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First BTK inhibitor advances toward approval for warm autoimmune hemolytic anemia

First BTK inhibitor advances toward approval for warm autoimmune hemolytic anemia

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By Newzino Staff |

FDA Breakthrough Designation Signals Potential End to Treatment Void in Rare Blood Disorder

February 9th, 2026: Breakthrough Therapy Designation for wAIHA

Overview

For 50,000 Americans living with warm autoimmune hemolytic anemia, there has never been a treatment specifically designed for their disease. On February 9, 2026, the Food and Drug Administration (FDA) granted breakthrough therapy designation to rilzabrutinib—marking the first time a Bruton's tyrosine kinase (BTK) inhibitor has reached this milestone for the condition. The designation signals the FDA's recognition that this drug may offer substantial improvement over existing therapies.

The stakes are significant: warm autoimmune hemolytic anemia (wAIHA) causes the immune system to destroy the body's own red blood cells, leading to severe anemia, fatigue, and potential organ damage. Current treatments—steroids and rituximab—fail roughly half of patients within two years. If rilzabrutinib succeeds in its ongoing phase 3 trial, it would become the first FDA-approved therapy specifically targeting this rare blood disorder.

Key Indicators

~50,000
Estimated U.S. patients with wAIHA
Approximately 1 in 8,000 Americans live with this rare autoimmune blood disorder.
0
FDA-approved therapies for wAIHA
No treatments have ever been specifically approved for this condition.
64%
Hemoglobin response rate in phase 2b trial
14 of 22 patients achieved hemoglobin response in the LUMINA 2 study.
$3.68B
Sanofi's acquisition cost for Principia Biopharma
The 2020 deal brought rilzabrutinib into Sanofi's immunology pipeline.

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People Involved

Karin Knobe
Karin Knobe
Global Head of Development, Rare Diseases at Sanofi (Leading rilzabrutinib development program)

Organizations Involved

Sanofi
Sanofi
Pharmaceutical Company
Status: Developing rilzabrutinib across multiple autoimmune indications

Global pharmaceutical company headquartered in Paris, with a growing immunology portfolio anchored by the $3.68 billion Principia Biopharma acquisition.

U.S. Food and Drug Administration
U.S. Food and Drug Administration
Federal Regulatory Agency
Status: Evaluating rilzabrutinib under breakthrough therapy pathway

U.S. agency responsible for drug safety and efficacy review, which grants breakthrough therapy designation to drugs showing substantial improvement over existing treatments for serious conditions.

Principia Biopharma
Principia Biopharma
Biotechnology Company (Acquired)
Status: Integrated into Sanofi

San Francisco-based biotech that developed rilzabrutinib using its proprietary TAILORED COVALENCY technology before being acquired by Sanofi.

Timeline

  1. Breakthrough Therapy Designation for wAIHA

    Regulatory

    FDA granted breakthrough therapy designation for rilzabrutinib in warm autoimmune hemolytic anemia, the first BTK inhibitor to receive this status for the condition. Japan simultaneously granted orphan drug designation.

  2. Wayrilz Approved for ITP

    Regulatory

    FDA approved rilzabrutinib (branded as Wayrilz) for adults with persistent or chronic immune thrombocytopenia, making it the first BTK inhibitor for the condition.

  3. Orphan Drug Designations Granted

    Regulatory

    FDA granted orphan drug status for rilzabrutinib in autoimmune hemolytic anemia and IgG4-related disease, providing market exclusivity incentives.

  4. Full ITP Data Presented at ASH Conference

    Scientific Presentation

    Detailed LUNA 3 results showed 64% response rate at 12 weeks and significant improvements in bleeding and fatigue symptoms.

  5. ITP Phase 3 Trial Succeeds

    Clinical Trial

    The LUNA 3 trial met its primary endpoint, showing rilzabrutinib doubled durable platelet response rates compared to placebo in immune thrombocytopenia.

  6. Pemphigus Trial Fails

    Clinical Trial

    Rilzabrutinib failed to outperform placebo in a phase 3 pemphigus trial, delivering a setback to Sanofi's autoimmune strategy.

  7. FDA Grants Fast Track for ITP

    Regulatory

    Rilzabrutinib received FDA fast track designation for immune thrombocytopenia, signaling regulatory interest in the BTK inhibitor approach.

  8. Sanofi Acquires Principia Biopharma

    Corporate

    Sanofi purchased Principia for $3.68 billion, gaining rilzabrutinib and its TAILORED COVALENCY platform to expand into autoimmune diseases.

  9. First BTK Inhibitor Approved for Cancer

    Industry Milestone

    FDA approved ibrutinib as the first BTK inhibitor, establishing the drug class for blood cancers and opening possibilities for autoimmune applications.

