Methods of treating immune thrombocytopenia by administering (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl) pyrazolo [3, 4-d] pyrimidin-1-yl] piperidin-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl) piperazin-1-yl] pent-2-enitrile

Abstract

Disclosed herein are methods for the treatment of immune thrombocytopenia, the methods comprising administering a compound selected from the group consisting of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl) pyrazolo [3, 4-b] pyrimidine-2-ketone, a compound selected from the group consisting of (R)-2-[3-[4-amino-3-(2- The present invention relates to at least one compound selected from the group consisting of 4-(4-(4-(4-oxetan-3-yl) piperazine-1-yl) penta-2-enenitrile (rizobrutinib) and pharmaceutically acceptable salts thereof, in particular, 4-(4, 4-d) pyrimidin-1-yl) piperidin-1-carbonyl)-4-methyl-4-[4-(oxetan-3-yl) piperazine-1-yl] penta-2-enenitrile (rizobrutinib).

Description

Technical Field

[0001] Disclosed herein are methods for treating immune thrombocytopenia. Also disclosed are BTK inhibitors and pharmaceutical compositions comprising the BTK inhibitors. Background Art

[0002] Immune thrombocytopenia, commonly referred to as ITP, is a rare autoimmune disease with a diverse pathophysiology that results in a high risk of bleeding, excessive bruising and fatigue, as well as the potential for life-threatening intracranial hemorrhage due to platelet destruction. ITP is characterized by immune-mediated (e.g., autoantibody-mediated) platelet destruction and impaired platelet production, resulting in thrombocytopenia, bleeding tendencies associated with morbidity and mortality, and adverse effects on the patient's quality of life (QOL).

[0003] Therapies currently used for adults with ITP include treatment with intravenous immunoglobulin (IVIG) and corticosteroids first, and then with splenectomy, thrombopoietin receptor agonists (TPO-RA), rituximab, fostamatinib (Fostamatinib) and immunosuppressive therapy (such as mycophenolate mofetil (MMF) and cyclosporine) treatment. In general, drug therapy (e.g., corticosteroids, IVIG or anti-D immunoglobulin therapy) is used for symptomatic patients with low platelet counts to reduce platelet destruction. Although most patients initially respond to corticosteroids, the sustained remission rate is very low. Second-line therapy for ITP includes rituximab and splenectomy, which is associated with the risk of sepsis and immunosuppression. In addition, thrombopoietin (TPO) mimetics (Bussel 2007) are approved for the treatment of patients with chronic ITP who do not respond sufficiently to corticosteroids, IVIG or splenectomy.

[0004] A new, safe, and effective oral treatment to maintain platelet counts in ITP patients would represent a significant therapeutic advantage over the current standard of care. As a non-limiting example, unmet needs in relapsed and refractory ITP include: improved remission rates and durability; avoidance of rapid platelet count increases / thrombotic risks; steroid-free regimens; and tolerable and safe therapies that ensure good patient QOL. Therefore, there is a need for new oral therapies for the treatment of ITP, including relapsed and refractory ITP, that address some or all of these limitations of existing treatment modalities.

[0005] Bruton's agammaglobulinemia tyrosine kinase (BTK) is an essential signal transduction element downstream of B cell receptor (BCR), Fc-γ receptor (FcγR) and Fc-ε receptor (FcεR). BTK is a non-receptor tyrosine kinase and a member of the TEC kinase family. BTK is essential for the maturation of the B cell lineage, and the inhibition of BTK activity in cells produces phenotypic changes consistent with BCR blockade. Illustratively, BTK inhibition leads to downregulation of various B cell activities (including cell proliferation, differentiation, maturation and survival), as well as upregulation of apoptosis.

[0006] Rather than acting as a "start / stop switch," BTK is best viewed as an immune function "regulator" (Crofford LJ et al., 2016; Pal Singh S et al., 2018). Important insights into BTK function have come from loss-of-function analyses in humans and mice. Individuals with loss-of-function mutations in the BTK gene suffer from X-linked agammaglobulinemia (XLA), a condition characterized by the complete absence of circulating B cells and plasma cells, and very low levels of all classes of immunoglobulins (Tsukada 1993, Vetrie 1993). This suggests the potential for BTK inhibition to suppress the production of autoantibodies, which are thought to be important in the development of autoimmune diseases such as ITP.

[0007] Although BTK is not expressed in T cells, natural killer cells or plasma cells, and has no traceable direct function in T cells or plasma cells (Sideras and Smith 1995; Mohamed et al., 2009), the enzyme regulates the activation of other hematopoietic cells (such as B cells, monocytes, basophils, mast cells, macrophages, neutrophils and platelets). For example, BTK plays a role in the activation of neutrophils, which are key players in the inflammatory response, which promotes wound healing but may also cause tissue damage (Volmering S et al., 2016).

[0008] Therefore, selective BTK inhibitors have the potential to target multiple pathways involved in inflammation and autoimmunity, including but not limited to: blocking BCR signaling; inhibiting plasma cell differentiation and antibody production; blocking IgG-mediated FcγR activation, phagocytosis, and inflammatory mediators in monocytes or macrophages; blocking IgE-mediated FcεR activation and degranulation in mast cells or basophils; and inhibiting activation, adhesion, recruitment, and reactive oxygen burst in neutrophils. Based on these effects, selective BTK inhibitors can block the initiation and progression of a variety of inflammatory diseases and reduce tissue damage caused by these diseases. Although individuals with loss-of-function mutations in the BTK gene have reduced humoral immunity and are susceptible to purulent bacterial and enteroviral infections, requiring treatment with intravenous immunoglobulin, it is predicted that inhibiting BTK in individuals with a complete immune system will not produce similar susceptibility to infection.

[0009] Several orally administered BTK inhibitors (BTKi), including Ibrutinib (PCI-32765) and Spebrutinib (CC-292), are currently on the market 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 has recently been approved by the U.S. Food and Drug Administration (FDA) for use in human mantle cell lymphoma, Waldenstrom's macroglobulinemia, and chronic lymphocytic leukemia. Ibrutinib also exhibits activity in other hematological malignancies (Wang 2013; Byrd 2013, Ibrutinib Package Insert, 2015). In addition, CC-292 has been reported to be well tolerated in a healthy volunteer population at a dose that provides 100% occupancy of the BTK enzyme (Evans 2013). In addition, 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 a variety of immune-mediated disorders such as pemphigus (NCT02704429), 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; MinTK et al., 2019; Gillooly KM 2017; Nadeem A et al., 2019).

[0010] Although covalent BTKi (such as ibrutinib and acalabrutinib) improves the selectivity problems that plague many first-generation kinase inhibitors, these inhibitors are generally irreversible, causing permanent modifications of both targeted and off-target kinases and 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 treatments for immune-mediated diseases (such as ITP) based on BTKi with reduced side effects.

[0011] Compound (I) is a BTK inhibitor having the following structure: Wherein *C is a stereochemical center. See PCT Publication No. WO 2014 / 039899, ​​which is incorporated herein by reference (eg, Example 31). (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, has the following structure: Also known as PRN1008 and Rilzabrutinib. This compound has been disclosed in several patent publications, such as PCT Publication Nos. WO 2014 / 039899, ​​WO 2015 / 127310, WO 2016 / 100914, WO 2016 / 105531, and WO 2018 / 005849, the contents of each of which are incorporated herein by reference.

[0012] Rizarutinib is a novel highly selective small molecule inhibitor of non-T cell leukocyte signaling via B cell receptor, FcγR and / or FcεR signaling of the BTK pathway. Rizarutinib acts as a reversible covalent BTK inhibitor and forms both non-covalent and covalent bonds with its target, allowing for enhanced selectivity and prolonged inhibition with low systemic exposure. Compared with first- and second-generation BTKi, Rizarutinib shows extremely low cross-reactivity with other molecules and a low risk of off-target effects (Smith PF et al., 2017). Importantly, the reversible binding of Rizarutinib minimizes the possibility of permanent modification of peptides (Serafimova IM 2012). In addition, relative to the covalent BTK inhibitor ibrutinib, Rizarutinib shows improved kinase selectivity. Preclinical studies in a wide range of kinase inhibition groups showed that 1 μM of Rizarutinib only achieved >90% inhibition of 6 kinases in 251 kinases that shared a common cysteine ​​in their active sites. In contrast, 1 μM of ibrutinib inhibits 21 kinases. The IC50 values ​​of rizabrutinib are 1.3 nM for BTK, 0.8 nM for tyrosine protein kinase TEC, 1.0 nM for myeloid tyrosine kinase on chromosome X (BMX), 1.2 nM for receptor-like kinase (RLK), 6.3 nM for B-cell lymphocyte kinase (BLK), and 11 nM for ERBB4. Further preclinical assays using rizabrutinib showed that binding to BTK persisted, while binding to other TEC family members decayed rapidly over time.

[0013] Rizarutinib has shown encouraging results for the treatment of immune-mediated diseases. Rizarutinib is the most advanced BTKi in development for autoimmune diseases (Phase 3, NCT03762265). In humans, Rizarutinib is rapidly absorbed after oral administration, with a short half-life (3-4h) and variable pharmacokinetics (PK) (Smith PF et al., 2017).

[0014] In a Phase 1 study of rizarutinib in 114 healthy volunteers, target BTK occupancy levels were safely and consistently exceeded, suggesting that rizarutinib may be highly effective in treating autoimmune diseases. In addition, preclinical and clinical PK / PD data showed that the therapeutic effect persisted even after the compound was cleared from the circulation, consistent with prolonged target residence time (Hill R et al., 2015) and high occupancy (>90% within four hours) (Smith PF et al., 2015).

[0015] Rizabrutinib has also demonstrated a favorable safety profile. Based on preclinical reproductive toxicity studies, rizabrutinib is not expected to impair fetal development or male fertility. In the Phase 1 study in healthy volunteers, the most commonly reported adverse events 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).

[0016] There is preliminary evidence to support the role of BTK inhibition in patients with autoimmune cytopenias (Rogers 2016, Montillo 2017), where in patients with chronic lymphocytic leukemia (CLL), after starting treatment with the BTK / EGFR / ITK inhibitor ibrutinib, continuous attacks of severe autoimmune hemolytic anemia and ITP ceased. Additionally and relevant to the treatment of ITP, in vitro rizzarutinib treatment significantly inhibited human B cell activation and blocked antibody (IgG, IgE)-mediated immune cell activation via Fc receptor signaling. In nonclinical studies, rizzarutinib showed a significant dose-dependent reduction in platelet loss (consumption) in a mouse model of ITP. Rizarutinib also showed rapid and significant anti-inflammatory effects in a rat collagen-induced arthritis model, a rat antibody-mediated Arthus model, spontaneous canine pemphigus foliaceus, and human pemphigus vulgaris (PV).

[0017] Although there is promising preliminary evidence supporting a role for rizabrutinib in patients with ITP, patient response to ITP therapy remains generally difficult to predict, and neither durable responses nor long-term remissions are guaranteed. In particular, there are few predictive markers for the efficacy of currently available ITP therapies, making it difficult to identify patients who will successfully respond to new therapies. Therefore, predicting response to current therapies is critical because it helps optimize the use of current and future therapies.

[0018] A recent ongoing Phase 1 / 2 trial (NCT03395210) of rizzarutinib in patients with ITP identified several possible predictors of successful response to rizzarutinib. The study examined a total of 11 baseline clinical variables in 45 patients who started with 400 mg rizzarutinib twice a day, revealing that patients with shorter duration of ITP and / or who had not previously used thrombopoietin receptor agonists or rituximab were more likely to respond to treatment with rizzarutinib. In addition, patients who had not previously used thrombopoietin receptor agonists were more likely to be early responders to rizzarutinib treatment. Summary of the invention

[0019] Disclosed herein is a method for treating immune thrombocytopenia (ITP) in a human patient in need thereof, said human patient having not received prior treatment with a thrombopoietin receptor agonist (TPO-RA) or rituximab, said method comprising administering to said human patient who has not received prior treatment with a TPO-RA or rituximab twice daily during a treatment period a therapeutically effective amount of a thrombocytopenia 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]pent-2-enenitrile and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof has at least one characteristic selected from the following: a platelet count of <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to the start of study treatment; and a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL, and an increase of ≥20,000 / μL). In some embodiments, the human patient in need thereof has a platelet count of <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to the start of study treatment. In some embodiments, the human patient in need thereof has a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL, and an increase of ≥20,000 / μL). In some embodiments, the human patient in need thereof has a platelet count <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to starting study treatment and has a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL with an increase of ≥20,000 / μL).

[0020] Also disclosed herein is a method for treating immune thrombocytopenia (ITP) in a human patient in need thereof who has not received prior treatment with a thrombopoietin receptor agonist (TPO-RA), the method comprising administering to the human patient who has not received prior treatment with a TPO-RA twice daily during a treatment period a therapeutically effective amount of a thrombopoietin-1-ylpiperidine-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl] -4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof has at least one characteristic selected from the following: a platelet count of <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to the start of study treatment; and a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL, and an increase of ≥20,000 / μL). In some embodiments, the human patient in need thereof has a platelet count of <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to the start of study treatment. In some embodiments, the human patient in need thereof has a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL, and an increase of ≥20,000 / μL). In some embodiments, the human patient in need thereof has a platelet count <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to starting study treatment and has a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL with an increase of ≥20,000 / μL).

[0021] Also disclosed herein is a method for treating immune thrombocytopenia (ITP) in a human patient in need thereof, said human patient having not received prior treatment with rituximab, said method comprising administering to said human patient who has not received prior treatment with rituximab twice daily during a treatment period a therapeutically effective amount of a drug selected from the group consisting of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4 -[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof has at least one characteristic selected from the following: a platelet count of <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to the start of study treatment; and a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL, and an increase of ≥20,000 / μL). In some embodiments, the human patient in need thereof has a platelet count of <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to the start of study treatment. In some embodiments, the human patient in need thereof has a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL, and an increase of ≥20,000 / μL). In some embodiments, the human patient in need thereof has a platelet count <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to starting study treatment and has a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL with an increase of ≥20,000 / μL). BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The number of patients who started rizabrutinib at each dose, the number of patients who completed the primary study, and the number of patients who entered the long-term extension are shown.

[0023] Figure 2 A summary of within-patient dose escalation levels of rizabrutinib is shown.

