Methods for treating immune thrombocytopenia by administering (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-D]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile

Abstract

A method for treating immune thrombocytopenia is disclosed, comprising administering 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 (PRN1008) and its pharmaceutically acceptable salts. Pharmaceutical compositions containing at least one compound selected from PRN1008 and its pharmaceutically acceptable salts are also disclosed.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 62 / 914,688, filed October 14, 2019, and U.S. Provisional Application No. 62 / 951,302, filed December 20, 2019, the contents of each of which are incorporated herein by reference in their entirety.

[0002] Disclosed herein are methods for treating immune thrombocytopenia. Also disclosed are BTK inhibitors and pharmaceutical compositions containing the same. [Background technology]

[0003] Immune thrombocytopenia, commonly referred to as ITP, is a rare autoimmune disease that results from platelet destruction, resulting in a high risk of bleeding, excessive bruising, and fatigue, as well as the potential for life-threatening bleeding. ITP is characterized by immune-mediated (e.g., autoantibody-mediated) platelet destruction and reduced platelet production, resulting in thrombocytopenia, a tendency toward bleeding that is associated with morbidity and mortality, and a negative impact on patients' quality of life (QOL).

[0004] Current treatments for adults with ITP include initial treatment with intravenous immunoglobulin (IVIG) and corticosteroids, followed by splenectomy, thrombopoietin receptor agonists (TPO-RAs), rituximab, fostamatinib, and other immunosuppressive therapies (e.g., mycophenolate mofetil (MMF) and cyclosporine). Pharmacotherapy (e.g., corticosteroids, IVIG, or anti-D immunoglobulin therapy) is generally used to reduce platelet destruction in patients with symptomatic low platelet counts. While most patients initially respond to corticosteroids, the rate of sustained remission is low. Second-line therapies for ITP include rituximab and splenectomy, which carry the risk of sepsis and immunosuppression. Additionally, thrombopoietin (TPO) mimetics (Bussel 2007) have been approved for the treatment of patients with chronic ITP who have not adequately responded to corticosteroids, IVIG, or splenectomy.

[0005] Novel, safe, and effective oral therapies for maintaining platelet counts in ITP patients would represent a substantial therapeutic advantage over current standard therapies. Illustratively, unmet needs in relapsed and refractory ITP include: improved remission rates and durability; avoidance of platelet count surges / thrombus formation risks; steroid-free regimens; and tolerable, safe therapies that ensure good patient quality of life. Thus, there is a need for novel oral therapies for treating ITP, including relapsed and refractory ITP, that address some or all of these limitations of existing therapies.

[0006] Bruton's agammaglobulinemia tyrosine kinase (BTK) is an essential signaling element downstream of the B cell receptor (BCR), Fc-gamma receptor (FcγR), and Fc-epsilon receptor (FcεR). BTK is a non-receptor tyrosine kinase and a member of the TEC family of kinases. BTK is essential for B cell lineage maturation, and inhibition of BTK activity in cells results in phenotypic changes consistent with BCR blockade. Illustratively, BTK inhibition results in downregulation of various B cell activities, including cell proliferation, differentiation, maturation, and survival, as well as upregulation of apoptosis.

[0007] Rather than operating as an "on-off switch," BTK is best thought of as an immune function "modulator" (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 develop X-linked agammaglobulinemia (XLA), a condition characterized by a complete absence of circulating B cells and plasma cells and very low levels of all immunoglobulins (Tsukada 1993; Vetrie 1993). This suggests that BTK inhibition may suppress the production of autoantibodies that are thought to be important in the pathogenesis of autoimmune diseases such as ITP.

[0008] Although BTK is not expressed in T cells, natural killer cells, and plasma cells and does not have a direct function found in T cells and plasma cells (Sideras and Smith 1995; Mohamed et al. 2009), this enzyme regulates the activation of other hematopoietic cells such as basophils, mast cells, macrophages, neutrophils, and platelets. For example, BTK plays a role in the activation of neutrophils, which are central to the inflammatory response, contributing to wound healing but also causing tissue damage (Volmering S et al. 2016).

[0009] Therefore, selective BTK inhibitors have the potential to target multiple pathways in inflammation and autoimmunity, including, but not limited to, blockade of the BCR; inhibition of plasma cell differentiation and antibody production; blockade of IgG-mediated FcγR activation, phagocytosis, and inflammatory mediators in monocytes or macrophages; blockade of IgE-mediated FcεR activation and degranulation in mast cells or basophils; and inhibition of activation, adhesion, recruitment, and oxidative burst in neutrophils. Based on these actions, selective BTK inhibitors may block the initiation and progression of various inflammatory diseases and reduce the tissue damage that results from these diseases. While individuals with loss-of-function mutations in the BTK gene have reduced humoral immunity and are susceptible to pyogenic bacterial and enteroviral infections that require treatment with intravenous immunoglobulin, inhibition of BTK in individuals with intact immune systems is not expected to result in similar susceptibility to infection.

[0010] 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, providing further clinical validation of the BTK target, was recently approved by the US Food and Drug Administration (FDA) for human use in mantle cell lymphoma, Waldenström's macroglobulinemia, and chronic lymphocytic leukemia. Ibrutinib has also demonstrated activity in other hematologic malignancies (Wang 2013, Byrd 2013, Imbruvica Package Insert, 2015). Additionally, CC-292 has been reported to be well tolerated in healthy volunteers at doses that provide 100% occupancy of the BTK enzyme (Evans 2013). Evobrutinib has also recently demonstrated efficacy in multiple sclerosis in a Phase 2 trial (Montalban X et al., 2019). Other BTKi compounds are in clinical development for various 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; Min TK et al., 2019; Gillooly KM 2017; Nadeem A et al., 2019).

[0011] Although covalent BTKi inhibitors such as ibrutinib and acalabrutinib have overcome the selectivity issues plaguing many first-generation kinase inhibitors, these inhibitors are typically irreversible, causing permanent alterations of both on- 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). Thus, there is a need for BTKi-based therapies with reduced side effects for immune-mediated diseases such as ITP.

[0012] Compound (I) has the following structure: [ka] is a BTK inhibitor, wherein: * C is a stereochemical center. See US Pat. No. 6,229,999, incorporated herein by reference, for example, Example 31.

[0013] The following structure: [ka] (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, also known as PRN1008 and rilzabrutinib. This compound has been disclosed in several patent publications, such as U.S. Patent No. 5,623, 624, 625, 626, 627, 628, 629, and U.S. Patent No. 5,629, 629, 630, and the contents of each of which are incorporated herein by reference.

[0014] PRN1008 is a novel, highly selective small molecule inhibitor of non-T-cell leukemia cells that signal through the B cell receptor FcγR and / or FcεR signaling of the BTK pathway. PRN1008 functions as a reversible, covalent BTK inhibitor, forming both non-covalent and covalent bonds with its target, enabling enhanced selectivity and prolonged inhibition with low systemic exposure. Compared to first- and second-generation BTKis, PRN1008 exhibits minimal cross-reactivity with other molecules, reducing the risk of off-target effects (Smith PF et al., 2017). Importantly, PRN1008's reversible binding minimizes the potential for permanently denatured peptides (Serafimova IM 2012). Furthermore, PRN1008 exhibits improved kinase selectivity compared to the covalent BTK inhibitor ibrutinib, with PRN1008 (1 μM) achieving >90% inhibition against 6 kinases compared to ibrutinib (1 μM) achieving >90% inhibition against 21 kinases out of a panel of 251 kinases.

[0015] PRN1008 has shown encouraging results for the treatment of immune-mediated diseases. PRN1008 is the most advanced BTKi in development for autoimmune diseases (Phase 3, NCT03762265) and the first BTKi to be evaluated for the treatment of pemphigus, a blistering disease induced by autoantibodies similar to ITP. In humans, PRN1008 is rapidly absorbed after oral administration, has a fast half-life (3-4 h), and variable pharmacokinetics (PK).

[0016] A Phase 1 study of PRN1008 in 114 healthy volunteers demonstrated robust and consistent target BTK occupancy, suggesting that PRN1008 may be highly effective in treating autoimmune diseases. Furthermore, preclinical and clinical PK / PD data demonstrated sustained therapeutic effects even after the compound was cleared from the circulation, consistent with extended target residence time (Hill R et al., 2015) and high occupancy (>90% within 4 hours) (Smith PF et al., 2015).

