Inclusion Criteria:

• Participant must be ≥18 years of age inclusive, at the time of signing the informed consent.
• Male and female participants with a confirmed diagnosis of primary wAIHA for at least 3 months who meet all of the following criteria:
  • Baseline averaged Hb level <10 g/dL with all individual Hb levels ≤10.5 g/dL at screening and at Day 1 before the first IMP dosing; baseline Hb value is defined as the average of available Hb values at screening (up to 4 weeks prior to Day 1) and at Day 1 prior to the first IMP administration. Hemoglobin baseline measurements at screening and at Day 1 must be at least 14 days after a blood transfusion, 14 days after a stabilized CS dose and 30 days after the treatment of rescue medications (IV Ig, and/or plasma exchange).
  • Evidence of hemolysis as defined by haptoglobin ≤25 mg/dL OR total bilirubin above the upper limit of normal (ULN) OR LDH above the ULN.
  • Positive direct antiglobulin test (DAT) (IgG or IgG + complement C3d pattern, or IgA or IgM warm autoantibodies [positive dual DAT]).
• Participants who have previously failed to maintain a sustained response after treatment with CS (CS-resistance [defined as failure to obtain hemoglobin response within 3 weeks on at least 1 mg/kg or 60 mg prednisone or equivalent per day], CS-dependent wAIHA [defined as need to continue on prednisone or equivalent at a dose of >10 mg/day to maintain a response]), or are intolerant or ineligible to CS (defined as with contraindications, preexisting medical conditions or CS-related complications that may render CS intolerant or ineligible per the best clinical judgement of the investigators).
• Participants with Eastern Cooperative Oncology Group (ECOG) performance status Grade 2 or lower.
• Participants who have an up-to-date vaccination status as per local guidelines. The last dose of live vaccines should be received ≥12 weeks from Day 1.
• Male and female patients:
  • Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    • Male participants,  Male participants are eligible to participate if they agree to the following during the intervention period and for at least 13 weeks after the last administration of study intervention:
      • Refrain from donating or cryopreserving sperm Plus either:
      • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR
      • Must agree to use contraception/barrier as detailed below A male condom; the participant should also be advised of the benefit for a female partner to use a highly effective method of contraception (as described in Appendix 4 Contraceptive and barrier guidance; Section 10.4.2) of the protocol as a condom may break or leak when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant
    • Female participants, A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
      • Is a woman of nonchildbearing potential (WONCBP) 
      • Is a woman of childbearing potential (WOCBP) and agrees to use a contraceptive method that is highly effective (with a failure rate of <1% per year), during the study intervention period (to be effective before starting the intervention) and for at least 4 weeks after the last administration of study intervention and agrees not to donate or cryopreserve eggs (ova, oocytes) for the purpose of reproduction during this period.
      • A WOCBP must have a negative highly sensitive pregnancy test (serum) as required by local regulations within 3 days before the first administration of study intervention.
        • If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
• Capable of giving signed informed consent as described in Appendix 1 of the protocol which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Evidence of treatment efficacy to rilzabrutinib as defined by Hb increase by ≥2 g/dL from baseline at ≥50% of the visits without receiving rescue therapy or blood transfusion during the last 8 weeks of the OLP.
• Completion of the 28-week OLP

Exclusion Criteria:

