Breaking Treatment Barriers: Targeting Complex Immune Dysregulation With BTK Inhibition in Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is a condition of complex immune dysregulation that causes low platelet counts, resulting in bleeding symptoms and potentially significant quality-of-life challenges.^1-6 Many patients worry about the unpredictable nature of their rare condition⁷, highlighting the need for new therapeutic approaches that address the root causes driving disease.

Exploring the role of Bruton’s tyrosine kinase (BTK) and complex immune dysregulation in ITP

Immune dysregulation arises from dysfunction in the innate and/or adaptive immune systems, which intricately communicate and influence one another, contributing to the complexity and severity of pathological outcomes such as autoimmunity and chronic inflammation.^8-10 In rare autoimmune conditions like ITP, BTK has a pivotal role in several immune cell functions, including B cell differentiation and antibody production, FcγR-mediated signaling in macrophages, and immune cells.^11-13 Treatments designed to selectively and reversibly target BTK can help address the various ways in which the immune system goes awry within complex immune dysregulation disorders.^13,14 Specific to ITP, complex immune dysregulation drives platelet destruction via an imbalance of proinflammatory factors and dysregulation of T cells.^1-3

This can mean that people living with ITP may face substantial disease burden including petechiae, mucosal bleeding (such as bleeding from inside the mouth or nose), bruising, heavy menstruation, and intercranial hemorrhage.^2-5 These symptoms are often accompanied by significant quality-of-life challenges, with 73%-85% of patients reporting reduced energy levels, limited ability to complete daily tasks, and difficulty concentrating, to name a few.⁶ Additionally, patients face an approximately two times higher risk of thrombotic events than the general population, despite having low platelet counts.¹⁵ Treatment management remains challenging, with approximately half of patients with ITP having changed treatment at least four times.¹⁶

In August 2025, the US Food and Drug Administration approved Wayrilz™ (rilzabrutinib), a multi-immune modulator, for the treatment of adult patients with persistent or chronic ITP who have had an insufficient response to a previous treatment.¹⁴ As a next-generation oral, reversible BTK inhibitor, Wayrilz addresses the root of ITP through multi-immune modulation. It provides targeted binding of BTK and long duration of action across two pathways within the immune system to help restore multifaceted immune balance in ITP.^14,17

Wayrilz is administered as a convenient oral treatment with a recommended dose of 400 mg twice daily.¹⁴

Achieving durable and rapid platelet response

The approval of Wayrilz was supported by positive data from the phase 3 LUNA-3 study,^a which evaluated the efficacy and safety of Wayrilz compared to placebo in 202 adults with persistent or chronic ITP who had an insufficient response to either intravenous immunoglobulin (IVIg/anti-D) or corticosteroids, or had intolerance or insufficient response to any appropriate course of standard ITP therapy.^14,17 The study population was heavily pretreated, with 46% (n=93) having received five or more prior unique ITP medications.^17,b Patients who achieved platelet count response at 12 weeks were eligible to continue the full 24-week double-blind (DB) period (64% of patients in the Wayrilz arm and 32% of patients in the placebo arm).^14,17

Patients receiving Wayrilz achieved significant durable platelet response^c by week 25 (23% in the Wayrilz arm vs. 0% in the placebo arm, p<0.0001), a faster time to first platelet response^d (36 days for all patients on Wayrilz, 15 days for Wayrilz responders,^e compared to not reached for patients on placebo), and longer duration of response^f (7 weeks with platelet response for all patients on Wayrilz, 11 weeks for Wayrilz responders, and less than one week for patients on placebo).¹⁴

^aLUNA-3 is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate the efficacy and safety of oral WAYRILZ (400 mg twice daily) for 24 weeks, followed by a 28-week open-label extension.^14,17

^bIncludes splenectomy. Multiple corticosteroids were counted as one therapy.^14,17

^cA platelet count of ≥50×10⁹/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.¹⁴

^dPlatelet count ≥50×10⁹/L or between ≥30×10⁹/L and <50×10⁹/L and at least doubled from baseline in the absence of rescue therapy.¹⁴

^eResponders had ≥1 platelet response ≥50×10⁹/L or ≥30×10⁹/L and <50×10⁹/L and at least doubled from baseline by week 13 without rescue therapy.¹⁷

^fPlatelet count ≥50×10⁹/L or between ≥30×10⁹/L and <50×10⁹/L and doubled from baseline. Platelet counts assessed within 4 weeks of rescue medication intake are considered as no response; weekly platelet counts missing for any reason were considered as no response.¹⁴

A post-hoc analysis of the LUNA-3 clinical study evaluated modified durable response by International Working Group (IWG) standards to assess platelet response. Modified durable response was defined as a platelet count of ≥30×10⁹/L and at least doubled from baseline, in the absence of bleeding, for ≥50% of assessments during the last 12 weeks of the DB period or the last 16 weeks of the open-label (OL) period, provided that ≥6 or ≥8 non-missing platelet counts were available in the DB and OL periods, respectively. The results showed the following percentages of patients with modified durable response: 34% and 44% during the DB period and 50% and 64% in the combined DB and OL period for all Wayrilz patients and those who had received 1-2 prior therapies, respectively.¹⁸ This post hoc analysis was not designed or powered to establish statistical significance. Results are only descriptive, and definitive conclusions cannot be made.

