Exploratory Study of Ianalumab in Adults with Primary Immune Thrombocytopenia (ITP) and Warm-antibody Autoimmune Hemolytic Anemia (wAIHA) who Have Previously Benefited from Ianalumab (VAY RE-HIT)

This exploratory study evaluates the clinical benefit of a second course of ianalumab in adult participants with primary immune thrombocytopenia (ITP) and warm-antibody autoimmune hemolytic anemia (wAIHA) who previously derived benefit from an initial course of treatment and subsequently experienced relapse. The primary objective addresses the need to assess retreatment efficacy in patients who initially responded to ianalumab therapy but later relapsed, providing critical data on the durability and repeatability of therapeutic response in these autoimmune cytopenias.

The secondary objectives include:

• For primary ITP participants receiving a second course of ianalumab: evaluation of the proportion of participants achieving response and complete response, and description of the need for rescue treatment and/or new ITP therapy across cohorts defined by parent study parameters and initial ianalumab dose.

• For wAIHA participants receiving a second course of ianalumab: assessment of the proportion of participants achieving response and complete response, and description of the use of rescue treatment and/or new wAIHA therapy across cohorts stratified by ianalumab treatment arm in the parent study (blinded ianalumab 3 mg/kg, blinded ianalumab 9 mg/kg, or cross-over ianalumab 9 mg/kg).

• For all participants: assessment of the safety profile of ianalumab, evaluation of the pharmacokinetics of a second course of ianalumab treatment, and assessment of the immunogenicity of a second course of ianalumab treatment.

This clinical trial enrolled a total of **34 participants** diagnosed with either **immune thrombocytopenia (ITP)** or **warm autoimmune hemolytic anemia (wAIHA)**. The study population included both **male and female subjects** aged **18 years and older**. Participants were selected based on their previous enrollment in parent trials where they had received either ianalumab or placebo and subsequently experienced treatment failure or relapse at least 2 years after their last infusion. For primary ITP participants, eligibility required documented treatment failure according to parent trial definitions following initial therapy with ianalumab or placebo in combination with first-line corticosteroids or second-line eltrombopag. For wAIHA participants, both primary and secondary cases were included, with eligibility requiring previously documented positive **direct antiglobulin test (DAT)** specific for anti-IgG or anti-IgA, prior durable response in parent trials, and relapsed disease with **hemoglobin concentration** between 5 g/dL and 10 g/dL along with anemia-related symptoms. The trial population represented a vulnerable population group. Participants were permitted to receive rescue medication, bridging therapy, or supportive care under specified conditions prior to screening, provided that baseline laboratory values for eligibility assessment were obtained before treatment initiation.

This is a phase 2b exploratory clinical trial evaluating the efficacy and safety of a second course of ianalumab in adult participants with primary immune thrombocytopenia (ITP) and warm-antibody autoimmune hemolytic anemia (wAIHA) who previously benefited from ianalumab treatment and subsequently experienced relapse. The trial is designed as an open-label study without randomization or blinding. Participants must have been previously enrolled in parent trials where they received ianalumab or placebo and demonstrated initial treatment benefit, followed by relapse occurring at least 2 years after the last infusion. The study will enroll male and female participants aged 18 years and older who meet specific disease-related criteria at the time of relapse.

The investigational medicinal product is VAY736, a concentrate for solution for infusion containing ianalumab, which is designated as an orphan drug. Ianalumab is administered via intravenous route at a maximum daily dose of 9 mg/kg, with a maximum total dose of 9 mg/kg over a treatment period of 16 weeks. Several auxiliary medicinal products are permitted during the trial, including entecavir (antiviral agent administered for up to 52 weeks), danazol (synthetic steroid and pituitary gonadotropin inhibitor administered orally for up to 60 weeks), glucocorticoids (administered for up to 60 weeks), anilides (administered for up to 44 weeks), antihistamines for systemic use (administered for up to 44 weeks), and other systemic hemostatics (administered for up to 60 weeks). Rescue medication and bridging therapy are permitted within 28 days prior to screening, and supportive care is allowed if it was received in the parent trial and has remained stable for at least 4 weeks prior to screening.

For participants with primary ITP, the main objective is to assess the benefit of a second course of ianalumab in those who derived benefit from the initial course and subsequently relapsed. The primary endpoint for ITP participants is treatment failure-free status at 12 months after the start of the second course of ianalumab, defined as the absence of platelet count below 30 G/L later than 8 weeks from the start of the second course, no use of rescue treatment later than 8 weeks from the second course, no start of new ITP treatment, no death, and ability to taper thrombopoietin receptor agonist by week 24. For participants with wAIHA, the main objective is to assess the benefit of a second course of ianalumab in those who had benefit from the initial course and subsequently relapsed. The primary endpoint for wAIHA participants is durable response, defined as 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 consecutive weeks between week 9 and week 25, in the absence of rescue or prohibited treatment prior to achieving that durable response.

