Efficacy and Safety of Ianalumab Versus Placebo in Warm Autoimmune Hemolytic Anemia Patients Post-Treatment Failure: A Phase 3 Randomized Double-Blind Study

The primary objective of this study is to demonstrate that either dose of **ianalumab** induces a durable hemoglobin response compared to placebo in patients with warm autoimmune hemolytic anemia (wAIHA) who have failed at least one line of treatment. This objective is clinically relevant as it addresses the efficacy of ianalumab in improving hemoglobin levels, which is a critical factor in managing wAIHA, a condition characterized by the premature destruction of red blood cells.

Secondary objectives include:

• Demonstrating that either dose of ianalumab maintains a durable hemoglobin response beyond the treatment period compared to placebo.
• Assessing the time to durable response, response, and complete response in each treatment group.
• Evaluating the quality of response in each treatment group.
• Assessing the need for rescue treatments in each treatment group.
• Evaluating the safety profile of ianalumab.
• Characterizing the pharmacokinetics of ianalumab.
• Assessing B-cell levels and immunoglobulin levels in each treatment group.
• Evaluating the immunogenicity against ianalumab.
• Assessing the quality of life in each treatment group.

The clinical trial involves a total of **59 participants** diagnosed with **warm autoimmune haemolytic anaemia (wAIHA)**. The study population includes both male and female subjects aged **18 years and older**. Participants were selected based on their documented history of primary or secondary wAIHA, confirmed by a positive direct antiglobulin test specific for anti-IgG or anti-IgA, and their insufficient response to or relapse after at least one line of treatment. This includes individuals with corticosteroid resistance, dependence, or intolerance. The trial population is characterized by a hemoglobin concentration between **5 g/dL and 10 g/dL** and the presence of symptoms related to anemia at screening and week 1. Participants were required to have a stable dose of supportive care for at least four weeks prior to randomization. The study includes a vulnerable population, and informed consent was obtained from all participants prior to any screening assessments. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is a **randomized, double-blind, controlled** study designed to evaluate the efficacy and safety of **ianalumab** (VAY736) compared to placebo in patients with **warm autoimmune hemolytic anemia** (wAIHA) who have failed at least one line of treatment. The trial aims to demonstrate that ianalumab induces a durable hemoglobin response in these patients. The study is expected to run until February 8, 2029, with recruitment having commenced on May 9, 2023. Participants will be involved in the study for a maximum treatment period of 16 weeks, during which they will receive either ianalumab or a placebo via **intravenous** infusion.

The sequence of study visits includes an initial **screening visit** to confirm eligibility based on criteria such as age, previous treatment history, and hemoglobin levels. Following randomization, participants will attend regular follow-up visits to monitor their response to treatment and assess any adverse events. The primary endpoint is the achievement of a durable hemoglobin response, defined as a hemoglobin level of at least 10 g/dL and an increase of at least 2 g/dL from baseline for a period of at least 8 weeks between weeks 9 and 25, without the need for rescue or prohibited treatment. Secondary endpoints include the duration of response, time to first response, and various safety and pharmacokinetic parameters.

The end-of-study visit will occur after the completion of the treatment period, where final assessments will be conducted to evaluate the overall efficacy and safety of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, require rescue treatment, or fail to comply with the study protocol. The trial is conducted under strict ethical guidelines, ensuring that all participants provide informed consent before any study-related procedures are performed.

The clinical trial involves the administration of **ianalumab**, marketed under the name VAY736, as the primary experimental medication. VAY736 is provided in the form of a concentrate for solution for infusion. The administration route is **intravenous**, with a maximum daily and total dose of 9 mg/kg. The treatment period for VAY736 is set at 16 weeks. Participant compliance will be monitored through regular assessments to ensure adherence to the dosing schedule.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in the study. The placebo is designed to match the VAY736 150 mg/1 mL concentrate for solution for infusion in appearance and administration method. The placebo is administered intravenously, following the same schedule as the experimental drug, to maintain the double-blind nature of the trial.

Several auxiliary treatments are also included in the study. **Epoetin alfa**, known for its role in stimulating erythropoiesis, is provided in the pharmaceutical form PHF00231MIG. The administration route is currently unspecified. **Danazol**, a synthetic steroid and pituitary gonadotropin inhibitor, is administered orally in the form PHF00005MIG. **Entecavir**, an antiviral agent, is included in the study in the form PHF00082MIG, with an unspecified route of administration. The maximum treatment period for these auxiliary treatments is 39 weeks for epoetin alfa and danazol, and 15 weeks for entecavir.

Other auxiliary treatments include **H2-receptor antagonists** and **glucocorticoids**, both with unspecified pharmaceutical forms and routes of administration. The maximum treatment period for these substances is 32 weeks for H2-receptor antagonists and 39 weeks for glucocorticoids. Participant compliance with these auxiliary treatments will be monitored to ensure consistency with the study protocol.

The efficacy of ianalumab (VAY736) in the treatment of **warm autoimmune hemolytic anemia (wAIHA)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is a binary variable indicating whether a patient achieves a durable hemoglobin (Hb) response, defined as Hb ≥10 g/dL and an increase of ≥2 g/dL from baseline, sustained for at least 8 weeks between weeks 9 and 25, without the need for rescue or prohibited treatment.

Secondary endpoints include the duration of response, time from randomization to achievement of durable response, first response, and first complete response. Additional measures include response rate, complete response rate, and hemoglobin level. The trial will also evaluate the number and proportion of participants receiving rescue treatment, time-standardized numbers of each type of rescue treatment, and changes from baseline in the time-standardized number of transfusions. Safety parameters, including the frequency of adverse events (AEs), will be monitored.

Pharmacokinetic (PK) parameters, such as ianalumab concentration in serum after the first and last dose, will be analyzed. B-cell levels will be assessed by changes from baseline in the frequency and absolute number of CD19+ B-cell counts, and the time to first occurrence of B-cell recovery. Immunoglobulin levels and the incidence and titer of anti-drug antibodies (ADA) in serum over time will also be measured. Patient-reported outcomes (PROs) will be evaluated for changes from baseline.