A method for treating persistent or chronic immune thrombocytopenia in children, adolescents, and adults by administering (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile.

Abstract

A method for treating children, adolescents and adults with persistent or chronic immune thrombocytopenia is disclosed, comprising administering at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof.

Description

Technical Field

[0001] Methods for treating immune thrombocytopenia are disclosed herein. Also disclosed are BTK inhibitors and pharmaceutical compositions containing the same.

Background Art

[0002] Immune thrombocytopenia (commonly referred to as ITP) is a rare acquired autoimmune disease with a worldwide estimated prevalence of 10-23 per 100,000 and an incidence of approximately 2-4 per 100,000 per year in the general population, including both adult 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). This disease, characterized by the autoantibody-mediated destruction of platelets and their progenitor cells, has a heterogeneous pathophysiology involving pathogenic immunoglobulin G (IgG) autoantibodies that target antigens on the surface of platelets and their progenitor cells (e.g., glycoprotein αIIb / β3 (GPIIb / IIIA), GPIa / IIa, and GPIb-IX-V) (Al-Samkari et al. 2020, Grodzielski et al. 2018, Zufferey et al. 2017). Autoantibody binding causes platelet destruction and impairment of platelet production through several mechanisms, including: antibody-coated cell phagocytosis by binding of autoantibodies to Fcγ receptors on macrophages, platelet clearance by C-type lectin receptor (CLEC4F) (e.g., Ashwell-Morell receptor) on liver Kupffer cells, platelet lysis by the membrane attack complex, phagocytosis by classical complement pathway activation, T cell-mediated cytotoxicity, and impairment of megakaryocyte viability (Grodzielski et al. 2018, Peerschke et al. 2010, Reis et al. 2019, Zufferey et al. 2017).

[0003] Destruction of mature platelets and impairment of platelet production result in thrombocytopenia (platelet count less than 100×10 9 / L), placing patients at risk of bleeding, excessive bruising and fatigue, and life-threatening intracranial hemorrhage. This predisposition to bleeding and thrombosis negatively affects the patient's 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 children and adults, leading to similar clinical symptoms and disease progression in both populations. Such similarities include the presentation, incidence, and type of bleeding when the platelet count is <20×10 9 / L, family history of thrombocytopenia (2% in children and 3% in adults), treatment success rates (80% in children and 71% in adults at presentation, 58% in children and adults at 6 months, and similar reduction rates in both groups at 12 months and 24 months) (Kuehne 2001, Schifferli 2018), and similar late remission rates in children and adults with persistent ITP and chronic ITP at 12 months and 24 months (Schifferli 2018).

[0005] There are differences between children and infants in terms of etiology, pathophysiology, and clinical course, but the currently available evidence indicates that the disease characteristics in pediatric participants aged 10 to less than 12 years are comparable to those in pediatric and adult populations over 12 years of age.

[0006] Current treatments for adults with ITP include initial treatment with intravenous immunoglobulin (IVIG) and corticosteroids (CS), followed by splenectomy, thrombopoietin receptor agonists (TPO-RA), rituximab, fostamatinib, and immunosuppressive therapies (e.g., mycophenolate mofetil (MMF) and cyclosporine). Generally, drug therapy (e.g., CS, IVIG, or anti-D immunoglobulin therapy) is used in symptomatic patients with low platelet counts to reduce platelet destruction and / or stimulate platelet production, with the aim of preventing bleeding (Cooper N and Ghanima W 2019, Kuter DJ 2022).

[0007] Standard treatment for adult patients with newly diagnosed ITP consists of treatment with CS such as high-dose dexamethasone or oral prednisone / prednisolone, and its long-term use should be avoided due to its significant toxicity and potential adverse events (Cooper N and Ghanima W 2019, Neunert et al. 2019). Most patients respond to CD initially, but the response is typically not sustained, and the rate of sustained remission is low (Cooper N and Ghanima W 2019). Other first-line treatments include IVIG and anti-D immunoglobulin.

[0008] Second-line treatments for ITP include rituximab, TPO-RA, fostamatinib, and splenectomy. Rituximab and TPO-RA show sustained response rates of 60–80%, while fostamatinib has a sustained response rate of approximately 18% in ITP patients with multiple prior treatments (Neunert et al. 2019, Mingot-Castellano et al. 2022, Singh et al. 2021). Splenectomy has the advantage of a high response rate and a sustained post-discontinuation remission rate of 60–70%, but it may be associated with short-term surgical complications and an increased long-term risk of thrombosis and infection (Mingot-Castellano et al. 2022, Singh et al. 2021). Additionally, thrombopoietin (TPO) mimetic drugs (Bussel 2007) are approved for the treatment of patients with chronic ITP who do not respond adequately to CS, IVIG, or splenectomy.

[0009] ITP patients requiring continuous treatment and those who do not respond to current treatments have elevated mortality rates compared to the general population (Frederiksen et al. 2014, Norgaard et al. 2011). Adult patients with chronic thrombocytopenia have up to a 10% risk of bleeding / internal bleeding that increases with age, and intracranial hemorrhage is reported in approximately 1-2% of patients (Adelborg et al. 2019, Neunert et al. 2015, Norgaard et al. 2011). In addition to the risk of bleeding, ITP patients may experience significant fatigue, cognitive impairment, fear of bleeding, and adverse effects on social and work activities, further demonstrating the existence of a great unmet need in this patient population (Frith et al. 2012, Terrell et al. 2020, Trotter P and Hill QA 2018).

[0010] Novel, safe, and effective oral therapies to maintain platelet counts and improve outcomes in ITP patients would offer greater therapeutic benefits than current standard treatments. Unmet needs in chronic and persistent ITP include, but are not limited to, improving remission rates and persistence, avoiding rapid increases in platelet count / thrombosis risk, steroid-free regimens, and well-tolerated and safe therapies that ensure a good patient quality of life. Therefore, there is a need for novel oral therapies to treat ITP, including chronic and persistent ITP, that address some or all of these limitations of existing treatments. Furthermore, given the heterogeneity of the underlying mechanisms of ITP development, a single therapy or combination of therapies that can target multiple disease-related pathways may be needed to induce a sufficient and sustained platelet response.

[0011] Bruton's agammaglobulinemia tyrosine kinase (BTK), an essential signaling element in B cells and innate immune cells, is expressed downstream of the B cell receptor (BCR), Fc gamma receptor (FcγR), and Fc epsilon receptor (FcεR), and provides direct regulation of the NLRP3 inflammasome. BTK is a non-receptor tyrosine kinase and a member of the TEC kinase family. BTK is essential for B cell differentiation, development, and antibody production. Exemplarily, inhibition of BTK activity results in phenotypic changes consistent with BCR blockade, including downregulation of cell proliferation, differentiation, maturation, and survival, as well as upregulation of apoptosis.

[0012] BTK is best viewed as a "modulator" of immune function rather than acting like an "on / off switch" (Crofford LJ et al., 2016; Pal Singh S et al., 2018). Key insights into BTK function are obtained from loss-of-function analyses in humans and mice. Individuals with loss-of-function mutations in the BTK gene develop X-linked agammaglobulinemia (XLA), characterized by the complete absence of circulating B cells and plasma cells, and have very low levels of all classes of immunoglobulins (Tsukada 1993; Vetrie 1993). This suggests that inhibition of BTK may suppress the production of autoantibodies that are thought to be important in the development of autoimmune diseases such as ITP.

[0013] BTK is not expressed in T cells, natural killer cells, or plasma cells, and does not have a direct function traceable in T cells or plasma cells (Sideras and Smith 1995, Mohamed et al., 2009). However, this enzyme regulates the activation of other hematopoietic cells such as B cells, monocytes, anti-basophils, mast cells, macrophages, neutrophils, and platelets. For example, BTK plays a role in the activation of neutrophils, which are key players in inflammatory responses that contribute to wound healing but can cause tissue damage (Volmering S et al., 2016).

[0014] Therefore, selective BTK inhibitors may target multiple pathways involved in inflammation and autoimmunity, including: BCR signaling, inhibition of B cell activation and autoantibody production, inhibition of plasma cell differentiation, inhibition of IgG-mediated FcγR activation, phagocytosis and inflammatory mediators in monocytes or macrophages, inhibition of IgE-mediated FcεR activation, migration and degranulation in mast cells or basophils, and inhibition of activation, adhesion, recruitment and oxidative burst in neutrophils. Based on these effects, selective BTK inhibitors may inhibit the onset and progression of various inflammatory diseases and mitigate tissue damage caused by these diseases. Individuals with loss-of-function mutations in the BTK gene have reduced humoral immunity, are susceptible to suppurative bacterial and enteroviral infections, and require treatment with intravenous immunoglobulin; however, inhibiting BTK in individuals with intact immune systems is not predicted to result in similar infection susceptibility.

[0015] Several orally administered BTK inhibitors (BTKi), including ibrutinib (PCI-32765) and spbrutinib (CC-292), are currently marketed or in clinical development for a range of indications (Lee A et al., 2017). For example, ibrutinib provides further clinical validation of the BTK target and was recently approved by the U.S. Food and Drug Administration (FDA) for human use in mantle cell lymphoma, Waldenström macroglobulinemia, and chronic lymphocytic leukemia. Ibrutinib has also demonstrated activity in other hematological malignancies (Wang 2013, Byrd 2013, Imbruvica Package Insert, 2015). In addition, CC-292 has been reported to be well-tolerated in healthy volunteer populations at doses resulting in 100% occupancy of the BTK enzyme (Evans 2013). Furthermore, evobrutinib recently demonstrated efficacy against multiple sclerosis in a Phase 2 trial (Montalban X et al., 2019). Other BTKi compounds are in clinical development for various immune-mediated disorders, including rheumatoid arthritis (NCT03823378, NCT03682705, NCT03233230) and asthma (NCT03944707) (Montalban X et al., 2019, Norman P 2016, Tam CS et al., 2018, Crawford JJ et al., 2018, Min TK et al., 2019, Gillooly KM 2017, Nadeem A et al., 2019).

[0016] Covalent BTKi such as ibrutinib and acalabrutinib have improved the selectivity issues that have plagued many first-generation kinase inhibitors. However, these inhibitors are usually irreversible and cause permanent modification of both on-target and off-target kinases, as well as side effects such as thrombocytopenia, anemia, platelet aggregation, and hepatotoxicity (RITUXAN Prescribing Information, 2018; Drug Record Kinase Inhibitors, 2019; Khan Y et al., 2019; Paydas S, 2019; IMBRUVICA, 2013; Rigg RA et al., 2016; Tang CPS et al., 2018). Therefore, there is a need for BTKi-based therapies for immune-mediated diseases such as ITP that have reduced side effects.

[0017] Compound (I) has the following structure: [ka] (In the formula, *C represents a stereochemical center.) It is a BTK inhibitor. See, for example, Example 31 of PCT Public International Publication No. 2014 / 039899, ​​which is incorporated herein by reference.

[0018] The following structure: [ka] (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile, also known as PRN1008 and rilzabrutinib, is disclosed in several patent publications, such as PCT Publications International Publication No. 2014 / 039899, ​​International Publication No. 2015 / 127310, International Publication No. 2016 / 100914, International Publication No. 2016 / 105531, International Publication No. 2018 / 005849 and International Publication No. 2021 / 150723 (the contents of each of these are incorporated herein by reference).

[0019] Rilzabrutinib is a novel, highly selective, and potent small molecule inhibitor of non-T cell leukocyte signaling via the BTK pathway's B cell receptor, FcγR, and / or FcεR signaling. With respect to ITP, rilzabrutinib may (1) inhibit B cell activation and (2) inhibit antibody-coated cell phagocytosis by FcγR in the spleen and liver (Bradshaw et al. 2021, Langrish et al. 2021, Owens et al. 2022).

[0020] Rilzabrutinib functions as a reversible covalent BTK inhibitor, forming both non-covalent and covalent bonds with its target. In particular, the reversible cysteine ​​bond enables highly selective and precise BTK inhibition without permanently modifying proteins and peptides (Langrish et al. 2021, Owens et al. 2022, Smith PF et al. 2017). The combination of these properties allows for improved selectivity and long-term inhibition with low systemic exposure. Compared to first- and second-generation BTKi, rilzabrutinib exhibits minimal cross-reactivity with other molecules and a low risk of off-target effects (Smith PF et al. 2017). Importantly, the reversible bond of rilzabrutinib minimizes the possibility of permanent peptide modification (Serafimova IM 2012). In addition, rilzabrutinib shows improved kinase selectivity compared to the covalent BTK inhibitor ibrutinib. Preclinical studies using a broad kinase enzyme inhibition panel showed that 1 μM ilzabrutinib achieved >90% inhibition against only 6 of 251 kinases that share a common cysteine ​​in their active sites. In contrast, 1 μM ibrutinib inhibited 21 kinases. The IC50 values ​​of ilzabrutinib were 1.3 nM against BTK, 0.8 nM against tyrosine protein kinase TEC, 1.0 nM against bone marrow tyrosine kinase (BMX) on chromosome X, 1.2 nM against receptor-like kinase (RLK), 6.3 nM against B-cell lymphocyte kinase (BLK), and 11 nM against ERBB4. Further preclinical assays with ilzabrutinib showed persistent binding to BTK but rapid breakdown over time in other TEC family members.

[0021] Rilzabrutinib has shown promising results in the treatment of immune-mediated diseases. In humans, rilzabrutinib is rapidly absorbed after oral administration, has a short half-life (3-4 hours), and exhibits pharmacokinetic variability (Smith PF et al., 2017).

[0022] In a Phase 1 trial of rilzabrutinib involving 114 healthy volunteers, target BTK occupancy levels were safely and consistently exceeded, suggesting that rilzabrutinib may be highly effective in treating autoimmune diseases. Furthermore, preclinical and clinical pharmacokinetic and pharmacodynamic data demonstrated that the therapeutic effect persisted even after the compound was cleared from the circulation, consistent with extended target residence time (Hill R et al., 2015) and high target occupancy (>90% within 4 hours and high sustained occupancy beyond 24 hours) (Smith PF et al., 2015).

[0023] Rilzabrutinib has demonstrated a favorable safety profile in clinical trials. In contrast to non-selective and irreversible BTK inhibitors, ilzabrutinib does not alter platelet aggregation in healthy volunteers or patients with ITP, and therefore does not cause bleeding problems (Langrish et al. 2021, von Hundelshausen and Seiss 2021). In addition to the irreversible BTK inhibitors, ilzabrutinib treatment, even when administered at doses significantly exceeding clinical doses, does not produce a clinically relevant effect on cardiac repolarization (ECG parameters including corrected QT interval) in healthy volunteers (N=51) (Lipsky and Lamanna 2020). In fact, the most reported adverse events in healthy volunteers were gastrointestinal adverse events, including nausea / vomiting and diarrhea. No serious adverse events or deaths were reported, and no participants discontinued treatment due to adverse events (Smith PF 2017). Furthermore, based on preclinical reproductive toxicity studies, rilzabrutinib is not expected to harm fetal development or male fertility.

[0024] Preliminary evidence supports the role of BTK in patients with autoimmune cytopenia (Rogers 2016, Montillo 2017), and in patients with chronic lymphocytic leukemia, severe autoimmune hyperlytic anemia and successive episodes of ITP were halted after initiation of treatment with ibrutinib, a BTK / EGFR / ITK inhibitor. Furthermore, in relation to the treatment of ITP, in vitro treatment with rilzabrutinib strongly inhibits human B cell activation and blocks antibody (IgG, IgE)-mediated activation of immune cells via Fc receptor signaling. In non-clinical studies, rilzabrutinib has demonstrated a significant dose-dependent reduction in thrombocytopenia (consumption) in a mouse model of ITP.

[0025] In Part A of an international, adaptive, open-label, dose-finding Phase 1 / 2 trial, treatment with ilzabrutinib was generally well-tolerated and provided rapid and sustained therapeutic effects in ITP patients previously treated with multiple therapies. Overall, 400 mg of ilzabrutinib twice daily was shown to be safe and effective.

[0026] Part B of the open-label Phase 1 / 2 trial continued to evaluate the safety and efficacy of 400 mg BID rilzabrutinib in patients with relapsed ITP. Adult patients (18–80 years old) received <30 × 10 doses at least 7 days apart, 15 days prior to the first dose. 9 Eligible patients had a baseline platelet count of ≥2 times at / L. They also had a past unsustained response to IVIG / anti-D or CS (platelet count ≥ 50 × 10). 9 Patients were required to have achieved 1 / L and to have failed ≥1 other non-IVIG, non-CS ITP therapy. Stable doses of CS / TPO-RA in combination with rilzabrutinib were permitted. The primary endpoints were safety and sustained platelet response (≥8 platelet counts ≥50 × 10¹⁶ in the past 12 weeks with rilzabrutinib without rescue medication). 9(defined by / L). Consistent with the results from Part A, ruzasibutinib demonstrated a rapid, stable, and sustainable platelet response in patients with relapsed ITP and a favorable safety profile in Part B. Notably, patients treated with ruzasibutinib maintained a median platelet count ≥ 50 × 10 9 [[ID=H2]] / L throughout the main treatment period and long-term extension (LTE) (Figure 1).