• Participants with clinically significant medical history or ongoing chronic illness that would jeopardize the safety of the participant or compromise the quality of the data derived from his or her participation in the study as determined by the Investigator.
• Participants with medical history of lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for the past 3 years.
• History of recurring (2 or more) serious infections requiring intravenous antibiotic therapy within the last 3 months before Day 1 (randomization) or active serious or moderate infection ongoing at Day 1.
• Participants with symptomatic herpes zoster within 3 months prior to screening.
• Participants with secondary wAIHA from any cause including drugs, Evans Syndrome, lymphoproliferative disorders (low count monoclonal B-cell lymphocytosis is allowed), infectious or autoimmune disease, or active hematologic malignancies. Participants with positive antinuclear antibodies but without a definitive diagnosis of an autoimmune disease are allowed.
• Participants with history of myelodysplastic syndrome.
• ECG findings:
  • QTcF >450 msec (males) or >470 msec (females), poorly controlled atrial fibrillation (ie, symptomatic patients or a ventricular rate above 100 beats/min on ECG), or other clinically significant abnormalities.
• Participants with history of coagulation or bleeding disorders.
• Participants with uncontrolled or active HBV infection: positive HBsAg and/or HBV DNA. Of note:
  • Participants can be eligible if anti-HBc IgG positive (with anti-HBs ≥10 mIU/mL) and HBsAg and HBV DNA are negative.
    • If anti-HBV therapy in relation with prior infection was started before initiation of IMP, the anti-HBV therapy and monitoring should continue throughout the study treatment period.
  • Participants with negative HBsAg and positive HBV DNA observed during the screening period will be evaluated by a specialist for start of anti-viral treatment: study treatment could be proposed if HBV DNA becomes negative and all the other study criteria are still met.
  • Active HCV infection: positive HCV RNA and positive anti-HCV.  Of note:
    • Participants with antiviral therapy for HCV started before initiation of IMP and positive HCV antibodies are eligible. The antiviral therapy for HCV should continue throughout the treatment period until seroconversion.
    • Participants with positive anti-HCV and undetectable HCV RNA without antiviral therapy for HCV at screening are eligible.
• HIV infection
• Participants with history of solid organ transplant.
• Participants with a history of active or latent tuberculosis (TB) (unless the participant has completed a full course of anti-tuberculosis therapy or it is documented by a specialist that the participant has been adequately treated and can begin treatment with an immunosuppressive agent); A positive test for TB (PPD or QuantiFERON-TB-Gold [QFT] or equivalent) performed at the screening visit or within the 3 months prior to screening. NOTE: A documented negative screening for TB or a negative QFT within 3 months prior to screening (and if required per local standard of care, a chest X-ray), is sufficient and no further screening with QFT is required; if clinically indicated the test may be repeated based on clinical judgment, borderline results, or clinical suspicion of TB infection.
• Positive COVID-19 molecular test (if COVID-19 testing required per local guidelines to be determined for each site).
• Any of the following laboratory abnormalities at the screening visit:
  • Neutrophils <1.5 × 109 /L
  • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >1.5 × ULN
  • Total bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if total bilirubin is fractionated and direct bilirubin <35%)
    • Eligibility of participants with Gilbert Syndrome confirmed by a genetic test will be determined by the investigator and Sponsor on a case-by-case basis
• Ferritin levels below the lower limit of normal.
• Prothrombin time (PT/INR) or activated partial thromboplastin time (aPTT) above the ULN and deemed to be clinically significant by the Investigator.
• Female who will be lactating during the study.
• Participants receiving >20 mg/day predniso(lo)ne or equivalent or who have had >10% change in CS dose within 14 days prior to Day 1 (randomization).
• Participants previously treated with rituximab (or other anti-CD20 monoclonal antibodies) with the last dose administered less than 12 weeks before Day 1 (randomization).
  • Participants treated with rituximab within 12 months before enrollment should have normal B-cell counts confirmed prior to Day 1 (randomization).
• Immunosuppressant drugs other than CS within 30 days or 5 half-lives (whichever is longer) of Day 1 (randomization).
• Concurrent treatment with erythropoietin unless the participant has been on a stable dose for 3 months prior to Day 1 (randomization).
• Concurrent use of iron supplementation unless the participant has been on a stable dose for at least 4 weeks prior to Day 1 (randomization).
• Ongoing need for the use of proton pump inhibitor drugs such as omeprazole and esomeprazole (however, it is acceptable to change to H2 receptor blocking drugs prior to Day 1 [randomization]).
• Use of known strong-to-moderate inducers or inhibitors of CYP3A within 14 days or 5 halflives (whichever is longer) of Day 1 (randomization) and until the last dose of IMP. A list of strong-to-moderate inhibitors/inducers s is included.
• Planned or concomitant use of any anticoagulants and platelet aggregation inhibiting drugs such as aspirin (except for low dose aspirin up to 100 mg per day), thienopyridines within 14 days of Day 1 (randomization).
• COVID-19 vaccine within 14 days prior to Day 1 or planned during the last 12 weeks of PAP.
• Planned surgery during the PAP.
• Concurrent treatment with other experimental/investigational drugs within 30 days or 5 halflives, whichever is longer, prior to treatment start.
  • Participants who previously received treatment with BTK inhibitors for wAIHA before Day 1 (randomization) are not eligible.
• Individuals accommodated in an institution because of regulatory or legal order; prisoners or participants who are legally institutionalized.
• Participant not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures.
• Participants are employees of the clinical study site or other individuals directly involved in the conduct of the study, or immediate family members of such individuals (in conjunction with section 1.61 of the ICH-GCP Ordinance E6).
• Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study.
• Participants who receive any therapy during the PAP and OLP (other than CS, transfusions, permitted rescue therapies) that may increase Hb levels in wAIHA (for example: danazol, rituximab, immunosuppressor or immunomodulator such as azathioprine, cyclosporine, and mycophenolate; and splenectomy).

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 03/10/2025. Questions regarding updates should be directed to the study team contact.