Efficacy and Safety of Rilzabrutinib in Adults with Warm Autoimmune Hemolytic Anemia: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the effect of **rilzabrutinib** on durable hemoglobin response (DHR) in participants with warm autoimmune hemolytic anemia (wAIHA) in the primary analysis population (PAP). This is clinically relevant as achieving a durable hemoglobin response is crucial for managing wAIHA, a condition characterized by the premature destruction of red blood cells, leading to anemia and associated symptoms.

Secondary objectives include:

• To evaluate the hemoglobin overall response (OR) in the PAP.
• To assess time to response (TTR).
• To evaluate the effect of rilzabrutinib on fatigue as measured by the FACIT-Fatigue scale.
• To evaluate the effect of rilzabrutinib on LDH, a marker of hemolysis.
• To assess the effect of rilzabrutinib treatment on rescue therapy requirement.
• To evaluate the effect of rilzabrutinib on dyspnea as measured by the FACIT-Dyspnea scale.
• To evaluate the safety and tolerability of rilzabrutinib in primary wAIHA participants.

The clinical trial involves a total of **75 participants** diagnosed with **autoimmune haemolytic anaemia**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, indicating adult participants. The participants were selected based on a confirmed diagnosis of primary warm autoimmune haemolytic anaemia (wAIHA) for at least three months. They have previously failed to maintain a sustained response after treatment with corticosteroids (CS), are CS-resistant, CS-dependent, or are intolerant or ineligible to CS due to contraindications or pre-existing medical conditions. All participants have an Eastern Cooperative Oncology Group (ECOG) performance status of Grade 2 or lower. The trial population includes individuals from a vulnerable population, and contraceptive use is required to be consistent with local regulations. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of **rilzabrutinib** in participants with warm autoimmune hemolytic anemia (wAIHA). The trial is structured in a parallel-group format with an open-label period and a long-term extension. The primary objective is to assess the effect of rilzabrutinib on durable hemoglobin response (DHR) in the participant population. The trial is expected to commence recruitment on June 15, 2025, and conclude by October 4, 2029, with a maximum treatment period of 224 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of primary wAIHA for at least three months, previous treatment history, and an Eastern Cooperative Oncology Group (ECOG) performance status of Grade 2 or lower. Following successful screening, participants will be randomized to receive either rilzabrutinib or a matched placebo, administered orally in the form of film-coated tablets. The maximum daily dose of rilzabrutinib is 800 mg, with a total dose not exceeding 1,254,400 mg over the treatment period.

Subsequent follow-up visits will be scheduled to monitor the participants' response to treatment, assess any adverse events, and evaluate secondary endpoints such as overall hemoglobin response, time to hemoglobin increase, changes in fatigue and dyspnea scores, and laboratory evaluations. The end-of-study visit will mark the conclusion of the participant's involvement, during which final assessments will be conducted to gather comprehensive data on the treatment's efficacy and safety.

Participant involvement is expected to last for the duration of the treatment period, with conditions for early termination including the occurrence of treatment-emergent adverse events, lack of efficacy, or withdrawal of consent. The trial's design ensures rigorous monitoring and data collection to support the evaluation of rilzabrutinib's therapeutic potential in managing wAIHA.

The clinical trial involves the administration of **Rilzabrutinib**, an experimental medication, to evaluate its efficacy and safety in participants with warm autoimmune hemolytic anemia (wAIHA). **Rilzabrutinib** is provided in the form of a **film-coated tablet** and is administered orally. The maximum daily dose is 800 mg, with a total maximum dose of 1,254,400 mg over a treatment period of 224 days. The active substance, **Rilzabrutinib**, is synthetically manufactured and originates from a mixture. The pharmaceutical product is developed by Sanofi Aventis Recherche et Développement (SAR) and is identified by the sponsor product code SAR444671. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to the experimental treatment, a matched placebo, referred to as "Sar444671 placebo - matched placebo for test," is utilized in the study. The placebo is designed to match the experimental medication in appearance but does not contain the active substance. The placebo serves as a comparator to assess the efficacy of **Rilzabrutinib** in a double-blind, placebo-controlled setting. The administration route and form of the placebo are not specified, but it is used to maintain the integrity of the study's blinding process.

The efficacy of rilzabrutinib in the treatment of **warm autoimmune hemolytic anemia (wAIHA)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of participants achieving a durable hemoglobin (Hb) response (DHR). Secondary endpoints include the proportion of participants achieving an overall Hb response, the time taken to achieve the first Hb increase by ≥2 g/dL from baseline without transfusion and rescue medication, and changes from baseline in fatigue and dyspnea severity scores as measured by the Functional Assessment of Chronic Illness Therapy (FACIT) scales. Additionally, changes in lactate dehydrogenase (LDH) levels and the proportion of participants requiring rescue therapy after Week 4 of treatment will be evaluated.

Data collection will occur at specified intervals throughout the trial, with particular attention to the absence of transfusion and rescue medication when assessing Hb increases. The FACIT scales will be employed to quantify changes in fatigue and dyspnea severity, providing a standardized method for evaluating patient-reported outcomes. The incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) will also be monitored, alongside clinical laboratory evaluations, vital signs, physical examinations, and electrocardiograms (ECG) to ensure comprehensive safety and efficacy assessment.