[0027] In Parts A and B, treatment with ruzasibutinib also resulted in an improvement in the patient platelet variability index (PVI), a recently developed metric for capturing the degree of platelet count variability and the severity of thrombocytopenia over a specific period (Li et al. 2021). PVI scores in the range of 0 (indicating low disease activity) to 6 (indicating high disease activity) were determined for the aggregates from Parts A and B using platelet count values obtained during the following periods: baseline, main treatment period (5, 9, 13, 17, 21, and 25 weeks), and LTE (29, 33, 37, 41, 45, and 49 weeks).

[0028] Overall, 71 patients with ITP received 400 mg ruzasibutinib BID either alone (n = 24) or in combination with ITP therapy (n = 47). For all patients at baseline, the median PVI score was 2 (interquartile range (IQR): 2, 3), while the median platelet count was 14 × 10 9 / L (IQR: 6 × 10 9 / L, 20 × 10 9 / L). Twenty-nine (41%) responder patients (achieved a platelet count of ≥ 50 × 10 9 / L two or more times consecutively and had a ≥ 20 × 10 9Among patients defined as having increased by ≥ / L (according to the primary endpoint of Part A), the median PVI during the main treatment period was 2 (IQR 1, 3), and among 42 (59%) non-responders, the median PVI during the main treatment period increased to 3 (IQR: 2, 3, Figure 2). Furthermore, for patients who responded during the LTE period, the median PVI score decreased to 1 (IQR: 0, 2). When evaluated based on treatment with rilzabrutinib alone or in combination with ITP therapy in 29 responding patients, the median PVI score decreased from baseline to the LTE period, regardless of whether the patient received combination ITP therapy (Figure 3).

[0029] Platelet counts increased in both responders and non-responders. Among responding patients, 18 × 10⁶ 9 The median baseline platelet count for / L was 76 × 10⁴ during the main treatment period. 9 Increased to / L, 89x10 during LTE 9 It rises to / L. On the other hand, in non-responsive patients, 11 × 10 9 The baseline median platelet count was also 17 × 10 during the main treatment period. 9 It increased slightly to / L.

[0030] Furthermore, many of the 71 patients who initiated rilzabrutinib 400 mg BID were early responders. Of the 29 responding patients (41%), 21 / 29 (72%) had a platelet count ≥ 30 × 10 at week 2. 9 They were early responders defined as achieving / L. Based on a univariate logistic regression model, a higher baseline platelet count was a significant predictor of both response to rilzabrutinib and early response, and prior use of TPO-RAS was not (p ≤ 0.05). Conversely, the use of ITP drugs in combination with TPO-RAS was not associated with predicting either response to rilzabrutinib or early response.

[0031] Evaluation of continuous variables by response outcomes showed that respondents (compared to non-responders) had a numerically shorter duration of ITP (8.9 vs. 14.3 years, p=0.07), significantly fewer prior treatments (7 vs. 13, p=0.03), and significantly higher baseline platelet counts (17 × 10⁻¹⁰). 9 / L vs 12×10 9 The study showed that early responders (compared to non-early responders) had a significantly shorter ITP duration (7.4 vs. 14.1 years, p=0.01), fewer previous ITP therapies (7 vs. 12, p=0.03), and higher baseline platelet counts (19 × 10⁶). 9 / L vs 12×10 9 ( / L, p=0.002). When continuous variables were evaluated based on previous TPO-RA use, patients without prior TPO-RA use (compared to those with prior TPO-RA use) had a significantly shorter ITP duration (7.4 vs. 13.7 years, p=0.04), fewer previous ITP therapies (5 vs. 12, p=0.0008), and a higher baseline platelet count (17 × 10⁻¹⁰). 9 / L vs 13×10 9 ( / L, p=0.03).

[0032] Across all categorical variables, a significant association was observed between being a responder (compared to non-responders) and having no prior use of TPO-RA (p=0.01). Both no prior use of TPO-RA (p=0.0008) and no prior use of rituximab (p=0.04) were significantly associated with improved early response.

[0033] Change from baseline in the ITP Bleeding Rating Scale (IBLS) score (0: no bleeding to 2: significant bleeding) was a secondary outcome measure to assess bleeding across nine anatomical sites (eight anatomical sites in males / postmenopausal women). Exploratory health-related quality of life (HRQOL) outcomes assessed the EuroQol-5-item 5-point scale (EQ-5D-5L) + Visual Analog Scale (EQ-VAS) and the ITP Patient Assessment Questionnaire (ITP-PAQ) score (0: worst to 100: best QOL). Overall, patients treated with ilzabrutinib showed sustained platelet response, high compliance, and improved HRQOL measures, particularly in patients with recurrent ITP who were difficult to manage. There was no evidence of increased bleeding with ilzabrutinib, and scores improved at skin sites. Clinically meaningful improvements in HRQOL were observed in multiple individuals and the overall HRQOL health domain after ilzabrutinib (Figure 5).

[0034] The 400 mg BID dose is being evaluated in the ongoing LUNA3 multicenter, double-blind, placebo-controlled phase 3 trial. The primary endpoint is sustained platelet response, with (1) ≥50 × 10⁶ platelets for at least two-thirds of the ≥8 available weekly scheduled platelet measurements during the last 12 weeks of the 24-week blinded treatment period in the absence of rescue therapy (e.g., 8 out of 12 or 6 out of 9). 9 (2) Achieving a platelet count of 50,000 / μL and having at least two available weekly scheduled platelet measurements of 50,000 / μL or higher during the last six weeks of a 24-week blinded treatment period, or (2) having ≥50 × 10 in ≥8 of 12 scheduled observations during the last 12 weeks of a 24-week double-blind treatment period in the absence of rescue therapy. 9 This is defined as achieving a platelet count of / L (EU and UK). The LUNA3 trial will further investigate the magnitude and duration of safety and efficacy of ilzabrutinib in adult and pediatric patients. [Overview of the project] [Means for solving the problem]

[0035] Disclosed herein is a method for treating immune thrombocytopenia (ITP) in a human patient having persistent or chronic ITP who requires such treatment, comprising: a therapeutically effective dose of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts, administered twice daily for a period of treatment to a human patient. The method comprises administering the treatment to a person who is identified to have an initial platelet count of <30,000 / μL without a single platelet count of >35,000 / μL in the two weeks prior to the treatment period, and further, the person is identified to have at least one feature selected from one or more of the following: a non-sustained prior response to IVIg, anti-D or CS, a documented intolerance or inadequate response to any appropriate course of standard ITP therapy, and a contraindication to any appropriate course of standard ITP therapy. In some embodiments, the person has a non-sustained prior response to one or more of the IVIg, anti-D or CS. In some embodiments, the person has a documented intolerance or inadequate response to any appropriate course of standard ITP therapy. In some embodiments, the person has a contraindication to any appropriate course of standard ITP therapy. In some embodiments, the person has a non-sustained prior response to one or more of the IVIg, anti-D or CS and a documented intolerance or inadequate response to any appropriate course of standard ITP therapy. In some embodiments, the patient has a prior, unsustained response to one or more IVIg, anti-D, or CS, and has a contraindication to any appropriate course of standard ITP therapy. In some embodiments, the human patient has a documented intolerance or inadequate response to any appropriate course of standard ITP therapy, and has a contraindication to any appropriate course of standard ITP therapy.In some embodiments, the human patient has a prior, unsustained response to one or more IVIg, anti-D, or CS, a documented intolerance or inadequate response to any appropriate course of standard ITP therapy, and a contraindication to any appropriate course of standard ITP therapy.

[0036] Disclosed herein is a method for treating immune thrombocytopenia (ITP) in a human patient having persistent or chronic ITP who requires such treatment, comprising administering to the human patient a therapeutically effective dose of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts twice daily for a period of treatment, wherein the human patient has had or been identified to have had an inadequate response to or intolerance to one or more prior treatments.

[0037] Disclosed herein is the use of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts for treating immunotoxic thrombocytopenia (ITP) in human patients having persistent or chronic ITP who require such treatment.

[0038] Disclosed herein are therapeutically effective amounts of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts, for use as a pharmaceutical for treating immune thrombocytopenia (ITP) in human patients with persistent or chronic ITP who require such treatment.

[0039] Disclosed herein are therapeutically effective amounts of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts, for use in treating immune thrombocytopenia (ITP) in human patients having persistent or chronic ITP who require such treatment.

[0040] Disclosed herein is the use of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts as a pharmaceutical for treating immune thrombocytopenia (ITP) in human patients having persistent or chronic ITP who require it. [Brief explanation of the drawing]

[0041] [Figure 1] This shows the median platelet count over the main treatment period and throughout the course of LTE. [Figure 1-1] Same as above. [Figure 2]Median IQR PVI and platelet counts are shown at baseline, during the main treatment period, and in response to rilzabrutinib during LTE. *Non-respondents were not eligible for LTE entry (LTE criteria included a platelet count of ≥50 × 10⁹ / L for ≥50% of the last 8 weeks of treatment). [Figure 3] This shows the median (IQR)PVI score in response patients who received rilzabrutinib monotherapy or in combination with ITP therapy at baseline, during the main treatment period, and during the LTE (Long-Term Recovery) period. Note: During the LTE period, there was a decrease of 2 patients in all groups except rilzabrutinib with TPO-RA / CS. [Figure 4A] This shows predictors of response to rilzabrutinib. (A) A single-variable logistic regression model of pooled predictors of response to rilzabrutinib is shown. *Due to the small number of patients, the model did not fit the ITP diagnosis group, and there was no prior CS use. (B) A summary of continuous variables by response to rilzabrutinib or prior TPO-RA use is shown. The horizontal bar represents mean + 1SD. * indicates an improvement in response of p<0.05 by a two-sample t-test assuming unequal variances. [Figure 4B] This shows predictors of response to rilzabrutinib. (A) A single-variable logistic regression model of pooled predictors of response to rilzabrutinib is shown. *Due to the small number of patients, the model did not fit the ITP diagnosis group, and there was no prior CS use. (B) A summary of continuous variables by response to rilzabrutinib or prior TPO-RA use is shown. The horizontal bar represents mean + 1SD. * indicates an improvement in response of p<0.05 by a two-sample t-test assuming unequal variances. [Figure 5] This shows the median change in HRQOL from baseline to HRQOL at week 25 during Part B of the Phase 1 / 2 trial. The MID reference value is provided in Mathias SD, et al. CMRO. 2009;25(2):375-383. [Figure 6]The trial schema is shown as a flowchart. ‡Week 25 is the final visit during the blinded treatment period and also marks the start of the open-label period. †After completion of long-term continuous administration, the patient receives the final day of the study drug and a final trial evaluation. [Figure 7] The decision-making flowchart for evaluating the response at week 13 is shown. After enrollment, patients will begin a blinded treatment period of up to 24 weeks (with rilzabrutinib or placebo), followed by a 28-week open-label period (all patients receive rilzabrutinib), and then a 4-week safety follow-up period or LTE. Patients who have not completed the initial 12 weeks of treatment are not eligible to proceed to the open-label period. At the end of the 12 weeks of treatment, participants will be evaluated for platelet response (≥50×10⁹ / L or ≥30×10⁹ / L to <50×10⁹ / L and at least a twofold increase from baseline at any given time) and the presence or absence of rescue medication in the 4 weeks prior to the increase in platelet count meeting the platelet response criteria. Responders who have not used rescue medication since week 8 will continue to be evaluated for eligibility to proceed to the blinded treatment period for a total of 24 weeks before entering the open-label period. Patients who do not respond or who receive rescue medication after week 8 may discontinue the study or enter a 28-week open-label period at the end of week 12 to receive rilzabrutinib 400 mg BID. [Figure 8] This shows the percentage of patients in the placebo and rilzabrutinib arms who achieved a sustained platelet response over a 24-week double-blind period. [Figure 9] This refers to the mean number of weeks in which platelet counts ≥ 50 × 10⁹ / L or ≥ 30 × 10⁹ / L to < 50 × 10⁹ / L and in the absence of rescue medication, with the platelet count at least doubling from baseline during a 24-week blinded period. [Figure 10] This indicates the time to the initial platelet count ≥ 50 × 10⁹ / L or the time to the initial platelet count ≥ 30 × 10⁹ / L to < 50 × 10⁹ / L, and the time to the initial platelet count at least double from baseline. [Figure 11] This shows the percentage of patients who required rescue therapy during a 24-week blinded treatment period. [Figure 12]This shows the change from baseline in the ITP-PAQ® physical fatigue score in adult patients (≥18 years old) at week 13 of treatment. [Figure 13] This shows the changes in physical fatigue over time up to week 25. [Figure 14] This shows the changes in bleeding as assessed by IBLS at 25 weeks. [Modes for carrying out the invention]

[0042] Definition: Unless otherwise specified, the following terms used in this specification and in the claims are defined for this application and have the following meanings. All undefined technical and scientific terms used in this application have the meanings generally understood by those skilled in the art to which this disclosure belongs.

[0043] As used herein, “one (a)” or “one (an)” entity refers to one or more entities; for example, “compound” refers to one or more compounds or at least one compound unless otherwise stated. Thus, the terms “one (a)” (or “one (an)”), “one or more” and “at least one” may be used synonymously herein.

[0044] Where used herein, the term “approximately” is used to mean an approximate range, roughly, or around that range. Where the term “approximately” is used with a numerical range, the range is modified by extending the upper and lower boundaries of the stated numerical value. Generally, the term “approximately” is used herein to modify a numerical value by a range of 5% above or below the indicated value. With regard to specific values, unless otherwise specified, it should be understood that specific values ​​for the subject population described herein (e.g., subjects of the clinical trial described) represent medians, means, or statistical values. Accordingly, aspects of this disclosure that require specific values ​​for subjects are supported herein by population data in which the relevant value is deemed to be a meaningful boundary setting for the subject population.

[0045] As used herein, the terms “active pharmaceutical ingredient” or “therapeutic agent” (“API”) refer to a biologically active compound.

[0046] As used herein, “adolescent” encompasses all patients between the ages of 12 and 18.

[0047] As used herein, the term “approved treatment” refers to a drug that has been approved by a regulatory authority in any country for its intended use.

[0048] As used herein, the terms “administer,” “give administration,” or “dosage” mean provision, supply, administration and / or prescription by either a healthcare professional or an authorized agent, and / or ingestion, ingestion or consumption by the patient or himself. For example, “administration” of an API to a patient means any route of introduction or delivery of the API to the patient (e.g., oral delivery). Administration includes self-administration and administration by another person.

[0049] As used herein, the term “baseline platelet count” or “baseline” means the mean platelet count obtained by determining the average of two platelet counts collected at least seven days apart 15 days prior to the start of treatment, and a third platelet count collected on day 1 of the trial. If any of these three counts are missing, the “baseline platelet count” or “baseline” shall be the average of the other counts.

[0050] As used herein, "BID" and "bid" are used interchangeably to refer to twice a day.

[0051] As used herein, “child” and “infant” encompass all patients <12 years of age. In some embodiments, a child may be 0 to <12 years of age. In some embodiments, a child may be 10 to <12 years of age.

[0052] As used herein, “immune thrombocytopenia” (ITP) encompasses, or at least refers to, other commonly used terms such as idiopathic thrombocytopenia and idiopathic thrombocytopenic purpura. There are three main types of ITP: acute (newly diagnosed), persistent, and chronic (long-term). Acute ITP lasts for less than three months, persistent ITP lasts for three to twelve months, and chronic ITP lasts for at least one year.

[0053] As used herein, the terms “initial platelet count” or “initial count” refer to the mean platelet count obtained by determining the average of at least two platelet counts taken at least five days apart prior to treatment.

[0054] As used herein, “ITP Kids' ITP Tool” and “ITP-KIT” refer to a combination of three disease-specific scales: a pediatric self-report designed to be completed by pediatric patients ≥ 7 years of age, a parent-surrogate report for pediatric patients < 7 years of age, and a parent-influence report. Respondents record their disease experience based on weekly recall. The scale yields a total score, which is the sum of items converted to a score from 0 to 100, with higher scores indicating a better disease-specific quality of life (QOL).