Secondary endpoints include response rate and complete response rate for both ITP and wAIHA participants, the number and proportion of participants receiving rescue treatment and/or new disease-specific therapy, frequency of adverse events and other safety parameters, number of severe infections and proportion of participants with severe infection, ianalumab concentration in serum, and incidence and titer of anti-ianalumab antibodies in serum over time. Principal inclusion criteria require signed informed consent obtained prior to participation, male and female participants aged 18 years and older, previous enrollment and treatment in specified parent trials with documented treatment failure or relapse according to protocol definitions, and specific disease-related parameters at screening. For ITP participants, platelet count results obtained prior to the start of rescue or bridging therapy must be collected within 30 days prior to screening. For wAIHA participants, previously documented positive direct antiglobulin test specific for anti-IgG or anti-IgA is required, along with relapsed wAIHA with hemoglobin concentration between 5 g/dL and 10 g/dL and presence of symptoms related to anemia during screening or within specified timeframes.

The estimated recruitment start date is November 2025, and the estimated end date of the trial is August 2030. Participants who meet the eligibility criteria will undergo screening procedures to confirm their suitability for the study. Following successful screening, eligible participants will receive the second course of ianalumab treatment according to the protocol-specified dosing regimen. Study visits will be conducted at regular intervals to assess efficacy endpoints, monitor safety parameters, collect blood samples for pharmacokinetic analysis and immunogenicity assessment, and evaluate disease-specific outcomes. The duration of participant involvement extends through the treatment period and follow-up phase, with assessments continuing until the end of the study. Early termination from the study may occur due to withdrawal of informed consent, loss to follow-up, development of safety concerns requiring discontinuation of treatment, initiation of prohibited concomitant medications, protocol violations, pregnancy, or at the discretion of the investigator or sponsor if continuation is deemed not in the best interest of the participant.

The experimental medication **VAY736** contains the active substance **ianalumab**, a protein-based therapeutic agent. The product is formulated as a **concentrate for solution for infusion** and is administered via the **intravenous** route. The maximum daily dose is **9 mg/kg**, with a maximum total dose of **9 mg/kg**. The maximum treatment period is **16 months**. VAY736 has been designated as an **orphan drug** under the designation number EU/3/25/3036. The sponsor product code for this investigational medicinal product is VAY736, manufactured by Novartis Pharma AG.

**Entecavir** is utilized as an auxiliary medication in this clinical trial. This **antiviral** agent contains entecavir as the active substance, which is of chemical origin. The maximum treatment period for entecavir is **52 weeks**. The route of administration is not specified in the available data.

**Danazol** serves as an auxiliary treatment in the study. This medication is classified as a synthetic steroid and **pituitary gonadotropin inhibitor**. Danazol contains danazol as the active substance of chemical origin and is administered via the **oral** route. The maximum treatment period for danazol is **60 weeks**.

**Glucocorticoids** are included as auxiliary medications in the trial. These agents belong to the ATC classification code H02AB. The maximum treatment period for glucocorticoids is **60 weeks**. The route of administration is not specified in the available data.

**Anilides**, classified under ATC code N02BE, are utilized as auxiliary medications. The maximum treatment period for anilides is **44 weeks**. The route of administration is not specified in the available data.

**Antihistamines for systemic use**, classified under ATC code R06A, are employed as auxiliary medications in the study. The maximum treatment period for antihistamines is **44 weeks**. The route of administration is not specified in the available data.

**Other systemic hemostatics**, classified under ATC code B02BX, are included as auxiliary treatments. The maximum treatment period for systemic hemostatics is **60 weeks**. The route of administration is not specified in the available data.

Efficacy will be assessed through distinct primary endpoints for participants with primary immune thrombocytopenia (ITP) and warm-antibody autoimmune hemolytic anemia (wAIHA). For ITP participants, the primary endpoint is treatment failure free status at 12 months after the start of the second course of ianalumab. Treatment failure is defined as any of the following: platelet count below 30 G/L later than 8 weeks from the start of the second course, use of rescue treatment later than 8 weeks from the second course, initiation of new ITP treatment, death, or inability to taper thrombopoietin receptor agonist by week 24. For wAIHA participants, the primary endpoint is durable response, defined as hemoglobin concentration of at least 10 g/dL and an increase of at least 2 g/dL from baseline, sustained for a minimum of 8 consecutive weeks between week 9 and week 25 in the absence of rescue or prohibited treatment prior to achieving that durable response.

Secondary endpoints for primary ITP participants include response rate and complete response rate, as well as the number and proportion of participants receiving rescue treatment and/or new ITP therapy. For wAIHA participants, secondary endpoints include response rate and complete response rate, and the number and proportion of participants who received rescue treatment and/or new wAIHA therapy. Additional secondary endpoints applicable to all participants include the frequency of adverse events and other safety parameters, the number of severe infections and proportion of participants with severe infection, ianalumab concentration in serum, and the incidence and titer of anti-ianalumab antibodies in serum over time.