Addressing Complex Immune Dysregulation in ITP: A Closer Look at Multi-Immune Modulation

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For decades, immune thrombocytopenia (ITP) has been evaluated and managed primarily through the lens of platelet count and bleeding risk, reflecting the defining clinical features of the disease. Yet growing evidence suggests that these measures may not capture the full burden that many patients experience.¹

A large global survey* evaluating patient-reported burden in ITP found that 85% of patients reported reduced energy levels and 73% reported difficulty concentrating, highlighting the extent to which patients define disease management through a broader lens than platelet counts alone. This survey also identified additional challenges, including anxiety related to maintaining stable platelet counts, which was reported by nearly one-half of patients, as well as uncertainty about disease course and the burden of ongoing treatment.² These effects can influence work, family responsibilities, social interactions, and overall quality of life.²

Clinicians are also increasingly considering whether conventional treatment goals fully reflect their patients’ lived experience. In a cross-sectional observational study of adults with chronic ITP (n=97), the median platelet count was 143×10⁹/L and bleeding scores were low (mean IBLS score of 0.04), yet 50% of patients reported clinically meaningful fatigue and 26% demonstrated cognitive impairment.^3,4 These realities are shaping interest in an evolving view on how chronic ITP is managed.

Understanding the Multi-System Complexity of Immune Thrombocytopenia

Reports of persistent symptoms, even amongst patients who have adequate platelet counts, have prompted closer examination of the biological drivers of ITP. Advances in understanding are revealing that ITP is not simply a disorder of platelet destruction. Rather, it is increasingly recognized as a complex immune-mediated disease involving dysregulation across both innate and adaptive immune pathways.^5,6

Research has shown that multiple components of the immune system contribute to disease pathogenesis. Autoreactive B-cells produce antibodies that target platelets and impair platelet production. T-cell abnormalities contribute to loss of immune tolerance and sustain autoimmune activity. At the same time, macrophages, inflammatory cytokines, and other innate immune pathways contribute to platelet clearance and ongoing immune dysfunction.⁶

While an important indicator of disease activity, platelet counts may reflect only one aspect of a much larger immune response. That shift in understanding has important implications for how we address unmet patient needs.⁷

Evolving the Approach to Disease Management

If both innate and adaptive immune pathways contribute to disease burden, then treatment approaches may need to evolve alongside the science. Multi-immune modulation is based on the idea that because both innate and adaptive immune pathways contribute to ITP, disease management may benefit from addressing both.⁸

Rather than focusing on a single downstream effect of disease, multi-immune modulation aims to impact multiple upstream immune processes involved in platelet destruction and impaired platelet production.^7,9 In this context, multi-immune modulation reflects a broader shift in how disease management is conceptualized. The goal is not only to improve platelet counts, but also to address the immune imbalance.⁷

Exploring the Use of BTK as a Strategic Target in Multi-Immune Modulation

Within this evolving treatment framework, Bruton’s tyrosine kinase (BTK) has emerged as a promising therapeutic target, as it plays a central role across multiple immune pathways.⁷ Within adaptive immunity, BTK contributes to B-cell activation and autoantibody production. Within innate immunity, it influences macrophage activity, inflammatory signaling, and other processes involved in chronic immune dysfunction.¹⁰

Because BTK sits at the intersection of several disease-driving pathways, it offers an opportunity to influence multiple aspects of disease biology through a single target. This has made BTK an area of growing interest in chronic immune-mediated diseases, including ITP.^7,10

Bringing Multi-Immune Modulation into Practice With WAYRILZ® (rilzabrutinib)

WAYRILZ® is an oral, reversible BTK inhibitor, designed for the treatment of adults with persistent or chronic ITP who have had an insufficient response to a previous treatment.¹¹ Approved in the United States in August 2025, WAYRILZ® was designed to selectively target BTK and modulate multiple immune pathways involved in ITP.^9,11

By targeting BTK, WAYRILZ® acts on pathways involved in autoantibody production, macrophage-mediated platelet destruction, and immune-cell activation.^9-10 This mechanism reflects the broader multi-immune modulation approach and is intended to address multiple contributors to disease. In this way, WAYRILZ® represents a practical application of the evolving understanding of ITP and a treatment approach designed to align with the complexity of the disease.¹⁰