[0055] As used herein, “ITP Patient Assessment Questionnaire®” and “ITP-PAQ®” are used interchangeably to refer to disease-specific scales designed to measure the quality of life (QOL) of adult patients with immune thrombocytopenia. Items employ a 4-week recall period, and responses are recorded on a 4, 5, or 7-point Likert scale. All item scores are converted to a continuum from 0 to 100, with higher scores representing better QoL, and are weighted equally to derive scale scores.

[0056] As used herein, the term "in combination with" means, when referring to two or more compounds, drugs, or additional active pharmaceutical ingredients, that two or more compounds, drugs, or active pharmaceutical ingredients be administered to the patient prior to each other, simultaneously, or sequentially during the course of treatment. Unless otherwise specified, two or more compounds, drugs, or active pharmaceutical ingredients may be administered on different schedules during the course of treatment, for example, one or more compounds, drugs, or active pharmaceutical ingredients may be administered once daily, and one or more other compounds, drugs, or active pharmaceutical ingredients may be administered twice daily.

[0057] As used herein, the amount expressed in the term "~mg of [X]" refers to the total amount in milligrams of [X], i.e., the free base. In some embodiments, rilzabrutinib may be administered as a pharmaceutically acceptable salt of rilzabrutinib, in which case the amount expressed in the term "~mg of rilzabrutinib" refers to the total amount in milligrams of rilzabrutinib, i.e., the free base, plus an equivalent amount of one or more pharmaceutically acceptable salts of rilzabrutinib based on the weight of the free base. For example, "400 mg of rilzabrutinib and at least one compound selected from its pharmaceutically acceptable salts" includes 400 mg of rilzabrutinib and one or more pharmaceutically acceptable salts at a concentration equivalent to 400 mg of rilzabrutinib.

[0058] As used herein, “pediatric patient” refers to a patient <18 years of age. In some embodiments, a pediatric patient may be 0 to <18 years of age. In some embodiments, a pediatric patient may be 10 to <18 years of age. In some embodiments, a pediatric patient may be 12 to <18 years of age.

[0059] As used herein, “pharmaceutically acceptable carrier or excipient” means a carrier or excipient that is generally safe and useful in preparing a pharmaceutical composition that is not biologically or otherwise undesirable, for example, a carrier or excipient that is acceptable for pharmaceutical use in mammals.

[0060] As used herein, the term “pharmaceutically acceptable salt” refers to an acid-added salt of an active pharmaceutical agent that is pharmaceutically acceptable and has the desired pharmacological activity of the API from which the salt is made. Pharmaceutically acceptable salts are well known in the art and include those derived from suitable inorganic and organic acids. Such salts include, but are not limited to, salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, or salts formed from organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, benzenesulfonic acid, and 4-toluenesulfonic acid. SMBerge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0061] As used herein, the terms "PRN1008", "rilzabrutinib", "(R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]penta-2-ennitrile", "compound of formula (I)", and "2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]-pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]penta-2-ennitrile" have the following structure: [ka] Used interchangeably to refer to compounds having , which is 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazine-1-yl]-(E and Z)-penta-2-ennitrile, (R)-2-[3-[4-amino-3-(2- Fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]penta-2-ennitrile, 1-piperidinepropanenitrile, 3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl]-α-[ It is also known as 2-methyl-2-[4-(3-oxetanyl)-1-piperazinyl]propyridene]-β-oxo-,(3R)-,(EZ)-2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-1-yl]penta-2-ennitrile, and its structure, according to the International Nonproprietary Names (INNs) published by the World Health Organization (https: / / cdn.who.int / media / docs / default-source / international-nonproprietary-names-(inn) / pl121.pdf?sfvrsn=69617906_15&download=true), is as follows: [ka] This also refers to compounds that possess the following properties. Compounds of formula (I) include the E isomer and the Z isomer, which are shown as wavy bonds in the structure shown above. Compounds of formula (I) can exist in salt form.

[0062] The dose of the (E) isomer of rilzabrutinib may contain less than about 1% by weight of the corresponding (Z) isomer as an impurity, and the dose of the (Z) isomer of rilzabrutinib may contain less than about 1% by weight of the corresponding (E) isomer as an impurity. When rilzabrutinib is expressed as a mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-ennitrile, it means that the amount of the (E) isomer or (Z) isomer in the mixture is greater than about 1% by weight. In some embodiments, the molar ratio of the (E) isomer to the (Z) isomer is 9:1. Rilzabrutinib or its pharmaceutically acceptable salts may also be referred to herein as “drug,” “activator,” “therapeutically active agent,” or “API.”

[0063] As used herein, "QD" and "qd" are used interchangeably to mean once a day.

[0064] As used herein, the term “therapeutic dose” refers to the amount of compound administered that produces the desired effect (e.g., improvement in ITP or its symptoms, or reduction in the severity of ITP or its symptoms). The exact amount of the effective dose will depend on the therapeutic purpose and will be determined by those skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0065] As used herein, the terms “to treat,” “to treat,” or “treatment,” when used in relation to a disorder or condition, include any effect, such as reduction, decrease, regulation, improvement, or elimination, resulting in improvement of the disorder or condition. Improvement of any symptom of a disorder or condition, or reduction of its severity, can be readily assessed according to standard methods and techniques known in the art.

[0066] As used herein, the term “response” refers to a change in platelet levels following administration of any appropriate standard ITP therapy.

[0067] Some embodiments of the present disclosure describe a method for treating immune thrombocytopenia (ITP) in a human patient having persistent or chronic ITP who requires such treatment, comprising: a therapeutically effective dose of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts, administered twice daily for a period of treatment to a human The method comprises administering to a patient, wherein the human patient requiring the method has been identified as having or having an initial platelet count of <30,000 / μL without a single platelet count of >35,000 / μL in the two weeks prior to the treatment period, and further, the human patient has been identified as having or having at least one feature selected from one or more of the following: a non-sustained prior response to IVIg, anti-D or CS, a documented intolerance or inadequate response to any appropriate course of standard ITP therapy, and a contraindication to any appropriate course of standard ITP therapy. In some embodiments, the human patient has a non-sustained prior response to one or more of IVIg, anti-D or CS. In some embodiments, the human patient has a documented intolerance or inadequate response to any appropriate course of standard ITP therapy. In some embodiments, the human patient has a contraindication to any appropriate course of standard ITP therapy. In some embodiments, the human patient has a non-sustained prior response to one or more of IVIg, anti-D or CS and a documented intolerance or inadequate response to any appropriate course of standard ITP therapy. In some embodiments, the patient has a prior, unsustained response to one or more IVIg, anti-D, or CS, and has a contraindication to any appropriate course of standard ITP therapy. In some embodiments, the human patient has a documented intolerance or inadequate response to any appropriate course of standard ITP therapy, and has a contraindication to any appropriate course of standard ITP therapy.In some embodiments, the human patient has a prior, unsustained response to one or more IVIg, anti-D, or CS, a documented intolerance or inadequate response to any appropriate course of standard ITP therapy, and a contraindication to any appropriate course of standard ITP therapy.

[0068] In some embodiments, human patients are identified as having an initial platelet count of <15,000 / μL. In some embodiments, human patients are identified as having an initial platelet count of <10,000 / μL. In some embodiments, human patients are identified as having an initial platelet count of <5,000 / μL. In some embodiments, human patients are identified as having an initial platelet count of <4,000 / μL. In some embodiments, human patients are identified as having an initial platelet count of <3,000 / μL. In some embodiments, human patients are identified as having an initial platelet count of <2,000 / μL. In some embodiments, human patients are identified as having an initial platelet count of <1,000 / μL.

[0069] In some embodiments, human patients have been identified as having an initial platelet count of ≥15,000 / μL. In some embodiments, human patients have been identified as having an initial platelet count of ≥20,000 / μL. In some embodiments, human patients have been identified as having an initial platelet count of ≥25,000 / μL. In some embodiments, human patients have been identified as having an initial platelet count of ≥30,000 / μL.

[0070] In some embodiments, human patients achieve a platelet response.

[0071] In some embodiments, human patients achieve a sustained platelet response.

[0072] In some embodiments, human patients achieve a complete platelet response.

[0073] In some embodiments, human patients achieve a stable platelet response.

[0074] In some embodiments, the human patient has at least one instance of a platelet count of ≥30,000 / μL during the treatment period. In some embodiments, the human patient has at least one instance of a platelet count of ≥35,000 / μL during the treatment period. In some embodiments, the human patient has at least one instance of a platelet count of ≥40,000 / μL during the treatment period. In some embodiments, the human patient has at least one instance of a platelet count of ≥45,000 / μL during the treatment period.

[0075] In some embodiments, the human patient has at least one instance of a platelet count of ≥30,000 / μL and at least twice the baseline platelet count during the treatment period. In some embodiments, the human patient has at least one instance of a platelet count of ≥35,000 / μL and at least twice the baseline platelet count during the treatment period. In some embodiments, the human patient has at least one instance of a platelet count of ≥40,000 / μL and at least twice the baseline platelet count during the treatment period. In some embodiments, the human patient has at least one instance of a platelet count of ≥45,000 / μL and at least twice the baseline platelet count during the treatment period.

[0076] In some embodiments, in which a human patient has at least one instance of a platelet count of ≥30,000 / μL and at least twice the baseline platelet count during the treatment period, the patient achieves that platelet count at least once within one week of the start of treatment. In some embodiments, the patient achieves that platelet count at least once within two weeks of the start of treatment. In some embodiments, the patient achieves that platelet count at least once within three weeks of the start of treatment. In some embodiments, the patient achieves that platelet count at least once within four weeks of the start of treatment. In some embodiments, the patient achieves that platelet count at least once within five weeks of the start of treatment. In some embodiments, the patient achieves that platelet count at least once within six weeks of the start of treatment. In some embodiments, the patient achieves that platelet count at least once within seven weeks of the start of treatment. In some embodiments, the patient achieves that platelet count at least once within eight weeks of the start of treatment. In some embodiments, the patient achieves that platelet count at least once within nine weeks of the start of treatment. In some embodiments, the patient achieves that platelet count at least once within ten weeks of the start of treatment. In some embodiments, the patient achieves that platelet count at least once within eleven weeks of the start of treatment. In some embodiments, the patient achieves their platelet count at least once within 12 weeks of the start of treatment. In some embodiments, the patient achieves their platelet count at least once within 13 weeks of the start of treatment. In some embodiments, the patient achieves their platelet count at least once within 14 weeks of the start of treatment. In some embodiments, the patient achieves their platelet count at least once within 15 weeks of the start of treatment. In some embodiments, the patient achieves their platelet count at least once within 16 weeks of the start of treatment. In some embodiments, the patient achieves their platelet count at least once within 17 weeks of the start of treatment. In some embodiments, the patient achieves their platelet count at least once within 18 weeks of the start of treatment. In some embodiments, the patient achieves their platelet count at least once within 19 weeks of the start of treatment.In some embodiments, the patient achieves their platelet count at least once within 20 weeks of the start of treatment. In some embodiments, the patient achieves their platelet count at least once within 21 weeks of the start of treatment. In some embodiments, the patient achieves their platelet count at least once within 22 weeks of the start of treatment. In some embodiments, the patient achieves their platelet count at least once within 23 weeks of the start of treatment. In some embodiments, the patient achieves their platelet count at least once within 24 weeks of the start of treatment.

[0077] In some embodiments, a human patient has at least one instance of a platelet count of ≥30,000 / μL and at least twice the baseline platelet count during the treatment period, in the absence of rescue medication. In some embodiments, a human patient has at least one instance of a platelet count of ≥35,000 / μL and at least twice the baseline platelet count during the treatment period, in the absence of rescue medication. In some embodiments, a human patient has at least one instance of a platelet count of ≥40,000 / μL and at least twice the baseline platelet count during the treatment period, in the absence of rescue medication. In some embodiments, a human patient has at least one instance of a platelet count of ≥45,000 / μL and at least twice the baseline platelet count during the treatment period, in the absence of rescue medication.

[0078] In some embodiments, a human patient has at least one platelet count of ≥30,000 / μL and at least twice the baseline platelet count during a 24-week treatment period. In some embodiments, a human patient has at least one platelet count of ≥35,000 / μL and at least twice the baseline platelet count during a 24-week treatment period. In some embodiments, a human patient has at least one platelet count of ≥40,000 / μL and at least twice the baseline platelet count during a 24-week treatment period. In some embodiments, a human patient has at least one platelet count of ≥45,000 / μL and at least twice the baseline platelet count during a 24-week treatment period.

[0079] In some embodiments, a human patient has at least one platelet count of ≥30,000 / μL and at least twice the baseline platelet count after a 6-month treatment period. In some embodiments, a human patient has at least one platelet count of ≥35,000 / μL and at least twice the baseline platelet count after a 6-month treatment period. In some embodiments, a human patient has at least one platelet count of ≥40,000 / μL and at least twice the baseline platelet count after a 6-month treatment period. In some embodiments, a human patient has at least one platelet count of ≥45,000 / μL and at least twice the baseline platelet count after a 6-month treatment period.

[0080] In some embodiments, the human patient has at least one instance of a platelet count of ≥50,000 / μL during the treatment period. In some embodiments, the human patient has at least one instance of a platelet count of ≥55,000 / μL during the treatment period. In some embodiments, the human patient has at least one instance of a platelet count of ≥60,000 / μL during the treatment period. In some embodiments, the human patient has at least one instance of a platelet count of ≥65,000 / μL during the treatment period. In some embodiments, the human patient has at least one instance of a platelet count of ≥70,000 / μL during the treatment period. In some embodiments, the human patient has at least one instance of a platelet count of ≥75,000 / μL during the treatment period. In some embodiments, the human patient has at least one instance of a platelet count of ≥80,000 / μL during the treatment period. In some embodiments, the human patient has at least one instance of a platelet count of ≥85,000 / μL during the treatment period. In some embodiments, the human patient has at least one instance of a platelet count of ≥90,000 / μL during the treatment period. In some embodiments, the human patient has at least one instance of a platelet count of ≥95,000 / μL during the treatment period.

[0081] In some embodiments, a human patient has at least one instance of a platelet count of ≥50,000 / μL during the treatment period in the absence of rescue medication. In some embodiments, a human patient has at least one instance of a platelet count of ≥55,000 / μL during the treatment period in the absence of rescue medication. In some embodiments, a human patient has at least one instance of a platelet count of ≥60,000 / μL during the treatment period in the absence of rescue medication. In some embodiments, a human patient has at least one instance of a platelet count of ≥65,000 / μL during the treatment period in the absence of rescue medication. In some embodiments, a human patient has at least one instance of a platelet count of ≥70,000 / μL during the treatment period in the absence of rescue medication. In some embodiments, a human patient has at least one instance of a platelet count of ≥75,000 / μL during the treatment period in the absence of rescue medication. In some embodiments, a human patient has at least one instance of a platelet count of ≥80,000 / μL during the treatment period in the absence of rescue medication. In some embodiments, a human patient has at least one instance of a platelet count of ≥85,000 / μL during the treatment period in the absence of rescue medication. In some embodiments, a human patient has at least one instance of a platelet count of ≥90,000 / μL during the treatment period in the absence of rescue medication. In some embodiments, a human patient has at least one instance of a platelet count of ≥95,000 / μL during the treatment period in the absence of rescue medication.

[0082] In some embodiments, the human patient has a platelet count of ≥50,000 / μL for at least two consecutive times, with platelet counts separated by ≥5 days in the absence of rescue medication during the treatment period. In some embodiments, the human patient has a platelet count of ≥55,000 / μL for at least two consecutive times, with platelet counts separated by ≥5 days in the absence of rescue medication during the treatment period. In some embodiments, the human patient has a platelet count of ≥60,000 / μL for at least two consecutive times, with platelet counts separated by ≥5 days in the absence of rescue medication during the treatment period. In some embodiments, the human patient has a platelet count of ≥65,000 / μL for at least two consecutive times, with platelet counts separated by ≥5 days in the absence of rescue medication during the treatment period. In some embodiments, the human patient has a platelet count of ≥70,000 / μL for at least two consecutive times, with platelet counts separated by ≥5 days in the absence of rescue medication during the treatment period. In some embodiments, the human patient has a platelet count of ≥75,000 / μL for at least two consecutive times, with platelet counts separated by ≥5 days in the absence of rescue medication during the treatment period. In some embodiments, the human patient has a platelet count of ≥80,000 / μL for at least two consecutive times, with platelet counts separated by ≥5 days in the absence of rescue medication during the treatment period. In some embodiments, the human patient has a platelet count of ≥85,000 / μL for at least two consecutive times, with platelet counts separated by ≥5 days in the absence of rescue medication during the treatment period. In some embodiments, the human patient has a platelet count of ≥90,000 / μL for at least two consecutive times, with platelet counts separated by ≥5 days in the absence of rescue medication during the treatment period. In some embodiments, the human patient has a platelet count of ≥95,000 / μL for at least two consecutive times, with platelet counts separated by ≥5 days in the absence of rescue medication during the treatment period.