[0017] PRN1008 also exhibits a favorable safety profile. Based on preclinical replication toxicity studies, PRN1008 is not expected to impair fetal growth or male fertility. In a 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).

[0018] Preliminary evidence supports the role of BTK inhibition in patients with autoimmune cytopenias, with a series of episodes of severe autoimmune hemolytic anemia and ITP ending after initiation of treatment with the BTK / EGFR / ITK inhibitor ibrutinib in patients with chronic lymphocytic leukemia (CLL) (Rogers 2016, Montillo 2017). Furthermore, in relation to the treatment of ITP, PRN1008 treatment significantly inhibits human B cell activation in vitro and blocks antibody (IgG, IgE)-mediated immune cell activation via Fc receptor signaling. In preclinical studies, PRN1008 demonstrated a significant dose-dependent reduction in platelet loss in a mouse model of immune thrombocytopenia. PRN1008 also demonstrated rapid and significant anti-inflammatory effects in a rat collagen-induced arthritis model, a rat antibody-mediated Arthritis model, spontaneous canine pemphigus foliaceus, and human pemphigus vulgaris (PV). [Prior art documents] [Patent documents]

[0019] [Patent Document 1] International Publication No. 2014 / 039899 [Patent Document 2] International Publication No. 2015 / 127310 [Patent Document 3] International Publication No. 2016 / 100914 [Patent Document 4] International Publication No. 2016 / 105531 [Patent Document 5] International Publication No. 2018 / 005849 Summary of the Invention [Means for solving the problem]

[0020] Disclosed herein is a method of treating immune thrombocytopenia (ITP) in a human patient, comprising administering to a human patient in need thereof 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 (PRN1008) and pharmaceutically acceptable salts thereof once daily or twice daily for the duration of treatment.

[0021] In some embodiments, the treatment period is 8 days. In some embodiments, the treatment period is 28 days. In some embodiments, the treatment period is 84 days. In some embodiments, the treatment period is 168 days.

[0022] 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 168 days.

[0023] In some embodiments, the treatment period is 8 to 28 days. In some embodiments, the treatment period is 8 to 84 days. In some embodiments, the treatment period is 8 to 168 days. In some embodiments, the treatment period is 28 to 84 days. In some embodiments, the treatment period is 28 to 168 days. In some embodiments, the treatment period is 84 to 168 days.

[0024] In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily or twice daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient twice daily.

[0025] In some embodiments, the method comprises administering 300 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to a human patient twice daily.

[0026] In some embodiments, the method comprises treating primary ITP. In some embodiments, the method comprises treating secondary ITP. In some embodiments, the method comprises treating chronic ITP. In some embodiments, the method comprises treating recurrent ITP. In some embodiments, the method comprises treating refractory ITP.

[0027] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least one characteristic selected from the following:

[0028] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered as monotherapy.

[0029] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered in combination with at least one concurrent ITP treatment.

[0030] Also disclosed herein is a method for increasing platelet count in a human patient with immune thrombocytopenia (ITP), comprising administering to the human patient once daily or twice daily for 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 (PRN1008) and pharmaceutically acceptable salts thereof.

[0031] In some embodiments, the method comprises increasing at least two consecutive platelet counts relative to a pre-administration baseline platelet count, hi some embodiments, the method comprises increasing at least two consecutive platelet counts relative to a pre-administration baseline platelet count without the need for rescue medication.

[0032] In some embodiments, the method comprises increasing the platelet count by at least 5,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing the platelet count by at least 10,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing the platelet count by at least 15,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing the platelet count by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0033] In some embodiments, the method comprises increasing at least 30% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least 40% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least 50% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least 60% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least 70% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0034] In some embodiments, the method comprises increasing at least two of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least three of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least four of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least five of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least six of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least seven of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0035] In some embodiments, the method comprises increasing at least two of the final six platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least three of the final six platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least four of the final six platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least five of the final six platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0036] In some embodiments, the pre-administration baseline platelet count is the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period. In some embodiments, the pre-administration baseline platelet count is the average of the human patient's two most recent platelet counts measured at least 7 days apart ... within 15 days before the start of the treatment period.

[0037] In some embodiments, consecutive platelet counts are measured at least 5 days apart.

[0038] In some embodiments, the treatment period is 8 days. In some embodiments, the treatment period is 28 days. In some embodiments, the treatment period is 84 days. In some embodiments, the treatment period is 168 days.

[0039] 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 168 days.

[0040] In some embodiments, the treatment period is 8 to 28 days. In some embodiments, the treatment period is 8 to 84 days. In some embodiments, the treatment period is 8 to 168 days. In some embodiments, the treatment period is 28 to 84 days. In some embodiments, the treatment period is 28 to 168 days. In some embodiments, the treatment period is 84 to 168 days.

[0041] In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily or twice daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient twice daily.

[0042] In some embodiments, the method comprises administering 300 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to a human patient twice daily.

[0043] In some embodiments, the human patient has primary ITP. In some embodiments, the human patient has secondary ITP. In some embodiments, the human patient has chronic ITP. In some embodiments, the human patient has recurrent ITP. In some embodiments, the human patient has refractory ITP.

[0044] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least one characteristic selected from the following:

[0045] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered as monotherapy.

[0046] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered in combination with at least one concurrent ITP treatment.

[0047] Also disclosed herein is a method for achieving a platelet count of at least 50,000 / μL in a human patient suffering from immune thrombocytopenia (ITP), comprising administering to the human patient 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 (PRN1008) and pharmaceutically acceptable salts thereof once daily or twice daily for a treatment period.

[0048] In some embodiments, the method comprises achieving at least two platelet counts of at least 50,000 / μL. In some embodiments, the method comprises achieving at least two platelet counts of at least 50,000 / μL without the need for rescue medication.

[0049] In some embodiments, the method comprises achieving at least two consecutive platelet counts of at least 50,000 / μL. In some embodiments, the method comprises achieving at least two consecutive platelet counts of at least 50,000 / μL without the need for rescue medication.

[0050] In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 30% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 35% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 40% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 45% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 50% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 55% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 60% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 65% of the platelet counts measured during the treatment period, hi some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 70% of the platelet counts measured during the treatment period.

[0051] In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least two of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least three of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least four of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least five of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least six of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least seven of the final eight platelet counts measured during the treatment period.

[0052] In some embodiments, the method comprises achieving a platelet count of at least 50,000 μL for at least two of the final six platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least three of the final six platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least four of the final six platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least five of the final six platelet counts measured during the treatment period.

[0053] In some embodiments, the method comprises increasing at least 30% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least 40% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least 50% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least 60% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least 70% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0054] In some embodiments, the method comprises increasing at least two of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least three of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least four of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least five of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least six of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least seven of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0055] In some embodiments, the method comprises increasing at least two of the final six platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least three of the final six platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least four of the final six platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least five of the final six platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0056] In some embodiments, the pre-administration baseline platelet count is the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period. In some embodiments, the pre-administration baseline platelet count is the average of the human patient's two most recent platelet counts before the start of the treatment period measured at least 7 days apart ... within 15 days before the start of the treatment period and the human patient's platelet count on the first day of the treatment period.

[0057] In some embodiments, consecutive platelet counts are measured at least 5 days apart.

[0058] In some embodiments, the treatment period is 8 days. In some embodiments, the treatment period is 28 days. In some embodiments, the treatment period is 84 days. In some embodiments, the treatment period is 168 days.

[0059] 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 168 days.

[0060] In some embodiments, the treatment period is 8 to 28 days. In some embodiments, the treatment period is 8 to 84 days. In some embodiments, the treatment period is 8 to 168 days. In some embodiments, the treatment period is 28 to 84 days. In some embodiments, the treatment period is 28 to 168 days. In some embodiments, the treatment period is 84 to 168 days.

[0061] In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily or twice daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient twice daily.

[0062] In some embodiments, the method comprises administering 300 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to a human patient twice daily.

[0063] In some embodiments, the human patient has primary ITP. In some embodiments, the human patient has secondary ITP. In some embodiments, the human patient has chronic ITP. In some embodiments, the human patient has recurrent ITP. In some embodiments, the human patient has refractory ITP.