[0024] Figure 3 IBLS bleeding scale scores at baseline (Cycle 1, Day 1) and Week 24 / end of study are shown for patients (n=34) who completed 24 weeks of rizarutinib. Bleeding symptoms were grouped by bleeding site and were scored based on a grade from lowest (0) to highest (3-4; fatal bleeding was grade 5), as defined and standardized by the ITP International Working Group. No grade 3, 4, or 5 bleeding events occurred at baseline or Week 24 / EOS; therefore, bars for these grades are not shown.

[0025] Figure 4Shown are median platelet counts over time for patients (N=60) starting rizabrutinib at all doses, including 400 mg twice daily, separated by responders and non-responders.

[0026] Figure 5 Shown are median platelet counts over time for patients (n=45) starting rizabrutinib at 400 mg twice daily, separated by responders and non-responders.

[0027] Figure 6 Shown are median platelet counts over time for patients (N=60) starting rizabrutinib at all doses, including 400 mg twice daily.

[0028] Figure 7 Shown are median platelet counts over time for patients (n=45) starting rizabrutinib at 400 mg twice daily.

[0029] Figure 8 Rizabrutinib dose and platelet response over time are shown.

[0030] Fig. 9 The percentage of patients in each subgroup who achieved ≥2 consecutive platelet counts (at least 5 days apart) ≥50,000 / μL with an increase from baseline of ≥20,000 / μL and did not require rescue medication within 4 weeks prior to the most recent elevated platelet count is shown.

[0031] Fig.10 Summaries of continuous variables for outcomes are shown for non-responders versus responders (upper panels) and non-early responders versus early responders (lower panels).

[0032] Fig.11 Shown are the number of patients who started rizabrutinib at each dose, the number of patients who achieved a major platelet response, and the number of patients who were early responders to rizabrutinib. DETAILED DESCRIPTION definition:

[0033] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this application and have the following meanings. All technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0034] As used herein, unless otherwise specified, "a or an" entity refers to one or more of the entity, e.g., a compound refers to one or more compounds or at least one compound. Therefore, the terms "a or an", "one or more", and "at least one" can be used interchangeably herein.

[0035] As used herein, the term "about" is used herein to mean approximately, in the region, roughly, or about. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the numerical value. In general, the term "about" is used herein to modify a numerical value to be higher and lower than the value with a difference of 5%. Regarding specific values, it should be understood that unless otherwise provided, the specific values ​​described herein for a subject population (e.g., a subject of the clinical trial) represent median values, mean values, or statistics. Therefore, aspects of the disclosure requiring specific values ​​of a subject are supported herein by population data as follows: wherein the relevant values ​​are evaluated as meaningful delimitations for a subject population.

[0036] As used herein, the term "active pharmaceutical ingredient" or "therapeutic agent" ("API") refers to a biologically active compound.

[0037] As used herein, the term "approved therapy" refers to a drug that has received regulatory authorization for its intended use in any country.

[0038] As used herein, the term "administer", "administering" or "administration" refers herein to providing, giving, dosing and / or prescribing by a medical practitioner or authorized agent, and / or placing, taking or consuming by a patient or individual himself. For example, "administering" an API to a patient refers to any route of introducing or delivering the API to the patient (e.g., oral delivery). Administration includes self-administration and administration by another person.

[0039] As used herein, the term "baseline platelet count" or "baseline" refers to the average platelet count obtained by determining the average of two platelet counts performed on two occasions not less than 7 days apart within 15 days before the start of treatment and a third count performed on the first day of the study. If any of the three counts is missing, the "baseline platelet count" or "baseline" is the average of the other counts. As used herein, "BID" and "bid" are used interchangeably to refer to twice a day.

[0040] As used herein, "immune thrombocytopenia" (ITP) encompasses or at least also refers to other commonly used terms such as idiopathic thrombocytopenia and idiopathic thrombocytopenic purpura. There are three main types of ITP: acute (short-term), persistent, and chronic (long-term). Acute ITP lasts less than three months, persistent ITP lasts 3-12 months, and chronic ITP lasts at least one year.

[0041] As used herein, when referring to two or more compounds, agents or additional active pharmaceutical ingredients, the term "in combination with" means that the two or more compounds, agents or active pharmaceutical ingredients are administered to the patient before, at the same time or after each other during the treatment period. Unless otherwise indicated, the two or more compounds, agents or active pharmaceutical ingredients can be administered on different schedules during the treatment period, for example, once a day with one or more compounds, agents or active pharmaceutical ingredients and twice a day with one or more other compounds, agents or active pharmaceutical ingredients.

[0042] As used herein, an amount expressed as "mg of [X]" refers to the total amount of [X], i.e., the free base, in milligrams. In some embodiments, rizarutinib may be administered as a pharmaceutically acceptable salt of rizarutinib, in which case the amount expressed as "mg of rizarutinib" refers to the total amount of rizarutinib, i.e., the free base, plus one or more pharmaceutically acceptable salts of rizarutinib in milligrams based on the weight equivalent of the free base therein. For example, "400 mg of at least one compound selected from rizarutinib and a pharmaceutically acceptable salt thereof" includes 400 mg of rizarutinib and one or more pharmaceutically acceptable salts of rizarutinib at a concentration equivalent to 400 mg of rizarutinib.

[0043] As used herein, "pharmaceutically acceptable carrier or excipient" means a carrier or excipient that can be used to prepare a pharmaceutical composition, which is generally safe and not biologically or otherwise undesirable, such as a carrier or excipient that is acceptable for pharmaceutical use in mammals.

[0044] As used herein, the term "pharmaceutically acceptable salt" refers to a salt form of an active agent, such as an acid addition salt, which is pharmaceutically acceptable and has the desired pharmacological activity of the API (the salt thereof is prepared). 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 with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.; or salts formed with organic acids such as formic acid, acetic acid, propionic acid, caproic 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, 4-toluenesulfonic acid, etc. SMBerge et al. describe pharmaceutically acceptable salts in detail in J.PharmaceuticalSciences, 1977, 66, 1-19.

[0045] As used herein, the terms “PRN1008,” “rizabrutinib,” “(R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile,” and “2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile” may be used interchangeably to refer to a compound having the following structure: It is also known as 2-[(3R)-2-[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]-(E and Z)-pent-2-enenitrile; (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile; 1-piperidinepropionitrile, 3-[4-amino- 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-α-[2-methyl-2-[4-(3-oxetanyl)-1-piperazinyl]propylidene]-β-oxo-, (3R)-; (EZ)-2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile; and according to the International Nonproprietary Name (INN) 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 ) has the following structure: The compounds of formula (I) include E and Z isomers as indicated by the wavy bonds in the structures shown above. The compounds of formula (I) may exist in the form of salts.

[0046] Since the isomers of rizabrutinib may contain less than 1% by weight of the corresponding (Z) isomer as an impurity; a dose of the (Z) isomer of rizabrutinib may contain less than about 1% by weight of the corresponding (E) isomer as an impurity. When rizabrutinib is expressed as a mixture of the (E) isomer and the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, it means that the amount of the (E) isomer or the (Z) isomer in the mixture is greater than about 1% by weight. In some embodiments, the molar ratio of (E) to (Z) isomers is 9:1. Rizabrutinib or a pharmaceutically acceptable salt thereof may also be referred to herein as a "drug," "active agent," "therapeutically active agent," or "API."

[0047] As used herein, "QD" and "qd" are used interchangeably to refer to once daily.

[0048] As used herein, the term "therapeutically effective amount" refers to the amount of a compound that produces the desired effect (e.g., improving ITP or a symptom of ITP, or reducing the severity of ITP or a symptom of ITP). The exact amount of an effective dose will depend on the purpose of the treatment and will be determined by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0049] As used herein, the term "treat," "treating," or "treatment," when used in conjunction with a disorder or condition, includes any effect that results in improvement of the disorder or condition, such as alleviation, reduction, modulation, improvement, or elimination. The improvement of any symptom of a disorder or condition or the reduction of its severity can be readily assessed according to standard methods and techniques known in the art.

[0050] Some embodiments of the present disclosure relate to methods for treating immune thrombocytopenia (ITP) in a human patient in need thereof who has not received prior treatment with a thrombopoietin receptor agonist (TPO-RA) or rituximab, the method comprising administering to the human patient who has not received prior treatment with a TPO-RA or rituximab twice daily during a treatment period a therapeutically effective amount of a drug selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidine-1-

[00136] The invention relates to a human patient comprising: a patient who is a patient having at least one compound of the group consisting of: -4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof has at least one characteristic selected from the group consisting of: a platelet count of <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to the start of study treatment; and a history of response to at least one prior line of treatment (platelet counts ≥50,000 / μL on two or more occasions with an increase of ≥20,000 / μL). In some embodiments, the human patient in need thereof has a platelet count of <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to the start of study treatment. In some embodiments, the human patient in need thereof has a history of response to at least one prior line of treatment (platelet counts ≥50,000 / μL on two or more occasions with an increase of ≥20,000 / μL). In some embodiments, the human patient in need thereof has a platelet count <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to starting study treatment and has a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL with an increase of ≥20,000 / μL).

[0051] In some embodiments, the TPO-RA is selected from recombinant thrombopoietin (rTPO), Romiplostim, Eltrombopag, and Avatrombopag. In some embodiments, the TPO-RA is rTPO. In some embodiments, the TPO-RA is Romiplostim. In some embodiments, the TPO-RA is Eltrombopag. In some embodiments, the TPO-RA is Avatrombopag.

[0052] In some embodiments, the human patient has not received prior treatment with rituximab.

[0053] In some embodiments, the human patient has a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL, and an increase of ≥20,000 / μL). In some embodiments, at least one prior therapy is selected from splenectomy, intravenous immunoglobulin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressive drugs. In some embodiments, the at least one prior therapy is splenectomy. In some embodiments, the at least one prior therapy is IVIG. In some embodiments, the at least one prior therapy is corticosteroids. In some embodiments, the at least one prior therapy is anti-D immunoglobulin therapy. In some embodiments, the at least one prior therapy is an immunosuppressive drug.

[0054] In some embodiments, the human patient achieves at least one platelet count that is at least 20,000 / μL higher than the baseline platelet count, wherein the baseline platelet count is the average of two platelet counts performed on two occasions not less than 7 days apart within 15 days before the start of treatment and a third count performed on the first day of the study. In some embodiments, the human patient achieves at least two platelet counts that are at least 20,000 / μL higher than the baseline platelet count. In some embodiments, the human patient achieves at least two consecutive platelet counts that are at least 20,000 / μL higher than the baseline platelet count, for example, at least 30,000 / μL higher than the baseline platelet count.

[0055] In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 20,000 / μL above the baseline platelet count at least five days apart (e.g., at least seven days apart). In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 20,000 / μL above the baseline platelet count at least five days apart. In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 20,000 / μL above the baseline platelet count at least seven days apart.

[0056] In some embodiments, the human patient achieves a platelet count of at least 50,000 / μL. In some embodiments, the human patient achieves at least two platelet counts of at least 50,000 / μL. In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 50,000 / μL.

[0057] In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 50,000 / μL at least five days (e.g., at least seven days) apart. In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 50,000 / μL at least five days apart. In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 50,000 / μL at least seven days apart.

[0058] In some embodiments, the human patient achieves at least one platelet count of at least 50,000 / μL within eight days of initiating treatment.

[0059] In some embodiments, the human patient has not received rescue medication during the four weeks prior to the most recent platelet count of at least 50,000 / μL.

[0060] In some embodiments, the human patient has suffered from ITP for six years or less. In some embodiments, the human patient has suffered from ITP for five years or less. In some embodiments, the human patient has suffered from ITP for four years or less. In some embodiments, the human patient has suffered from ITP for three years or less. In some embodiments, the human patient has suffered from ITP for two years or less. In some embodiments, the human patient has suffered from ITP for less than one year.

[0061] In some embodiments, the human patient has ITP for at least 1 year prior to the start of the treatment period. In some embodiments, the human patient has ITP for at least 2 years prior to the start of the treatment period. In some embodiments, the human patient has ITP for at least 3 years prior to the start of the treatment period. In some embodiments, the human patient has ITP for at least 4 years prior to the start of the treatment period. In some embodiments, the human patient has ITP for at least 5 years prior to the start of the treatment period. In some embodiments, the human patient has ITP for at least 6 years prior to the start of the treatment period. In some embodiments, the human patient has ITP for at least 7 years prior to the start of the treatment period. In some embodiments, the human patient has ITP for at least 8 years prior to the start of the treatment period. In some embodiments, the human patient has ITP for at least 9 years prior to the start of the treatment period.

[0062] In some embodiments, the human patient has suffered from ITP for at least 10 years prior to the start of the treatment period. In some embodiments, the human patient has suffered from ITP for at least 20 years prior to the start of the treatment period. In some embodiments, the human patient has suffered from ITP for at least 30 years prior to the start of the treatment period. In some embodiments, the human patient has suffered from ITP for at least 40 years prior to the start of the treatment period. In some embodiments, the human patient has suffered from ITP for at least 50 years prior to the start of the treatment period.

[0063] In some embodiments, the human patient has a history of receiving at least one prior ITP therapy prior to the start of the treatment period. In some embodiments, the human patient has a history of receiving at least two prior ITP therapies prior to the start of the treatment period. In some embodiments, the human patient has a history of receiving at least three prior ITP therapies prior to the start of the treatment period. In some embodiments, the human patient has a history of receiving at least four prior ITP therapies prior to the start of the treatment period. In some embodiments, the human patient has a history of receiving at least five prior ITP therapies prior to the start of the treatment period.

[0064] In some embodiments, the human patient has a platelet count between 2,000 / μL and 33,000 / μL on two occasions within 15 days prior to the start of the treatment period and no less than 7 days apart.

[0065] In some embodiments, the human patient underwent a splenectomy prior to initiation of the treatment period.

[0066] In some embodiments, the human patient has a history of response to at least one previous line of treatment, wherein at least one previous therapy is selected from splenectomy, intravenous immunoglobulin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressive drugs. 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 IVIG. In some embodiments, the human patient has a history of response to corticosteroids. 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 immunosuppressive drugs.