“The IWG criteria represent an additional clinically meaningful tool to evaluate the potential benefits of ITP treatment. These standardized criteria are specifically designed to guide treatment decisions in real world hematology practice and may provide a more comprehensive assessment of therapeutic response that complements the rigorous response thresholds of randomized clinical trials,” said Dr. Amit Mehta, a board-certified hematologist and medical oncologist. “When we evaluate ITP treatments through the lens of IWG criteria, we often see a more complete picture of how patients are responding from multiple angles, which is critical for partnering with patients and their families to make informed decisions about their care.”

Additional outcomes with Wayrilz: rescue therapy use and bleeding assessment scores

Wayrilz demonstrated benefits in rescue medication use (secondary study endpoint) and ITP Bleeding Scale scores (exploratory endpoint).^14,17 Use of rescue medication was required by 58% of patients receiving placebo and 33% of those receiving Wayrilz.^14,17,g The least square mean change in ITP Bleeding Scale score at week 25 from baseline was −0.04 with Wayrilz and +0.05 with placebo, with positive numbers indicating more bleeding.^17,h This exploratory analysis was not designed or powered to detect differences between treatment groups.

^gRescue therapy use was assessed regardless of the criteria for durable response.^14,17

^hAs measured by the ITP Bleeding Scale (IBLS), which was designed to assess and quantify bleeding symptoms in patients with ITP. It includes 11 site-specific grades to evaluate bleeding severity across different body areas.¹⁷

Evaluated for Patient-Reported Health-Related Quality of Life

Patient reported mean change from baseline in the Immune Thrombocytopenia Patient Assessment Questionnaire (ITP-PAQ) overall score and domains at week 25. The ITP-PAQ assesses domains including overall health-related quality of life (HRQoL), fatigue/sleep, activity, social activity, women's reproductive health, psychological health, bother-physical health, symptoms, fear, and work. The results of these analyses are descriptive only and were not powered for statistical significance. The patient-reported nature of the data may impact the reliability of findings. Definitive conclusions cannot be made.

Patients receiving Wayrilz reported an overall 10.6-point improvement across nine HRqOL measures, compared to a 2.3-point increase in patients receiving placebo, based on the ITP-PAQ.¹⁷

An established safety profile

Data from the LUNA-3 clinical study have established a safety profile for Wayrilz in patients with ITP.¹⁴ The most common adverse reactions (incidence ≥10%) were diarrhea, nausea, headache, abdominal pain, and COVID-19. WAYRILZ may cause serious side effects such as: serious infections and liver problems, including drug-induced liver injury.¹⁴ Individuals who can become pregnant must use effective contraception while taking Wayrilz and for 1 week after the last dose. Pregnancy status should be verified before initiating treatment.¹⁴

With its novel approach addressing the complex immune dysregulation of ITP through BTK inhibition, Wayrilz may be appropriate for patients with prior treatment challenges, offering a new therapeutic option in the ITP treatment landscape.¹⁴

To learn more about Wayrilz, please visit Wayrilz.com.

WAYRILZ (rilzabrutinib) Important Safety Information

What is WAYRILZ?

WAYRILZ is a prescription medicine that is used to treat adults with persistent or chronic immune thrombocytopenia (ITP) who received a prior treatment that did not work well enough.

It is not known if WAYRILZ is safe and effective in children.

IMPORTANT SAFETY INFORMATION

What should I tell my healthcare provider before taking WAYRILZ?

Tell your healthcare provider about all of your medical conditions, including if you:

• have liver problems
• have kidney problems
• are pregnant or plan to become pregnant. WAYRILZ may harm your unborn baby. If you are able to have a baby, your healthcare provider will do a pregnancy test before starting treatment with WAYRILZ. Females who are able to become pregnant should use an effective birth control during treatment with WAYRILZ and for 1 week after the last dose.
• are breastfeeding or plan to breastfeed. Do not breastfeed during treatment with WAYRILZ and for at least 1 week after the last dose.