[0064] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least one characteristic selected from the following:

[0065] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered as monotherapy.

[0066] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered in combination with at least one concurrent ITP treatment.

[0067] Also disclosed herein are methods for achieving at least one platelet count of at least 50,000 / μL and increasing at least one platelet count by at least 20,000 / μL in a human patient with immune thrombocytopenia (ITP), comprising administering to the human patient once daily or twice daily for 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 (PRN1008) and pharmaceutically acceptable salts thereof.

[0068] In some embodiments, the method comprises achieving at least two platelet counts of at least 50,000 / μL. In some embodiments, the method comprises achieving at least two platelet counts of at least 50,000 / μL without the need for rescue medication.

[0069] In some embodiments, the method comprises achieving at least two consecutive platelet counts of at least 50,000 / μL. In some embodiments, the method comprises achieving at least two consecutive platelet counts of at least 50,000 / μL without the need for rescue medication.

[0070] In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 30% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 35% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 40% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 45% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 50% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 55% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 60% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 65% of the platelet counts measured during the treatment period, hi some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 70% of the platelet counts measured during the treatment period.

[0071] In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least two of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least three of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least four of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least five of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least six of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least seven of the final eight platelet counts measured during the treatment period.

[0072] In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least two of the final six platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least three of the final six platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least four of the final six platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least five of the final six platelet counts measured during the treatment period.

[0073] In some embodiments, consecutive platelet counts are measured at least 5 days apart.

[0074] In some embodiments, the treatment period is 8 days. In some embodiments, the treatment period is 28 days. In some embodiments, the treatment period is 84 days. In some embodiments, the treatment period is 168 days.

[0075] 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 168 days.

[0076] In some embodiments, the treatment period is 8 to 28 days. In some embodiments, the treatment period is 8 to 84 days. In some embodiments, the treatment period is 8 to 168 days. In some embodiments, the treatment period is 28 to 84 days. In some embodiments, the treatment period is 28 to 168 days. In some embodiments, the treatment period is 84 to 168 days.

[0077] In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily or twice daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient twice daily.

[0078] In some embodiments, the method comprises administering 300 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to a human patient twice daily.

[0079] In some embodiments, the human patient has primary ITP. In some embodiments, the human patient has secondary ITP. In some embodiments, the human patient has chronic ITP. In some embodiments, the human patient has recurrent ITP. In some embodiments, the human patient has refractory ITP.

[0080] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least one characteristic selected from the following:

[0081] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered as monotherapy.

[0082] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered in combination with at least one concurrent ITP treatment.

[0083] Also disclosed herein is a method for achieving a platelet count of at least 30,000 / μL in a human patient suffering from immune thrombocytopenia (ITP), comprising administering to the human patient 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 (PRN1008) and pharmaceutically acceptable salts thereof once daily or twice daily for a treatment period.

[0084] In some embodiments, the treatment period is 8 days. In some embodiments, the treatment period is 28 days. In some embodiments, the treatment period is 84 days. In some embodiments, the treatment period is 168 days.

[0085] 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 168 days.

[0086] In some embodiments, the treatment period is 8 to 28 days. In some embodiments, the treatment period is 8 to 84 days. In some embodiments, the treatment period is 8 to 168 days. In some embodiments, the treatment period is 28 to 84 days. In some embodiments, the treatment period is 28 to 168 days. In some embodiments, the treatment period is 84 to 168 days.

[0087] In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily or twice daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient twice daily.

[0088] In some embodiments, the method comprises administering 300 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to a human patient twice daily.

[0089] In some embodiments, the human patient has primary ITP. In some embodiments, the human patient has secondary ITP. In some embodiments, the human patient has chronic ITP. In some embodiments, the human patient has recurrent ITP. In some embodiments, the human patient has refractory ITP.

[0090] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least one characteristic selected from the following:

[0091] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered as monotherapy.

[0092] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered in combination with at least one concurrent ITP treatment.

[0093] Exemplary embodiment 1: Without limitation, some embodiments of the present disclosure include:

[0094] 1. A method of treating immune thrombocytopenia (ITP) in a human patient in need thereof, comprising administering to the human patient once daily or twice daily for 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 (PRN1008) and pharmaceutically acceptable salts thereof, wherein the human patient: A mean plasma count of 3,000 / μL to 33,000 / μL for the most recent platelet count before the start of the treatment period, the second most recent platelet count before the start of the treatment period, and the platelet count on the first day of the treatment period; A history of at least four prior ITP treatments prior to the start of the treatment period; and Splenectomy before the start of the treatment period A method having at least one feature selected from the following:

[0095] 2. A method for increasing platelet count in a human patient with immune thrombocytopenia (ITP), comprising administering to the human patient once daily or twice daily for 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 (PRN1008) and pharmaceutically acceptable salts thereof, wherein the human patient: mean plasma count of 3,000 / μL to 33,000 / μL for the most recent platelet count before the start of the treatment period, the second most recent platelet count before the start of the treatment period, and the first day platelet count of the treatment period; A history of at least four prior ITP treatments prior to the start of the treatment period; and Splenectomy before the start of the treatment period A method having at least one feature selected from the following:

[0096] 3. The method of embodiment 2, wherein increasing the platelet count comprises increasing the platelet count by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0097] 4. The method of embodiment 2 or 3, wherein increasing the platelet count comprises increasing at least 50% of the platelet count measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0098] 5. The method of any one of embodiments 2 to 4, wherein increasing the platelet count comprises increasing at least two consecutive platelet counts compared to the pre-administration baseline platelet count.

[0099] 6. The method of any one of embodiments 3-5, wherein the pre-administration baseline platelet count is the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period.

[0100] 7. A method for achieving a platelet count of at least 50,000 / μL in a human patient with immune thrombocytopenia (ITP), comprising administering to the human patient once daily or twice daily for 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 (PRN1008) and pharmaceutically acceptable salts thereof, wherein the human patient: a mean plasma count of 3,000 / μL to 33,000 / μL for the most recent platelet count before the start of the treatment period, the second most recent platelet count before the start of the treatment period, and the platelet count on the first day of the treatment period; A history of at least four prior ITP treatments prior to the start of the treatment period; and Splenectomy before the start of the treatment period A method having at least one feature selected from the following:

[0101] 8. The method of embodiment 7, wherein achieving a platelet count comprises achieving at least two platelet counts of at least 50,000 / μL.

[0102] 9. The method of embodiment 7 or 8, wherein achieving the platelet count comprises achieving at least two consecutive platelet counts of at least 50,000 / μL.

[0103] 10. The method of any one of embodiments 7-9, wherein achieving a platelet count comprises achieving a platelet count of at least 50,000 / μL for at least 50% of the platelet counts measured during the treatment period.

[0104] 11. The method of any one of embodiments 7-10, wherein achieving a platelet count comprises achieving a platelet count of at least 50,000 / μL in at least four of the final eight platelet counts measured during the treatment period.

[0105] 12. The method of any one of embodiments 7-11, wherein achieving a platelet count comprises achieving a platelet count of at least 50,000 / μL in at least four of the final six platelet counts measured during the treatment period.

[0106] 13. A method for achieving at least one platelet count of at least 50,000 / μL and increasing at least one platelet count by at least 20,000 / μL in a human patient with immune thrombocytopenia (ITP), comprising administering to the human patient 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 (PRN1008) and pharmaceutically acceptable salts thereof once daily or twice daily for a treatment period, wherein the human patient: mean plasma count of 3,000 / μL to 33,000 / μL for the most recent platelet count before the start of the treatment period, the second most recent platelet count before the start of the treatment period, and the platelet count on the first day of the treatment period; A history of at least four prior ITP treatments prior to the start of the treatment period; and Splenectomy before the start of the treatment period A method having at least one feature selected from the following:

[0107] 14. The method of embodiment 13, wherein achieving a platelet count comprises achieving at least two platelet counts of at least 50,000 / μL.

[0108] 15. The method of embodiment 13 or 14, wherein achieving the platelet count comprises achieving at least two consecutive platelet counts of at least 50,000 / μL.