[0067] In some embodiments, the human patient has a history of receiving IVIG. In some embodiments, the human patient has a history of receiving corticosteroids. In some embodiments, the human patient has a history of receiving anti-D immunoglobulin therapy. In some embodiments, the human patient has a history of receiving at least one immunosuppressive drug. In some embodiments, the human patient has a history of receiving at least one immunosuppressive drug selected from fostamatinib, mycophenolate mofetil (MMF) and cyclosporine. In some embodiments, the human patient has a history of receiving fostamatinib. In some embodiments, the human patient has a history of receiving mycophenolate mofetil (MMF). In some embodiments, the human patient has a history of receiving cyclosporine.

[0068] In some embodiments, the response to prior ITP therapy comprises a platelet count of ≥50,000 / μL.

[0069] In some embodiments, the human patient suffers from primary ITP. In some embodiments, the human patient suffers from secondary ITP. In some embodiments, the human patient does not suffer from chronic ITP. In some embodiments, the human patient suffers from persistent ITP. In some embodiments, the human patient suffers from chronic ITP. In some embodiments, the human patient suffers from recurrent ITP. In some embodiments, the human patient suffers from refractory ITP.

[0070] In some embodiments, the treatment period is at least 8 days. In some embodiments, the treatment period is at least 28 days. In some embodiments, the treatment period is at least 84 days. In some embodiments, the treatment period is at least 169 days.

[0071] In some embodiments, the method comprises administering to the human patient 400 mg twice daily 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]pent-2-enenitrile and pharmaceutically acceptable salts thereof. In some embodiments, the at least one compound consists of at least one compound selected from the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof. In some embodiments, the at least one compound consists of at least one compound selected from the group consisting of the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof. In some embodiments, the 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]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile or pharmaceutically acceptable salts thereof.

[0072] In other embodiments, the method comprises administering 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile twice daily to the human patient. In some embodiments, the at least one compound is the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. In some embodiments, the at least one compound is the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. In some embodiments, the at least one compound consists of a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.

[0073] In some embodiments, the at least one compound is administered orally to the human patient. In some embodiments, the at least one compound is administered to the human patient in the form of at least one tablet. In some embodiments, the at least one compound is administered with water. In some embodiments, the at least one compound is administered with food. In some embodiments, the at least one compound is not administered with food.

[0074] Some embodiments of the present disclosure relate to methods for treating immune thrombocytopenia (ITP) in a human patient in need thereof, said human patient having not received prior treatment with a thrombopoietin receptor agonist (TPO-RA), said method comprising administering to said human patient who has not received prior treatment with a TPO-RA twice daily during a treatment period a therapeutically effective amount of a thrombopoietin-1-ylpiperidin-2-ylpiperidin-3-ylpiperidin-4-ylpiperidin-1-ylpiperidin-4-ylpiperidin-4-ylpiperidin-4-ylpiperidin-4-ylpiperidin-4-ylpiperidin-4-ylpiperidin-4-ylpiperidin-4-ylpiperidin-4-ylpiperidin-1-ylpiperidin-4-ylpiperidin-4-ylpiperidin-4-ylpiperidin-4-ylpiperidin-1 -carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof has at least one characteristic selected from the following: a platelet count of <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to the start of study treatment; and a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL, and an increase of ≥20,000 / μL). In some embodiments, the human patient in need thereof has a platelet count of <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to the start of study treatment. In some embodiments, the human patient in need thereof has a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL, and an increase of ≥20,000 / μL). In some embodiments, the human patient in need thereof has a platelet count <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to starting study treatment and has a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL with an increase of ≥20,000 / μL).

[0075] In some embodiments, the TPO-RA is selected from recombinant thrombopoietin (rTPO), romiplostim, eltrombopag, and avatrombopag. In some embodiments, the TPO-RA is rTPO. In some embodiments, the TPO-RA is romiplostim. In some embodiments, the TPO-RA is eltrombopag. In some embodiments, the TPO-RA is avatrombopag.

[0076] In some embodiments, the human patient has not received prior treatment with rituximab.

[0077] In some embodiments, the human patient has a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL, and an increase of ≥20,000 / μL). In some embodiments, at least one prior therapy is selected from splenectomy, intravenous immunoglobulin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressive drugs. In some embodiments, the at least one prior therapy is splenectomy. In some embodiments, the at least one prior therapy is IVIG. In some embodiments, the at least one prior therapy is corticosteroids. In some embodiments, the at least one prior therapy is anti-D immunoglobulin therapy. In some embodiments, the at least one prior therapy is an immunosuppressive drug.

[0078] In some embodiments, the human patient achieves at least one platelet count that is at least 20,000 / μL higher than the baseline platelet count, wherein the baseline platelet count is the average of two platelet counts performed on two occasions not less than 7 days apart within 15 days before the start of treatment and a third count performed on the first day of the study. In some embodiments, the human patient achieves at least two platelet counts that are at least 20,000 / μL higher than the baseline platelet count. In some embodiments, the human patient achieves at least two consecutive platelet counts that are at least 20,000 / μL higher than the baseline platelet count, for example, at least 30,000 / μL higher than the baseline platelet count.

[0079] In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 20,000 / μL above the baseline platelet count at least five days apart (e.g., at least seven days apart). In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 20,000 / μL above the baseline platelet count at least five days apart. In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 20,000 / μL above the baseline platelet count at least seven days apart.

[0080] In some embodiments, the human patient achieves a platelet count of at least 50,000 / μL. In some embodiments, the human patient achieves at least two platelet counts of at least 50,000 / μL. In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 50,000 / μL.

[0081] In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 50,000 / μL at least five days (e.g., at least seven days) apart. In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 50,000 / μL at least five days apart. In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 50,000 / μL at least seven days apart.

[0082] In some embodiments, the human patient achieves at least one platelet count of at least 50,000 / μL within eight days of initiating treatment.

[0083] In some embodiments, the human patient has not received rescue medication during the four weeks prior to the most recent platelet count of at least 50,000 / μL.

[0084] In some embodiments, the human patient has suffered from ITP for six years or less. In some embodiments, the human patient has suffered from ITP for five years or less. In some embodiments, the human patient has suffered from ITP for four years or less. In some embodiments, the human patient has suffered from ITP for three years or less. In some embodiments, the human patient has suffered from ITP for two years or less. In some embodiments, the human patient has suffered from ITP for less than one year.

[0085] In some embodiments, the human patient has a history of receiving at least one prior ITP therapy prior to the start of the treatment period. In some embodiments, the human patient has a history of receiving at least two prior ITP therapies prior to the start of the treatment period. In some embodiments, the human patient has a history of receiving at least three prior ITP therapies prior to the start of the treatment period. In some embodiments, the human patient has a history of receiving at least four prior ITP therapies prior to the start of the treatment period. In some embodiments, the human patient has a history of receiving at least five prior ITP therapies prior to the start of the treatment period.

[0086] In some embodiments, the human patient has a platelet count between 2,000 / μL and 33,000 / μL on two occasions within 15 days prior to the start of the treatment period and no less than 7 days apart.

[0087] In some embodiments, the human patient underwent a splenectomy prior to initiation of the treatment period.

[0088] In some embodiments, the human patient has a history of receiving rituximab prior to the start of the treatment period.

[0089] In some embodiments, the human patient has a history of response to at least one previous line of treatment, wherein at least one previous therapy is selected from splenectomy, intravenous immunoglobulin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressive drugs. 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 IVIG. In some embodiments, the human patient has a history of response to corticosteroids. 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 immunosuppressive drugs.

[0090] In some embodiments, the human patient has a history of receiving IVIG. In some embodiments, the human patient has a history of receiving corticosteroids. In some embodiments, the human patient has a history of receiving anti-D immunoglobulin therapy. In some embodiments, the human patient has a history of receiving at least one immunosuppressive drug. In some embodiments, the human patient has a history of receiving at least one immunosuppressive drug selected from fostamatinib, mycophenolate mofetil (MMF) and cyclosporine. In some embodiments, the human patient has a history of receiving fostamatinib. In some embodiments, the human patient has a history of receiving mycophenolate mofetil (MMF). In some embodiments, the human patient has a history of receiving cyclosporine.

[0091] In some embodiments, the response to prior ITP therapy comprises a platelet count of ≥50,000 / μL.

[0092] In some embodiments, the human patient suffers from primary ITP. In some embodiments, the human patient suffers from secondary ITP. In some embodiments, the human patient does not suffer from chronic ITP. In some embodiments, the human patient suffers from persistent ITP. In some embodiments, the human patient suffers from chronic ITP. In some embodiments, the human patient suffers from recurrent ITP. In some embodiments, the human patient suffers from refractory ITP.

[0093] In some embodiments, the treatment period is at least 8 days. In some embodiments, the treatment period is at least 28 days. In some embodiments, the treatment period is at least 84 days. In some embodiments, the treatment period is at least 169 days.

[0094] In some embodiments, the method comprises administering to the human patient 400 mg twice daily 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]pent-2-enenitrile and pharmaceutically acceptable salts thereof. In some embodiments, the at least one compound consists of at least one compound selected from the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof. In some embodiments, the at least one compound consists of at least one compound selected from the group consisting of the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof. In some embodiments, the 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]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile or pharmaceutically acceptable salts thereof.

[0095] In other embodiments, the method comprises administering 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile twice daily to the human patient. In some embodiments, the at least one compound is the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. In some embodiments, the at least one compound is the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. In some embodiments, the at least one compound consists of a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.

[0096] In some embodiments, the at least one compound is administered orally to the human patient. In some embodiments, the at least one compound is administered to the human patient in the form of at least one tablet. In some embodiments, the at least one compound is administered with water. In some embodiments, the at least one compound is administered with food. In some embodiments, the at least one compound is not administered with food.

[0097] Some embodiments of the present disclosure relate to methods for treating immune thrombocytopenia (ITP) in a human patient in need thereof, said human patient having not received prior treatment with rituximab, said method comprising administering to said human patient who has not received prior treatment with rituximab twice daily during a treatment period a therapeutically effective amount of a thrombocytopenia selected from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4- At least one compound of methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof has at least one characteristic selected from the following: a platelet count of <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to the start of study treatment; and a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL, and an increase of ≥20,000 / μL). In some embodiments, the human patient in need thereof has a platelet count of <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to the start of study treatment. In some embodiments, the human patient in need thereof has a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL, and an increase of ≥20,000 / μL). In some embodiments, the human patient in need thereof has a platelet count <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to starting study treatment and has a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL with an increase of ≥20,000 / μL).

[0098] In some embodiments, the human patient has a history of response to at least one prior line of treatment (two or more platelet counts ≥50,000 / μL, and an increase of ≥20,000 / μL). In some embodiments, at least one prior therapy is selected from splenectomy, intravenous immunoglobulin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressive drugs. In some embodiments, the at least one prior therapy is splenectomy. In some embodiments, the at least one prior therapy is IVIG. In some embodiments, the at least one prior therapy is corticosteroids. In some embodiments, the at least one prior therapy is anti-D immunoglobulin therapy. In some embodiments, the at least one prior therapy is an immunosuppressive drug.

[0099] In some embodiments, the human patient achieves at least one platelet count that is at least 20,000 / μL higher than the baseline platelet count, wherein the baseline platelet count is the average of two platelet counts performed on two occasions not less than 7 days apart within 15 days before the start of treatment and a third count performed on the first day of the study. In some embodiments, the human patient achieves at least two platelet counts that are at least 20,000 / μL higher than the baseline platelet count. In some embodiments, the human patient achieves at least two consecutive platelet counts that are at least 20,000 / μL higher than the baseline platelet count, for example, at least 30,000 / μL higher than the baseline platelet count.

[0100] In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 20,000 / μL above the baseline platelet count at least five days apart (e.g., at least seven days apart). In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 20,000 / μL above the baseline platelet count at least five days apart. In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 20,000 / μL above the baseline platelet count at least seven days apart.

[0101] In some embodiments, the human patient achieves a platelet count of at least 50,000 / μL. In some embodiments, the human patient achieves at least two platelet counts of at least 50,000 / μL. In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 50,000 / μL.

[0102] In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 50,000 / μL at least five days (e.g., at least seven days) apart. In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 50,000 / μL at least five days apart. In some embodiments, the human patient achieves at least two consecutive platelet counts of at least 50,000 / μL at least seven days apart.

[0103] In some embodiments, the human patient achieves at least one platelet count of at least 50,000 / μL within eight days of initiating treatment.

[0104] In some embodiments, the human patient has not received rescue medication during the four weeks prior to the most recent platelet count of at least 50,000 / μL.

[0105] In some embodiments, the human patient has suffered from ITP for six years or less. In some embodiments, the human patient has suffered from ITP for five years or less. In some embodiments, the human patient has suffered from ITP for four years or less. In some embodiments, the human patient has suffered from ITP for three years or less. In some embodiments, the human patient has suffered from ITP for two years or less. In some embodiments, the human patient has suffered from ITP for less than one year.

[0106] In some embodiments, the human patient has a history of receiving at least one prior ITP therapy prior to the start of the treatment period. In some embodiments, the human patient has a history of receiving at least two prior ITP therapies prior to the start of the treatment period. In some embodiments, the human patient has a history of receiving at least three prior ITP therapies prior to the start of the treatment period. In some embodiments, the human patient has a history of receiving at least four prior ITP therapies prior to the start of the treatment period. In some embodiments, the human patient has a history of receiving at least five prior ITP therapies prior to the start of the treatment period.

[0107] In some embodiments, the human patient has a platelet count between 2,000 / μL and 33,000 / μL on two occasions within 15 days prior to the start of the treatment period and no less than 7 days apart.

[0108] In some embodiments, the human patient underwent a splenectomy prior to initiation of the treatment period.

[0109] In some embodiments, the human patient has a history of receiving at least one TPO-RA before the treatment period begins. In some embodiments, the TPO-RA is selected from recombinant thrombopoietin (rTPO), romiplostim, eltrombopag and avatrombopag. In some embodiments, the TPO-RA is rTPO. In some embodiments, the TPO-RA is romiplostim. In some embodiments, the TPO-RA is eltrombopag. In some embodiments, the TPO-RA is avatrombopag.

[0110] In some embodiments, the human patient has a history of response to at least one previous line of treatment, wherein at least one previous therapy is selected from splenectomy, intravenous immunoglobulin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressive drugs. 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 IVIG. In some embodiments, the human patient has a history of response to corticosteroids. 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 immunosuppressive drugs.

