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EP-4735001-A1 - METHODS FOR TREATING PERSISTENT OR CHRONIC IMMUNE THROMBOCYTOPENIA IN CHILDREN, ADOLESCENTS AND ADULTS BY ADMINISTERING (R)-2-[3-[4-AMINO-3-(2-FLUORO-4-PHENOXY- PHENYL)PYRAZOLO[3,4-D]PYRIMIDIN-1-YL]PIPERIDINE-1-CARBONYL]-4- METHYL-4-[4-(OXETAN-3-YL)PIPERAZIN-1-YL]PENT-2-ENENITRILE

EP4735001A1EP 4735001 A1EP4735001 A1EP 4735001A1EP-4735001-A1

Abstract

Methods for treating children, adolescents and adults with persistent or chronic immune thrombocytopenia comprising administering at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof are disclosed.

Inventors

  • DAAK, Ahmed
  • LEE, MICHELLE
  • GUO, Hailing

Assignees

  • Principia Biopharma Inc.

Dates

Publication Date
20260506
Application Date
20240627

Claims (20)

  1. 1. A method for treating immune thrombocytopenia (ITP) in a human patient with persistent or chronic ITP in need thereof comprising administering to the human patient a therapeutically effective amount of at least one compound chosen from (R)- 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3 -yl)piperazin- 1 -yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof twice a day for a treatment period, wherein the human patient in need thereof has an initial platelet count of <30,000/pL with no single platelet count >35,000/pL in the 2 weeks prior to the treatment period, and further wherein the human patient has at least one characteristic chosen from: a. a prior response to one or more of IVIg, anti-D, or CSs that was not sustained; b. a documented intolerance or insufficient response to any appropriate courses of standard-of-care ITP therapies; and c. a contraindication for any appropriate courses of standard-of-care ITP therapies.
  2. 2. The method of claim 1, wherein the human patient has an initial platelet count of <15,000/pL.
  3. 3. The method of claim 1, wherein the human patient has an initial platelet count of >15,000/pL.
  4. 4. The method of any one of the preceding claims, wherein the human patient achieves a platelet response.
  5. 5. The method of any one of the preceding claims, wherein the human patient achieves a durable platelet response.
  6. 6. The method of any one of the preceding claims, wherein the human patient achieves a complete platelet response.
  7. 7. The method of any one of the preceding claims, wherein the human patient achieves a stable platelet response.
  8. 8. The method of any one of the preceding claims, wherein the human patient has at least one platelet count of >30,000/pL during the treatment period.
  9. 9. The method of any one of the preceding claims, wherein the human patient has at least one platelet count of >30,000/pL and at least a doubling of the baseline platelet count during the treatment period.
  10. 10. The method of any one of the preceding claims, wherein the human patient has at least one platelet count of >30,000/pL and at least a doubling of the baseline platelet count in the absence of rescue medication during the treatment period.
  11. 11. The method of any one of the preceding claims, wherein the human patient has at least one platelet count of >30,000/pL and at least a doubling of the baseline platelet count during a 24-week treatment period.
  12. 12. The method of any one of the preceding claims, wherein the human patient has at least one platelet count of >30,000/pL and at least a doubling of the baseline platelet after a 6-month treatment period.
  13. 13. The method of any one of the preceding claims, wherein the human patient has at least one platelet count >50,000/pL during the treatment period.
  14. 14. The method of any one of the preceding claims, wherein the human patient has at least one platelet count >50,000/pL in the absence of rescue medication during the treatment period.
  15. 15. The method of any one of the preceding claims, wherein the human patient has at least 2 consecutive platelet counts of >50,000/pL, wherein the platelet counts are >5 days apart, in the absence of rescue medication during the treatment period.
  16. 16. The method of any one of the preceding claims, wherein the human patient has platelet counts of >50,000/pL for at least two-thirds of at least 8 available weekly platelet counts during the last 12 weeks of a 24-week treatment period, further wherein a. at least 2 available weekly platelet counts are >50,000/pL during the last 6 weeks of a 24-week treatment period; and b. the human patient does not require rescue medication.
  17. 17. The method of any one of the preceding claims, wherein the human patient has platelet counts of >50,000/pL for at least 8 platelet counts during the last 12 weeks of a 24-week treatment period, further wherein the patient does not require rescue medication.
  18. 18. The method of any one of the preceding claims, wherein the human patient has no two consecutive platelet counts <50,000/pL, wherein the platelet counts occur at least 4 weeks apart within a period of 24 weeks following at least one platelet count of >50,000/pL within 12 weeks of initiating rilzabrutinib treatment.
  19. 19. The method of any one of the preceding claims, wherein the human patient has platelet counts of >50,000 for 4 out of the last 8 weeks of a 24-week treatment period.
  20. 20. The method of any one of the preceding claims, wherein the human patient has platelet counts >50,000/pL on >4 of 6 biweekly platelet counts between weeks 14 and 24 of a 24-week treatment period.