[0109] 16. The method of any one of embodiments 13-15, wherein achieving a platelet count comprises achieving a platelet count of at least 50,000 / μL for at least 50% of the platelet counts measured during the treatment period.

[0110] 17. The method of any of embodiments 13-16, wherein achieving a platelet count comprises achieving a platelet count of at least 50,000 / μL in at least four of the final eight platelet counts measured during the treatment period.

[0111] 18. The method of any of embodiments 13-17, wherein achieving a platelet count comprises achieving a platelet count of at least 50,000 / μL in at least four of the final six platelet counts measured during the treatment period.

[0112] 19. The method of any of embodiments 13-18, wherein achieving a platelet count comprises increasing the platelet count measured during the treatment period by at least 50% by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0113] 20. The method of embodiment 19, wherein the pre-administration baseline platelet count is the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period.

[0114] 21. A method for achieving a platelet count of at least 30,000 / μL in a human patient with immune thrombocytopenia (ITP), comprising administering to the human patient once daily or twice daily for 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 (PRN1008) and pharmaceutically acceptable salts thereof, wherein the human patient: mean plasma count of 3,000 / μL to 33,000 / μL for the most recent platelet count before the start of the treatment period, the second most recent platelet count before the start of the treatment period, and the platelet count on the first day of the treatment period; A history of at least four prior ITP treatments prior to the start of the treatment period; and Splenectomy before the start of the treatment period A method having at least one feature selected from the following:

[0115] 22. The method of embodiment 21, wherein achieving a platelet count comprises achieving a platelet count of at least 30,000 / μL for at least 50% of the platelet counts measured during the treatment period.

[0116] 23. The method of embodiment 21 or 22, wherein achieving a platelet count comprises achieving a platelet count of at least 30,000 / μL for at least 75% of the platelet counts measured during the treatment period.

[0117] 24. The method of any one of embodiments 1-23, wherein serial platelet counts are measured at least 5 days apart.

[0118] 25. The method of any one of embodiments 1-24, wherein the human patient has a mean plasma count of 3,000 / μL to 33,000 / μL for the most recent platelet count before the start of the treatment period, the second most recent platelet count before the start of the treatment period, and the platelet count on the first day of the treatment period.

[0119] 26. The method of any one of embodiments 1-24, wherein the human patient has an average plasma count of 3,000 / μL to 15,000 / μL for the most recent platelet count before the start of the treatment period, the second most recent platelet count before the start of the treatment period, and the platelet count on the first day of the treatment period.

[0120] 27. The method of any one of embodiments 1-26, wherein the human patient has a medical history of at least four prior ITP treatments prior to the start of the treatment period.

[0121] 28. The method of any one of embodiments 1 to 27, wherein the human patient underwent splenectomy prior to the start of the treatment period.

[0122] 29. The method of any one of embodiments 1 to 28, wherein the human patient has primary ITP.

[0123] 30. The method of any one of embodiments 1-28, wherein the human patient has secondary ITP.

[0124] 31. The method of any one of embodiments 1-28, wherein the human patient has chronic ITP.

[0125] 32. The method of any one of embodiments 1-28, wherein the human patient has recurrent ITP.

[0126] 33. The method of any one of embodiments 1-32, wherein the human patient has refractory ITP.

[0127] 34. The method of any one of embodiments 1 to 33, wherein there are no approved therapeutic options available for human patients.

[0128] 35. The method of any one of embodiments 1-34, wherein the human patient has a platelet count of less than 30,000 / μL before the start of the treatment period.

[0129] 36. The method of any one of embodiments 1 to 35, wherein the human patient has two platelet counts of less than 30,000 / μL before the start of the treatment period.

[0130] 37. The method of any one of embodiments 1-36, wherein the human patient has two platelet counts less than 30,000 / μL prior to the start of the treatment period, and the two counts are measured more than 7 days apart within 15 days prior to the start of the treatment period.

[0131] 38. The method of any one of embodiments 1-37, wherein the at least four prior ITP treatments are selected from corticosteroids, thrombopoietin receptor agonists, intravenous immunoglobulin, anti-D immunoglobulin, and rituximab.

[0132] 39. The method of any one of embodiments 1 to 38, wherein the treatment period is at least 8 days.

[0133] 40. The method of any one of embodiments 1 to 38, wherein the treatment period is at least 28 days.

[0134] 41. The method of any one of embodiments 1 to 38, wherein the treatment period is at least 84 days.

[0135] 42. The method of any one of embodiments 1 to 38, wherein the treatment period is at least 168 days.

[0136] 43. The method of any of embodiments 1-42, comprising administering 400 mg of at least one compound selected from PRN1008 and its pharmaceutically acceptable salts to a human patient once daily or twice daily.

[0137] 44. The method of any of embodiments 1-43, comprising administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to a human patient once daily.

[0138] 45. The method of any of embodiments 1-43, comprising administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to a human patient twice daily.

[0139] 46. ​​The method of any of embodiments 1-42, comprising administering 300 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to a human patient twice daily.

[0140] 47. The method of any one of embodiments 1-46, wherein at least one compound is administered as monotherapy.

[0141] 48. The method of any one of embodiments 1-46, wherein at least one compound is administered in combination with at least one concurrent ITP treatment.

[0142] 49. The method of embodiment 48, wherein at least one concurrent ITP therapy is selected from a corticosteroid and a thrombopoietin receptor agonist.

[0143] 50. The method of embodiment 48 or 49, wherein at least one concurrent ITP treatment is selected from corticosteroids, eltrombopag, and romiplostim.

[0144] 51. The method of any one of embodiments 1-50, wherein the at least one compound comprises at least one compound selected from the (E)-isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-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.

[0145] 52. The method of any one of embodiments 1-50, wherein the at least one compound comprises at least one compound selected from the (Z)-isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-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.

[0146] 53. The method of any one of embodiments 1-50, wherein at least one compound comprises 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 a pharmaceutically acceptable salt thereof.

[0147] 54. The method of any one of embodiments 1-53, wherein at least one compound is administered orally to a human patient.

[0148] 55. The method of any one of embodiments 1-54, wherein at least one compound is administered to the human patient in the form of at least one tablet.

[0149] 56. The method of any one of embodiments 1-55, wherein at least one compound is administered with a glass of water.

[0150] 57. The method of any one of embodiments 1-56, wherein at least one compound is administered with food.

[0151] 58. The method of any one of embodiments 1-56, wherein at least one compound is administered without food.

[0152] Exemplary embodiment 2: Without limitation, some embodiments of the present disclosure include:

[0153] 1. A method of treating immune thrombocytopenia in a human patient, comprising: A method comprising administering to a patient a dose 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 (PRN1008) selected from 400 mg once daily (QD), 300 mg twice daily (BID), and 400 mg BID.

[0154] 2. The method of embodiment 1, wherein PRN1008 comprises 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.

[0155] 3. The method of embodiment 1, wherein PRN1008 is formulated as a pharmaceutical composition.

[0156] 4. The method of embodiment 3, wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable carriers or excipients.

[0157] 5. The method of embodiment 4, wherein the pharmaceutical composition comprises microcrystalline cellulose, crospovidone, and sodium stearyl fumarate together with a film coating.

[0158] 6. The method of embodiment 1, further comprising repeating administration of PRN1008 to the patient during the treatment period.

[0159] 7. The method of embodiment 1, wherein the dose is 400 mg BID of PRN1008.

[0160] 8. The method of embodiment 1, wherein the patient is administered an initial dose of 400 mg QD of PRN1008, and after 28 days, the dose is escalated to a higher dose of 300 mg BID or 400 mg BID of PRN1008.

[0161] 9. The method of embodiment 1, wherein the patient is administered an initial dose of 300 mg BID of PRN1008, and after 28 days, the dose is increased to 400 mg BID of PRN1008.

[0162] 10. The method of embodiment 6, wherein the treatment period is for up to 168 days.

[0163] 11. The method of embodiment 6, wherein the treatment period ranges from 28 days to 168 days.

[0164] 12. The method of embodiment 6, wherein the treatment period is at least 8 days.

[0165] 13. The method of embodiment 6, wherein the treatment period ranges from 8 to 28 days.

[0166] 14. The method of embodiment 1, wherein, prior to administration, the patient's platelet count is less than 30,000 / μL for two or more consecutive platelet counts.