The approval was supported by findings from the phase 3 LUNA 3 study in adults with persistent or chronic ITP who had an insufficient response to or were ineligible for standard of care. In the 24-week double-blind period, 23% (n=31/133) of patients treated with WAYRILZ® achieved a durable platelet response^**, compared with 0% (n=0/69) of patients who received placebo. Most patients in the WAYRILZ® arm completed the study (47%) vs placebo control (14%), with the main reason for discontinuation being a lack of platelet response per predefined levels. Additional phase 3 findings have also suggested broader clinical effects. At Week 25, the LS mean difference in ITP Bleeding Scale score with WAYRILZ® versus placebo was -0.09; this exploratory analysis was not designed or powered to detect differences between treatment groups. Rescue therapy was required in 33% of patients receiving WAYRILZ® compared with 58% of those receiving placebo.^9,11

Improvements in quality-of-life measures were also observed. In a descriptive, patient-reported analysis that was not powered for statistical significance, patients receiving WAYRILZ® reported an overall 10.6-point improvement across nine health-related quality-of-life measures compared with a 2.3-point increase in the placebo arm, based on The Immune Thrombocytopenia Patient Assessment Questionnaire, a clinical tool designed to measure ITP symptoms. The patient-reported nature of the data may impact the reliability of findings. In clinical studies, the most common adverse reactions (incidence ≥10%) to WAYRILZ® included diarrhea, nausea, headache, stomach area (abdominal) pain, and COVID-19. These are not all the possible side effects of WAYRILZ®. Taken together, these findings contribute to a broader discussion about how treatment impact is assessed in ITP and the importance of considering impacts beyond platelet response alone.^7,9,11

To learn more about WAYRILZ® and Multi-Immune Modulation, please visit Wayrilz.com.

WAYRILZ (rilzabrutinib) Important Safety Information

INDICATION

WAYRILZ® (rilzabrutinib) is indicated for the treatment of adult patients with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Serious Infections: An increased risk of serious infections (including bacterial, viral, or fungal) can occur in patients treated with Bruton’s tyrosine kinase (BTK) inhibitors, including WAYRILZ®. Fatal pneumonia occurred in one participant treated with WAYRILZ® in the LUNA-3 trial. Other serious infections [one each (0.8%)] included COVID-19 infection, wound infection, urinary tract infection and kidney abscess. Monitor patients for signs and symptoms of infection and treat appropriately.
Hepatotoxicity, Including Drug-Induced Liver Injury (DILI): Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of DILI, can occur in patients treated with BTK inhibitors. Elevations of liver transaminases occurred with WAYRILZ® in the ITP clinical trials and were generally mild to moderate in severity. Evaluate bilirubin and transaminases at baseline and as clinically indicated during treatment with WAYRILZ®. For patients who develop abnormal liver tests after WAYRILZ®, monitor more frequently. If DILI is suspected, withhold WAYRILZ®. Upon confirmation of DILI, discontinue WAYRILZ®.

Embryo-Fetal Toxicity: Based on findings from preliminary animal reproduction studies, WAYRILZ® may cause fetal harm when administered to a pregnant woman. Verify pregnancy status of females of reproductive potential prior to initiating WAYRILZ® treatment. Advise females of reproductive potential to use effective contraception while taking WAYRILZ® and for 1 week after the final dose.

ADVERSE REACTIONS

Most common adverse reactions reported (incidence ≥10%) were diarrhea, nausea, headache, abdominal pain, and COVID-19.

DRUG INTERACTIONS

• Avoid concomitant use of WAYRILZ® with strong or moderate CYP3A inhibitors, which increases the risk of WAYRILZ® adverse reactions. If short term use of these inhibitors cannot be avoided, interrupt treatment with WAYRILZ®. Avoid concomitant use of grapefruit, starfruit and products containing these fruits, and Seville oranges with WAYRILZ®.
• Avoid concomitant use with a strong or moderate CYP3A inducer, which may reduce WAYRILZ® efficacy.
• Administer the dose of WAYRILZ® at least 2 hours before administration of an antacid or histamine H2 receptor antagonist. Avoid concomitant use of proton pump inhibitors with WAYRILZ®. Concomitant use of acid reducing agents may reduce WAYRILZ® efficacy.
• Rilzabrutinib is a moderate inhibitor of CYP3A and increases exposure of these substrates. Monitor for adverse reactions and consider dosage adjustment of the CYP3A substrate.
• Rilzabrutinib is an inhibitor of P-gp, BCRP and OATP1B in vitro. The effect of concomitant use of WAYRILZ® with OATP1B and BCRP substrates has not been established in clinical studies. Monitor for adverse reactions of the concurrently administered P-gp, BCRP, or OATP1B substrate more frequently where minimal substrate concentration changes may lead to serious adverse reactions.