[0083] In some embodiments, the human patient has a platelet count of ≥50,000 / μL for at least two-thirds of the available weekly platelet counts during the last 12 weeks of a 24-week treatment period, and furthermore, at least two available weekly platelet counts are ≥50,000 / μL during the last 6 weeks of a 24-week treatment period, and the human patient does not require rescue medication. In some embodiments, the human patient has a platelet count of ≥50,000 / μL for at least eight available weekly platelet counts during the last 12 weeks of a 24-week treatment period, and furthermore, the patient does not require rescue medication. In some embodiments, the human patient has a platelet count of ≥50,000 / μL for 12 platelet counts during the last 12 weeks of a 24-week treatment period. In some embodiments, at least two available weekly platelet counts are ≥55,000 / μL during the last 6 weeks of a 24-week treatment period. In some embodiments, the number of platelets available weekly for at least two weeks is ≥60,000 / μL during the last six weeks of a 24-week treatment period. In some embodiments, the number of platelets available weekly for at least two weeks is ≥65,000 / μL during the last six weeks of a 24-week treatment period. In some embodiments, the number of platelets available weekly for at least two weeks is ≥70,000 / μL during the last six weeks of a 24-week treatment period. In some embodiments, the number of platelets available weekly for at least two weeks is ≥75,000 / μL during the last six weeks of a 24-week treatment period. In some embodiments, the number of platelets available weekly for at least two weeks is ≥80,000 / μL during the last six weeks of a 24-week treatment period. In some embodiments, the number of platelets available weekly for at least two weeks is ≥85,000 / μL during the last six weeks of a 24-week treatment period. In some embodiments, the number of platelets available weekly for at least two weeks is ≥90,000 / μL during the last six weeks of a 24-week treatment period. In some embodiments, the available weekly platelet count is ≥95,000 / μL for at least two weeks during the last six weeks of a 24-week treatment period. In some embodiments, the available weekly platelet count is ≥100,000 / μL for at least two weeks during the last six weeks of a 24-week treatment period.In some embodiments, at least two available weekly platelet counts are ≥250,000 / μL during the last six weeks of a 24-week treatment period.

[0084] In some embodiments, human patients do not have two consecutive platelet counts of ≤50,000 / μL, and platelet counts occur at least 4 weeks apart within a 24-week period, following at least one platelet count of ≥50,000 / μL within 12 weeks of initiating rilzabrutinib treatment.

[0085] In some embodiments, the human patient has a platelet count of ≥50,000 for four weeks out of the last eight weeks of a 24-week treatment period. In some embodiments, the human patient has a platelet count of ≥55,000 for four weeks out of the last eight weeks of a 24-week treatment period. In some embodiments, the human patient has a platelet count of ≥60,000 for four weeks out of the last eight weeks of a 24-week treatment period. In some embodiments, the human patient has a platelet count of ≥65,000 for four weeks out of the last eight weeks of a 24-week treatment period. In some embodiments, the human patient has a platelet count of ≥70,000 for four weeks out of the last eight weeks of a 24-week treatment period. In some embodiments, the human patient has a platelet count of ≥75,000 for four weeks out of the last eight weeks of a 24-week treatment period. In some embodiments, the human patient has a platelet count of ≥80,000 for four weeks out of the last eight weeks of a 24-week treatment period. In some embodiments, the human patient has a platelet count of ≥85,000 for four weeks out of the last eight weeks of a 24-week treatment period. In some embodiments, the human patient has a platelet count of ≥90,000 for four weeks out of the last eight weeks of a 24-week treatment period. In some embodiments, the human patient has a platelet count of ≥95,000 for four weeks out of the last eight weeks of a 24-week treatment period. In some embodiments, the human patient has a platelet count of ≥100,000 for four weeks out of the last eight weeks of a 24-week treatment period. In some embodiments, the human patient has a platelet count of ≥250,000 for four weeks out of the last eight weeks of a 24-week treatment period.

[0086] In some embodiments, a human patient has a platelet count of ≥50,000 / μL in ≥4 of 6 bi-weekly platelet counts during weeks 14 to 24 of a 24-week treatment period. In some embodiments, a human patient has a platelet count of ≥50,000 / μL in ≥4 of 6 bi-weekly platelet counts during weeks 14 to 24 of a 24-week treatment period. In some embodiments, a human patient has a platelet count of ≥50,000 / μL in ≥5 of 6 bi-weekly platelet counts during weeks 14 to 24 of a 24-week treatment period. In some embodiments, a human patient has a platelet count of ≥50,000 / μL in ≥60,000 / μL during weeks 14 to 24 of a 24-week treatment period. In some embodiments, a human patient has a platelet count of ≥55,000 / μL. In some embodiments, a human patient has a platelet count of ≥60,000 / μL. In some embodiments, the human patient has a platelet count of ≥65,000 / μL. In some embodiments, the human patient has a platelet count of ≥70,000 / μL. In some embodiments, the human patient has a platelet count of ≥75,000 / μL. In some embodiments, the human patient has a platelet count of ≥80,000 / μL. In some embodiments, the human patient has a platelet count of ≥85,000 / μL. In some embodiments, the human patient has a platelet count of ≥90,000 / μL. In some embodiments, the human patient has a platelet count of ≥95,000 / μL. In some embodiments, the human patient has a platelet count of ≥100,000 / μL. In some embodiments, the human patient has a platelet count of ≥250,000 / μL.

[0087] In some embodiments, the human patient has a platelet count of ≥50,000 for ≥2-thirds of the ≥10 available weekly platelet counts during the last 16 weeks of the 53-week treatment period, and furthermore, at least 3 available weekly platelet counts are ≥50,000 / μL during the last 8 weeks of the 53-week treatment period, and the human patient does not require rescue medication. In some embodiments, the human patient has a platelet count of ≥50,000 for 16 available weekly platelet counts during the last 16 weeks of the 53-week treatment period, and a platelet count of ≥50,000 for ≥2-thirds of the ≥10 available weekly platelet counts during the last 16 weeks of the 53-week treatment period. In some embodiments, the human patient has a platelet count of ≥55,000 / μL. In some embodiments, the human patient has a platelet count of ≥60,000 / μL. In some embodiments, the human patient has a platelet count of ≥65,000 / μL. In some embodiments, the human patient has a platelet count of ≥70,000 / μL. In some embodiments, the human patient has a platelet count of ≥75,000 / μL. In some embodiments, the human patient has a platelet count of ≥80,000 / μL. In some embodiments, the human patient has a platelet count of ≥85,000 / μL. In some embodiments, the human patient has a platelet count of ≥90,000 / μL. In some embodiments, the human patient has a platelet count of ≥95,000 / μL. In some embodiments, the human patient has a platelet count of ≥100,000 / μL. In some embodiments, the human patient has a platelet count of ≥250,000 / μL.

[0088] In some embodiments, the human patient has a platelet count of ≥50,000 for ≥10 of the available weekly platelet counts during the last 16 weeks of the 53-week treatment period, and at least 3 available weekly platelet counts are ≥50,000 / μL during the last 8 weeks of the 53-week treatment period, and the human patient does not require rescue medication. In some embodiments, the human patient does not require rescue medication during the last 8 weeks of the 53-week treatment period. In some embodiments, the human patient does not require rescue medication during the last 16 weeks of the 53-week treatment period. In some embodiments, the human patient does not require rescue medication during the 53-week treatment period.

[0089] In some embodiments, during a 24-week treatment period, in the absence of rescue medication, the human patient has at least one instance of a platelet count of ≥50,000 / μL or at least one instance of a platelet count of ≥30,000 / μL to <50,000 / μL and at least twice the baseline platelet count. In some embodiments, during a 24-week treatment period, in the absence of rescue medication, the human patient has at least one instance of a platelet count of ≥50,000 / μL. In some embodiments, during a 24-week treatment period, in the absence of rescue medication, the human patient has at least one instance of a platelet count of ≥50,000 / μL and at least twice the baseline platelet count. In some embodiments, during a 24-week treatment period, in the absence of rescue medication, the human patient has at least one instance of a platelet count of ≥30,000 / μL to <50,000 / μL and at least twice the baseline platelet count.

[0090] In some embodiments, the human patient has at least one platelet count of ≥100,000 / μL during the treatment period, and this at least one platelet count occurs when there is no bleeding. In some embodiments, the human patient has at least one platelet count of ≥150,000 / μL. In some embodiments, the human patient has at least one platelet count of ≥200,000 / μL.

[0091] In some embodiments, a human patient has at least two consecutive platelet counts of ≥100,000 / μL during the treatment period, separated by ≥5 days, in the absence of rescue medication. In some embodiments, a human patient has at least one platelet count of ≥150,000 / μL. In some embodiments, a human patient has at least one platelet count of ≥200,000 / μL.

[0092] In some embodiments, the human patient has at least one instance of a platelet count of ≥250,000 / μL during the treatment period. In some embodiments, the human patient has at least one instance of a platelet count of ≥300,000 / μL. In some embodiments, the human patient has at least one instance of a platelet count of ≥350,000 / μL. In some embodiments, the human patient has at least one instance of a platelet count of ≥400,000 / μL.

[0093] In some embodiments, the human patient has at least one instance of a platelet count of ≥450,000 / μL during the treatment period.

[0094] In some embodiments, the human patient has at least one platelet count in the range of 30,000 / μL to 100,000 / μL during the treatment period, the at least one platelet count being at least twice the baseline platelet count, and occurring without bleeding. In some embodiments, the human patient has at least one platelet count in the range of 30,000 / μL to 250,000 / μL. In some embodiments, the human patient has at least one platelet count in the range of 30,000 / μL to 450,000 / μL. In some embodiments, a human patient receives at least one dose of 30,000 / μL to 100,000 / μL, 35,000 / μL to 100,000 / μL, 40,000 / μL to 100,000 / μL, 45,000 / μL to 100,000 / μL, 50,000 / μL to 100,000 / μL, 55,000 / μL to 100,000 / μL, 60,000 / μL to 100, Having platelet counts in the range of 000 / μL, 65,000 / μL~100,000 / μL, 70,000 / μL~100,000 / μL, 75,000 / μL~100,000 / μL, 80,000 / μL~100,000 / μL, 85,000 / μL~100,000 / μL, 90,000 / μL~100,000 / μL, or 95,000 / μL~100,000 / μL. In some embodiments, a human patient receives at least one dose of 30,000 / μL to 35,000 / μL, 30,000 / μL to 40,000 / μL, 30,000 / μL to 45,000 / μL, 30,000 / μL to 50,000 / μL, 30,000 / μL to 55,000 / μL, 30,000 / μL to 60,000 / μL, and 30,000 / μL to 65,000 / μL. Having platelet counts in the range of 00 / μL, 30,000 / μL~70,000 / μL, 30,000 / μL~75,000 / μL, 30,000 / μL~80,000 / μL, 30,000 / μL~85,000 / μL, 30,000 / μL~90,000 / μL, 30,000 / μL~95,000 / μL, or 30,000 / μL~100,000 / μL.In some embodiments, a human patient receives at least one dose of 30,000 / μL to 35,000 / μL, 35,000 / μL to 40,000 / μL, 40,000 / μL to 45,000 / μL, 45,000 / μL to 50,000 / μL, 50,000 / μL to 55,000 / μL, 55,000 / μL to 60,000 / μL, and 60,000 / μL to 65,000 / μL. The platelet count is in the range of 00 / μL, 65,000 / μL~70,000 / μL, 70,000 / μL~75,000 / μL, 75,000 / μL~80,000 / μL, 80,000 / μL~85,000 / μL, 85,000 / μL~90,000 / μL, 90,000 / μL~95,000 / μL, or 95,000 / μL~100,000 / μL.

[0095] In some embodiments, the human patient has at least one platelet count in the range of ≥30,000 / μL to <50,000 / μL and at least twice the baseline platelet count during the treatment period.

[0096] In some embodiments, human patients receive combination therapy with TPO-RA. In some embodiments, human patients receive combination therapy with at least one TPO-RA selected from rTPO, romiplostim, eltrombopag, and avathrombopag. In some embodiments, human patients receive combination therapy with rTPO. In some embodiments, human patients receive combination therapy with romiplostim. In some embodiments, human patients receive combination therapy with eltrombopag. In some embodiments, human patients receive combination therapy with avathrombopag.

[0097] In some embodiments, the human patient has a history of response to or has been identified as having a history of response to at least one prior treatment line, the at least one prior therapy being selected from splenectomy, rituximab, TPO-RA, intravenous immunoglobulin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressants. In some embodiments, the human patient has a history of response to splenectomy. In some embodiments, the human patient has a history of response to rituximab. In some embodiments, the human patient has a history of response to TPO-RA. In some embodiments, the human patient has a history of response to intravenous immunoglobulin (IVIG). In some embodiments, the human patient has a history of response to corticosteroids. In some embodiments, the patient has a history of response to at least one corticosteroid selected from dexamethasone or oral prednisone / prednisolone. In some embodiments, the patient has a history of response to dexamethasone. In some embodiments, the patient has a history of response to oral prednisone / prednisolone. In some embodiments, the human patient has a history of response to anti-D immunoglobulin therapy. In some embodiments, the human patient has a history of response to immunosuppressants. In some embodiments, the human patient has a history of response to at least one immunosuppressant selected from fostamatinib, mycophenolate mofetil (MMF), and cyclosporine prior to the start of the treatment period. In some embodiments, the human patient has a history of response to fostamatinib. In some embodiments, the human patient has a history of response to mycophenolate mofetil (MMF). In some embodiments, the human patient has a history of response to cyclosporine.

[0098] In some embodiments, human patients do not require rescue medication during the treatment period.

[0099] In some embodiments, human patients are identified as having undergone or having undergone a splenectomy prior to the initiation of treatment.

[0100] In some embodiments, human patients are identified as having taken or having a history of taking rituximab prior to the start of the treatment period. In some embodiments, human patients have not received prior treatment with rituximab.

[0101] In some embodiments, the human patient is identified as having a history of taking or having taken at least one TPO-RA prior to the start of the treatment period. In some embodiments, the human patient is identified as having a history of taking or having taken at least one TPO-RA selected from rTPO, romiplostim, eltrombopag, and avathrombopag prior to the start of the treatment period. In some embodiments, the human patient is identified as having a history of taking or having taken rTPO. In some embodiments, the human patient is identified as having a history of taking or having taken romiplostim. In some embodiments, the human patient is identified as having a history of taking or having taken eltrombopag. In some embodiments, the human patient is identified as having a history of taking or having taken avathrombopag. In some embodiments, the human patient has not received prior treatment with one or more TPO-RAs.

[0102] In some embodiments, human patients are identified as having a history of taking intravenous immunoglobulin (IVIG) prior to the start of the treatment period.

[0103] In some embodiments, human patients are identified as having a history of taking or having taken at least one corticosteroid prior to the start of the treatment period. In some embodiments, human patients are identified as having a history of taking or having taken at least one corticosteroid selected from dexamethasone or oral prednisone / prednisolone prior to the start of the treatment period. In some embodiments, human patients are identified as having a history of taking or having taken dexamethasone. In some embodiments, human patients are identified as having a history of taking or having taken oral prednisone / prednisolone.

[0104] In some embodiments, human patients are identified as having received or having a history of receiving anti-D immunoglobulin therapy prior to the start of the treatment period.

[0105] In some embodiments, human patients are identified as having a history of taking or having taken at least one immunosuppressant prior to the start of the treatment period. In some embodiments, human patients are identified as having a history of taking or having taken at least one immunosuppressant selected from fostamatinib, mycophenolate mofetil (MMF), and cyclosporine prior to the start of the treatment period. In some embodiments, human patients are identified as having a history of taking or having taken fostamatinib. In some embodiments, human patients are identified as having a history of taking or having taken mycophenolate mofetil (MMF). In some embodiments, human patients are identified as having a history of taking or having taken cyclosporine.

[0106] In some embodiments, human patients have been identified as having responded to or being responsive to previous ITP therapy.

[0107] In some embodiments, the response to previous ITP therapy included a platelet count of <50,000 / μL. In some embodiments, the response to previous ITP therapy included a platelet count of <45,000 / μL. In some embodiments, the response to previous ITP therapy included a platelet count of <40,000 / μL. In some embodiments, the response to previous ITP therapy included a platelet count of <35,000 / μL. In some embodiments, the response to previous ITP therapy included a platelet count of <30,000 / μL. In some embodiments, the response to previous ITP therapy included a platelet count of <25,000 / μL. In some embodiments, the response to previous ITP therapy included a platelet count of <20,000 / μL. In some embodiments, the response to previous ITP therapy included a platelet count of <15,000 / μL. In some embodiments, the response to previous ITP therapy included a platelet count of <10,000 / μL. In some embodiments, the response to prior ITP therapy included a platelet count of <5,000 / μL. In some embodiments, the response to prior ITP therapy included a platelet count of <4,000 / μL. In some embodiments, the response to prior ITP therapy included a platelet count of <3,000 / μL. In some embodiments, the response to prior ITP therapy included a platelet count of <2,000 / μL. In some embodiments, the response to prior ITP therapy included a platelet count of <1,000 / μL.