[0167] 15. The method of embodiment 1, wherein after administration throughout the treatment period, the patient has two or more consecutive platelet counts of ≧50,000 / μL at least 5 days apart.

[0168] 16. The method of embodiment 15, wherein the treatment period ranges from 28 days to 168 days.

[0169] 17. The method of embodiment 6, wherein after administration throughout the treatment period, the patient has a stable response of platelet counts of 50,000 / μL or greater during the treatment period and an increase in platelet count from baseline of ≧20,000 / μL.

[0170] 18. The method of embodiment 15, wherein the patient has a rapid onset of response within 1 to 2 weeks (7 to 14 days) corresponding to an increased platelet count of about 50,000 / μL to 100,000 / μL.

[0171] 19. The method of embodiment 15, wherein the patient has a rapid onset of response within 1 to 2 weeks (7 to 14 days) corresponding to an increased platelet count of 60,000 / μL to 90,000 / μL.

[0172] 20. The method of embodiment 16, wherein the rapid onset of the response is within one week (7 days).

[0173] 21. The method of embodiment 16, wherein the patient is administered an initial dose of 300 mg BID or 400 mg BID of PRN1008.

[0174] 22. The method of embodiment 1, wherein, prior to administration, the patient has relapsed or refractory idiopathic thrombocytopenia that is primary or secondary to another disease suffered by the patient.

[0175] 23. The method of embodiment 1, wherein the patient has secondary ITP.

[0176] 24. The method of embodiment 21, wherein the patient is administered a dose of 400 mg BID.

[0177] 25. The method of embodiment 1, wherein the patient is also receiving one or more concomitant medications.

[0178] 26. The method of embodiment 25, wherein the one or more co-medications are selected from corticosteroids, eltrombopag, and romiplostim.

[0179] 27. A method of treating immune thrombocytopenia in a human patient, comprising: 1. A method comprising administering to a patient a dose selected from 400 mg once daily (QD), 300 mg twice daily (BID), and 400 mg BID of 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 (PRN1008), wherein prior to administration, the patient's platelet count is less than 30,000 / μL for two or more consecutive platelet counts, and after administration, the patient has a stable platelet response of 50,000 / μL or greater for the treatment period.

[0180] 28. The method of embodiment 27, wherein the dose is 400 mg BID of PRN1008.

[0181] 29. A method of treating immune thrombocytopenia in a human patient, comprising: 1. A method comprising administering to a patient a dose selected from 400 mg once daily (QD), 300 mg twice daily (BID), and 400 mg BID of 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 (PRN1008), wherein prior to administration, the patient's platelet count is less than 30,000 / μL for two or more consecutive platelet counts, and after administration throughout the treatment period, the patient achieves two or more consecutive platelet counts of ≥ 50,000 / μL at least 5 days apart and an increase in platelet count of ≥ 20,000 / μL from baseline.

[0182] 30. The method of embodiment 29, wherein the dose is 400 mg BID of PRN1008. [Brief explanation of the drawings]

[0183] [Figure 1A]FIG. 1 illustrates the reversible covalent binding mechanism of PRN1008, allowing for optimized clinical activity with minimal drug exposure and the benefits associated with reversibility. [Figure 1B] FIG. 1 shows PK exposure (ng / mL) and % BTK inhibition over 25 h for PRN1008. [Figure 2] FIG. 1 shows the dose escalation rules for the dose-ranging portion of an adaptive, open-label, dose-ranging Phase 1 / 2 study investigating PRN1008 in patients with ITP. [Figure 3A] FIG. 1 shows the effect of 1 μM PRN1008 on platelet function assessed in vitro in platelets from normal healthy volunteer blood using a standard panel of platelet agonists. [Figure 3B] FIG. 1 shows the effect of 1 μM PRN1008 on platelet function assessed in vitro in platelets from the blood of ITP patients using a standard panel of platelet agonists. [Figure 4] FIG. 1 shows the effect of 1 μM ibrutinib on platelet function assessed in vitro in platelets from normal healthy volunteer blood using a standard panel of platelet agonists. [Figure 5] FIG. 1 shows platelet count response over time for patients with secondary ITP enrolled in a Phase 1 / 2 study investigating PRN1008 in patients with ITP. [Figure 6] Platelet count response over time for Phase 1 / 2 ITP dose-finding study patients (n=10) initiated on a low starting dose (QD dosing) of PRN1008 (data cutoff: November 13, 2019). [Figure 7] Platelet count response over time for Phase 1 / 2 ITP dose-finding study patients (n=21) initiated on a high starting dose (BID dosing) of PRN1008 (data cutoff: November 13, 2019). [Figure 8] FIG. 1 shows summary statistics for platelet responses in Phase 1 / 2 ITP patients (data cutoff: November 13, 2019). [Figure 9]Platelet count response over time for Phase 1 / 2 ITP patients (n=32) initiated on PRN1008 400 mg bid (data cutoff: April 22, 2020). [Figure 10] Figure 1 shows summary statistics for platelet responses in Phase 1 / 2 ITP patients (data cutoff: April 22, 2020). DETAILED DESCRIPTION OF THE INVENTION

[0184] Definition: 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 undefined technical and scientific terms used in this application have the meaning commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0185] As used herein, the indefinite article "a" or "an" attached to an entity means one or more of that entity; for example, a compound followed by an indefinite article means one or more compounds or at least one compound unless otherwise specified. Thus, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein.

[0186] As used herein, the term "about" means approximately, in the region of, roughly, or near. When used in conjunction with a numerical range, the term "about" modifies that range by extending the upper and lower limits of the stated numerical values ​​above and below. Generally, the term "about" is used herein to modify a numerical value by a 5% variance above and below the stated value. With respect to specific values, it should be understood that the specific values ​​described herein for a subject population (e.g., subjects in a described clinical trial) represent median, average, or statistical numbers unless otherwise specified. Therefore, aspects of the present disclosure requiring specific values ​​in subjects are supported by population data in which the relevant values ​​are assessed as meaningful delimitations for the subject population.

[0187] As used herein, the term "active pharmaceutical ingredient" or "therapeutic agent" ("API") means a biologically active compound.

[0188] As used herein, the terms "administer," "administering," or "administration" refer herein to supplying, giving, dispensing, and / or prescribing by a physician or authorized representative, and / or taking, ingesting, or consuming by a patient or person themselves. For example, "administration" of an API to a patient refers to any route of introducing or delivering the API to a patient (e.g., oral delivery). Administration includes self-administration and administration by another.

[0189] As used herein, "BID" and "bid" are used interchangeably to mean twice a day.

[0190] As used herein, "immune thrombocytopenia" (ITP) encompasses or at least refers to other commonly used terms such as idiopathic thrombocytopenia and idiopathic thrombocytopenic purpura. There are two main types of ITP: short-term (acute) and chronic (long-term). Acute ITP usually lasts less than six months, while chronic ITP can last six months or longer. ITP affects multiple age groups and can be seen in children, teenagers, and adults.

[0191] As used herein, the term "in combination with," when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, refers to the administration of the two or more compounds, agents, or active pharmaceutical ingredients to a patient before, simultaneously with, or after each other during a treatment period. Unless otherwise specified, the two or more compounds, agents, or active pharmaceutical ingredients may be administered on different schedules during a treatment period, such as, for example, one or more compounds, agents, or active pharmaceutical ingredients being administered once daily and one or more other compounds, agents, or active pharmaceutical ingredients being administered twice daily.

[0192] As used herein, an amount expressed as "[X] mg" refers to [X], i.e., the total amount in milligrams of the free base. In some embodiments, PRN1008 can be administered as a pharmaceutically acceptable salt of PRN1008, in which case an amount expressed as "mg of PRN1008" refers to the total amount in milligrams of PRN1008, i.e., the free base, plus an equivalent amount by weight of the free base in one or more pharmaceutically acceptable salts of PRN1008. For example, "400 mg of at least one compound selected from PRN1008 and a pharmaceutically acceptable salt thereof" includes 400 mg of PRN1008 and one or more pharmaceutically acceptable salts of PRN1008 in a concentration equivalent to 400 mg of PRN1008.