[0111] In some embodiments, the human patient has a history of receiving IVIG. In some embodiments, the human patient has a history of receiving corticosteroids. In some embodiments, the human patient has a history of receiving anti-D immunoglobulin therapy. In some embodiments, the human patient has a history of receiving at least one immunosuppressive drug. In some embodiments, the human patient has a history of receiving at least one immunosuppressive drug selected from fostamatinib, mycophenolate mofetil (MMF) and cyclosporine. In some embodiments, the human patient has a history of receiving fostamatinib. In some embodiments, the human patient has a history of receiving mycophenolate mofetil (MMF). In some embodiments, the human patient has a history of receiving cyclosporine.

[0112] In some embodiments, the response to prior ITP therapy comprises a platelet count of ≥50,000 / μL.

[0113] In some embodiments, the human patient suffers from primary ITP. In some embodiments, the human patient suffers from secondary ITP. In some embodiments, the human patient does not suffer from chronic ITP. In some embodiments, the human patient suffers from persistent ITP. In some embodiments, the human patient suffers from chronic ITP. In some embodiments, the human patient suffers from recurrent ITP. In some embodiments, the human patient suffers from refractory ITP.

[0114] In some embodiments, the treatment period is at least 8 days. In some embodiments, the treatment period is at least 28 days. In some embodiments, the treatment period is at least 84 days. In some embodiments, the treatment period is at least 169 days.

[0115] In some embodiments, the method comprises administering to the human patient 400 mg twice daily 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]pent-2-enenitrile and pharmaceutically acceptable salts thereof. In some embodiments, the at least one compound consists of at least one compound selected from the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof. In some embodiments, the at least one compound consists of at least one compound selected from the group consisting of the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof. In some embodiments, the 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]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile or pharmaceutically acceptable salts thereof.

[0116] In other embodiments, the method comprises administering 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile twice daily to the human patient. In some embodiments, the at least one compound is the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. In some embodiments, the at least one compound is the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. In some embodiments, the at least one compound consists of a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.

[0117] In some embodiments, the at least one compound is administered orally to the human patient. In some embodiments, the at least one compound is administered to the human patient in the form of at least one tablet. In some embodiments, the at least one compound is administered with water. In some embodiments, the at least one compound is administered with food. In some embodiments, the at least one compound is not administered with food. Pharmaceutical composition:

[0118] In some embodiments of the present disclosure, rizzarutinib is administered as part of a pharmaceutical composition comprising: at least one compound selected from rizzarutinib and pharmaceutically acceptable salts thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is in the form of at least one tablet.

[0119] In some embodiments of the present disclosure, rizzarutinib is orally administered as part of a pharmaceutical composition comprising: at least one compound selected from rizzarutinib and a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is in the form of at least one tablet. In some embodiments, the pharmaceutical composition is in the form of at least one tablet containing 100 mg or 300 mg of rizzarutinib. In some embodiments, the pharmaceutical composition is in the form of at least one tablet containing 100 mg of rizzarutinib. In some embodiments, the pharmaceutical composition is in the form of at least one tablet containing 300 mg of rizzarutinib.

[0120] In some embodiments, rizabrutinib is administered in the form of a film-coated tablet.

[0121] In some embodiments of the present disclosure, rizzarutinib is administered in the form of at least one tablet comprising: at least one compound selected from rizzarutinib and pharmaceutically acceptable salts thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, rizzarutinib is administered in the form of at least one tablet comprising: at least one compound selected from rizzarutinib and pharmaceutically acceptable salts thereof; at least one filler; at least one disintegrant; at least one lubricant; and at least one film coating. In some embodiments, the at least one filler is microcrystalline cellulose. In some embodiments, the at least one disintegrant is cross-linked polyvinylpyrrolidone. In some embodiments, the at least one lubricant is sodium stearyl fumarate.

[0122] In some embodiments, rizabrutinib is administered with a glass of water.

[0123] In some embodiments, rizabrutinib is administered with food.

[0124] In some embodiments, rizabrutinib is administered without food.

[0125] The proportion and nature of any pharmaceutically acceptable excipients may be determined by the chosen route of administration and standard pharmaceutical practice. Unless any conventional pharmaceutically acceptable excipient is incompatible with rizarutinib, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any one or more other components of the pharmaceutical composition, its use is encompassed within the scope of the present disclosure.

[0126] Some non-limiting examples of materials that can be used as pharmaceutically acceptable excipients include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, and walnut oil. Rice oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other nontoxic compatible substances used in pharmaceutical formulations.

[0127] Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, ed. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York also discloses additional non-limiting examples of pharmaceutically acceptable excipients, as well as known techniques for their preparation and use.

[0128] One skilled in the art can readily select the appropriate administration form and route depending on the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. Example

[0129] The following examples are intended to be illustrative and are not meant to limit the scope of the present disclosure in any way. abbreviation: AE adverse event ALP alkaline phosphatase ALT Alanine aminotransferase ANC absolute neutrophil count aPTT activated partial thromboplastin time ASH American Society of Hematology AST Aspartate aminotransferase AUC Area under the plasma concentration-time curve bid / BID twice a day (morning and evening) BP BTK Bruton's tyrosine kinase C Cycle CA Administration CBC Complete blood count CI confidence interval CL / F Apparent total clearance of drug from plasma after oral administration CLL Chronic lymphocytic leukemia Cmax Maximum observed plasma concentration CPK Creatine phosphokinase CRF Case Report Form CRO Contract Research Organization CS Corticosteroids CTCAE Common Terminology Standards for AE CYP Cytochrome P450 D Day DLT Dose-limiting toxicity DNF Not suitable EC Ethics Committee ECG Electrocardiogram EDC Electronic Data Capture EQ-5D VAS Euro-QoL 5-dimensional visual analogue scale FSH Follicle Stimulating Hormone GCP Good Clinical Practice GFR Glomerular filtration rate H2 Histamine type 2 (receptor) HCV Hepatitis C virus HDPE High Density Polyethylene HIV Human immunodeficiency virus HR HRQOL Health-related quality of life IB Researcher's Handbook IBLS ITP Bleeding Scale ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) IDSM Independent Data Security Monitor IR Immediate Release IRB Institutional Review Board (Human Research Ethics Committee) ITP Immune thrombocytopenic purpura ITP-BAT Idiopathic Thrombocytopenic Purpura Bleeding Assessment Tool ITT-E intention-to-treat exposure IV IVIG intravenous immunoglobulin LPLV Last participant last visit LTE Long Term Extension MAD Multiple ascending dose (experimental) MedDRA Medical Dictionary for Regulatory Activities NK Natural Killer (cell) NSAID Nonsteroidal anti-inflammatory drugs OTC Physical Examination PK Pharmacokinetics PO Oral PT / INR Prothrombin time / International Normalized Ratio PV Pemphigus vulgaris PVG Pharmacovigilance qd / QD once a day Q2d / Q2D every other day QoL Quality of life QTcF QT interval corrected for heart rate (Fridiricia correction) rTPO recombinant thrombopoietin RR Resting heart rate SAE Serious Adverse Event SAP Statistical Analysis Program SC Subcutaneous SI International System of Units (French) (International System of Units (English)) SMC Safety Audit Committee SUSAR Suspected unexpected serious adverse reaction TEAE Treatment-emergent adverse events Tmax The time of maximum observed plasma concentration TPO Thrombopoietin TPO-RA Thrombopoietin receptor agonist t 1 / 2 Elimination half-life ULN Upper limit of normal USUBJID Unique Subject Identifier VAS Visual Analogue Scale WBC WHODD World Health Organization Drug Dictionary Example 1: An adaptive, open-label, dose-finding, phase 1 / 2 study investigating the safety, pharmacokinetics, and clinical activity of the oral BTK inhibitor rizarutinib in patients with relapsed / refractory immune thrombocytopenia (Part A)

[0130] An ongoing Phase 1 / 2 clinical trial (NCT03395210) investigating the safety, pharmacokinetics, and clinical activity of the oral BTK inhibitor rizarutinib in patients with relapsed / refractory immune thrombocytopenia (ITP) began enrolling patients on March 22, 2018. As of October 26, 2022, the estimated primary completion date of the study is March 2023, and the estimated study completion date is March 2024. To date, rizarutinib has been well tolerated in patients with ITP, and no treatment-related bleeding or thrombotic events have been reported. In addition, positive preliminary results have been observed in highly treatment-resistant and refractory patient populations. Of the 60 patients enrolled in the study, 24 achieved a major platelet response. In addition, of the 45 patients who started rizarutinib at a dose of 400 mg twice daily, 18 achieved a major platelet response. In addition, 14 patients who started rizabrutinib 400 mg twice daily achieved ≥50 × 10 9 / L platelet count (ie, early response).

[0131] Key inclusion criteria for the Phase 1 / 2 study were: adults aged 18-80 years with relapsed / refractory ITP; ITP either primary or secondary to another disease (e.g., systemic lupus erythematosus, chronic lymphocytic leukemia); no other available / approved treatment options; 1 platelet count <30,000 / μL on ≥2 occasions; and adequate hematologic, hepatic, and renal function. Key exclusion criteria included: pregnant or lactating women; current drug or alcohol abuse; history of solid organ transplant; and positive screening for HIV, hepatitis B, or hepatitis C. Enrolled patients had low platelet counts, relapsed under prior therapy in the absence of available and approved treatment options, or were refractory to prior therapy, and could continue on corticosteroids and / or thrombopoietin mimetics during the study. For example, stable concomitant corticosteroid (CS) or thrombopoietin receptor agonist (TPO-RA) therapy was allowed during the study.

[0132] The sample size used in the study was based on clinical considerations intended to obtain a sufficiently high level of confidence in the study results using the normal approximation method. Supervision

[0133] This study was designed and conducted in accordance with the Good Clinical Practice guidelines in accordance with the International Conference on Harmonization E6 and in accordance with the Declaration of Helsinki. The study protocol and informed consent documents were reviewed and approved by the ethics committee of each participating institution. All patients provided written informed consent.

[0134] The sponsor (Principia / Sanofi) and the principal investigator collaborated in designing the trial. The conduct of the trial was supervised by the sponsor; the data were collected by the investigators and analyzed by the sponsor. The first author is responsible for the content of the first draft of the manuscript; medical writing assistance was provided by the sponsor. All the authors reviewed and provided feedback on drafts, approved the final manuscript for submission, and vouch for the accuracy and completeness of the data, the fidelity of the trial to the protocol, and the complete reporting of adverse events. Participants

[0135] Eligible patients with immune thrombocytopenia were aged 18-80 years (upper age limit 65 years in Norway / Czech Republic) and had platelet counts < 30 × 10 on 2 occasions no less than 7 days apart within 15 days before study entry. 9 / L. Patients were required to have responded to ≥1 prior immune thrombocytopenia therapy (including splenectomy) but were unable to maintain a response to prior / concomitant therapy at baseline. Inclusion criteria:

[0136] The following inclusion criteria are used to inform enrollment of patients in Phase 1 / 2 studies (including, for example, dose escalation studies). 1. Male and female patients aged 18 to 80 years old ( Czech Republic and Norway only : Age range 18 to 65) 2. Immune-related ITP (primary and secondary) 3. Refractory or relapsed patients with no available and approved treatment options, whose platelet counts were <30,000 / μL on two occasions no less than 7 days apart within 15 days before starting study treatment 4. History of response (two or more platelet counts ≥50,000 / μL with increases ≥20,000 / μL) to at least one prior line of therapy (where splenectomy is considered one line of therapy) 5. Adequate blood, liver and kidney function (absolute neutrophil count ≥1.5×10 9 / L, Hgb>9g / dL, AST / ALT≤1.5×ULN, albumin≥3g / dL, total bilirubin≤1.5×ULN, estimated GFR>60 (Cockcroft and Gault method) (C1D1 pre-dose can be checked as early as day -3 before C1D1) 6. Female patients of reproductive potential must agree to use highly effective contraceptive methods (hormonal contraceptive methods that inhibit ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal ligation, vasectomized spouses, sexual abstinence) for the duration of active treatment in the study. Unless surgically sterilized, postmenopausal women should have menopause confirmed by FSH testing. 7. Ability to provide written informed consent and agree to a timeline for evaluation

[0137] Additionally, participants cannot begin the enrollment process until all entry criteria are met.In the event of uncertainty as to the clinical significance of an abnormal screening test result (laboratory or any other test), the test may be repeated. Exclusion criteria:

[0138] The following exclusion criteria were used to inform the enrollment of patients in Phase 1 / 2 studies (including, for example, dose escalation studies). 1. Pregnant or lactating women 2. ECG findings of QTcF >450 msec (males) or >470 msec (females), poorly controlled atrial fibrillation (i.e., symptomatic patients or ventricular rate greater than 100 beats / min on ECG), or other clinically significant abnormalities 3. History or current active malignancy that requires or may require chemotherapy or surgery during the trial, except for non-melanoma skin cancer 4. Blood transfusion or blood products or plasmapheresis within 2 weeks before Day 1 5. Change in corticosteroid and / or TPO agonist dose within 2 weeks prior to Day 1 (change of more than 10% from the daily dose on Day 1) 6. Use of rescue medication other than corticosteroids or TPO in exclusion #5 within 2 weeks prior to Day 1 7. Immunosuppressive drugs other than corticosteroids—these drugs should be discontinued for at least 14 days prior to Day 1 8. Treatment with rituximab or splenectomy within 3 months before Day 1 9. Continued need for proton pump inhibitor medications, such as omeprazole and esomeprazole (it is acceptable to switch patients to H2 receptor blocking medications before Day 1) 10. Concomitant use of known strong to moderate CYP3A (including CYP3A4) inducers or inhibitors within 3 days or 5 half-lives (whichever is longer) of Day 1 11. Use of CYP3A sensitive substrate drugs with narrow therapeutic index within 3 days or 5 half-lives (whichever is longer) of study drug administration, including but not limited to alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus or terfenadine 12. Planned or concomitant use of any anticoagulant and platelet aggregation inhibitor, such as aspirin, NSAID, thienopyridine (within 14 days of planned medication until the end of follow-up) 13. Patients who have received any study drug within 30 days or at least 5 times the elimination half-life of the drug (whichever is longer) before receiving the first dose of the study drug; patients should not be using study devices at the time of administration 14. Current drug or alcohol abuse 15. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant intestinal resection that would prevent adequate absorption of the study drug 16. History of solid organ transplantation 17. Positive screening for HIV, hepatitis B (surface and core antibodies not related to vaccination), or hepatitis C (anti-HCV antibodies confirmed by Hep C RNA) 18. History of serious infection requiring intravenous therapy within the last 3 months prior to Day 1 19. Clinically significant cognitive impairment (≥ Grade 1) or a history indicating an increased risk of cognitive impairment during the study 20. Received a live vaccine within 28 days before Day 1 or plans to receive a live vaccine during the study 21. Plan surgery within the time frame of the medication period 22. Any other clinically significant disease, condition or medical history that the investigator believes would interfere with patient safety, study evaluations and / or study procedures

[0139] In addition, participants must have met all entry criteria to be enrolled in the study. Participants who do not meet the entry criteria may be rescreened once at the investigator's discretion after informing the study medical monitor. Experimental Design

[0140] This is a global Phase 1-2 adaptive, open-label, dose-finding study of oral rizabrutinib conducted in 8 countries (Principia Biopharma Inc, a Sanofi company, South San Francisco, CA) (NCT03395210; EudraCT 2017-004012-19). Rizabrutinib was administered in a 3+3 design with intra-patient dose escalation ( Figure 1 ). The initial dose can be 200 mg once a day (qd), 400 mg once a day, 300 mg twice a day (bid; 600 mg / day), or 400 mg twice a day (800 mg / day; maximum). If no response is observed at a particular dose level for 28 days in 3 patients from the sentinel cohort, the next higher dose is considered as the starting dose. If a response is observed at a low dose in 1 of the 3 patients, the cohort is increased by 3 more patients. If a patient experiences a platelet response, the dose remains unchanged for the next cycle.