[0108] In some embodiments, the response to previous ITP therapy was not sustained.

[0109] In some embodiments, patients have or have been identified as having documented intolerance to standard ITP therapy.

[0110] In some embodiments, patients have or have been identified as having contraindications to standard ITP therapy.

[0111] In some embodiments, human patients have primary ITP.

[0112] In some embodiments, the human patient is ≥18 years old. In some embodiments, the human patient is an adult.

[0113] In some embodiments, the human patient is <18 years old. In some embodiments, the human patient is a pediatric patient.

[0114] In some embodiments, the human patient is between 12 and <18 years old. In some embodiments, the human patient is a young adult.

[0115] In some embodiments, the human patient is <12 years old. In some embodiments, the human patient is 10 to <12 years old. In some embodiments, the human patient is a child.

[0116] In some embodiments, the human patient is between 10 and <18 years old.

[0117] In some embodiments, human patients are identified as having ITP or having ITP over a period of >1 year. In some embodiments, human patients are identified as having ITP or having ITP over a period of >2 years. In some embodiments, human patients are identified as having ITP or having ITP over a period of >3 years. In some embodiments, human patients are identified as having ITP or having ITP over a period of >4 years. In some embodiments, human patients are identified as having ITP or having ITP over a period of >5 years. In some embodiments, human patients are identified as having ITP or having ITP over a period of >10 years. In some embodiments, human patients are identified as having ITP or having ITP over a period of >15 years. In some embodiments, human patients are identified as having ITP or having ITP over a period of >20 years. In some embodiments, human patients are identified as having ITP or having ITP over a period of >25 years. In some embodiments, human patients are identified as having ITP or having ITP over a period of >30 years. In some embodiments, human patients have been identified as having ITP for a period of >35 years. In some embodiments, human patients have been identified as having ITP for a period of >40 years. In some embodiments, human patients have been identified as having ITP for a period of >45 years. In some embodiments, human patients have been identified as having ITP for a period of >50 years.

[0118] In some embodiments, the human patient does not have chronic ITP.

[0119] In some embodiments, human patients have persistent ITP.

[0120] In some embodiments, human patients have chronic ITP.

[0121] In some embodiments, human patients have recurrent ITP.

[0122] In some embodiments, human patients have refractory ITP.

[0123] In some embodiments, the treatment period is at least 168 days. In some embodiments, the treatment period is at least 364 days. In some embodiments, the treatment period is at least 392 days. In some embodiments, the treatment period is at least 728 days.

[0124] In some embodiments, the method involves administering 400 mg of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts to a human patient twice daily. In some embodiments, at least one compound comprises at least one compound selected from the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts. In some embodiments, at least one compound comprises at least one compound selected from the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts. In some embodiments, at least one compound comprises a mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the method involves administering 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile to a human patient twice daily. In some embodiments, at least one compound is the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile. In some embodiments, at least one compound is the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]penta-2-ennitrile. In some embodiments, at least one compound consists of a mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]penta-2-ennitrile.

[0126] In some embodiments, at least one compound is administered orally to a human patient. In some embodiments, at least one compound is administered to a human patient in the form of at least one tablet. In some embodiments, at least one compound is administered with water.

[0127] In some embodiments, the patient is ≥18 years old. In some embodiments, the patient is an adult.

[0128] In some embodiments, the patient is <18 years old. In some embodiments, the patient is a pediatric patient.

[0129] In some embodiments, the patient is between 12 and <18 years old. In some embodiments, the patient is a young adult.

[0130] In some embodiments, the patient is between 10 and <12 years old. In some embodiments, the patient is a child.

[0131] In some embodiments, the patient experiences fatigue reduction. In some embodiments where the patient experiences fatigue reduction, the human patient experiences fatigue reduction within one week of the start of treatment. In some embodiments, the human patient experiences fatigue reduction within two weeks of the start of treatment. In some embodiments, the human patient experiences fatigue reduction within three weeks of the start of treatment. In some embodiments, the human patient experiences fatigue reduction within four weeks of the start of treatment. In some embodiments, the human patient experiences fatigue reduction within five weeks of the start of treatment. In some embodiments, the human patient experiences fatigue reduction within six weeks of the start of treatment. In some embodiments, the human patient experiences fatigue reduction within seven weeks of the start of treatment. In some embodiments, the human patient experiences fatigue reduction within eight weeks of the start of treatment. In some embodiments, the human patient experiences fatigue reduction within nine weeks of the start of treatment. In some embodiments, the human patient experiences fatigue reduction within ten weeks of the start of treatment. In some embodiments, the human patient experiences fatigue reduction within eleven weeks of the start of treatment. In some embodiments, human patients experience fatigue reduction within 12 weeks of the start of treatment. In some embodiments, human patients experience fatigue reduction within 13 weeks of the start of treatment. In some embodiments, human patients experience fatigue reduction within 14 weeks of the start of treatment. In some embodiments, human patients experience fatigue reduction within 15 weeks of the start of treatment. In some embodiments, human patients experience fatigue reduction within 16 weeks of the start of treatment. In some embodiments, human patients experience fatigue reduction within 17 weeks of the start of treatment. In some embodiments, human patients experience fatigue reduction within 18 weeks of the start of treatment. In some embodiments, human patients experience fatigue reduction within 19 weeks of the start of treatment. In some embodiments, human patients experience fatigue reduction within 20 weeks of the start of treatment. In some embodiments, human patients experience fatigue reduction within 21 weeks of the start of treatment. In some embodiments, human patients experience fatigue reduction within 22 weeks of the start of treatment. In some embodiments, human patients experience fatigue reduction within 23 weeks of the start of treatment.In some embodiments, human patients experience fatigue reduction within 24 weeks of the start of treatment. In some embodiments, human patients experience fatigue reduction within 53 weeks of the start of treatment. In some embodiments, human patients experience fatigue reduction as determined using the ITP Patient Assessment Questionnaire (ITP-PAQ) (ITP-PAQ). In some embodiments, human patients experience fatigue reduction as determined using the ITP Kids' ITP Tool (ITP-KIT).

[0132] In some embodiments, human patients experience a change from baseline in IBLS at weeks 13 and 15 of the treatment period. In some embodiments, human patients experience a change from baseline in IBLS at week 25 of the treatment period.

[0133] In some embodiments, human patients experience an improvement in quality of life. In some embodiments, human patients experience an improvement in quality of life as determined by ITP-KIT.

[0134] In some embodiments, human patients experience changes from baseline in the following items of the ITP-PAQ(trademark): symptoms, both-physical health, activity, fatigue / sleep, psychological health, fears, social activity, female reproductive health, and work. In some embodiments, human patients experience changes from baseline in the symptom item of the ITP-PAQ(trademark). In some embodiments, human patients experience changes from baseline in the physical health item of the ITP-PAQ(trademark). In some embodiments, human patients experience changes from baseline in the activity item of the ITP-PAQ(trademark). In some embodiments, human patients experience changes from baseline in the fatigue / sleep item of the ITP-PAQ(trademark). In some embodiments, human patients experience changes from baseline in the psychological health item of the ITP-PAQ(trademark). In some embodiments, human patients experience changes from baseline in the fear item of the ITP-PAQ(trademark). In some embodiments, human patients experience a change from baseline in the social activity item of the ITP-PAQ®. In some embodiments, human patients experience a change from baseline in the female reproductive health item of the ITP-PAQ®. In some embodiments, human patients experience a change from baseline in the occupation item of the ITP-PAQ®.

[0135] In some embodiments, human patients experience less frequent or milder bleeding than human patients administered a therapeutically effective dose of another BTK inhibitor.

[0136] In some embodiments, a human patient is identified as refractory to at least one previous line of treatment, e.g., at least two, e.g., at least three, e.g., at least four, e.g., at least five, e.g., at least six, e.g., at least seven, e.g., at least eight, e.g., at least nine, e.g., at least ten, e.g., at least eleven, e.g., at least twelve, e.g., at least thirteen, e.g., at least four, e.g., at least fifteen, e.g., at least sixteen, e.g., at least seventeen. In some embodiments, a patient is identified as refractory to at least one previous line of treatment. In some embodiments, a patient is identified as refractory to at least two previous lines of treatment. In some embodiments, a patient is identified as refractory to at least three previous lines of treatment. In some embodiments, a patient is identified as refractory to at least four previous lines of treatment. In some embodiments, a patient is identified as refractory to at least five previous lines of treatment. In some embodiments, the patient is identified as refractory to at least six previous lines of treatment. In some embodiments, the patient is identified as refractory to at least seven previous lines of treatment. In some embodiments, the patient is identified as refractory to at least eight previous lines of treatment. In some embodiments, the patient is identified as refractory to at least nine previous lines of treatment. In some embodiments, the patient is identified as refractory to at least ten previous lines of treatment. In some embodiments, the patient is identified as refractory to at least eleven previous lines of treatment.In some embodiments, the patient is identified as refractory to at least 12 previous lines of treatment. In some embodiments, the patient is identified as refractory to at least 13 previous lines of treatment. In some embodiments, the patient is identified as refractory to at least 14 previous lines of treatment. In some embodiments, the patient is identified as refractory to at least 15 previous lines of treatment. In some embodiments, the patient is identified as refractory to at least 16 previous lines of treatment. In some embodiments, the patient is identified as refractory to at least 17 previous lines of treatment.

[0137] Some embodiments of the present disclosure relate to a method for treating immune thrombocytopenia (ITP) in a human patient having persistent or chronic ITP who requires such treatment, comprising administering to the human patient a therapeutically effective dose of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts twice daily for a period of treatment, wherein the human patient has had or been identified to have had an inadequate response to or intolerance to one or more prior treatments.

[0138] Some embodiments of the present disclosure relate to the use of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts for treating immunotoxic thrombocytopenia (ITP) in human patients having persistent or chronic ITP who require such treatment.

[0139] Some embodiments of the present disclosure relate to at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts, for use as a pharmaceutical for treating immune thrombocytopenia (ITP) in human patients having persistent or chronic ITP who require it.

[0140] Some embodiments of the present disclosure relate to at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and pharmaceutically acceptable salts thereof for use in treating immunotoxic thrombocytopenia (ITP) in human patients having persistent or chronic ITP who require such treatment.

[0141] Some embodiments of the present disclosure relate to the use of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts as a pharmaceutical for treating immune thrombocytopenia (ITP) in human patients having persistent or chronic ITP who require it.

[0142] Pharmaceutical composition: In some embodiments of the present disclosure, rilzabrutinib is administered as part of a pharmaceutical composition comprising at least one compound selected from rilzabrutinib and its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is in the form of at least one tablet.

[0143] In some embodiments of this disclosure, rilzabrutinib is administered orally as part of a pharmaceutical composition comprising at least one compound selected from rilzabrutinib and its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is in the form of at least one tablet.

[0144] In some embodiments, rilzabrutinib is administered in the form of a film-coated tablet.

[0145] In some embodiments of the present disclosure, rilzabrutinib is administered in the form of at least one tablet comprising at least one compound selected from rilzabrutinib and its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient. In some embodiments, rilzabrutinib is administered in the form of at least one tablet comprising at least one compound selected from rilzabrutinib and its pharmaceutically acceptable salts, at least one filler, at least one disintegrant, at least one lubricant, and at least one film coating.

[0146] In some embodiments, rilzabrutinib is administered with a glass of water.

[0147] The proportion and nature of any pharmaceutically acceptable excipients are determined by the chosen route of administration and standard pharmacokinetics. Unless a conventional pharmaceutically acceptable excipient is incompatible with rilzabrutinib, such as by producing an undesirable biological effect or otherwise adversely interacting with other components of the pharmaceutically acceptable composition, its use is intended to be within the scope of this disclosure.

[0148] Some non-limiting examples of materials that can act as pharmaceutically acceptable excipients include: (1) sugars, e.g., lactose, glucose, and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, e.g., cocoa butter and suppository wax; (9) oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil. Examples include (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurylate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic, suitable substances used in pharmaceutical formulations.

[0149] Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988-1999, Marcel Dekker, New York also disclose non-limiting examples of additional pharmaceutically acceptable excipients and known techniques for their preparation and use.

[0150] Those skilled in the art can easily select the appropriate dosage form and route of administration depending on the disorder or condition being treated, the stage of the disorder or condition, and other relevant circumstances. [Examples]

[0151] The following embodiments are illustrative and are not intended to limit the scope of this disclosure.

[0152] Abbreviation: API Active Pharmaceutical Ingredients ALT (Alanine Aminotransferase) AST (Aspartate Aminotransferase) Bid / BID twice a day (morning and evening) BTK Bruton's tyrosine kinase CS corticosteroids ECG (Electrocardiogram) EQ-5D-5L EuroQol-5 5-item method HRQOL (Health-Related Quality of Life) IBLS ITP Bleeding Assessment Scale ICH International Conference on Harmonisation of Regulation of Pharmaceuticals for Human Use ICMJE International Committee of Medical Journal Editors IgG (Immunoglobulin G) ITP Immune Thrombocytopenic Purpura ITP-KIT ITP Kids' ITP Tool ITP-PAQ (Trademark) ITP Patient Assessment Questionnaire (Trademark) IV Intravenous IVIG (Intravenous Immunoglobulin) IWG International Working Group Long-term continuous administration of LTE MID Minimum Significant Difference NE cannot be estimated PO oral qd / QD once a day Q2d / Q2D every other day QOL (Quality of Life) QTc heart rate corrected QT interval QT interval with QTcF Fridericia correction rTPO recombinant thrombopoietin SI (International System of Units) TPO Thrombopoietin TPO-RA Thrombopoietin receptor agonist ULN normal upper limit VAS (Visual Analog Scale) WHODD (World Health Organization) Drugs and Medical Devices

[0153] Example 1: Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study with open-label extension to evaluate the efficacy and safety of oral rilzabrutinib (PRN1008) in adults, adolescents, and children with persistent or chronic immune thrombocytopenia (ITP) (LUNA3) Exam Overview The LUNA3 trial is an ongoing, multicenter, randomized, double-blind, placebo-controlled, parallel-group, interventional Phase 3 trial evaluating the efficacy and safety of oral rilzabrutinib in adult and pediatric patients with persistent or chronic ITP (Study to evaluate rilzabrutinib in adults, adolescents and children with persistent or chronic immune thrombocytopenia (ITP), Phase 3, multicenter, randomized, double-blind, placebo-controlled, open-label, extended-treatment parallel-group trial to evaluate the efficacy and safety of oral rilzabrutinib (PRN1008) in adults, adolescents and children with persistent or chronic immune thrombocytopenia (ITP)). LUNA3 has unique design features, including both 194 adult patients and 30 pediatric patients.

[0154] Theoretical basis of the exam The LUNA3 Phase 3 trial will compare the magnitude, duration, and stability of the efficacy and safety (compared to placebo) of rilzabrutinib in adults with persistent or chronic ITP and investigate findings in pediatric patients. In this trial, a sustained response (primary endpoint) will be defined as (1) ≥8 of the available weekly scheduled platelet counts during the last 12 weeks of a 24-week blinded treatment period in the absence of rescue therapy (e.g., 8 out of 12 or 6 out of 9), with a platelet count of ≥50 × 10⁶. 9(2) Achieving a platelet count of 50,000 / μL and having at least two available weekly scheduled platelet measurements of 50,000 / μL or higher during the last six weeks of a 24-week blinded treatment period, or (2) having ≥50 × 10 in ≥8 of 12 scheduled observations during the last 12 weeks of a 24-week double-blind treatment period in the absence of rescue therapy. 9 This is defined as achieving a platelet count of / L (EU and UK).

[0155] The International Working Group (IWG) determined that platelet response should be 30 × 10 9 / L~100×10 9 Full response is defined as achieving either / L or at least twice the platelet count from the baseline count. 9 A platelet count is defined as either / L, and both endpoints require the absence of bleeding (Rodeghiero et al. 2009). While lower platelet levels are sufficient to establish a platelet response as defined by the IWG guidelines, clinical trials of approved ITP therapies have set the threshold for establishing a platelet response as ≥50 × 10⁶. 9 The / L count is commonly used (Bussel et al. 2018, Ghanima et al. 2015, Jurczak et al. 2018, Kuter et al. 2008).