Scenarios

1

FDA Approves First Targeted Therapy for Warm Autoimmune Hemolytic Anemia

Discussed by: Industry analysts at Seeking Alpha, GuruFocus; hematology experts at American Society of Hematology

The LUMINA 3 phase 3 trial meets its primary endpoint, demonstrating rilzabrutinib significantly improves hemoglobin response compared to placebo. FDA grants approval, establishing the first targeted therapy for wAIHA. Sanofi captures a rare disease market with significant unmet need, validating the $3.68 billion Principia acquisition. The approval opens pathways for BTK inhibitors in additional autoimmune conditions.

2

Phase 3 Trial Falls Short, Development Paused

Discussed by: Fierce Biotech, BioPharma Dive analysts who covered the 2021 pemphigus failure

The LUMINA 3 trial fails to demonstrate statistically significant improvement over placebo, echoing the 2021 pemphigus setback. While the phase 2b results showed promise with a 64% response rate, the placebo-controlled phase 3 design exposes a smaller-than-expected treatment effect. Sanofi may continue development with modified trial design or combination approaches, but approval timeline extends significantly.

3

Competitor Reaches Market First

Discussed by: Lancet Haematology editorial on expanding wAIHA treatment options; Frontiers in Immunology review

Other investigational therapies—including complement inhibitors like pegcetacoplan, neonatal Fc receptor blockers like nipocalimab, or anti-CD38 antibodies like daratumumab—complete development faster than rilzabrutinib. While breakthrough designation accelerates FDA interaction, it doesn't guarantee first-to-market status. Sanofi may face competition in a condition previously lacking any approved therapies.

4

Approval with Limited Label, Restricted Use

Discussed by: FDA regulatory analysts, clinical trial investigators cited in American Society of Hematology publications

FDA approves rilzabrutinib with a narrow indication—restricted to patients who have failed multiple prior therapies—limiting market potential. Safety concerns observed in the broader BTK inhibitor class (bleeding, infections) lead to black box warnings or Risk Evaluation and Mitigation Strategy requirements. Uptake remains modest despite breakthrough designation.

Historical Context

Rituximab Off-Label Adoption for Autoimmune Hemolytic Anemia (2000s)

2001-2015

What Happened

Rituximab, originally approved for non-Hodgkin lymphoma in 1997, began showing efficacy in autoimmune hemolytic anemia through case reports and small studies. Physicians adopted it off-label for steroid-refractory patients, achieving 70-80% response rates. Despite widespread use, no manufacturer pursued a formal FDA approval for this indication.

Outcome

Short Term

Rituximab became the de facto second-line therapy for wAIHA worldwide, despite lacking FDA approval for this use.

Long Term

The pattern demonstrated how rare disease patients rely on off-label treatments when no approved therapies exist. It also showed pharmaceutical companies rarely invest in approval studies for small patient populations without financial incentives.

Why It's Relevant Today

Rilzabrutinib's path illustrates a potential shift: orphan drug incentives and breakthrough therapy pathways now make rare autoimmune conditions commercially viable targets. If approved, it would be the first treatment specifically developed and approved for wAIHA.

Ibrutinib: BTK Inhibitors Enter Medicine (2013)

November 2013

What Happened

The FDA approved ibrutinib as the first Bruton's tyrosine kinase inhibitor for mantle cell lymphoma. The drug targeted a kinase long studied in immunology, opening a new therapeutic class. Ibrutinib's irreversible binding mechanism caused off-target effects including cardiac arrhythmias and bleeding.

Outcome

Short Term

Ibrutinib transformed treatment for certain blood cancers and generated billions in revenue for Pharmacyclics and AbbVie.

Long Term

Second-generation BTK inhibitors with improved selectivity emerged. Researchers began exploring BTK inhibition for autoimmune diseases, hypothesizing that blocking B-cell activation could treat conditions beyond cancer.

Why It's Relevant Today

Rilzabrutinib represents the autoimmune application of BTK inhibition that researchers envisioned after ibrutinib's success. Its reversible binding mechanism addresses some safety concerns that limited ibrutinib's use, potentially enabling chronic treatment for autoimmune conditions.

FDA Breakthrough Therapy Designation Impact (2012-Present)

July 2012-Present

What Happened

Congress created the breakthrough therapy designation under the FDA Safety and Innovation Act to accelerate development of drugs for serious conditions. The FDA received over 1,500 requests by 2024, granting approximately 39%. Designated drugs receive intensive FDA guidance, eligibility for rolling review, and organizational commitment to expedite development.

Outcome

Short Term

Breakthrough-designated drugs moved through development 21 months faster on average than non-designated drugs.

Long Term

Over 317 breakthrough-designated products received FDA approval by 2024. The designation became a significant validator for investors and a predictor of eventual approval.

Why It's Relevant Today

Rilzabrutinib's breakthrough designation for wAIHA signals FDA recognition that existing off-label treatments are inadequate. The designation substantially increases the probability of approval and accelerates the timeline for patients who currently have no specifically approved options.

10 Sources:
+4
GlobeNewswire Sanofi Blood (American Society of Hematology) ScienceDirect National Organization for Rare Disorders Journal of Clinical Medicine American Journal of Managed Care Precision for Medicine Sanofi Journal of Clinical Medicine