Description

METHODS FOR TREATING PERSISTENT OR CHRONIC IMMUNE THROMBOCYTOPENIA IN CHILDREN, ADOLESCENTS AND ADULTS BY ADMINISTERING (R)-2- [3- [4- AMINO-3-(2-FLUORO-4-PHENOXY- PHENYL)PYRAZOLO[3,4-D]PYRIMIDIN-l-YL]PIPERIDINE-l-CARBONYL]-4- METHYL-4-[4-(OXETAN-3-YL)PIPERAZIN-l-YL]PENT-2-ENENITRILE [0001] Disclosed herein are methods for treating immune thrombocytopenia. BTK inhibitors and pharmaceutical compositions comprising the same are also disclosed. [0002] Immune thrombocytopenia, commonly referred to as ITP, is a rare acquired autoimmune disease with an estimated global prevalence of 10-23 per 100,000 people and an incidence of approximately 2-4 per 100,000 person-years in the general population, including both adult patients and patients under 18 years of age (Abrahamson et al. 2009, Christiansen et al. 2019, Feudjo-Tepie et al. 2008, Schoonen et al. 2009, Segal JB and Powe NR 2006, Terrell DR et al. 2010, Yong et al. 2010). The disease, which is characterized by the autoantibody-mediated destruction of platelets and their progenitor cells, has a heterogeneous pathophysiology that includes pathogenic immunoglobulin G (IgG) autoantibodies targeting antigens on the surface of platelets and their progenitor cells (e.g., glycoproteins allb/p3 (GPIIb/IIIA), GPIa/IIa, and GPIb-IX-V) (Al-Samkari et al. 2020, Grodzielski et al. 2018, Zufferey et al. 2017). Autoantibody binding triggers platelet destruction and impaired platelet production through a number of mechanisms, including: antibody-coated cell phagocytosis through binding of autoantibodies to Fey receptors on macrophages; platelet clearance by C- type lectin receptor (CLEC4F) on hepatic Kupffer cells (e.g., Ashwell-Morell receptors); platelet lysis by the membrane attack complex; phagocytosis due to classical complement pathway activation; T cell-mediated cytotoxicity; and impaired megakaryocyte viability (Grodzielski et al. 2018, Peerschke et al. 2010, Reis et al. 2019, Zufferey et al. 2017). [0003] The destruction of mature platelets and the impairment of platelet production results in thrombocytopenia (a platelet count below 100* 109/L), putting patients at a high risk for bleeding, excessive bruising, and fatigue, as well as for life threatening intracranial bleeding. This predisposition to bleeding and thrombosis has an adverse impact on patient quality of life (QOL) (Adelborg et al. 2019, Efficace et al. 2016, Rodeghiero et al. 2009). [0004] The pathophysiology of persistent and chronic ITP is similar in adolescents and adults, leading to similar clinical presentation and disease progression in both populations. Such similarities include presenting platelet counts, incidence and type of bleeding when platelet counts are <20 x 109/L, family history of thrombocytopenia (2% in children and 3% in adults), rates of treatment (80% of children and 71% of adults at presentation and 58% of children and adults at 6 months, with similarly decreasing rates within both groups at 12 and 24 months) (Kuhne 2001; Schiff erli 2018) and similar late remission rates among children and adults with persistent and chronic ITP at 12 and 24 months (Schiff erli 2018). [0005] Although there are differences between the adolescents and young children in terms of the etiology, pathophysiology, and clinical course, the currently available evidence shows that the disease characteristics in pediatric participants between 10 and less than 12 years of age is comparable to children above 12 years of age and adult population. [0006] Current therapies for adults with ITP include initial treatment with intravenous immunoglobulin (IVIG) and corticosteroids (CS), and subsequent treatment with splenectomy, thrombopoietin receptor agonists (TPO-RAs), rituximab, fostamatinib, and immunosuppressive therapies (such as, e.g., my cophenolate mofetil (MMF) and cyclosporine). In general, pharmacotherapy (e.g., CS, IVIG, or anti-D immunoglobulin therapy) is used for symptomatic patients with low platelet counts for reducing platelet destruction and/or stimulating platelet production, with the goal of preventing bleeding (Cooper N and Ghanima W 2019, Kuter DJ 2022). [0007] The standard therapy for adult patients with newly diagnosed ITP consists of treatment with CS such as high-dose dexamethasone or oral prednisone/prednisolone, the prolonged use of which is associated with significant toxicity and should be avoided due to the potential for adverse events (Cooper N and Ghanima W 2019, Neunert et al. 2019). While most patients respond initially to CS, responses are typically not durable, and the rate of continued remission is low (Cooper N and Ghanima W 2019). Other first line therapies include IVIG and anti-D immunoglobulin. [0008] Second line therapies for ITP include rituximab, TPO-RAs, fostamatinib, and splenectomy. Rituximab and TPO-RAs have shown durable on-treatment response rates of 60-80%, while fostamatinib has a durable response rate of -18% in a population of heavily pretreated ITP patients (Ne