[0193] As used herein, "pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is useful in preparing pharmaceutical compositions that are generally safe and not biologically or otherwise undesirable, such as, for example, a carrier or excipient that is acceptable for mammalian pharmaceutical use.

[0194] As used herein, the term "pharmaceutically acceptable salt" refers to a salt form, e.g., an acid addition salt, of an active drug substance that is pharmaceutically acceptable and retains the desired pharmacological activity of the API from which the salt is made. Pharmaceutically acceptable salts are well known in the art and include those derived from suitable inorganic and organic acids. Such salts include, but are not limited to, salts formed 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, hexanoic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, etc. S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0195] As used herein, the terms "PRN1008", "rilzabrutinib", "(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" refer to the compound of the structure: [ka] are used interchangeably to refer to compounds having

[0196] A dose of PRN1008 may contain less than about 5% by weight of the corresponding (S) enantiomer as an impurity, e.g., less than about 1% by weight of the corresponding (S) enantiomer as an impurity. Similarly, a dose of the (E) isomer of PRN1008 may contain less than about 1% by weight of the corresponding (Z) isomer as an impurity; a dose of the (Z) isomer of PRN1008 may contain less than about 1% by weight of the corresponding (E) isomer as an impurity. When PRN1008 is referred to as 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, it means that the amount of the (E) or (Z) isomer in the mixture is greater than about 1% by weight. In some embodiments, the molar ratio of the (E) to the (Z) isomer is 9: 1. PRN1008 or a pharmaceutically acceptable salt thereof is also referred to herein as a "drug," "active agent," "therapeutically active agent," or "API."

[0197] As used herein, "QD" and "qd" are used interchangeably to mean once daily.

[0198] As used herein, the term "therapeutically effective amount" refers to the amount of compound administered that produces the desired effect (e.g., amelioration of ITP or symptoms of ITP, or lessening the severity of ITP or symptoms of ITP). The precise amount of the effective dose will depend on the purpose of the treatment, and can be ascertained by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0199] As used herein, the terms "treat," "treating," or "treatment," when used in reference to a disorder or condition, include any effect that results in improvement of the disorder or condition, e.g., alleviating, reducing, modulating, ameliorating, or eliminating. Improvement or alleviation of the severity of any symptom of a disorder or condition can be readily assessed according to standard methods and techniques known in the art.

[0200] Some embodiments of the present disclosure relate to a method of treating immune thrombocytopenia (ITP) in a human patient, comprising administering 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 (PRN1008) and pharmaceutically acceptable salts thereof to a human patient in need thereof once daily or twice daily for a treatment period.

[0201] In some embodiments, the treatment period is 8 days. In some embodiments, the treatment period is 28 days. In some embodiments, the treatment period is 84 days. In some embodiments, the treatment period is 168 days.

[0202] 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 168 days.

[0203] In some embodiments, the treatment period is 8 to 28 days. In some embodiments, the treatment period is 8 to 84 days. In some embodiments, the treatment period is 8 to 168 days. In some embodiments, the treatment period is 28 to 84 days. In some embodiments, the treatment period is 28 to 168 days. In some embodiments, the treatment period is 84 to 168 days.

[0204] In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily or twice daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient twice daily.

[0205] In some embodiments, the method comprises administering 300 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to a human patient twice daily.

[0206] In some embodiments, the method comprises treating primary ITP. In some embodiments, the method comprises treating secondary ITP. In some embodiments, the method comprises treating chronic ITP. In some embodiments, the method comprises treating recurrent ITP. In some embodiments, the method comprises treating refractory ITP.

[0207] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least one characteristic selected from the following:

[0208] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least two characteristics selected from the following:

[0209] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least three characteristics selected from the following:

[0210] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy The present invention has at least four characteristics selected from the following:

[0211] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy The present invention has at least five characteristics selected from the following:

[0212] In some embodiments, the human patient has the following characteristics prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has all of the above.

[0213] In some embodiments, the human patient is between 21 and 74 years of age prior to the start of the treatment period.

[0214] In some embodiments, the human patient has two platelet counts below 30,000 / μL prior to the start of the treatment period. In some embodiments, the human patient has two platelet counts below 30,000 / μL prior to the start of the treatment period, wherein the two counts are taken seven or more days apart. In some embodiments, the human patient has two platelet counts below 30,000 / μL prior to the start of the treatment period, wherein the two counts are taken seven or more days apart within 15 days prior to the start of the treatment period.

[0215] In some embodiments, the human patient has a platelet count of less than 30,000 / μL for at least two consecutive platelet counts before the start of the treatment period. In some embodiments, the human patient has a platelet count of less than 30,000 / μL for at least two consecutive platelet counts before the start of the treatment period, wherein the two counts are taken seven or more days apart. In some embodiments, the human patient has a platelet count of less than 30,000 / μL for at least two consecutive platelet counts before the start of the treatment period, wherein the two counts are taken seven or more days apart within 15 days before the start of the treatment period.

[0216] In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 28,000 / μL. In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 28,000 / μL, where the two counts are measured seven or more days apart. In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 28,000 / μL, where the two counts are measured seven or more days apart and within 15 days prior to initiation of a treatment period.

[0217] In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 33,000 / μL. In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 33,000 / μL, where the two counts are measured seven or more days apart. In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 33,000 / μL, where the two counts are measured seven or more days apart and within 15 days prior to initiation of a treatment period.

[0218] In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 28,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts measured at least 7 days apart before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 28,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts measured at least 7 days apart before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 28,000 / μL within 15 days before the start of the treatment period.

[0219] In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 15,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, is between 3,000 / μL and 15,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, within 15 days before the start of the treatment period, is between 3,000 / μL and 15,000 / μL.

[0220] In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 33,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, is between 3,000 / μL and 33,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, within 15 days before the start of the treatment period, is between 3,000 / μL and 33,000 / μL.

[0221] In some embodiments, the human patient has had ITP for at least 2 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 3 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 4 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 5 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 6 months before the start of the treatment period.

[0222] In some embodiments, the human patient has had ITP for at least one year before the start of the treatment period. In some embodiments, the human patient has had ITP for at least two years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least three years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least four years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least five years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least six years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least seven years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least eight years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least nine years before the start of the treatment period.

[0223] In some embodiments, the human patient has had ITP for at least 10 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 20 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 30 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 40 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 50 years before the start of the treatment period.

[0224] In some embodiments, the human patient has a history of 1 to 41 prior ITP treatments prior to the start of the treatment period. In some embodiments, the human patient has a history of 1 to 54 prior ITP treatments prior to the start of the treatment period.

[0225] In some embodiments, the human patient has a history of at least one prior ITP treatment before the start of the treatment period. In some embodiments, the human patient has a history of at least two prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least three prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least four prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least five prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least six prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least seven prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least eight prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least nine prior ITP treatments before the start of the treatment period.

[0226] In some embodiments, the human patient has a medical history of at least 10 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 15 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 20 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 25 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 30 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 35 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 40 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 45 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 50 prior ITP treatments before the start of the treatment period.

[0227] In some embodiments, the at least one prior ITP treatment is selected from corticosteroids, thrombopoietin receptor agonists, intravenous immunoglobulin, anti-D immunoglobulin, and rituximab.

[0228] In some embodiments, the human patient underwent a splenectomy prior to the start of the treatment period.

[0229] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered as monotherapy.

[0230] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered in combination with at least one concurrent ITP treatment.

[0231] In some embodiments, the at least one concurrent ITP therapy is selected from a corticosteroid and a thrombopoietin receptor agonist, hi some embodiments, the at least one concurrent ITP therapy is selected from a corticosteroid, eltrombopag, and romiplostim.

[0232] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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.

[0233] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 pharmaceutically acceptable salts thereof.

[0234] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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.

[0236] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 pharmaceutically acceptable salts thereof.

[0237] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 a pharmaceutically acceptable salt thereof.

[0238] Some embodiments of the present disclosure relate to a method of increasing platelet count in a human patient with immune thrombocytopenia (ITP), comprising administering to the human patient once daily or twice daily for 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 (PRN1008) and pharmaceutically acceptable salts thereof.

[0239] In some embodiments, the method comprises increasing at least two consecutive platelet counts relative to a pre-administration baseline platelet count, hi some embodiments, the method comprises increasing at least two consecutive platelet counts relative to a pre-administration baseline platelet count without the need for rescue medication.