[0141] Intra-patient dose escalation was permitted every 28 days at the investigator's discretion to improve response. Safety / efficacy data were reviewed by the Safety Monitoring Committee prior to escalation to higher doses in all patients. The initial study protocol specified a 12-week treatment period; this was subsequently extended to 24 weeks of treatment and 4 weeks of safety follow-up thereafter. Only stable concomitant glucocorticoids / TPO-RAs with a dosing change of ≤10% were allowed throughout the treatment period (unless rescue criteria were triggered) within the 2 weeks prior to the start of rizabrutinib. Platelet count ≥50×10 9 / L or platelet count ≥30×10 9 / L and a response of ≥50% twice baseline during the last 8 weeks of rizabrutinib can continue in the long-term extension phase of 400 mg twice daily. Patients discontinued treatment if dose-limiting toxicity occurred or if rescue criteria were triggered. If a patient required rescue therapy or an increase in concomitant ITP medication exceeded 10% of the daily dose on Day 1, the patient received rescue therapy according to standard of care, discontinued the study, and was considered a non-responder on subsequent efficacy measures. Evaluate:

[0142] After providing written informed consent, subjects typically completed the following clinical assessments: physical examination; medical history; concomitant medications; weight; height; vital signs; ITP-BAT or IBLS bleeding scale; QOL assessment EQ-5D VAS; online cognitive testing; and safety assessments.

[0143] As part of the study, subjects typically complete the following laboratory and ECG evaluations: 1. Urinalysis: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrite, urobilinogen, and leukocytes measured by dip stick or local requirements 2. Hepatitis B and C, HIV 3. Pregnancy testing is only performed on women of childbearing potential. Serum pregnancy test at screening, urine pregnancy test at other visits 4. FSH: used to confirm postmenopausal status in women of reproductive potential who have undergone nonsurgical sterilization 5. ABO and Rh blood types 6. Immature platelet fraction and mean platelet volume (available at local laboratory) 7. Serum chemistry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), total, direct, and indirect bilirubin levels, alkaline phosphatase (ALP), albumin, creatinine, urea, total protein, sodium, chloride, calcium, phosphate, potassium, glucose (random), and creatine phosphokinase (CPK) 8. Hematology (CBC), including differential and reticulocyte count 9. T / B / NK / Monocyte Counts by Flow Cytometry 10.PT / INR PTT 11.TPO level 12. Hemolysis panel consisting of Coombs test and haptoglobin level 13. Platelet Autoantibody Panel (Australia only: test not included) 14. PK sampling at different times 15.12-lead ECG (single and triplicate)

[0144] Laboratory evaluations can be performed at both the central and local laboratories if needed.

[0145] Safety assessments included the following: frequency, severity, and relationship of AEs; changes in clinical laboratory tests; physical examination, ECG, vital signs, and cognitive function. AEs were coded using the Medical Dictionary for Regulatory Activities, version 20.1, and severity was graded according to the National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE), version 4.0. Dose-limiting toxicities (DLTs) during the rizabrutinib treatment period were predefined in the study protocol. Hematological DLTs included: absolute neutrophil count (ANC) <500 / μL for ≥5 days; grade 3 or higher hemoglobin decrease in the absence of pre-existing grade 2 hemoglobin decrease; febrile neutropenia with absolute ANC <1000 / mm 3and a single temperature > 38.3°C or a temperature that persists ≥ 38°C for more than 1 hour; or a bleeding event of grade ≥ 3 or higher requiring platelet transfusion. Non-hematologic DLTs included any grade ≥ 3 non-hematologic toxicity according to NCI CTCAE version 4.0, except for the following: fatigue, laboratory TEAEs, nausea, vomiting, diarrhea, or systemic reactions that returned to baseline or grade 1 (e.g., fever, headache) within 7 days; or any toxicity that was determined by the investigator to be necessary to interrupt study drug for > 7 days.

[0146] Rescue medication (intravenous immunoglobulin [IVIG], high-dose corticosteroids, platelet transfusions, or anti-D immune globulin transfusions) may be used if the patient's platelet count declines significantly, which the investigator believes places the patient at significant risk for a safety event. Patients who receive rescue medication during the study discontinue rizabrutinib treatment. The response status of patients who receive rescue therapy during the study will be evaluated based on the platelet count until the start of rescue therapy.

[0147] In the dose escalation study, after the first dose at the start of each new higher dosing level, patients remained in the clinic for 6 hours with intensive PK sampling. Dosage form:

[0148] In this study, rizzarutinib was administered as a film-coated tablet. Rizarutinib tablets were packaged in white high-density polyethylene (HDPE) bottles with child-resistant induction seal caps; these bottles are intended to be stored at 2°C-8°C and can be shipped at room temperature without ice. In addition, the bottles can be stored at room temperature for up to 2 weeks.

[0149] Each film-coated tablet of lizarutinib contains 100 mg or 300 mg of lizarutinib API. In addition, the tablet also contains microcrystalline cellulose (filler), cross-linked polyvinylpyrrolidone (disintegrant), sodium stearyl fumarate (lubricant) and non-functional film coating. The 100 mg tablet is round in shape and orange in color. The 300 mg tablet is oval in shape and white in color.

[0150] Based on previous studies, food appears to have no effect on the extent of rizabrutinib absorption but reduces the rate of absorption (longer mean T of approximately 2.5 hours). max Therefore, rizabrutinib tablets should be taken with a glass (approximately 8 ounces) of water, but may be taken with or without food, i.e., no fasting period is required. Analyzed groups:

[0151] The screening population for this study included all participants who provided informed consent and had undergone a screening assessment for study participation.

[0152] The safety population includes all participants who received at least one dose of rizarutinib. The safety population is used for all safety analyses. For safety assessments by IDSM, 3 evaluable patients are required for abandoning the dose level due to futility, defined as compliance of the dose at that dose level ≥ 75%. During the study, patients were replaced if necessary to meet this requirement.

[0153] The intention-to-treat exposed (ITT-E) population included all participants who received at least one dose of rizabrutinib.

[0154] The pharmacokinetic analysis population included all participants who received at least one dose of rizabrutinib and had at least one plasma concentration value included in the PK analysis. The pharmacokinetic analysis population was used for all PK analyses.

[0155] Participants who discontinued the study prematurely for reasons other than TEAEs could be replaced at the sponsor's discretion to ensure a sufficient number of evaluable participants.

[0156] Patients who withdraw from the study prior to the scheduled end-of-study visit are considered to have withdrawn prematurely from the study. Participants in this study have the right to withdraw at any time for any reason. In addition, the Investigator may have withdrawn a participant from the study for the occurrence of intercurrent illness, AEs, treatment failure following a prescribed procedure, noncompliance with the study and / or study procedures, or any other reason that the Investigator believes that termination of the study is in the best interest of the participant. Safety and Toxicity Management:

[0157] An independent data safety monitor (IDSM) selected from expert clinicians in the field of ITP provided independent monitoring of the Phase 1 / 2 study. The Safety Monitoring Committee (SMC), consisting of the IDSM as chair, the principal investigator, the study medical monitor, and the sponsor's medical monitor, also closely monitored the conduct of the study, met approximately quarterly, and recommended study modifications or terminations to the sponsor based on a review of safety and efficacy information. SMC findings that impacted patient safety in this study were reported to the local competent authority (CA) and IRB / EC.

[0158] IDSM conducted a "sentinel cohort" safety evaluation. Data from "sentinel patients" at each dose level were reviewed by IDSM to select the starting dose for additional new patients. After review, IDSM may decide that the starting dose for new patients should be abandoned due to ineffectiveness (lack of platelet response), increased to the next planned dosing level, maintained or reduced. New patients entering the study started at a dose level determined by IDSM based on the following: (1) If ≥2 / 3 or ≥2 / 6 of those sentinel patients had a DLT at any dose level, that level was determined as the "maximum administered dose" and the starting dose (new patients) and continuing dose (patients already on study) were set at a lower dosing level (or if the current sentinel dose cohort is 200 mg once daily, the study was suspended); (2) If two or more persistent platelet responses (3 out of 4 counts) were observed in sentinel patients at the current starting dose level, the starting dose would not be escalated. Clinical adverse events

[0159] The AE collection period begins at the time of the first screening / qualification assessment and will end at the end of the study for each patient. AE is any adverse medical event that occurs in a participant or clinical study participant to whom the drug is administered and is not necessarily causally related to the intervention. Therefore, AE can be any adverse and unexpected sign (e.g., including abnormal laboratory test results), symptom or disease related to the time of the use of the study product, whether or not it is considered to be related to the product. Instruct the investigator to record in detail all AEs encountered during the clinical study from the date of the participant's consent to the study follow-up period. Pre-existing conditions that worsened during the study were reported as AEs. Relationship of adverse events to study drugs

[0160] Instruct investigators to use their knowledge of the study participants, the circumstances surrounding the event, and an evaluation of any potential alternative causes to determine whether the AE can be considered related to the study drug, indicating "yes" or "no" accordingly. Investigators are asked to consider the following information in assessing relatedness: (1) the temporal relationship of the onset of the event to the initiation of study drug; (2) the course of the event, with particular consideration of the effects of dose reduction, discontinuation of study drug, or reintroduction of study drug (if applicable); (3) the known association of the event to the study drug or to similar treatments; (4) the known association of the event to the condition being studied; (5) the presence of risk factors in the study participants or the use of concomitant medications known to increase the occurrence of the event; and (6) the presence of non-treatment-related factors known to be associated with the occurrence of the event.

[0161] Investigators were instructed to follow up AEs based on the PK characteristics of the drug, especially those of grade 3 or higher in severity, until stable or until 4 weeks after the last dose (considered as the last follow-up). Laboratory and ECG abnormalities

[0162] Investigators are instructed to record as a single diagnosis on the AE page of the CRF any abnormal laboratory or ECG result that occurs during treatment that is clinically significant, i.e., meets one or more of the following criteria. As non-limiting examples, laboratory and ECG abnormalities with clinical symptoms that result in a change in study medication (e.g., dose modification, interruption, or permanent discontinuation) or require a change in concomitant therapy (e.g., addition, interruption, discontinuation, or any other change in concomitant medication, therapy, or treatment) should be recorded as an AE, where any laboratory or ECG result abnormality that meets the criteria for a serious adverse event (SAE) in addition to being reported as an AE is reported as such. Adverse event severity grading

[0163] Investigators were instructed to report all clinical AEs encountered during the study. The intensity of AEs was graded based on the NCI CTCAE version 4.0 or higher. For any AEs not identified in the CTCAE, an explanation of the intensity grading can be found below:

[0164] Grade 1: Mild; asymptomatic or mildly symptomatic; clinical or diagnostic observation only; intervention not indicated.

[0165] Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limitation to instrumental activities of daily living that are age-appropriate.

[0166] Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; disabling; limiting self-care activities of daily living.

[0167] A serious adverse event (SAE) is any experience (clinical AE or abnormal laboratory test) suggesting a significant hazard, contraindication, side effect, or precaution. At any dose level, an SAE must meet at least one of the following criteria: fatal (resulting in a fatal outcome); life-threatening; requiring inpatient hospitalization or prolongation of existing hospitalization; resulting in persistent or significant disability / incapacity; congenital anomaly / birth defect; or medically significant or requiring intervention to prevent one or more of the above outcomes. Investigators are instructed to report life-threatening events, or any event with a fatal outcome should be reported as an SAE. pregnancy

[0168] Any female clinical trial participant who becomes pregnant during the study should be instructed to stop taking the study drug and inform the investigator immediately. Pregnancies that occur up to 90 days after completion of study medication should also be reported to the investigator. Ethical considerations:

[0169] The task of the investigator is to ensure that the research is conducted in full compliance with the principles of the Declaration of Helsinki or the laws and regulations of the country in which the research is conducted, whichever provides greater protection for individuals. In addition, the research adheres to the principles outlined in the current ICH Tripartite Guideline for Good Clinical Practice, or complies with local law if it provides greater protection for participants.

[0170] Signed and dated informed consent should be obtained from each participant prior to participation in the study after a full explanation of the purpose, methods, objectives, and potential risks of the study. The investigator or designee must have explained that the participant is completely free to refuse entry into the study or to withdraw from the study at any time for any reason. Physical examination procedures:

[0171] At screening and follow-up visits in the study, a complete physical examination consisted of checking the normality or abnormality of the following body systems: general appearance, skin, eyes, ears, nose, throat, heart, chest / breast, abdomen, nervous system, lymph nodes, spine, and extremities (skeletal) and online cognitive tests of learning and memory. An abbreviated physical examination consisted of checking the normality or abnormality of the following body systems: general appearance, skin, abdomen, and cardiopulmonary examination. Only height was recorded at screening. Blood pressure (BP), pulse rate, temperature, and respiratory rate were recorded at specific time points.