[0156] ≥30×10 9 A sustained platelet response, defined as a platelet count of 1 / L that at least doubles from baseline at 6 months, is the target of ITP therapy as an endpoint to measure clinical benefit over time (Neunert et al. 2019). For the recently approved drug fostamatinib, the primary endpoint was two-thirds of the platelet count during the last 12 weeks of the blinded period (6 visits): ≥4 of the 6 bi-weekly visits (weeks 14, 16, 18, 20, 22, and 24) with a platelet count of ≥50 × 10⁶. 9A sustained response was demonstrated when the platelet count met the threshold of / L (Bussel J et al. 2018, Bussel J et al. 2019). The definition of this sustained response is ≥30 × 10⁻¹⁰ 9 Not at the point of fixation of platelet count / L, but ≥ 50 × 10 9 Based on the percentage of available platelet counts per L, which doubles from baseline at 6 months as defined in the guidelines, it becomes possible to take into account the number of missing platelets (Neunert et al. 2019). A significant number of both adults, adolescents, and children with ITP have low platelet counts (<30 × 10⁶). 9 It is associated with fatigue (L) and is thought to be caused by a chronic inflammatory state and immunodysregulation (Trotter and Hill 2018, Hill QA and Newland AC 2015, Newton et al. 2011). To date, reports from randomized, placebo-controlled clinical trials have shown that available ITP therapies have not demonstrated significant improvement in fatigue. Item 10 (Fatigue / Sleep) of the ITP Patient Assessment Questionnaire (ITP-PAQ®) is used to quantify the effect of ilzabrutinib treatment on fatigue as an important secondary endpoint.

[0157] Patients enrolled in this trial were expected to have previously responded to at least one prior ITP therapy and support a diagnosis of primary ITP by exclusion (negative diagnosis), and preliminary findings based on the Phase 2 trial results suggest that patients who have not received rituximab and TPO-RA may achieve better response rates (Kuter et al. 2022).

[0158] Patient eligibility and recruitment Eligible patients must have primary ITP (Provan et al. 2019) and have had a period of >3 months if ≥18 years of age, or >6 months if 10–<12 years (EU countries only) or 12–<18 years (all countries). Patients must have had a single platelet count of >35 × 10¹⁶ within 14 days prior to the first dose of rilzabrutinib. 9 Without becoming / L, <30×109 The patient should have an initial platelet count of 50 × 10¹L. In addition, the patient should have a previous response to CS or IVIG / anti-D (platelet count ≥ 50 × 10¹L). 9 Patients should have a stable dose of CS and / or TPO-RA. Previous responses should not persist, and instead, patients must have a documented intolerance, a history of inadequate response, or a contraindication to any of the appropriate assumptions for standard ITP therapy. Patients on stable doses of CS and / or TPO-RA are eligible to participate. Adequate hematological, hepatic, and renal function (absolute neutrophil count ≥ 1.5 × 10⁻¹⁰) 9 The following are required: aspartate aminotransferase / alanine aminotransferase ≤1.5 × upper normal [ULN], albumin ≥3 g / dL, total bilirubin ≤1.5 × ULN [unless Gilbert's syndrome is demonstrated], estimated glomerular filtration rate by Cockcroft-Gault >50), and hemoglobin level >9 g / dL (within one week prior to day 1 of the test). Additional eligibility criteria are outlined in Table 1.

[0159] [Table 1]

[0160] [Table 2]

[0161] [Table 3]

[0162] Patients with known secondary ITP are ineligible for enrollment. Important exclusion criteria also include the use of platelet transfusions or any other rescue medication (e.g., IVIG) intended to increase platelet count, changes in CS and / or TPO-RA dose (more than 10% change from current dose) within two weeks prior to trial entry, and administration of live vaccines within 28 days prior to day 1 of the trial (or intention to administer live vaccines during the trial). Specifically, administration of COVID-19 vaccines within two weeks prior to trial treatment and during the last 12 weeks of the blinded treatment period is not permitted due to potential confounding effects on the primary endpoint (Kuter DJ 2021, Lee et al. 2022).

[0163] Study design and intervention For each patient, the trial will last up to 60 weeks, from the start of the screening period to the end of the trial visit. After providing written informed consent, patients entered a 28-day screening period, and eligible patients were randomized in a 2:1 ratio to receive oral treatment with either rilzabrutinib 400 mg BID or placebo, along with an optional stable dose of standard CS and / or TPO-RA therapy.

[0164] Randomization was based on the status of splenectomy (with / without) and the severity of the disease (platelet count < 15 × 10⁻¹⁰). 9 / L ratio ≥ 15 × 10 9 Stratification by / L) is performed separately for adult and pediatric patients. After randomization, patients initiate a blinded treatment period of up to 24 weeks, followed by a 28-week open-label period if all patients receive rilzabrutinib, followed by a 4-week safety follow-up or long-term extension (LTE) phase (Figure 6). Stable doses of concomitant ITP medications (oral CS and / or TPO-RA treatment) were acceptable in both treatment arms, with dose reductions permitted. CS and / or TPO-RA administration should follow the product characteristics outlined in the corresponding current prescribing information and / or country-specific marketing authorization.

[0165] At the end of 12 weeks of treatment with rilzabrutinib 400 mg BID or placebo, patients are evaluated for achieving a platelet response, which is defined as an increase in platelet count meeting the platelet response criteria, or at least in the absence of rescue medication, of ≥50 × 10⁻¹⁰ 9 / L or ≥30×10 9 / L~<50×10 9 Platelet count is defined as a platelet count of / L and at least twice the platelet count from baseline (Figure 7). Baseline is defined as the mean of two eligible platelet counts at screening and the platelet count on day 1 prior to the first dose of rilzabrutinib or placebo. Responders then continue the blinded treatment period for an additional 12 weeks (24 weeks total) before entering the 28-week open-label period, while non-responders may discontinue the study or enter the 28-week open-label period at the end of week 12 while receiving rilzabrutinib 400 mg BID. Regardless of the selection of non-responders, the initial study dosing assignment remains blinded.

[0166] Patients will be evaluated for eligibility to enter the LTE at the end of the open-label period (i.e., after 28 weeks of treatment with rilzabrutinib 400 mg BID). After completing the open-label period, in ≥50% of patients who visited the hospital during the last 8 weeks of the open-label period without receiving rescue therapy during rilzabrutinib treatment, platelet count ≥50 × 10⁶ 9 / L or ≥30×10 9 Any participant who demonstrates a cerebrospinal response defined as a platelet count of ≥50 × 10¹⁶ / L and at least a doubling from baseline is permitted to enter the LTE. In the LTE part, platelet counts are measured over 12 weeks at three scheduled visits, with a platelet count of ≥50 × 10¹⁶ / L. 9 If the patient is in the / L group, reduction or discontinuation of concomitant CS and / or TPO-RA doses is permitted. Patients entering the LTE group will continue treatment until the time when the last participant entering the LTE group is expected to complete 12 months.

[0167] During the 24-week Phase 1 trial, the treatment will be double-blinded to the Principal Investigator / clinical trial team and the patient, in accordance with local regulations / policies, after consultation with the sponsor's medical monitor, unless deblinding is deemed medically necessary by the Principal Investigator. The Principal Investigator of the treatment trial is responsible for ensuring that the treatment is administered in accordance with the trial protocol. Patients may temporarily discontinue the trial due to a suspected adverse event or a local / national emergency declared by a government agency (e.g., a pandemic), and may resume treatment under the close supervision of the Principal Investigator of the trial if the continuing eligibility criteria are met, or withdraw from the trial due to a life-threatening or Grade 4 treatment-related adverse event, a severe allergic reaction, pregnancy, any medical condition / personal condition that the Principal Investigator believes poses a significant risk to the patient, human immunodeficiency or hepatitis B / C virus infection, a protocol violation that impairs data interpretation, or abnormal liver function tests.

[0168] Evaluation items and evaluation The primary endpoint of this trial was a sustained platelet response, (1) ≥50 × 10⁶ for at least two-thirds of the ≥8 available weekly scheduled platelet measurements during the last 12 weeks of a 24-week blinded treatment period in the absence of rescue therapy. 9 Achieving a platelet count of / L, with ≥2 available weekly scheduled platelet measurements ≥50 × 10 during the last 6 weeks of a 24-week blinded treatment period. 9 (1) The condition is that / L, or (2) ≥8 of 12 scheduled observations during the last 12 weeks of a 24-week double-blind treatment period in the absence of rescue therapy, with ≥50 × 10 9 The primary secondary efficacy endpoint is defined as achieving a platelet count of 50 × 10¹⁶ / L (EU and UK) (Table 2). The primary secondary efficacy endpoint is a platelet count ≥ 50 × 10¹⁶ during a 24-week blinded treatment period in the absence of rescue medication. 9 / L or ≥30×10 9 / L~<50×10 9 Weeks with platelet counts of / L and at least double the baseline, and ≥30 × 10 during a 24-week blinded treatment period in the absence of rescue medication. 9 / L and the number of weeks in which the platelet count has at least doubled from baseline, ≥ 50 × 10 9 / L or ≥30×10 9 / L~<50×10 9 The metrics included time to the first doubling of platelet counts / L and baseline, the proportion of patients requiring rescue therapy during a 24-week blinded treatment period, and the change from baseline in the physical fatigue score of the ITP Patient Assessment Questionnaire (ITP-PAQ) in adult patients (≥18 years) at week 13 of treatment.

[0169] [Table 4]

[0170] [Table 5]

[0171] [Table 6]

[0172] [Table 7]

[0173] [Table 8]

[0174] [Table 9]

[0175] [Table 10]

[0176] Secondary safety endpoints include the assessment of the frequency and severity of adverse and bleeding events occurring during treatment. Safety will be assessed by the incidence, severity, and causal relationship of adverse events occurring during treatment, including clinically significant changes in physical examination, vital signs, electrocardiogram, and laboratory parameters. The severity of adverse events will be assessed based on the revised Common Terminology Criteria for Adverse Events version 5.0. Additional endpoints are detailed in Table 2.

[0177] Disease-specific assessment tools include the Idiopathic Thrombocytopenic Purpura Bleeding Scale (IBLS), a bleeding assessment including 11 site-specific grades evaluated historically at nine anatomical sites over the period prior to hospital visit; the ITP-PAQ®, a disease-specific scale designed to measure the quality of life of adult patients with ITP; and the ITP Kids' ITP Tool (ITP-KIT), an assessment based on a combination of three disease-specific scales and self-report assessments specifically designed for pediatric patients with ITP (Mathias et al. 2007, Mathias et al. 2016, Page et al. 2007). General health-related quality of life is assessed using the EuroQol-EQ-5D-5L scale, a patient's overall impression scale regarding severity (general, fatigue, and change). These assessments will be conducted every four weeks during the blinded and open-label periods. For the first year of the LTE, they will be conducted every 28 days, and thereafter every three months.

[0178] Statistical considerations All randomized patients were included in the intention-to-treat population, and all randomized patients exposed to ≥1 dose of the study drug were included in the safety population. The primary response endpoint was evaluated between the two arms using the Cochrane-Mantel-Henzel test. An adult sample size of approximately 194 was selected to achieve >85% power to detect a 20% difference in response rates (e.g., 25% in the rilzabrutinib arm vs. 5% in the placebo arm), with approximately 129 adult patients (≥18 years) in the rilzabrutinib arm and 65 in the placebo arm. A pediatric sample size of 30 patients (20 in the rilzabrutinib arm and 10 in the placebo arm) was determined based on clinical practice and disease experience to adequately account for safety and efficacy in patients with ITP.

[0179] Data monitoring, collection, auditing, and control plans are detailed in the trial protocol to ensure data quality. To ensure patient safety, the principal investigator of the trial will proactively follow each patient and promptly notify the sponsor of any adverse events, and an independent data safety monitoring committee will periodically review and evaluate safety data for unblinded patients. No formal interim analysis is planned for the double-blind portion of the trial, and the final analysis will be completed at the end of the trial. Additional analyses of the open-label and long-term extension portions may be conducted at the discretion of the sponsor.

[0180] Example 2: Basic characteristics of adult patients with previously treated immunothrombocytopenia enrolled in the LUNA3 Phase 3 placebo-controlled trial of rilzabrutinib. The purpose of this trial was to investigate the basic patient characteristics of adult patients in the LUNA3 trial.

[0181] Eligible patients are those who have had primary ITP for a period of >3 months in adults (≥18 years) and >6 months in adolescents (12–17 years) and pediatric patients (10–12 years, EU only), and whose two mean platelet counts within 2 weeks prior to treatment are <30 × 10⁶ 9The result was / L (Kuter et al. 2023). The patient had a past unsustained response to corticosteroids (CS) or intravenous immunoglobulin (IVIg) / anti-D (platelet count ≥ 50 × 10 9 The patient had either / L) or had documented intolerance or an inadequate response to any appropriate assumption of standard ITP therapy.

[0182] Patients were assessed based on their splenectomy status (yes / no) and the severity of their thrombocytopenia (platelet count < 15 × 10 9 / L or ≥15×10 9 Participants were stratified by / L) and then randomized in a 2:1 ratio to receive oral rilzabrutinib 400 mg BID or placebo for up to 24 weeks (double-blind period), followed by 28 weeks of open-label treatment, followed by 4 weeks of safety follow-up, or continued long-term treatment if eligible. After the first 12 weeks, non-responders could either directly participate in the open-label part or discontinue the study.

[0183] Concurrent stable baseline doses of CS and / or thrombopoietin receptor agonists (TPO-RAs) were acceptable. Patients who received rescue medication were permitted to continue the study treatment. The primary endpoint was ≥50 × 10 for ≥8 of the available weekly measurements in two-thirds of the last 12 weeks of the 24-week blinded treatment period in the absence of rescue therapy. 9 / L platelet count (≥50 × 10 at least two times within the last 6 weeks) 9 This was a sustained platelet response, defined as achieving (including / L).

[0184] result Overall, as of September 28, 2023, 202 adults with a median age of 47 years (range, 18–80 years) were enrolled from 154 study sites (see Table 3). Enrollment for adults is complete, and enrollment for children is ongoing. The majority of adults were female (63%), Caucasian (62%) or Asian (32%), and not Hispanic / Latino (77%). Geographical regions from which patients were enrolled included Asia / Pacific (35%), Western Europe (24%), South America (17%), Eastern Europe (16%), and North America (8%). Patients had ITP for a median period of 7.7 years, and 75% had a period of >3 years. The median baseline platelet count was 15 × 10⁶. 9 / L, and 48% of patients had a baseline platelet count <15 × 10⁶ 9 The patient had / L. Overall, the patients had a median of 4 (range: 1-17) prior ITP therapies, 73% had ≥3 prior ITP therapies, and 28% had undergone prior splenectomy. The most common prior ITP therapies were CS (96%), TPO-RA (66%), and IVIg (53%), and the patients' prior responses are shown in Table 3.

[0185] [Table 11]

[0186] [Table 12]

[0187] Example 3: Results of a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study with open-label duration to evaluate the efficacy and safety of oral rilzabrutinib (PRN1008) in adults, adolescents, and children with persistent or chronic immune thrombocytopenia (ITP) (LUNA3). Over a 24-week double-blind period, a total of N=202 adults received treatment with 400 mg BID of rilzabrutinib (N=133) or placebo (N=69). The primary endpoint of this study was the percentage of patients achieving a sustained response, with (1) having ≥50 × 10⁶ of at least two-thirds of the ≥8 available weekly scheduled platelet measurements during the last 12 weeks of the 24-week blinded treatment period in the absence of rescue therapy (e.g., 8 out of 12 or 6 out of 9). 9 (2) Achieving a platelet count of 50,000 / μL and having at least two available weekly scheduled platelet measurements of 50,000 / μL or higher during the last six weeks of a 24-week blinded treatment period, or (2) having ≥50 × 10 in ≥8 of 12 scheduled observations during the last 12 weeks of a 24-week double-blind treatment period in the absence of rescue therapy. 9 This is defined as achieving a platelet count of 50 × 10¹⁶ / L (EU and UK) (see Table 2). The primary secondary endpoint is a platelet count ≥ 50 × 10¹⁶ during a 24-week blinded treatment period in the absence of rescue medication. 9 Number of weeks with / L or ≥30 × 10 9 / L~<50×10 9 / L and the number of weeks in which the platelet count has at least doubled from baseline, ≥ 50 × 10 9 Time to the first platelet count of / L or ≥30 × 10 9 / L~<50×10 9 This included time to the first doubling of platelet counts / L and baseline, the proportion of patients requiring rescue therapy during a 24-week blinded treatment period, the change from baseline in ITP-PAQ® physical fatigue score in adult patients (≥18 years) at week 13 of treatment, and the change from baseline in IBLS assessment at week 25 (EU and UK only) (see Table 2).