[0240] In some embodiments, the method comprises increasing the platelet count by at least 5,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing the platelet count by at least 10,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing the platelet count by at least 15,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing the platelet count by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0241] In some embodiments, the method comprises increasing at least 30% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least 40% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least 50% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least 60% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least 70% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0242] In some embodiments, the method comprises increasing at least two of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least three of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least four of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least five of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least six of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least seven of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0243] In some embodiments, the method comprises increasing at least two of the final six platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least three of the final six platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least four of the final six platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least five of the final six platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0244] In some embodiments, the pre-administration baseline platelet count is the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period. In some embodiments, the pre-administration baseline platelet count is the average of the human patient's two most recent platelet counts measured at least 7 days apart ..., within 15 days before the start of the treatment period.

[0245] In some embodiments, consecutive platelet counts are measured at least 5 days apart.

[0246] In some embodiments, the treatment period is 8 days. In some embodiments, the treatment period is 28 days. In some embodiments, the treatment period is 84 days. In some embodiments, the treatment period is 168 days.

[0247] 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 168 days.

[0248] In some embodiments, the treatment period is 8 to 28 days. In some embodiments, the treatment period is 8 to 84 days. In some embodiments, the treatment period is 8 to 168 days. In some embodiments, the treatment period is 28 to 84 days. In some embodiments, the treatment period is 28 to 168 days. In some embodiments, the treatment period is 84 to 168 days.

[0249] In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily or twice daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient twice daily.

[0250] In some embodiments, the method comprises administering 300 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to a human patient twice daily.

[0251] In some embodiments, the human patient has primary ITP. In some embodiments, the human patient has secondary ITP. In some embodiments, the human patient has chronic ITP. In some embodiments, the human patient has recurrent ITP. In some embodiments, the human patient has refractory ITP.

[0252] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least one characteristic selected from the following:

[0253] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least two characteristics selected from the following:

[0254] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least three characteristics selected from the following:

[0255] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy The present invention has at least four characteristics selected from the following:

[0256] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy The present invention has at least five characteristics selected from the following:

[0257] In some embodiments, the human patient has the following characteristics prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has all of the above.

[0258] In some embodiments, the human patient is between 21 and 74 years of age prior to the start of the treatment period.

[0259] In some embodiments, the human patient has two platelet counts below 30,000 / μL prior to the start of the treatment period. In some embodiments, the human patient has two platelet counts below 30,000 / μL prior to the start of the treatment period, wherein the two counts are taken seven or more days apart. In some embodiments, the human patient has two platelet counts below 30,000 / μL prior to the start of the treatment period, wherein the two counts are taken seven or more days apart within 15 days prior to the start of the treatment period.

[0260] In some embodiments, the human patient has a platelet count of less than 30,000 / μL for at least two consecutive platelet counts prior to the start of the treatment period. In some embodiments, the human patient has a platelet count of less than 30,000 / μL for at least two consecutive platelet counts prior to the start of the treatment period, wherein the two counts are taken seven or more days apart. In some embodiments, the human patient has a platelet count of less than 30,000 / μL for at least two consecutive platelet counts prior to the start of the treatment period, wherein the two counts are taken seven or more days apart within 15 days prior to the start of the treatment period.

[0261] In some embodiments, the average of the two most recent platelet counts for the human patient before the start of the treatment period is between 3,000 / μL and 28,000 / μL. In some embodiments, the average of the two most recent platelet counts for the human patient before the start of the treatment period is between 3,000 / μL and 28,000 / μL, where the two counts are measured seven or more days apart. In some embodiments, the average of the two most recent platelet counts for the human patient before the start of the treatment period is between 3,000 / μL and 28,000 / μL, where the two counts are measured seven or more days apart and within 15 days before the start of the treatment period.

[0262] In some embodiments, the average of the two most recent platelet counts for the human patient before the start of the treatment period is between 3,000 / μL and 33,000 / μL. In some embodiments, the average of the two most recent platelet counts for the human patient before the start of the treatment period is between 3,000 / μL and 33,000 / μL, where the two counts are measured seven or more days apart. In some embodiments, the average of the two most recent platelet counts for the human patient before the start of the treatment period is between 3,000 / μL and 33,000 / μL, where the two counts are measured seven or more days apart and within 15 days before the start of the treatment period.

[0263] In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 28,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, is between 3,000 / μL and 28,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, within 15 days before the start of the treatment period, is between 3,000 / μL and 28,000 / μL.

[0264] In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 15,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, is between 3,000 / μL and 15,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, within 15 days before the start of the treatment period, is between 3,000 / μL and 15,000 / μL.

[0265] In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 33,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, is between 3,000 / μL and 33,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, within 15 days before the start of the treatment period, is between 3,000 / μL and 33,000 / μL.

[0266] In some embodiments, the human patient has had ITP for at least 2 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 3 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 4 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 5 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 6 months before the start of the treatment period.

[0267] In some embodiments, the human patient has had ITP for at least one year before the start of the treatment period. In some embodiments, the human patient has had ITP for at least two years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least three years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least four years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least five years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least six years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least seven years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least eight years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least nine years before the start of the treatment period.

[0268] In some embodiments, the human patient has had ITP for at least 10 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 20 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 30 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 40 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 50 years before the start of the treatment period.

[0269] In some embodiments, the human patient has a history of 1 to 41 prior ITP treatments prior to the start of the treatment period. In some embodiments, the human patient has a history of 1 to 54 prior ITP treatments prior to the start of the treatment period.

[0270] In some embodiments, the human patient has a history of at least one prior ITP treatment before the start of the treatment period. In some embodiments, the human patient has a history of at least two prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least three prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least four prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least five prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least six prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least seven prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least eight prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least nine prior ITP treatments before the start of the treatment period.

[0271] In some embodiments, the human patient has a medical history of at least 10 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 15 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 20 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 25 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 30 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 35 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 40 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 45 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 50 prior ITP treatments before the start of the treatment period.

[0272] In some embodiments, the at least one prior ITP treatment is selected from corticosteroids, thrombopoietin receptor agonists, intravenous immunoglobulin, anti-D immunoglobulin, and rituximab.

[0273] In some embodiments, the human patient has undergone a splenectomy prior to the start of the treatment period.

[0274] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered as monotherapy.

[0275] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered in combination with at least one concurrent ITP treatment.

[0276] In some embodiments, the at least one concurrent ITP therapy is selected from a corticosteroid and a thrombopoietin receptor agonist, hi some embodiments, the at least one concurrent ITP therapy is selected from a corticosteroid, eltrombopag, and romiplostim.

[0277] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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.

[0278] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 pharmaceutically acceptable salts thereof.

[0279] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 a pharmaceutically acceptable salt thereof.

[0280] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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.

[0281] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 pharmaceutically acceptable salts thereof.

[0282] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 a pharmaceutically acceptable salt thereof.

[0283] Some embodiments of the present disclosure relate to methods of achieving a platelet count of at least 50,000 / μL in a human patient with immune thrombocytopenia (ITP), comprising administering to the human patient once daily or twice daily for 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 (PRN1008) and pharmaceutically acceptable salts thereof.

[0284] In some embodiments, the method comprises achieving at least two platelet counts of at least 50,000 / μL. In some embodiments, the method comprises achieving at least two platelet counts of at least 50,000 / μL without the need for rescue medication.

[0285] In some embodiments, the method comprises achieving at least two consecutive platelet counts of at least 50,000 / μL. In some embodiments, the method comprises achieving at least two consecutive platelet counts of at least 50,000 / μL without the need for rescue medication.

[0286] In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 30% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 35% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 40% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 45% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 50% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 55% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 60% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 65% of the platelet counts measured during the treatment period, hi some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 70% of the platelet counts measured during the treatment period.

[0287] In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least two of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least three of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least four of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least five of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least six of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least seven of the final eight platelet counts measured during the treatment period.

[0288] In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least two of the final six platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least three of the final six platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least four of the final six platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least five of the final six platelet counts measured during the treatment period.