[0172] A single 12-lead ECG assessment is also obtained at a specific time point to confirm eligibility and ensure real-time safety assessment of participants in the study. For ECG assessment, participants should have been in a resting position for at least 10 minutes before any measurement. Body posture should also be maintained throughout each ECG assessment. In particular, changes in heart rate should be avoided. During the rest period before ECG and ECG recording time, there should be no environmental interference (TV, radio, conversation).

[0173] Heart rate (HR), QRS duration and respiratory rate (RR) and QT interval were recorded. Changes in T wave and U wave morphology and overall ECG interpretation were recorded. All ECG recordings were performed using a standard high-quality, high-fidelity digital electrocardiogram machine equipped with computer-based interval measurement. For triplicate ECG assessments, at least three interpretable ECG records (no artifacts) were collected at each time point within a time period of ±10 minutes at each time point. Laboratory Testing Procedures:

[0174] Laboratory assessments were performed at a central laboratory, with consideration given to ad hoc local laboratory testing if necessary. Laboratory safety tests were collected at specific time points. Additional blood or urine samples may be collected at the investigator's discretion if the results of any test are outside the reference range, or if clinical symptoms dictate additional testing to monitor the participant's safety. In cases where the clinical significance of an abnormal laboratory result is considered uncertain, screening laboratory tests may be repeated prior to Day 1 to confirm eligibility. In the event of unexplained clinically significant abnormal laboratory test values, the tests should be repeated promptly and followed up until they return to the normal range, are considered clinically stable, and / or an appropriate explanation for the abnormality is found. ending:

[0175] The primary endpoints were safety and platelet count response. Safety was graded according to NCI CTCAE version 4.0. Platelet response was defined as the proportion of patients who achieved ≥2 consecutive platelet counts (≥5 days apart) ≥50 × 10 9 / L, and the increase from baseline is ≥20×10 9 / L and no immune thrombocytopenia rescue medication was used within 4 weeks before the most recent elevated platelet count. In the event of a missing platelet count, the mean of the nonmissing platelet counts was used.

[0176] The secondary efficacy endpoint was platelet count ≥50×10 9 / L per week, 4 of the last 8 platelet counts ≥50×10 9 The proportion of patients with platelet counts ≥50 × 10 / L, the change in mean platelet count from baseline to day 1 in patients treated for >4 weeks, and the proportion of patients with platelet counts ≥50 × 10 9 / L weeks, platelet count ≥ 30 × 10 9 / L and the number of weeks until the first platelet count ≥ 50 × 10 9 / L. Secondary safety endpoints included the use of rescue medication at the end of the treatment period, the proportion of patients with ≥ grade 2 bleeding events, and bleeding scale scores (using the Immune Thrombocytopenia Specific Bleeding Assessment Tool (ITP-BAT) (Rodeghiero et al., 2013) and / or the Immune Thrombocytopenia Bleeding Scale (IBLS)). Post hoc analyses of responders and non-responders, as well as subgroup analyses of platelet response, were included, which evaluated the potential impact of baseline patient and disease characteristics. Statistical analysis:

[0177] The safety population includes all patients who receive ≥1 dose of rizarutinib. The intended treatment population includes all patients enrolled in the study. With an initial sample size of 24 and an expected efficacy rate of 40% (i.e., platelet response in 15 evaluable patients), the study can use the normal approximation method to produce 80% confidence, i.e., the true proportion will be ≥24% (80% CI ± 16%). The sample size was later increased to better evaluate the outcome at the highest twice-daily dose of 400mg. Sixty patients were enrolled, so that about 15 patients completed 24 weeks of treatment, and ≥10 patients completed 24 weeks of rizarutinib with a starting dose of 400mg twice a day.

[0178] Descriptive statistics and frequency tabulations summarized the data for each dose and overall. The primary efficacy endpoint and binomial confidence interval (CI) were analyzed by the Clopper-Pearson method. Time-to-event estimates were performed using Kaplan-Meier. result Patient characteristics:

[0179] The study began on March 22, 2018 (data cutoff May 4, 2021); these results include all 60 patients who were enrolled in the study and subsequently had the option to continue in the long-term extension ( Figure 1 Three patients who completed the original regimen of 12 weeks of treatment were also included. The median age of the patients was 50 years (range, 19-74 years), and 57% were female (Table 1). The median baseline platelet count was 15×10 9 / L(Range, 2×10 9 / L-33×10 9 / L). The median duration of immune thrombocytopenia was 6.3 years (range, 0.4-52.5 years), and patients had received a median of 4 (range, 1-17) prior unique immune thrombocytopenia therapies. The most common prior therapies were glucocorticoids (92%), TPO-RAs (including eltrombopag or romiplostim) (58%), IVIG (43%), and rituximab (40%); 25% of patients had a prior splenectomy. Insufficient platelet counts (<30 × 10 9 Patients receiving glucocorticoids / TPO-RAs who were on 100 mg / dL continued to receive stable doses of these medications.

[0180] Table 1. Characteristics of patients at baseline (safety population). *Disease duration is the difference between the date of first rizabrutinib dose and the date of initial diagnosis. Unique ITP therapy was identified using CMDECOD (standardized or lexicographically derived text description of CMTRT or CMMODIFY), and splenectomy could be considered as a prior ITP therapy. Stable concomitant glucocorticoids / TPO-RA were defined as a dose change of ≤10% within 2 weeks prior to starting rizabrutinib, as permitted by the protocol. treat:

[0181] Patients received rizarutinib for a median of 167.5 days (range, 4-293 days). Nine patients started treatment at 200 mg once daily; during treatment, 2 of these patients maintained the 200 mg dose once daily, 1 patient had the dose escalated to a maximum of 400 mg once daily, 3 patients had the dose escalated to a maximum of 300 mg twice daily (600 mg / day), and 3 patients had the dose escalated to a maximum of 400 mg twice daily (800 mg / day; n=3) ( Figure 2 ). One patient who started rizarutinib at 400 mg once daily was dose-escalated to a maximum dose of 400 mg twice daily. Of the five patients who started at 300 mg twice daily (600 mg / day), three were dose-escalated to a maximum dose of 400 mg twice daily. All 45 patients who started at 400 mg twice daily remained on this dose with no dose reductions / interruptions due to adverse events and no dose-limiting toxicities.

[0182] Overall, 40 patients received concomitant medication (excluding rescue medication). TPO-RA in 24 patients and glucocorticoids in 23 patients were the most commonly used. Among the 24 patients who achieved the primary efficacy endpoint, 4 patients only received concomitant TPO-RA, 8 patients only received glucocorticoids, 3 patients received concomitant TPO-RA and glucocorticoids, and 9 patients did not receive them. Importantly, these patients were considered to be inadequate responders at baseline. Security:

[0183] Rescue medication was used in seven (12%) patients (1 patient 200 mg once daily, 1 patient 300 mg twice daily, 5 patients 400 mg twice daily; Table 2). In four patients, the use of rescue medication was the reason for study discontinuation (as required by the study protocol). The other two patients received rescue medication but discontinued due to unrelated adverse events. One patient received rescue medication after discontinuing the study due to lack of response.

[0184] Table 2. Patients who received one or more rescue medications and information on their discontinuations during the study due to adverse events, lack of response, and / or use of rescue medication. *Rizabrutinib dose when using rescue medication.

[0185] Thirty-one of 60 patients (52%) who started rizabrutinib at all doses and 38 of 45 patients (84%) who started rizabrutinib at 400 mg twice daily experienced ≥1 treatment-related, treatment-emergent adverse event; all were Grade 1 or 2 and transient (Tables 3A and 3B; Table 4).

[0186] The most common treatment-related, treatment-emergent adverse events of any grade observed in patients starting rizabrutinib at all doses were diarrhea (32%), nausea (30%), and fatigue (10%) (Table 3A and Table 4). One patient had a treatment-related grade 1 contusion (bleeding), and 1 patient had a treatment-related grade 2 erysipelas (infection) that resolved after treatment. No treatment-related grade ≥3 or serious adverse events were observed. There were no signs or symptoms of adverse events commonly associated with BTK inhibitors (i.e., neutropenia, treatment-related infections, bleeding, thrombotic events, fungal infections, or atrial fibrillation). Among the 45 patients who started rizabrutinib at 400 mg twice daily, the most commonly observed treatment-related, treatment-emergent adverse events of any grade were diarrhea (36%), nausea (31%), and fatigue (9%) (Table 3B). There were no treatment-related bleeding or thrombotic events of grade ≥2.

[0187] One patient died unrelated to treatment; this patient discontinued 400 mg of rizabrutinib twice daily on day 8 due to worsening of pre-existing Evans syndrome and died 135 days after study entry. The IBLS bleeding scale scores in each domain showed no increase from baseline to the end of treatment, but there was improvement in bleeding at the skin and oral sites ( Figure 3 ).

[0188] Table 3A. Summary of treatment-emergent adverse events by grade (treatment-related events occurring in ≥5%; safety population; N=60 patients who started rizabrutinib at all doses). — indicates zero events *All treatment-related TEAEs were Grade 1 or 2; none were Grade ≥ 3. Eight patients experienced grade 3 / 4 TEAEs due to any cause and unrelated to rizabrutinib treatment (multiple events may occur in a single patient), including grade 3 anemia (n=2); one patient each had grade 3 abnormal alanine aminotransferase level, contusion, gastrointestinal bleeding, hematoma, immune thrombocytopenia, myelofibrosis, or thrombocytopenia; and one patient each had grade 4 Evans syndrome or thrombocytopenia.

[0189] Table 3B. Summary of treatment-emergent adverse events by grade in N = 45 patients who started rizabrutinib at 400 mg twice daily (Treatment-related events occurring in ≥5%) *All treatment-related TEAEs were Grade 1 or 2; none were Grade ≥ 3.

[0190] Table 4. Summary of treatment-emergent adverse events by grade (occurring in ≥2 patients regardless of cause or treatment-related in ≥1 patient; safety population; N=60). — indicates zero event; TEAE, treatment-emergent adverse event. *All treatment-related TEAEs were Grade 1 or 2; none were Grade ≥ 3. Eight patients experienced grade 3 / 4 TEAEs due to any cause and unrelated to rizabrutinib treatment (multiple events may occur in a single patient), including grade 3 anemia (n=2); one patient each had grade 3 abnormal alanine aminotransferase level, contusion, gastrointestinal bleeding, hematoma, immune thrombocytopenia, myelofibrosis, or thrombocytopenia; and one patient each had grade 4 Evans syndrome or thrombocytopenia. Other infections and infestations not listed in the table that were not related to treatment and occurred in individual patients included Grade 1 Candida infection, fungal skin infection, and osteomyelitis; and Grade 2 infected skin ulcer and oral herpes, respectively.

[0191] Seven patients experienced TEAEs leading to discontinuation of study drug (4 (7%) patients had gastrointestinal (GI) disorders, 2 (4%) had lymphatic system disorders, and 1 (2%) had administration site disorders). Except for Grade 1 fatigue in 1 patient and Grade 2 GI disorders in 2 patients, all TEAEs were unrelated to rizabrutinib treatment. All TEAEs leading to discontinuation of study drug were Grade 1 or 2 in severity, with the exception of Grade 3 GI bleeding, Grade 4 thrombocytopenia, and Grade 4 Evans syndrome, which occurred in 1 patient each. Four TEAEs leading to discontinuation of study drug were reported as serious adverse events (Grade 2 rectal bleeding, Grade 3 GI bleeding, Grade 4 thrombocytopenia, and Grade 4 Evans syndrome); none of them were related to rizabrutinib treatment. effect:

[0192] For this 24-week study, all 60 patients were evaluable for efficacy. The primary endpoint (≥2 consecutive platelet counts ≥50 × 10-10 without the need for rescue medication) was achieved in 24 patients (40%; 95% CI, 28%-53%). 9 / L, and the increase from baseline is ≥20×10 9 / L) (Table 5). Depending on the dose level at any time during the study (patients can respond at more than one dose level), 1 of 9 patients (11%) achieved the primary endpoint at 200 mg once daily, 2 of 8 patients (25%) achieved the primary endpoint at 400 mg once daily, 4 of 12 patients (33%) achieved the primary endpoint at 300 mg twice daily, and 20 of 52 patients (38%) achieved the primary endpoint at 400 mg twice daily. Of the 45 patients who started and maintained rizarutinib at a dose of 400 mg twice daily throughout the study, 18 (40%) patients achieved a major platelet response (Table 5; Table 6 Efficacy by initial dose).

[0193] Table 5. Efficacy outcomes. Note: Efficacy endpoints by initial dose level of rizabrutinib for the 24-week study (and prior to long-term extension) are reported in Table 6. CI, confidence interval (based on the Wilson score method). The width of the confidence intervals is not adjusted for multiplicity and should not be used to definitively infer power. *The primary endpoint of platelet response was defined as ≥2 consecutive platelet counts (at least 5 days apart) ≥50×10 9 / L, and the increase from baseline is ≥20×10 9 / L and no rescue medication was required in the 4 weeks before the most recent elevated platelet count. The primary endpoint was achieved at any time with a dose of 200 mg once daily (n=1), 400 mg once daily (n=2), 300 mg twice daily (n=4), and 400 mg twice daily (n=20); the primary endpoint could be achieved at different doses in the same patient. Post hoc analysis of responding patients.

[0194] Table 6. Efficacy outcomes by initial dose of rizabrutinib. CI, confidence interval (based on Wilson score); NA, not applicable; NE, not evaluated. The width of the confidence intervals was not adjusted for multiplicity and should not be used to definitively infer efficacy. *The primary endpoint of platelet response was defined as ≥2 consecutive platelet counts (at least 5 days apart) ≥50×10 9 / L, and the increase from baseline is ≥20×10 9 / L and no rescue medication was required in the 4 weeks before the most recent elevated platelet count.