Tell your healthcare provider about all the medicines you take, including prescription and over‑the‑counter medicines, vitamins, and herbal supplements. Taking WAYRILZ with certain other medicines may affect how WAYRILZ works and can cause side effects. WAYRILZ may also affect how other medicines work.

What should I avoid while taking WAYRILZ?

You should avoid grapefruit, starfruit and products that have these fruits, and Seville oranges (often used in marmalades) during treatment with WAYRILZ. These products may increase the amount of WAYRILZ in your blood, which increases the risk of side effects of WAYRILZ.

What are the possible side effects of WAYRILZ?

WAYRILZ may cause serious side effects, including:

• Serious infections. WAYRILZ can increase the risk of infections, including serious infections that can lead to death. Your healthcare provider will check you for signs and symptoms of infection during your treatment with WAYRILZ. Tell your healthcare provider right away if you get any signs or symptoms of infection, including fever, chills, or flu-like symptoms.
• Liver problems including Drug-Induced Liver Injury (DILI). Liver problems, which may be severe, life-threatening, or lead to death have happened in people treated with Bruton’s tyrosine kinase (BTK) inhibitors. Your healthcare provider will do blood tests to check your liver before and as necessary during treatment with WAYRILZ. Tell your healthcare provider right away if you have any signs or symptoms of liver problems, including stomach-area (abdominal) pain or discomfort, dark or “tea-colored” urine, or yellowing of the skin or the white part of your eyes.

The most common side effects of WAYRILZ include diarrhea, nausea, headache, stomach area (abdominal) pain, and COVID-19.

These are not all of the possible side effects of WAYRILZ.

Please see accompanying full Prescribing Information, including Patient Information.

REFERENCES

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2. Qiao J, Liu Y, Li X, et al. Elevated expression of NLRP3 in patients with immune thrombocytopenia. lmmunol Res. 2016;64(2):431-437. doi:10.1007/s12026-015-8686-5
3. Schifferli A, Cavalli F, Godeau B, et al. Understanding immune thrombocytopenia: looking out of the box. Front Med (Lausanne). 2021;8:613192. doi:10.3389/fmed.2021.613192
4. Kistangari G, Mccrae KR. Immune thrombocytopenia. Hematol Oncol Clin North Am. 2013;27(3):495-520. doi: 10.1016/j.hoc.2013.03.001
5. Audia S, Bonnette B. Emerging therapies in immune thrombocytopenia. J Clin Med. 2021;10(5):1004. doi:10.3390/jcm10051004
6. 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(2):199-207. doi:10.1002/ajh.26036
7. Cooper N, Kruse A, Kruse C, et al. Immune thrombocytopenia (ITP) World Impact Survey (iWISh): Patient and physician perceptions of diagnosis, signs and symptoms, and treatment. Am J Hematol. 2021;96(2):188-198. doi:10.1002/ajh.26045
8. Marshall JS, Warrington R, Watson W, Kim HL. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):49. Published 2018 Sep 12. doi:10.1186/s13223-018-0278-1
9. 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
10. Zhang H, Gao J, Tang Y, Jin T, Tao J. Inflammasomes cross-talk with lymphocytes to connect the innate and adaptive immune response. J Adv Res. 2023;54:181-193. doi:10.1016/j.jare.2023.01.012
11. Zhu S, Gokhale S, Jung J, et al. Multifaceted immunomodulatory effects of the BTK inhibitors ibrutinib and acalabrutinib on different immune cell subsets – beyond B lymphocytes. Front Cell Dev Biol. 2021; 9:727531.
12. Neys SFH, Hendriks RW, Corneth OBJ. Targeting Bruton's tyrosine kinase in inflammatory and autoimmune pathologies. Front Cell Dev Biol. 2021;9:668131.
13. Kuter DJ, Bussel JB, Ghanima W, et al. Rilzabrutinib versus placebo in adults and adolescents with persistent or chronic immune thrombocytopenia: LUNA 3 phase III study. Ther Adv Hematol.2023;14:20406207231205431.
14. WAYRILZ. Prescribing information. Sanofi; 2025. Accessed September 18, 2025.
15. Kuter DJ, Gouia I, Cordoba M, et al. Clinical burden of illness in patients with persistent or chronic primary immune thrombocytopenia treated with advanced therapies in the United States. Poster presented at: American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, CA. Abstract 3944
16. Cooper N, Kruse C, Deneen Morgan S, et al. Patient survey in immune thrombocytopenia (ITP): Identifying unmet needs related to treatment and disease control in patients living in the United States. Br J Haematol. 2025;207(3):1038-1046. doi:10.1111/bjh.20257 https://products.sanofi.us/wayrilz/wayrilz.pdf
17. 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. doi:10.1182/blood.2024027336
18. Sanofi. Data on file. 2025.

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