[0188] This trial met its primary efficacy endpoint. Patients treated with ilzabrutinib experienced a statistically superior sustained platelet response compared to those treated with placebo. While none of the placebo-treated patients achieved a platelet response, 23% of patients in the ilzabrutinib arm achieved a sustained platelet response (p<0.0001; see Table 4 and Figure 8).

[0189] [Table 13]

[0190] This study also met its primary secondary efficacy endpoint. Rilzabrutinib treatment resulted in a greater number of weeks of platelet response during the double-blind treatment period, with rilzabrutinib-treated patients having a platelet count of ≥50 × 10¹⁶ compared to placebo-treated patients (<1 week). 9 Patients experienced a platelet count of ≥30 × 10¹⁰ / L for an average of 7 weeks (p<0.0001), and compared to placebo-treated patients <1, platelet counts were ≥30 × 10¹⁰. 9 / L~<50×10 9 We observed platelet counts that were at least double the baseline level ( / L) on average over 7 weeks (p<0.0001; see Table 5 and Figure 9).

[0191] In addition, the initial platelet count ≥ 50 × 10 9 Time to / L or initial platelet count ≥ 30 × 10 9 / L~<50×10 9 The time to platelet count / L and at least a doubling of baseline was significantly shorter in the rilzabrutinib arm than in the placebo arm. In the rilzabrutinib arm, 25% of participants achieved a platelet response by day 10, compared to 50% of participants by day 36 (median time to response). This median was not achieved in the placebo arm. Notably, participants in the rilzabrutinib arm were 3.1 times more likely to experience a platelet response compared to participants in the placebo arm (hazard ratio 3.1, p<0.0001, see Table 6 and Figure 10).

[0192] Overall, a lower proportion of participants in the rilzabrutinib arm was associated with a greater need for rescue therapy over the 24-week double-blind period, and rilzabrutinib was significantly associated with a 52% reduction in the need for rescue therapy (hazard ratio 0.48, p=0.0007; see Table 7 and Figure 11). Furthermore, the time to rescue therapy was significantly longer in the rilzabrutinib group than in the placebo group. By day 16, 25% of participants in the placebo group had received rescue therapy. The median time to rescue therapy in the placebo group was 56 days, but participants in the rilzabrutinib arm did not reach this median.

[0193] Patients treated with rilzabrutinib also experienced improvements in their ITP-PAQ® physical fatigue scores. Compared to patients receiving placebo, those receiving rilzabrutinib showed a significant improvement in fatigue at week 13 (see Table 8 and Figure 12). Furthermore, a numerically greater treatment effect on fatigue was observed at week 25 compared to week 13 (Figure 13).

[0194] Finally, ilzabrutinib treatment was associated with a significant reduction in bleeding, as assessed by IBLS at week 25. Patients treated with 400 mg BID of ilzabrutinib had a mean change in LS (SE) of -0.040 (0.0169) from baseline, while patients treated with placebo experienced a mean change in LS (SE) of 0.047 (0.0226) (p=0.0006, see Table 9 and Figure 14).

[0195] [Table 14]

[0196] [Table 15]

[0197] [Table 16]

[0198] [Table 17]

[0199] [Table 18]

[0200] Rilzabrutinib 400 mg BID was generally well-tolerated in adult patients with ITP. Similar proportions of participants in both the placebo and ilzabrutinib arm experienced TEAEs (including TEAE ≥ G3) and SAEs. In the ilzabrutinib arm, the most frequent TEAEs were diarrhea (32.3%), nausea (20.3%), and headache (18%).

[0201] Embodiment Non-limiting embodiments of this disclosure include: 1. A method for treating immune thrombocytopenia (ITP) in a human patient having persistent or chronic ITP who requires such treatment, comprising administering to the human patient twice daily for a treatment period an effective dose of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts, wherein the human patient requiring such treatment has been identified to have or has an initial platelet count of <30,000 / μL without a single platelet count of >35,000 / μL in the two weeks prior to the treatment period, and further, the human patient, a. Previous unsustained response to one or more IVIg, anti-D, or CS. b. Documented intolerance or inadequate response to any appropriate course of standard ITP therapy, and c. Contraindications to any appropriate course of standard ITP therapy A method having or identified as having at least one feature selected from the following. 2. The method according to Embodiment 1, wherein a human patient has or has been identified as having an initial platelet count of <15,000 / μL. 3. The method according to Embodiment 1, wherein a human patient has or has been identified to have an initial platelet count of ≥15,000 / μL. 4. A method according to any one of Embodiments 1 to 3, wherein a human patient achieves a platelet response. 5. A method according to any one of Embodiments 1 to 4, wherein a human patient achieves a sustained platelet response. 6. The method according to any one of embodiments 1 to 5, wherein a human patient achieves a complete platelet response. 7. The method according to any one of embodiments 1 to 6, wherein a human patient achieves a stable platelet response. 8. The method according to any one of Embodiments 1 to 7, wherein the human patient has a platelet count of ≥30,000 / μL at least once during the treatment period. 9. The method according to any one of Embodiments 1 to 8, wherein the human patient has at least one instance during the treatment period of a platelet count of ≥30,000 / μL and at least twice the baseline platelet count. 10. The method according to any one of Embodiments 1 to 9, wherein a human patient has at least one instance of a platelet count of ≥30,000 / μL and at least twice the baseline platelet count during the treatment period, in the absence of rescue medication. 11. The method according to any one of Embodiments 1 to 10, wherein the human patient has at least one instance of platelet count ≥30,000 / μL and at least twice the baseline platelet count during a 24-week treatment period. 12. The method according to any one of Embodiments 1 to 11, wherein a human patient has at least one platelet count of ≥30,000 / μL and at least twice the baseline platelet count after a 6-month treatment period. 13. The method according to any one of Embodiments 1 to 12, wherein the human patient has at least one instance of a platelet count of ≥50,000 / μL during the treatment period. 14. The method according to any one of claims 1 to 13, wherein a human patient has at least one instance of a platelet count of ≥50,000 / μL during the treatment period in the absence of a rescue drug. 15. The method according to any one of Embodiments 1 to 14, wherein a human patient has a platelet count of ≥50,000 / μL for at least two consecutive times during the treatment period in the absence of rescue medication, with platelet counts separated by ≥5 days. 16. Human patients had a platelet count of ≥50,000 / μL for at least two-thirds of the available weekly platelet counts for at least eight times during the last 12 weeks of the 24-week treatment period, and further, a. At least two available weekly platelet counts were ≥50,000 / μL during the last 6 weeks of the 24-week treatment period, and b. The method according to any one of embodiments 1 to 15, wherein the human patient does not require rescue medication. 17. The method according to any one of Embodiments 1 to 16, wherein a human patient has a platelet count of ≥50,000 / μL for at least 8 times during the last 12 weeks of a 24-week treatment period, and furthermore, the patient does not require rescue medication. 18. The method according to any one of Embodiments 1 to 17, wherein the human patient does not have a platelet count of ≤50,000 / μL for two consecutive periods, and the platelet count occurs at least 4 weeks apart within a 24-week period, following at least one platelet count of ≥50,000 / μL within 12 weeks of initiation of rilzabrutinib treatment. 19. The method according to any one of Embodiments 1 to 18, wherein a human patient has a platelet count of ≥50,000 for four weeks during the last eight weeks of a 24-week treatment period. 20. The method according to any one of Embodiments 1 to 19, wherein a human patient has a platelet count of ≥50,000 / μL in ≥4 of 6 bi-weekly platelet counts during weeks 14 to 24 of a 24-week treatment period. 21. Human patients had a platelet count of ≥50,000 for ≥10 weekly platelet counts for ≥2 / 3 of the available weekly platelet counts during the last 16 weeks of a 53-week treatment period, and further, a. At least three available weekly platelet measurements are ≥50,000 / μL during the last 8 weeks of the 53-week treatment period, and b. The human patient does not require a rescue drug, the method according to any one of Embodiments 1 to 20. 22. The human patient, during a 24-week treatment period, in the absence of a rescue drug, a. has at least one platelet count of ≥50,000 / μL, or b. has at least one platelet count of ≥30,000 / μL to <50,000 / μL and at least twice the baseline platelet count, the method according to any one of Embodiments 1 to 21. 23. The human patient has at least one platelet count of ≥100,000 / μL during the treatment period, and at least one platelet count occurs when there is no bleeding, the method according to any one of Embodiments 1 to 22. 24. The human patient has at least two consecutive platelet counts ≥100,000 / μL at least 5 days apart during the treatment period, in the absence of a rescue drug, the method according to any one of Embodiments 1 to 23. 25. The human patient has at least one platelet count of ≥250,000 / μL during the treatment period, the method according to any one of Embodiments 1 to 24. 26. The human patient has at least one platelet count of ≥450,000 / μL during the treatment period, the method according to any one of Embodiments 1 to 25. 27. The human patient has at least one platelet count in the range of 30,000 / μL to 100,000 / μL during the treatment period, and at least one platelet count is at least twice the baseline platelet count and occurs when there is no bleeding, the method according to any one of Embodiments 1 to 5. 28. The human patient has at least one platelet count in the range of ≥30,000 / μL to <50,000 / μL and at least twice the baseline platelet count during the treatment period, the method according to any one of Embodiments 1 to 7 or 27. 29. The method according to any one of Embodiments 1 to 28, wherein a human patient receives combination therapy with TPO-RA. 30. The method according to any one of Embodiments 1 to 29, wherein a human patient receives combination therapy with at least one TPO-RA selected from rTPO, romiplostim, eltrombopag, and avathrombopag. 31. The method according to any one of Embodiments 1 to 30, wherein a human patient has or has been identified to have a history of response to at least one prior line of treatment, the at least one prior therapy being selected from splenectomy, rituximab, TPO-RA, intravenous immunoglobulin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressants. 32. The method according to any one of claims 1 to 31, wherein the human patient does not require rescue medication during the treatment period. 33. The method according to any one of Embodiments 1 to 32, wherein the human patient has undergone or is identified to have undergone a splenectomy prior to the start of the treatment period. 34. The method according to any one of Embodiments 1 to 33, wherein the human patient has a history of taking rituximab prior to the start of the treatment period or has been identified as having a history of taking rituximab. 35. The method according to any one of Embodiments 1 to 33, wherein the human patient has not received prior treatment with rituximab. 36. The method according to any one of Embodiments 1 to 35, wherein the human patient has a history of taking or has been identified as having taken at least one TPO-RA prior to the start of the treatment period. 37. The method according to any one of Embodiments 1 to 36, wherein a human patient has a history of taking or has been identified as having a history of taking at least one TPO-RA selected from rTPO, romiplostim, eltrombopag, and avathrombopag prior to the start of the treatment period. 38. The method according to any one of Embodiments 1 to 35, wherein the human patient has not received prior treatment with one or more TPO-RAs. 39. The method according to any one of Embodiments 1 to 38, wherein the human patient has a history of taking intravenous immunoglobulin (IVIG) prior to the start of the treatment period, or has been identified as having a history of taking it. 40. The method according to any one of Embodiments 1 to 39, wherein the human patient has a history of taking or has been identified as having taken at least one corticosteroid prior to the start of the treatment period. 41. The method according to any one of Embodiments 1 to 40, wherein a human patient has a history of taking or has been identified as having taken at least one corticosteroid selected from dexamethasone or oral prednisone / prednisolone prior to the start of the treatment period. 42. The method according to any one of Embodiments 1 to 41, wherein the human patient is identified as having a history of receiving or having received anti-D immunoglobulin therapy prior to the commencement of the treatment period. 43. The method according to any one of Embodiments 1 to 42, wherein the human patient has a history of taking or has been identified as having taken at least one immunosuppressant drug prior to the start of the treatment period. 44. The method according to any one of Embodiments 1 to 43, wherein a human patient has a history of taking or has been identified as having taken at least one immunosuppressant selected from fostamatinib, mycophenolate mofetil (MMF), and cyclosporine prior to the start of the treatment period. 45. The method according to any one of Embodiments 1 to 44, wherein a human patient has responded to or has been identified as responding to prior ITP therapy. 46. ​​The method according to any one of Embodiments 1 to 45, wherein the response to previous ITP therapy included a platelet count of <50,000 / μL. 47. The method according to any one of Embodiments 1 to 46, wherein the response to previous ITP therapy was not sustained. 48. The method according to any one of Embodiments 1 to 47, wherein the patient has or has been identified as having a documented intolerance to standard treatment ITP therapy. 49. The method according to any one of Embodiments 1 to 48, wherein the patient has or has been identified as having a contraindication to standard ITP therapy. 50. The method according to any one of Embodiments 1 to 49, wherein a human patient has primary ITP. 51. The method according to any one of Embodiments 1 to 50, wherein the human patient is ≥18 years of age. 52. The method according to any one of Embodiments 1 to 50, wherein the human patient is <18 years of age. 53. The method according to any one of Embodiments 1 to 52, wherein a human patient has or has been identified as having ITP for a period of >1 year. 54. The method according to any one of embodiments 1 to 52, wherein the human patient does not have chronic ITP. 55. A human patient having persistent ITP, according to any one of Embodiments 1 to 52. 56. The method according to any one of embodiments 1 to 52, wherein a human patient has chronic ITP. 57. The method according to any one of embodiments 1 to 52, wherein a human patient has recurrent ITP. 58. The method according to any one of Embodiments 1 to 52, wherein a human patient has refractory ITP. 59. The method according to any one of Embodiments 1 to 58, wherein the treatment period is at least 168 days. 60. The method according to any one of Embodiments 1 to 59, wherein the treatment period is at least 364 days. 61. The method according to any one of Embodiments 1 to 60, wherein the treatment period is at least 392 days. 62. The method according to any one of embodiments 1 to 61, wherein the treatment period is at least 728 days. The method according to any one of Embodiments 1 to 62, comprising administering 63,400 mg of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and pharmaceutically acceptable salts thereof to a human patient twice daily. 64. The method according to any one of Embodiments 1 to 63, wherein at least one compound is selected from the (E) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts. 65. The method according to any one of Embodiments 1 to 63, wherein at least one compound is selected from the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts. 66. The method according to any one of Embodiments 1 to 63, wherein at least one compound comprises a mixture of the (E) isomer and the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile or a pharmaceutically acceptable salt thereof. 67. The method according to any one of Embodiments 1 to 60, comprising administering 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile to a human patient twice daily. 68. The method according to any one of Embodiments 1 to 62 or 67, wherein at least one compound is an (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile. 69. The method according to any one of Embodiments 1 to 62 or 67, wherein at least one compound is a (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile. 70. The method according to any one of Embodiments 1 to 62 or 67, wherein at least one compound comprises a mixture of the (E) isomer and the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile. 71. The method according to any one of Embodiments 1 to 70, wherein at least one compound is administered orally to a human patient. 72. The method according to any one of Embodiments 1 to 71, wherein at least one compound is administered to a human patient in the form of at least one tablet. 73. The method according to any one of Embodiments 1 to 72, wherein at least one compound is administered with water. 74. The method according to any one of Embodiments 1-50 or 52-73, wherein the patient is 10 to <18 years of age. 75. The method according to any one of Embodiments 1-50 or 52-74, wherein the patient is 12 to <18 years of age. 76. The method according to any one of Embodiments 1-50 or 52-74, wherein the patient is 10 to <12 years of age. 77. The method according to any one of embodiments 1 to 76, wherein the patient experiences a reduction in fatigue. 78. The method according to any one of Embodiments 1 to 77, wherein a human patient experiences fatigue reduction as determined using the ITP Patient Assessment Questionnaire (ITP-PAQ) (ITP-PAQ). 79. The method according to any one of Embodiments 1 to 78, wherein a human patient experiences fatigue reduction as determined using ITP Kids' ITP Tool (ITP-KIT). 80. The method according to any one of Embodiments 1 to 79, wherein a human patient experiences a change from baseline in IBLS at weeks 13 and 15 of the treatment period. 81. The method according to any one of Embodiments 1 to 80, wherein a human patient experiences a change from baseline in IBLS at 25 weeks of the treatment period. 82. The method according to any one of Embodiments 1 to 81, wherein a human patient experiences an improvement in quality of life. 83. The method according to any one of Embodiments 1 to 82, wherein a human patient experiences an improvement in quality of life as determined by ITP-KIT. 84. The method according to any one of Embodiments 1 to 83, wherein a human patient experiences a change from baseline in the following items: symptoms of ITP-PAQ®, physical health discomfort, activity, fatigue / sleep, psychological health, fear, social activity, female reproductive health, and work. 85. The method according to any one of claims 1 to 84, wherein human patients experience less frequent or milder bleeding than human patients administered a therapeutically effective dose of another BTK inhibitor. 86. The method according to Embodiment 1, wherein a human patient has been identified as refractory to or has been refractory to at least one prior line of treatment, e.g., at least two, e.g., at least three, e.g., at least four, e.g., at least five, e.g., at least six, e.g., at least seven, e.g., at least eight, e.g., at least nine, e.g., at least ten, e.g., at least eleven, e.g., at least twelfth, e.g., at least thirteenth, e.g., at least fourteenth, e.g., at least fifteenth, e.g., at least sixteenth, e.g., at least seventeenth prior line of treatment. 87. A method for treating immune thrombocytopenia (ITP) in a human patient having persistent or chronic ITP who requires such treatment, comprising administering to the human patient twice daily for a duration of treatment an effective dose of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts, wherein the human patient has or has been identified as having an inadequate response to or intolerance to one or more prior treatments. 88. Use of a therapeutically effective dose of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts for the treatment of immune thrombocytopenia (ITP) in human patients with persistent or chronic ITP who require such treatment. For use as a medicament for treating immune thrombocytopenia (ITP) in human patients with persistent or chronic ITP who require it, at a therapeutically effective amount, at least one compound selected 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]penta-2-enenitrile and its pharmaceutically acceptable salts. For use in treating immune thrombocytopenia (ITP) in human patients with persistent or chronic ITP who require it, at a therapeutically effective amount, at least one compound selected 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]penta-2-enenitrile and its pharmaceutically acceptable salts. Use of at least one compound selected 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]penta-2-enenitrile and its pharmaceutically acceptable salts, at a therapeutically effective amount, as a medicament for treating immune thrombocytopenia (ITP) in human patients with persistent or chronic ITP who require it.