[0195] Overall, platelet counts ≥ 50 × 10 9 The mean percentage of weeks with ≥50 × 10 / L was 29%; post hoc analysis showed that the mean percentage of responding patients meeting the primary endpoint was 65%. Based on the safety profile of low grade and consistent efficacy observed at the highest evaluated dose, the minimum effective dose of rizarutinib was determined to be 400 mg twice daily. Increments beyond 400 mg twice daily were not tested. ≥4 of the final 8 platelet counts were ≥50 × 10 9 The proportion of patients with platelet counts above 400 mg / L was 17 (28%) overall and 14 (31%) for patients starting at 400 mg twice daily (Table 5). The mean change from baseline to mean platelet count after Day 1 for patients completing >4 weeks of treatment was 29 × 10 9 / L(SD,40×10 9 / L), and 31 × 10 for patients starting with 400 mg twice daily 9 / L(SD,43×10 9 / L). In the overall patient population, ≥50×10 9 / L and ≥30×10 9Platelet counts of ≥50×10 / L were maintained for a median of 1 week and a median of 5 weeks, respectively. When evaluating responders meeting the primary efficacy platelet count in the overall population (n=24) and those starting with 400 mg twice daily (n=18), these respective groups maintained ≥50×10 9 The median platelet count was ≥30×10 / L at 16 and 14 weeks, and the median platelet count was ≥30×10 / L in both groups. 9 / L median platelet count 21 weeks ( Figure 4 and Figure 5 ). Until the first platelet count ≥50×10 9 The median time to achieve 400 mg / L was 11.5 days for all patients and 12.5 days for those who started with 400 mg twice daily ( Figure 6-Figure 8 , Table 5, Table 6).

[0196] Major platelet responses were generally comparable in the subgroups of patients with chronic immune thrombocytopenia (duration >12 months) and persistent immune thrombocytopenia (duration 3-12 months), heavily pretreated with ≥4 prior immune thrombocytopenia therapies, and those who had received rizabrutinib monotherapy, concomitant immune thrombocytopenia therapy, or prior splenectomy ( Fig. 9 ).

[0197] This clinical study demonstrates that BTK inhibition with rizarutinib is effective in suppressing immune-mediated platelet destruction in immune thrombocytopenia, thereby providing a novel mechanism for targeting potential immune thrombocytopenia pathology. Patients have experienced immune thrombocytopenia for a median duration of 6.3 years, using a median of four unique prior therapies. It is worth noting that eligibility is based on the inability to maintain adequate response to prior / concomitant therapy (including splenectomy) and the continued need for treatment. At all doses, oral rizarutinib was associated with only low-grade toxicity, consistent with early clinical studies in healthy volunteers (Smith PF et al., 2017) and planned doses from preclinical studies (Langrish CL et al., 2021). Although follow-up was limited, there was no evidence of infection, thrombotic events, arrhythmias, liver toxicity, or increased bleeding commonly associated with BTK inhibitors and / or TPO-RAs (Aguilar C, 2018; Shatzel JJ et al., 2017; Ghanima W et al., 2018; von Hundelshausen P and Seiss W, 2021). In addition, no patient had a platelet count >400×10 9 / L. The safety profile of rizarutinib was consistent with previous Phase 1 healthy volunteer results (Smith PF et al., 2017).

[0198] Rizabrutinib resulted in a rapid platelet response and a clinically significant platelet response (≥50 × 10 9 / L). Important treatment factors for patients with immune thrombocytopenia are rapid improvement and maintenance of a durable response over time. 9 The median time to platelet counts of 1 / L was rapid, at 11.5 days, and platelet counts were maintained for a median of 72% of the weeks in responders during the 24-week treatment period. Importantly, platelet responses were consistent across baseline subgroups.

[0199] No standard treatment recommendations exist for patients with multiple relapses of immune thrombocytopenia. Treatment / study comparisons are further complicated by a range of time points and platelet response endpoints. The most recent ASH treatment guidelines for immune thrombocytopenia lasting ≥3 months recommend TPO-RA, rituximab, or splenectomy (Neunert et al., 2019). Immunomodulatory agents used for relapsed immune thrombocytopenia include the spleen tyrosine kinase inhibitor fostamatinib (Tavalisse (Fostamatinib) Prescribing Information, 2020) and the anti-CD20 antibody rituximab (Ghanima W et al., 2015; Deshayes S et al., 2019; Tjonnfjord E et al., 2020). Although splenectomy has a high durable remission rate (approximately 60%-70% of patients), it is generally considered less favorable due to potential surgical complications, higher risk of infectious / thromboembolic events, and increased lifelong risk of sepsis due to encapsulated microorganisms (Cooper N and Ghanima W, 2019; Kojouri K et al., 2004). Treatment selection is generally individualized based on patient age / characteristics, comorbidities, disease duration, bleeding frequency, treatment availability, and patient preference (Neunert et al., 2019). Despite significant advances in immune thrombocytopenia treatment options over the past 15 years, a subset of patients remain refractory to existing therapies and remain difficult to achieve durable remission. Because our patients were heavily pretreated and many were considered by investigators to have limited treatment options, BTK inhibition with rizarutinib provides a novel therapeutic approach by targeting immune-mediated platelet destruction and impaired platelet production.

[0200] This phase 1-2, dose-finding clinical study established the role of BTK inhibition in the treatment of immune thrombocytopenia. Overall, oral rizarutinib showed rapid and lasting clinical activity in up to half of patients with immune thrombocytopenia who had received multiple prior therapies, with a low-grade safety profile. Rizarutinib was shown to be safe and effective at a dose of 400 mg twice a day. Example 2: An adaptive, open-label, dose-finding, phase 1 / 2 study investigating the safety, pharmacokinetics, and clinical activity of the oral BTK inhibitor rizarutinib in patients with relapsed / refractory immune thrombocytopenia (Part B)

[0201] Part B of the open-label, Phase 1 / 2 study continues to evaluate the safety and efficacy of 400 mg of rizabrutinib twice daily in patients with recurrent ITP who had ≥2 baseline platelet counts <30 × 10 9 Adult patients (age 18-80 years) with ≥50% platelet count or ≥50% platelet count (≥50% platelet count) who were eligible for treatment. 9 / L) and had failed ≥1 other non-IVIG, non-CS ITP therapy. Stable doses of concomitant CS / TPO-RA were allowed with rizabrutinib. The primary endpoints were safety and durable platelet response (defined as platelet counts ≥50 × 10-10 for ≥8 weeks out of the last 12 weeks of rizabrutinib without rescue medication). 9 Consistent with the results of Part A, rizabrutinib demonstrated rapid, stable, and durable platelet responses in patients with recurrent ITP and had a favorable safety profile in Part B.

[0202] Change from baseline in the ITP Bleeding Scale (IBLS) score (0 no bleeding to 2 significant bleeding) was a secondary endpoint evaluating bleeding at 9 anatomic sites (8 anatomic sites for men / postmenopausal women). Exploratory health-related quality of life (HRQOL) endpoints were assessed using the EuroQol-5 Dimensions 5 Levels (EQ-5D-5L) + Visual Analog Scale (EQ-VAS) and the ITP Patient Assessment Questionnaire TM (ITP-PAQ) score (0 worst to 100 best QOL). Overall, patients treated with rizabrutinib demonstrated sustained platelet response, high compliance, and improvements on HRQOL measures in patients with difficult-to-treat recurrent ITP. There was no evidence of increased bleeding with rizabrutinib, and scores at skin sites improved. Clinically meaningful improvements in HRQOL were observed in multiple individual and overall HRQOL health domains after taking rizabrutinib. Example 3: Clinical Predictors of Response to Rizabrutinib Therapy in Patients with Immune Thrombocytopenia: Exploratory Analysis of a Phase 1 / 2 Study

[0203] In 45 patients who started 400 mg rizabrutinib twice daily (BID) (see Example 1), 11 baseline clinical variables and pharmacokinetic (PK) exposure at steady state were selected as potential predictors of platelet response. Platelet response was defined as ≥2 consecutive platelet counts ≥50×10 9 / L (≥5 days apart) and an increase of ≥20×10 9 / L and no rescue medication in the 4 weeks before the most recent elevated platelet count, and early response defined as a platelet count ≥50 × 10-10 as of day 8 9 / L. Clinical predictors were selected based on clinical considerations expected to be associated with platelet responses and evaluated by univariate logistic regression models. For continuous variables, t-tests were used to test differences, while for categorical variables, Fisher's exact test was used. Based on post hoc analysis from a previously established population PK model, PK exposure at steady state was estimated. result

[0204] Among the 45 patients who started on 400 mg of rizabrutinib twice daily, the median age was 49 years (Table 1). Patients had a median ITP duration of 6.1 years, 15×10 9 The median platelet count was 2.3 / L and the median number of prior ITP therapies was four. Twenty-four percent of patients had undergone splenectomy prior to starting treatment. Eighteen patients achieved a major platelet response, of which 14 were early responders ( Fig.11 ).

[0205] Based on the univariate logistic regression model, significant predictors of response to rizabrutinib were shorter duration of ITP (P = .04) and no prior use of thrombopoietin receptor agonists (TPO-RAs; P = .03) or rituximab (P = .02; Table 7). The absence of prior rituximab therapy was also a significant predictor of early responders (P = .02; Table 7). In contrast, the use of concomitant ITP medications (TPO-RAs or corticosteroids) was not associated with predicting response or early response to rizabrutinib treatment. Similar results were noted when continuous variables were assessed by mean difference. Responders had a significantly shorter mean duration of ITP (P < .01) and a lower number of prior treatment lines (P = .01) compared with their counterparts, as did early responders (P < .01 for both; Fig.10). Among categorical variables assessed by comparing proportions of patients, significant associations with being a responder versus a non-responder were observed in the absence of prior use of a TPO-RA (P = .05) and in the absence of prior rituximab therapy (P = .03). Responders were 29% versus 64% in patients with versus without prior TPO-RA use, and 23% versus 57% in those with versus without prior rituximab use. The absence of prior rituximab was also significantly associated with an early response to rizabrutinib (P = .02), with 48% of these patients being early responders compared to 14% of those who received prior rituximab. None of the PK exposure measures significantly affected response to rizabrutinib.

[0206] Table 7. Individual logistic regression model results. P values ​​< 0.05 were considered significant.

