight, clinical laboratory tests, and electrocardiograms. The primary endpoint is a hierarchical combination of time to all-cause mortality and the frequency of cardiovascular hospitalizations, alongside the incidence of treatment-emergent adverse events.

The expected duration of participant involvement is until the end of the study, with the primary evaluation treatment period extending to Week 50. Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The end-of-study visit will include a comprehensive evaluation to assess the long-term effects of the treatment. The trial's design ensures rigorous monitoring and data collection to support the evaluation of CAEL-101's potential benefits in this patient population.

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 of other origin. The pharmaceutical form is a solution intended for **intravenous use**. The dosage is specified as up to 1000 mg/m² per day, with the maximum treatment period extending to 9999 days. The administration schedule and frequency are determined by the study protocol, and participant compliance is monitored throughout the trial. CAEL-101 is designated as an orphan drug, indicating its use in treating a rare condition, specifically Mayo stage IIIb AL amyloidosis.

In addition to the experimental treatment, the study includes a non-experimental treatment component, which involves the use of a **placebo**. The placebo is an isotonic solution containing **potassium chloride Ph. Eur.** and **sodium chloride Ph. Eur.**, also administered as a **solution for infusion** via the **intravenous route**. The placebo serves as a comparator to evaluate the efficacy and safety of CAEL-101 in combination with plasma cell dyscrasia treatment. The dosing schedule for the placebo mirrors that of the experimental treatment to maintain the study's double-blind design. Compliance with the administration of the placebo is similarly monitored to ensure the integrity of the trial results.

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 treatment-naïve patients with Mayo Stage IIIb 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 during the Primary Evaluation Treatment Period (PETP), frequency of CVH in PETP, and 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 critical 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's efficacy against placebo, both in combination with standard plasma cell dyscrasia treatment. The trial is designed to provide comprehensive insights into the potential benefits of **CAEL-101** in improving survival rates and reducing cardiovascular complications in the specified patient population.