USE IN SPECIFIC POPULATIONS

• Lactation: Due to the potential for adverse reactions in a breastfed child, advise lactating women not to breastfeed while taking WAYRILZ® and for at least 1 week after the final dose
• Hepatic Impairment: Avoid administration of WAYRILZ® in patients with moderate or severe hepatic impairment (Child-Pugh class B-C)
• Renal Impairment: Avoid use in patients with severe renal impairment

Please see full Prescribing Information.

Editor’s Notes

*I-WISh was an online, cross-sectional survey of 1507 patients with ITP and 472 hematologists or hemato-oncologists who treat patients with ITP in 13 countries. The patient questionnaire collected information on demographics and diagnosis, symptoms of ITP, HRQoL and emotion associated with ITP, impact of ITP on work, finances, and support, treatment received, and patient and physician relationship.

**A platelet count ≥50x10^9/L for ≥5 of at least 8 non-missing weekly measurements during the last 12 weeks of the DB period, including ≥2 such responses in the last 6 weeks without rescue therapy.

References

1. Cooper N, Ghanima W. Immune thrombocytopenia. N Engl J Med. 2019;381(10):945-955. doi:10.1056/NEJMcp1810479.
2. Cooper N, Kruse A, Kruse C, et al. Immune thrombocytopenia (ITP) World Impact Survey (I-WISh): Impact of ITP on health-related quality of life. Am J Hematol. 2021;96:199–207. DOI: 10.1002/ajh.26036.
3. Kuter DJ, Panch S, Piatek C, Rodriguez MB, Daak A, Kissell J, et al. Fatigue in adults with immune thrombocytopenia (ITP): a cross-sectional observational study. Presented at: European Hematology Association (EHA) 2026 Congress; June 2026. Abstract EHA-3121.
4. Cooper N, Panch S, Piatek C, Rodriguez MB, Daak A, Kissell J, et al. Cognitive dysfunction in adults with immune thrombocytopenia (ITP): a cross-sectional observational study. Presented at: European Hematology Association (EHA) 2026 Congress; June 2026. Abstract EHA-3125.
5. Andreescu M. Immune thrombocytopenia: evolving concepts in pathophysiology and immune dysregulation. Front Hematol. 2023;2:1191178. doi:10.3389/frhem.2023.1191178.
6. Zufferey A, Kapur R, Semple JW. Pathogenesis and therapeutic mechanisms in immune thrombocytopenia. J Clin Med. 2017;6(2):16. doi:10.3390/jcm6020016.
7. Labanca C, et al. Multi-immune modulation and the evolving treatment landscape in immune thrombocytopenia. Eur J Haematol. 2025;115:4-15.
8. Wang R, Lan C, Benlagha K, et al. The interaction of innate immune and adaptive immune system. MedComm (2020). 2024;5(10):e714. Published 2024 Sep 15. doi:10.1002/mco2.714.
9. Kuter DJ, Ghanima W, Cooper N, et al; LUNA3 Trial Group. Safety and efficacy of rilzabrutinib vs placebo in adults with immune thrombocytopenia: the phase 3 LUNA3 study. Blood. 2025;145(24):2914-2926.
10. Langrish CL, Bradshaw JM, Francesco MR, et al. Preclinical efficacy and anti-inflammatory mechanisms of action of the Bruton tyrosine kinase inhibitor rilzabrutinib for immune-mediated disease. J Immunol. 2021;206(7):1454-1468.
11. WAYRILZ (rilzabrutinib). Prescribing information. Sanofi; August 2025. Accessed June 2026. https://products.sanofi.us/wayrilz/wayrilz.pdf.

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