[0207] In patients heavily pretreated with ITP, the strongest predictors of response appeared to be short duration of ITP and no history of rituximab therapy, suggesting that more treatment-naïve patients were more likely to respond to rizabrutinib therapy than those who received prior ITP medications. Implementation plan: Non-limiting embodiments of the present disclosure include: 1. A method for treating immune thrombocytopenia (ITP) in a human patient in need thereof who has not received prior treatment with a thrombopoietin receptor agonist (TPO-RA) or rituximab, the method comprising administering to the human patient who has not received prior treatment with a TPO-RA or rituximab twice daily during a treatment period a therapeutically effective amount 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]pent-2-enenitrile and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof has at least one characteristic selected from the group consisting of: a. Platelet count <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to starting study treatment; and b. History of response to at least one prior line of therapy (two or more platelet counts ≥50,000 / μL with an increase of ≥20,000 / μL). 2. A method for treating immune thrombocytopenia (ITP) in a human patient in need thereof who has not received prior treatment with a thrombopoietin receptor agonist (TPO-RA), the method comprising administering to the human patient who has not received prior treatment with a TPO-RA twice daily during a treatment period a therapeutically effective amount of at least one compound selected from the group consisting of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof has at least one characteristic selected from the group consisting of: a. Platelet count <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to starting study treatment; and b. History of response to at least one prior line of therapy (two or more platelet counts ≥50,000 / μL with an increase of ≥20,000 / μL). 3. A method for treating immune thrombocytopenia (ITP) in a human patient in need thereof who has not received prior treatment with rituximab, the method comprising administering to the human patient who has not received prior treatment with rituximab twice daily during a treatment period a therapeutically effective amount 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]pent-2-enenitrile and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof has at least one characteristic selected from the group consisting of: a. Platelet count <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to starting study treatment; and b. History of response to at least one prior line of therapy (two or more platelet counts ≥50,000 / μL with an increase of ≥20,000 / μL). 4. The method according to any one of embodiments 1 or 2, wherein the TPO-RA is selected from: recombinant thrombopoietin (rTPO), romiplostim, eltrombopag and avatrombopag. 5. The method of any one of embodiments 1-2 or 4, wherein the patient has not received prior treatment with rituximab. 6. The method of any one of embodiments 1-5, wherein the at least one prior line of treatment, wherein at least one prior therapy is selected from splenectomy, intravenous immunoglobulin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressive drugs. 7. A method according to any one of embodiments 1-6, wherein the patient achieves at least one platelet count that is at least 20,000 / μL above a baseline platelet count, wherein the baseline platelet count is the average of two platelet counts performed on two occasions no less than 7 days apart within 15 days prior to the start of treatment and a third count performed on the first day of the study. 8. The method of any one of embodiments 1-7, wherein the patient achieves at least two platelet counts that are at least 20,000 / μL above the baseline platelet count. 9. The method of embodiment 8, wherein the patient achieves at least two consecutive platelet counts that are at least 20,000 / μL above the baseline platelet count. 10. The method of any one of embodiments 8 or 9, wherein at least two consecutive platelet counts that are at least 20,000 / μL above the baseline platelet count are separated by at least five days, such as at least seven days. 11. The method of any one of embodiments 1-10, wherein the patient achieves a platelet count of at least 50,000 / μL. 12. The method of any one of embodiments 1-11, wherein the patient achieves at least two platelet counts of at least 50,000 / μL. 13. The method of embodiment 12, wherein the patient achieves at least two consecutive platelet counts of at least 50,000 / μL. 14. The method according to any one of embodiments 12 or 13, wherein the at least two consecutive platelet counts of at least 50,000 / μL are separated by at least five days, such as at least seven days. 15. The method of any one of embodiments 1-14, wherein the human patient achieves at least one platelet count of at least 50,000 / μL within eight days of starting treatment. 16. The method of any one of embodiments 11-15, wherein the human patient has not received rescue medication during the four weeks prior to the most recent platelet count of at least 50,000 / μL. 17. The method of any one of embodiments 1-16, wherein the human patient has been suffering from ITP for six years or less. 18. The method of any one of embodiments 1-17, wherein the human patient has a history of receiving at least one prior ITP therapy prior to the start of the treatment period. 19. The method of any one of embodiments 1-18, wherein the human patient has a history of receiving at least two prior ITP therapies prior to the start of the treatment period. 20. The method of any one of embodiments 1-19, wherein the human patient has a history of receiving at least three prior ITP therapies prior to the start of the treatment period. 21. The method of any one of embodiments 1-20, wherein the human patient has a history of receiving at least four prior ITP therapies prior to the start of the treatment period. 22. The method of any one of embodiments 1-21, wherein the human patient has a history of receiving at least five prior ITP therapies prior to the start of the treatment period. 23. The method of any one of embodiments 1-22, wherein the human patient has a platelet count between 2,000 / μL and 33,000 / μL on two occasions within 15 days prior to the start of the treatment period and no less than 7 days apart. 24. The method of any one of embodiments 1-23, wherein the human patient underwent a splenectomy prior to the start of the treatment period. 25. The method according to any one of embodiments 2 or 4-24, wherein the human patient has a history of receiving rituximab prior to the start of the treatment period. 26. The method of any one of embodiments 3-25, wherein the human patient has a history of receiving at least one TPO-RA prior to the start of the treatment period. 27. The method of embodiment 26, wherein the at least one TPO-RA is selected from rTPO, romiplostim, eltrombopag, and avatrombopag. 28. The method of any one of embodiments 1-27, wherein the patient has a history of response to at least one prior line of treatment, wherein at least one prior therapy is selected from splenectomy, intravenous immunoglobulin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressive drugs. 29. The method of any one of embodiments 1-28, wherein the human patient has a history of receiving intravenous immunoglobulin (IVIG) prior to the start of the treatment period. 30. The method of any one of embodiments 1-28, wherein the human patient has a history of receiving corticosteroids prior to the start of the treatment period. 31. A method according to any one of embodiments 1-28, wherein the human patient has a history of receiving anti-D immunoglobulin therapy prior to the start of the treatment period. 32. A method according to any one of embodiments 1-28, wherein the human patient has a history of receiving at least one immunosuppressive drug prior to the start of the treatment period. 33. The method according to embodiment 32, wherein the at least one immunosuppressive drug is selected from fostamatinib, mycophenolate mofetil (MMF) and cyclosporine. 34. The method of any one of embodiments 28-33, wherein the response to prior ITP therapy comprises a platelet count of ≥50,000 / μL. 35. The method of any one of embodiments 1-34, wherein the human patient suffers from primary ITP. 36. The method of any one of embodiments 1-34, wherein the human patient suffers from secondary ITP. 37. The method of any one of embodiments 1-34, wherein the human patient does not suffer from chronic ITP. 38. The method of any one of embodiments 1-34, wherein the human patient suffers from persistent ITP. 39. The method of any one of embodiments 1-34, wherein the human patient suffers from chronic ITP. 40. The method of any one of embodiments 1-34, wherein the human patient suffers from recurrent ITP. 41. The method of any one of embodiments 1-34, wherein the human patient has refractory ITP. 42. The method of any one of embodiments 1-41, wherein the treatment period is at least 8 days. 43. A method according to any one of embodiments 1-42, wherein the treatment period is at least 28 days. 44. The method of any one of embodiments 1-43, wherein the treatment period is at least 84 days. 45. The method of any one of embodiments 1-44, wherein the treatment period is at least 169 days. 46. ​​A method according to any one of embodiments 1-45, comprising administering to the human patient 400 mg twice a day 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]pent-2-enenitrile and pharmaceutically acceptable salts thereof. 47. A method according to any one of embodiments 1-46, wherein the at least one compound is composed of: at least one compound selected from the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and its pharmaceutically acceptable salts. 48. A method according to any one of embodiments 1-46, wherein the at least one compound is composed of: at least one compound selected from the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and its pharmaceutically acceptable salts. 49. A method according to any one of embodiments 1-46, wherein the at least one compound consists of: a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile or pharmaceutically acceptable salts of the foregoing isomers. 50. A method according to any one of embodiments 1-45, comprising administering 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile twice daily to the human patient. 51. A method according to any one of embodiments 1-45 or 50, wherein at least one of the compounds is the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. 52. A method according to any one of embodiments 1-45 or 50, wherein at least one of the compounds is the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. 53. A method according to any one of embodiments 1-45 or 50, wherein the at least one compound consists of: a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. 54. The method according to any one of embodiments 1-53, wherein the at least one compound is administered orally to the human patient. 55. The method according to any one of embodiments 1-54, wherein the at least one compound is administered to the human patient in the form of at least one tablet. 56. The method according to any one of embodiments 1-55, wherein the at least one compound is administered with water. 57. The method of any one of embodiments 1-56, wherein the at least one compound is administered with food. 58. The method of any one of embodiments 1-57, wherein the at least one compound is administered without food. 59. The method of any one of embodiments 1-58, wherein the human patient has been suffering from ITP for four years or less.

[0208] Unless the context clearly indicates the contrary or other meaning, a claim or description including "or" or "and / or" between at least one member of a group is deemed to be satisfactory if one, more than one, or all of the group members are present in, used in, or otherwise associated with a given product or process. The present disclosure includes embodiments in which exactly one member of the group is present in, used in, or otherwise associated with a given product or process. The present disclosure includes embodiments in which more than one or all of the group members are present in, used in, or otherwise associated with a given product or process.

[0209] When a range is given, the endpoints are included. In addition, unless otherwise indicated or otherwise clear based on the context and the understanding of those of ordinary skill in the art, the values ​​expressed as ranges in various embodiments of the present disclosure can assume any specific value or sub-range within the range, accurate to one-tenth of the unit of the lower limit of the range (unless the context clearly indicates otherwise).

[0210] For the purpose of clarity and understanding, the foregoing disclosure has been described in some detail by way of illustration and example. Therefore, it should be understood that the above description is intended to be illustrative rather than restrictive. Therefore, the scope of the disclosure should not be determined with reference to the above description, but should be determined with reference to the following appended claims and the full scope of equivalents described in these claims.

Claims

1. A method for treating immune thrombocytopenia (ITP) in a human patient in need thereof who has not received prior treatment with a thrombopoietin receptor agonist (TPO-RA) or rituximab, the method comprising administering to the human patient who has not received prior treatment with a TPO-RA or rituximab twice daily during a treatment period a therapeutically effective amount 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]pent-2-enenitrile and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof has at least one characteristic selected from the group consisting of: a. Platelet count <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to starting study treatment; and b. History of response to at least one prior line of therapy (two or more platelet counts ≥50,000 / μL with an increase of ≥20,000 / μL).

2. A method for treating immune thrombocytopenia (ITP) in a human patient in need thereof who has not received prior treatment with a thrombopoietin receptor agonist (TPO-RA), the method comprising administering to the human patient who has not received prior treatment with a TPO-RA twice daily during a treatment period a therapeutically effective amount of at least one compound selected from the group consisting of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof has at least one characteristic selected from the group consisting of: a. Platelet count <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to starting study treatment; and b. History of response to at least one prior line of therapy (two or more platelet counts ≥50,000 / μL with an increase of ≥20,000 / μL).

3. A method for treating immune thrombocytopenia (ITP) in a human patient in need thereof who has not received prior treatment with rituximab, the method comprising administering to the human patient who has not received prior treatment with rituximab twice daily during a treatment period a therapeutically effective amount 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]pent-2-enenitrile and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof has at least one characteristic selected from the group consisting of: a. Platelet count <33,000 / μL on two occasions no less than 7 days apart within 15 days prior to starting study treatment; and b. History of response to at least one prior line of therapy (two or more platelet counts ≥50,000 / μL with an increase of ≥20,000 / μL).

4. The method according to claim 1 or 2, wherein the TPO-RA is selected from the group consisting of recombinant thrombopoietin (rTPO), romiplostim, eltrombopag and avatrombopag.

5. The method of any one of claims 1-2 or 4, wherein the patient has not received prior treatment with rituximab.

6. The method of any one of claims 1-5, wherein the at least one prior line of treatment, wherein at least one prior therapy is selected from splenectomy, intravenous immunoglobulin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressive drugs.

7. The method of any one of claims 1-6, wherein the patient achieves at least one platelet count that is at least 20,000 / μL above a baseline platelet count, wherein the baseline platelet count is the average of two platelet counts performed on two occasions no less than 7 days apart within 15 days prior to starting treatment and a third count performed on the first day of the study.

8. The method of any one of claims 1-7, wherein the patient achieves at least two platelet counts that are at least 20,000 / μL above the baseline platelet count.

9. The method of claim 8, wherein the patient achieves at least two consecutive platelet counts that are at least 20,000 / μL above the baseline platelet count.

10. The method of any one of claims 8 or 9, wherein at least two consecutive platelet counts of at least 20,000 / μL above the baseline platelet count are separated by at least five days, such as at least seven days.

11. The method of any one of claims 1-10, wherein the patient achieves a platelet count of at least 50,000 / μL.

12. The method of any one of claims 1-11, wherein the patient achieves at least two platelet counts of at least 50,000 / μL.

13. The method of claim 12, wherein the patient achieves at least two consecutive platelet counts of at least 50,000 / μL.

14. The method of claim 12 or 13, wherein the at least two consecutive platelet counts of at least 50,000 / μL are at least five days apart, such as at least seven days apart.

15. The method of any one of claims 1-14, wherein the human patient achieves at least one platelet count of at least 50,000 / μL within eight days of initiating treatment.

16. The method of any one of claims 11-15, wherein the human patient has not received rescue medication during the four weeks prior to the most recent platelet count of at least 50,000 / μL.

17. The method of any one of claims 1-16, wherein the human patient has suffered from ITP for six years or less.

18. The method of any one of claims 1-17, wherein the human patient has a history of receiving at least one prior ITP therapy prior to the start of the treatment period.

19. The method of any one of claims 1-18, wherein the human patient has a history of receiving at least two prior ITP therapies prior to the start of the treatment period.

20. The method of any one of claims 1-19, wherein the human patient has a history of receiving at least three prior ITP therapies prior to the start of the treatment period.

21. The method of any one of claims 1-20, wherein the human patient has a history of receiving at least four prior ITP therapies prior to the start of the treatment period.

22. The method of any one of claims 1-21, wherein the human patient has a history of receiving at least five prior ITP therapies prior to the start of the treatment period.

23. The method of any one of claims 1-22, wherein the human patient has a platelet count between 2,000 / μL and 33,000 / μL on two occasions within 15 days and no less than 7 days apart prior to the start of the treatment period.

24. The method of any one of claims 1-23, wherein the human patient underwent a splenectomy prior to the start of the treatment period.

25. The method of any one of claims 2 or 4-24, wherein the human patient has a history of receiving rituximab prior to the start of the treatment period.

26. The method of any one of claims 3-25, wherein the human patient has a history of receiving at least one TPO-RA prior to the start of the treatment period.

27. The method of claim 26, wherein the at least one TPO-RA is selected from rTPO, romiplostim, eltrombopag, and avatrombopag.

28. The method of any one of claims 1-27, wherein the patient has a history of response to at least one prior line of treatment, wherein at least one prior therapy is selected from splenectomy, intravenous immunoglobulin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressive drugs.

29. The method of any one of claims 1-28, wherein the human patient has a history of receiving intravenous immunoglobulin (IVIG) prior to the start of the treatment period.

30. The method of any one of claims 1-28, wherein the human patient has a history of receiving corticosteroids prior to the start of the treatment period.

31. The method of any one of claims 1-28, wherein the human patient has a history of receiving anti-D immunoglobulin therapy prior to the start of the treatment period.

32. The method of any one of claims 1-28, wherein the human patient has a history of receiving at least one immunosuppressive drug prior to the start of the treatment period.

33. The method of claim 32, wherein the at least one immunosuppressive drug is selected from fostamatinib, mycophenolate mofetil (MMF), and cyclosporine.

34. The method of any one of claims 28-33, wherein the response to prior ITP therapy comprises a platelet count of ≥50,000 / μL.

35. The method of any one of claims 1-34, wherein the human patient suffers from primary ITP.

36. The method of any one of claims 1-34, wherein the human patient suffers from secondary ITP.

37. The method of any one of claims 1-34, wherein the human patient does not suffer from chronic ITP.

38. The method of any one of claims 1-34, wherein the human patient suffers from persistent ITP.

39. The method of any one of claims 1-34, wherein the human patient suffers from chronic ITP.

40. The method of any one of claims 1-34, wherein the human patient suffers from recurrent ITP.

41. The method of any one of claims 1-34, wherein the human patient has refractory ITP.

42. The method of any one of claims 1-41, wherein the treatment period is at least 8 days.

43. The method of any one of claims 1-42, wherein the treatment period is at least 28 days.

44. The method of any one of claims 1-43, wherein the treatment period is at least 84 days.

45. The method of any one of claims 1-44, wherein the treatment period is at least 169 days.

46. ​​The method according to any one of claims 1-45, comprising administering to the human patient 400 mg twice daily 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]pent-2-enenitrile and pharmaceutically acceptable salts thereof.

47. The method according to any one of claims 1-46, wherein the at least one compound is composed of composition: At least one compound selected from the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and its pharmaceutically acceptable salts.

48. The method according to any one of claims 1-46, wherein the at least one compound is composed of composition: At least one compound selected from the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and its pharmaceutically acceptable salts.

49. The method according to any one of claims 1-46, wherein the at least one compound is composed of composition: A mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile or pharmaceutically acceptable salts thereof.

50. The method of any one of claims 1-45, comprising administering to the human patient 400 mg twice daily of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.

51. The method of any one of claims 1-45 or 50, wherein the at least one compound is the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.

52. The method of any one of claims 1-45 or 50, wherein the at least one compound is the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.

53. according to the method described in any one of claims 1-45 or 50, wherein said at least one compound is composed of composition: A mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.

54. The method of any one of claims 1-53, wherein the at least one compound is administered orally to the human patient.

55. The method according to any one of claims 1-54, wherein the at least one compound is administered to the human patient in the form of at least one tablet.

56. The method of any one of claims 1-55, wherein the at least one compound is administered with water.

57. The method of any one of claims 1-56, wherein the at least one compound is administered with food.

58. The method of any one of claims 1-57, wherein the at least one compound is administered without food.

59. The method of any one of claims 1-58, wherein the human patient has been suffering from ITP for four years or less.

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