[0202] Any claim or description containing "or" or "and / or" among at least one member of a group is considered satisfied unless otherwise stated or the context makes other meanings clear, if one, two or more, or all of the members of the group are present in, used in, or otherwise related to a given product or process. This disclosure includes embodiments in which one member of the group is present in, used in, or otherwise related to a given product or process. This disclosure includes embodiments in which two or more, or all, members of the group are present in, used in, or otherwise related to a given product or process.

[0203] Where a range is indicated, it includes the endpoints. Furthermore, unless otherwise stated or unless the context and the understanding of those skilled in the art make it clear, a value expressed as a range may take any specific value or subrange within the ranges described in different embodiments of this disclosure, up to one-tenth of the lower limit of that range, unless the context clearly indicates otherwise.

[0204] The foregoing disclosure is described in some detail as examples and illustrations for clarity and understanding. Therefore, it should be understood that the foregoing description is intended as an illustration and not as an limitation. Accordingly, the scope of the foregoing disclosure should not be determined by reference to the foregoing description, but rather by reference to the attached claims, along with the entire scope of equivalents to which such claims are granted.

Claims

1. A method for treating immune thrombocytopenia (ITP) in a human patient having persistent or chronic ITP who requires such treatment, comprising administering to the human patient a therapeutically effective dose of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts twice daily for a period of treatment, wherein the human patient having such treatment had an initial platelet count of <30,000 / μL without a single platelet count of >35,000 / μL in the two weeks prior to the period of treatment, and further, the human patient a. Previous unsustained response to one or more IVIg, anti-D, or CS. b. Documented intolerance or inadequate response to any appropriate course of standard ITP therapy, and c. Contraindications to any appropriate course of standard ITP therapy A method having at least one feature selected from.

2. The method according to claim 1, wherein the human patient has an initial platelet count of <15,000 / μL.

3. The method according to claim 1, wherein the human patient has an initial platelet count of ≥ 15,000 / μL.

4. The method according to any one of claims 1 to 3, wherein the human patient achieves a platelet response.

5. The method according to any one of claims 1 to 4, wherein the human patient achieves a sustained platelet response.

6. The method according to any one of claims 1 to 5, wherein the human patient achieves a complete platelet response.

7. The method according to any one of claims 1 to 6, wherein the human patient achieves a stable platelet response.

8. The method according to any one of claims 1 to 7, wherein the human patient has at least one instance of a platelet count of ≥30,000 / μL during the treatment period.

9. The method according to any one of claims 1 to 8, wherein the human patient has at least one instance during the treatment period in which the platelet count is ≥30,000 / μL and at least twice the baseline platelet count.

10. The method according to any one of claims 1 to 9, wherein the human patient, during the treatment period, in the absence of a rescue drug, has at least one instance of a platelet count of ≥30,000 / μL and at least twice the baseline platelet count.

11. The method according to any one of claims 1 to 10, wherein the human patient has at least one instance during a 24-week treatment period of platelets ≥ 30,000 / μL and at least twice the baseline platelet count.

12. The method according to any one of claims 1 to 11, wherein the human patient has at least one instance of platelet count ≥30,000 / μL and at least twice the baseline platelet count after a treatment period of 6 months.

13. The method according to any one of claims 1 to 12, wherein the human patient has at least one instance of a platelet count of ≥50,000 / μL during the treatment period.

14. The method according to any one of claims 1 to 13, wherein the human patient has at least one instance of a platelet count of ≥50,000 / μL in the absence of a rescue drug during the treatment period.

15. The method according to any one of claims 1 to 14, wherein the human patient has a platelet count of ≥50,000 / μL for at least two consecutive times during the treatment period in the absence of a rescue drug, and the platelet counts are separated by ≥5 days.

16. The aforementioned human patient had a platelet count of ≥50,000 / μL for at least two-thirds of the available weekly platelet counts for at least eight times during the last 12 weeks of the 24-week treatment period, and further, a. At least two available weekly platelet counts were ≥50,000 / μL during the last six weeks of the 24-week treatment period, and b. The method according to any one of claims 1 to 15, wherein the human patient does not require rescue medication.

17. The method according to any one of claims 1 to 16, wherein the human patient has a platelet count of ≥50,000 / μL for at least eight platelet counts during the last 12 weeks of a 24-week treatment period, and furthermore, the patient does not require rescue medication.

18. The method according to any one of claims 1 to 17, wherein the human patient does not have a platelet count of ≤50,000 / μL for two consecutive periods, and the platelet count occurs at least 4 weeks apart within a 24-week period, following at least one platelet count of ≥50,000 / μL within 12 weeks of initiation of rilzabrutinib treatment.

19. The method according to any one of claims 1 to 18, wherein the human patient has a platelet count of ≥ 50,000 for four weeks of the last eight weeks of a 24-week treatment period.

20. The method according to any one of claims 1 to 19, wherein the human patient has a platelet count of ≥50,000 / μL in ≥4 of 6 bi-weekly platelet counts during weeks 14 to 24 of a 24-week treatment period.

21. The aforementioned human patient had a platelet count of ≥50,000 for ≥10 of the available weekly platelet counts during the last 16 weeks of the 53-week treatment period, and further, a. At least three available weekly platelet counts were ≥ 50,000 / μL during the last eight weeks of the 53-week treatment period, and b. The method according to any one of claims 1 to 20, wherein the human patient does not require rescue medication.

22. The aforementioned human patient, during the 24-week treatment period, in the absence of rescue medication, a. At least one instance of a platelet count of ≥50,000 / μL, or b. At least one instance of platelet count ≥30,000 / μL to <50,000 / μL and at least twice the baseline platelet count. The method according to any one of claims 1 to 21, comprising:

23. The method according to any one of claims 1 to 22, wherein the human patient has at least one instance of a platelet count of ≥100,000 / μL during the treatment period, and the at least one instance of a platelet count occurs when there is no bleeding.

24. The method according to any one of claims 1 to 23, wherein the human patient has, during the treatment period, in the absence of a rescue drug, at least two consecutive platelet counts of ≥100,000 / μL, separated by ≥5 days.

25. The method according to any one of claims 1 to 24, wherein the human patient has at least one instance of a platelet count of ≥250,000 / μL during the treatment period.

26. The method according to any one of claims 1 to 25, wherein the human patient has at least one instance of a platelet count of ≥450,000 / μL during the treatment period.

27. The method according to any one of claims 1 to 5, wherein the human patient has at least one instance of a platelet count in the range of 30,000 / μL to 100,000 / μL during the treatment period, the at least one instance of platelet count being at least twice the baseline platelet count, and occurring in the absence of bleeding.

28. The method according to any one of claims 1 to 7 or 27, wherein the human patient has at least one instance during the treatment period of platelets in the range of ≥30,000 / μL to <50,000 / μL and at least twice the baseline platelet count.

29. The method according to any one of claims 1 to 28, wherein the human patient receives treatment in combination with TPO-RA.

30. The method according to any one of claims 1 to 29, wherein the human patient receives combination therapy with at least one TPO-RA selected from rTPO, romiplostim, eltrombopag, and avathrombopag.

31. The method according to any one of claims 1 to 30, wherein the human patient has a history of response to at least one prior line of treatment, and at least one prior therapy is selected from splenectomy, rituximab, TPO-RA, intravenous immunoglobulin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressants.

32. The method according to any one of claims 1 to 31, wherein the human patient does not require a rescue drug during the treatment period.

33. The method according to any one of claims 1 to 32, wherein the human patient has undergone splenectomy before the start of the treatment period.

34. The method according to any one of claims 1 to 33, wherein the human patient has a history of taking rituximab prior to the commencement of the treatment period.

35. The method according to any one of claims 1 to 33, wherein the human patient has not received prior treatment with rituximab.

36. The method according to any one of claims 1 to 35, wherein the human patient has a history of taking at least one TPO-RA before the start of the treatment period.

37. The method according to any one of claims 1 to 36, wherein the human patient has a history of taking at least one TPO-RA selected from rTPO, romiplostim, eltrombopag, and avathrombopag prior to the commencement of the treatment period.

38. The method according to any one of claims 1 to 35, wherein the human patient has not received prior treatment with one or more TPO-RAs.

39. The method according to any one of claims 1 to 38, wherein the human patient has a history of taking intravenous immunoglobulin (IVIG) prior to the commencement of the treatment period.

40. The method according to any one of claims 1 to 39, wherein the human patient has a history of taking at least one corticosteroid prior to the commencement of the treatment period.

41. The method according to any one of claims 1 to 40, wherein the human patient has a history of taking at least one corticosteroid selected from dexamethasone or oral prednisone / prednisolone prior to the commencement of the treatment period.

42. The method according to any one of claims 1 to 41, wherein the human patient has a history of receiving anti-D immunoglobulin therapy prior to the commencement of the treatment period.

43. The method according to any one of claims 1 to 42, wherein the human patient has a history of taking at least one immunosuppressant drug prior to the commencement of the treatment period.

44. The method according to any one of claims 1 to 43, wherein the human patient has a history of taking at least one immunosuppressant selected from fostamatinib, mycophenolate mofetil (MMF), and cyclosporine prior to the commencement of the treatment period.

45. The method according to any one of claims 1 to 44, wherein the human patient had a response to the prior ITP therapy.

46. The method according to any one of claims 1 to 45, wherein the response to the aforementioned prior ITP therapy included a platelet count of <50,000 / μL.

47. The method according to any one of claims 1 to 46, wherein the response to the aforementioned prior ITP therapy was not sustained.

48. The method according to any one of claims 1 to 47, wherein the patient has a documented intolerance to standard ITP therapy.

49. The method according to any one of claims 1 to 48, wherein the patient has a contraindication to standard ITP therapy.

50. The method according to any one of claims 1 to 49, wherein the human patient has primary ITP.

51. The method according to any one of claims 1 to 50, wherein the human patient is ≥ 18 years old.

52. The method according to any one of claims 1 to 50, wherein the human patient is <18 years of age.

53. The method according to any one of claims 1 to 52, wherein the human patient has ITP for a period of >1 year.

54. The method according to any one of claims 1 to 52, wherein the human patient does not have chronic ITP.

55. The method according to any one of claims 1 to 52, wherein the human patient has persistent ITP.

56. The method according to any one of claims 1 to 52, wherein the human patient has chronic ITP.

57. The method according to any one of claims 1 to 52, wherein the human patient has recurrent ITP.

58. The method according to any one of claims 1 to 52, wherein the human patient has refractory ITP.

59. The method according to any one of claims 1 to 58, wherein the treatment period is at least 168 days.

60. The method according to any one of claims 1 to 59, wherein the treatment period is at least 364 days.

61. The method according to any one of claims 1 to 60, wherein the treatment period is at least 392 days.

62. The method according to any one of claims 1 to 61, wherein the treatment period is at least 728 days.

63. The method according to any one of claims 1 to 62, comprising administering to the human patient 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and pharmaceutically acceptable salts thereof twice daily.

64. The method according to any one of claims 1 to 63, wherein the at least one compound comprises at least one compound selected from the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and pharmaceutically acceptable salts thereof.

65. The method according to any one of claims 1 to 63, wherein the at least one compound comprises at least one compound selected from the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and pharmaceutically acceptable salts thereof.

66. The method according to any one of claims 1 to 63, wherein the at least one compound comprises a mixture of the (E) isomer and the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile or a pharmaceutically acceptable salt thereof.

67. The method according to any one of claims 1 to 60, comprising administering 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile to the human patient twice daily.

68. The method according to any one of claims 1 to 62 or 67, wherein the at least one compound is an (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile.

69. The method according to any one of claims 1 to 62 or 67, wherein the at least one compound is a (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile.

70. The method according to any one of claims 1 to 62 or 67, wherein the at least one compound comprises a mixture of the (E) isomer and the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile.

71. The method according to any one of claims 1 to 70, wherein the at least one compound is administered orally to the human patient.

72. The method according to any one of claims 1 to 71, wherein the at least one compound is administered to the human patient in the form of at least one tablet.

73. The method according to any one of claims 1 to 72, wherein the at least one compound is administered together with water.

74. The method according to any one of claims 1 to 50 or 52 to 73, wherein the patient is 10 to <18 years old.

75. The method according to any one of claims 1 to 50 or 52 to 74, wherein the patient is 12 to <18 years old.

76. The method according to any one of claims 1 to 50 or 52 to 74, wherein the patient is 10 to <12 years old.

77. The method according to any one of claims 1 to 76, wherein the patient experiences a reduction in fatigue.

78. The method according to any one of claims 1 to 77, wherein the human patient experiences fatigue reduction as determined using the ITP Patient Assessment Questionnaire (ITP-PAQ) (ITP-PAQ).

79. The method according to any one of claims 1 to 78, wherein the human patient experiences fatigue reduction as determined using ITP Kids' ITP tool (ITP-KIT).

80. The method according to any one of claims 1 to 79, wherein the human patient experiences a change from baseline in IBLS at weeks 13 and 15 of the treatment period.

81. The method according to any one of claims 1 to 80, wherein the human patient experiences a change from baseline in IBLS at 25 weeks of the treatment period.

82. The method according to any one of claims 1 to 81, wherein the human patient experiences an improvement in quality of life.

83. The method according to any one of claims 1 to 82, wherein the human patient experiences an improvement in quality of life as determined by the ITP-KIT.

84. The method according to any one of claims 1 to 83, wherein the human patient experiences changes from baseline in the following items: symptoms of the ITP-PAQ™, physical health discomfort, activity, fatigue / sleep, psychological health, fear, social activity, female reproductive health and work.

85. The method according to claim 1, wherein the human patient is refractory to at least one previous line of treatment, for example at least two, for example at least three, for example at least four, for example at least five, for example at least six, for example at least seven, for example at least eight, for example at least nine, for example at least ten, for example at least 11, for example at least 12, for example at least 13, for example at least 14, for example at least 15, for example at least 16, for example at least 17 previous lines of treatment.

86. A method for treating immune thrombocytopenia (ITP) in a human patient having persistent or chronic ITP requiring such treatment, comprising administering to the human patient a therapeutically effective dose of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and pharmaceutically acceptable salts thereof twice daily for a period of treatment, wherein the human patient has an inadequate response to or intolerance to one or more prior treatments.

87. Use of a therapeutically effective amount of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts for the treatment of immune thrombocytopenia (ITP) in human patients with persistent or chronic ITP who require such treatment.

88. A therapeutically effective amount of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and pharmaceutically acceptable salts thereof, for use as a pharmaceutical for treating immune thrombocytopenia (ITP) in human patients with persistent or chronic ITP who require such treatment.

89. A therapeutically effective amount of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and pharmaceutically acceptable salts thereof, for use in treating immune thrombocytopenia (ITP) in human patients with persistent or chronic ITP who require such treatment.

90. Use of a therapeutically effective amount of at least one compound selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile and its pharmaceutically acceptable salts as a pharmaceutical for treating immune thrombocytopenia (ITP) in human patients with persistent or chronic ITP who require it.

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