[0289] In some embodiments, the method comprises increasing at least 30% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least 40% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least 50% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least 60% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least 70% of the platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0290] In some embodiments, the method comprises increasing at least two of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least three of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least four of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least five of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least six of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least seven of the final eight platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0291] In some embodiments, the method comprises increasing at least two of the final six platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least three of the final six platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least four of the final six platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count. In some embodiments, the method comprises increasing at least five of the final six platelet counts measured during the treatment period by at least 20,000 / μL compared to the pre-administration baseline platelet count.

[0292] In some embodiments, the pre-administration baseline platelet count is the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period. In some embodiments, the pre-administration baseline platelet count is the average of the human patient's two most recent platelet counts before the start of the treatment period measured at least 7 days apart ... within 15 days before the start of the treatment period and the human patient's platelet count on the first day of the treatment period.

[0293] In some embodiments, consecutive platelet counts are measured at least 5 days apart.

[0294] In some embodiments, the treatment period is 8 days. In some embodiments, the treatment period is 28 days. In some embodiments, the treatment period is 84 days. In some embodiments, the treatment period is 168 days.

[0295] 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 168 days.

[0296] In some embodiments, the treatment period is 8 to 28 days. In some embodiments, the treatment period is 8 to 84 days. In some embodiments, the treatment period is 8 to 168 days. In some embodiments, the treatment period is 28 to 84 days. In some embodiments, the treatment period is 28 to 168 days. In some embodiments, the treatment period is 84 to 168 days.

[0297] In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily or twice daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient twice daily.

[0298] In some embodiments, the method comprises administering 300 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to a human patient twice daily.

[0299] In some embodiments, the human patient has primary ITP. In some embodiments, the human patient has secondary ITP. In some embodiments, the human patient has chronic ITP. In some embodiments, the human patient has recurrent ITP. In some embodiments, the human patient has refractory ITP.

[0300] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least one characteristic selected from the following:

[0301] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least two characteristics selected from the following:

[0302] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least three characteristics selected from the following:

[0303] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy The present invention has at least four characteristics selected from the following:

[0304] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy The present invention has at least five characteristics selected from the following:

[0305] In some embodiments, the human patient has the following characteristics prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has all of the above.

[0306] In some embodiments, the human patient is between 21 and 74 years of age prior to the start of the treatment period.

[0307] In some embodiments, the human patient has two platelet counts below 30,000 / μL prior to the start of the treatment period. In some embodiments, the human patient has two platelet counts below 30,000 / μL measured at least 7 days apart prior to the start of the treatment period. In some embodiments, the human patient has two platelet counts below 30,000 / μL prior to the start of the treatment period measured at least 7 days apart within 15 days prior to the start of the treatment period.

[0308] In some embodiments, the human patient has a platelet count of less than 30,000 / μL for at least two consecutive platelet counts taken 7 or more days apart prior to the start of the treatment period. In some embodiments, the human patient has a platelet count of less than 30,000 / μL for at least two consecutive platelet counts taken 7 or more days apart prior to the start of the treatment period. In some embodiments, the human patient has a platelet count of less than 30,000 / μL for at least two consecutive platelet counts taken 7 or more days apart within 15 days prior to the start of the treatment period.

[0309] In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 28,000 / μL. In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 28,000 / μL, where the two counts are measured seven or more days apart. In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 28,000 / μL, where the two counts are measured seven or more days apart and within 15 days prior to initiation of a treatment period.

[0310] In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 33,000 / μL. In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 33,000 / μL, where the two counts are measured seven or more days apart. In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 33,000 / μL, where the two counts are measured seven or more days apart and within 15 days prior to initiation of a treatment period.

[0311] In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 28,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, is between 3,000 / μL and 28,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, within 15 days before the start of the treatment period, is between 3,000 / μL and 28,000 / μL.

[0312] In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 15,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, is between 3,000 / μL and 15,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, within 15 days before the start of the treatment period, is between 3,000 / μL and 15,000 / μL.

[0313] In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 33,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, is between 3,000 / μL and 33,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, within 15 days before the start of the treatment period, is between 3,000 / μL and 33,000 / μL.

[0314] In some embodiments, the human patient has had ITP for at least 2 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 3 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 4 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 5 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 6 months before the start of the treatment period.

[0315] In some embodiments, the human patient has had ITP for at least one year before the start of the treatment period. In some embodiments, the human patient has had ITP for at least two years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least three years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least four years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least five years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least six years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least seven years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least eight years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least nine years before the start of the treatment period.

[0316] In some embodiments, the human patient has had ITP for at least 10 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 20 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 30 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 40 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 50 years before the start of the treatment period.

[0317] In some embodiments, the human patient has a history of 1 to 41 prior ITP treatments prior to the start of the treatment period. In some embodiments, the human patient has a history of 1 to 54 prior ITP treatments prior to the start of the treatment period.

[0318] In some embodiments, the human patient has a history of at least one prior ITP treatment before the start of the treatment period. In some embodiments, the human patient has a history of at least two prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least three prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least four prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least five prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least six prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least seven prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least eight prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least nine prior ITP treatments before the start of the treatment period.

[0319] In some embodiments, the human patient has a medical history of at least 10 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 15 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 20 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 25 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 30 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 35 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 40 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 45 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 50 prior ITP treatments before the start of the treatment period.

[0320] In some embodiments, the at least one prior ITP treatment is selected from corticosteroids, thrombopoietin receptor agonists, intravenous immunoglobulin, anti-D immunoglobulin, and rituximab.

[0321] In some embodiments, the human patient underwent a splenectomy prior to the start of the treatment period.

[0322] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered as monotherapy.

[0323] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered in combination with at least one concurrent ITP treatment.

[0324] In some embodiments, the at least one concurrent ITP therapy is selected from a corticosteroid and a thrombopoietin receptor agonist, hi some embodiments, the at least one concurrent ITP therapy is selected from a corticosteroid, eltrombopag, and romiplostim.

[0325] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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.

[0326] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 pharmaceutically acceptable salts thereof.

[0327] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 a pharmaceutically acceptable salt thereof.

[0328] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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.

[0329] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 pharmaceutically acceptable salts thereof.

[0330] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 a pharmaceutically acceptable salt thereof.

[0331] Some embodiments of the present disclosure relate to methods of achieving at least one platelet count of at least 50,000 / μL and increasing at least one platelet count by at least 20,000 / μL in a human patient with immune thrombocytopenia (ITP), comprising administering to the human patient once daily or twice daily for 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 (PRN1008) and pharmaceutically acceptable salts thereof.

[0332] In some embodiments, the method comprises achieving at least two platelet counts of at least 50,000 / μL. In some embodiments, the method comprises achieving at least two platelet counts of at least 50,000 / μL without the need for rescue medication.

[0333] In some embodiments, the method comprises achieving at least two consecutive platelet counts of at least 50,000 / μL. In some embodiments, the method comprises achieving at least two consecutive platelet counts of at least 50,000 / μL without the need for rescue medication.

[0334] In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 30% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 35% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 40% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 45% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 50% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 55% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least 60% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least 65% of the platelet counts measured during the treatment period, hi some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least 70% of the platelet counts measured during the treatment period.

[0335] In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least two of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least three of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least four of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least five of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least six of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL in at least seven of the final eight platelet counts measured during the treatment period.

[0336] In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least two of the final six platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least three of the final six platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least four of the final six platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 50,000 / μL for at least five of the final six platelet counts measured during the treatment period.

[0337] In some embodiments, consecutive platelet counts are measured at least 5 days apart.

[0338] In some embodiments, the treatment period is 8 days. In some embodiments, the treatment period is 28 days. In some embodiments, the treatment period is 84 days. In some embodiments, the treatment period is 168 days.

[0339] 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 168 days.

[0340] In some embodiments, the treatment period is 8 to 28 days. In some embodiments, the treatment period is 8 to 84 days. In some embodiments, the treatment period is 8 to 168 days. In some embodiments, the treatment period is 28 to 84 days. In some embodiments, the treatment period is 28 to 168 days. In some embodiments, the treatment period is 84 to 168 days.

[0341] In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily or twice daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient twice daily.

[0342] In some embodiments, the method comprises administering 300 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to a human patient twice daily.

[0343] In some embodiments, the human patient has primary ITP. In some embodiments, the human patient has secondary ITP. In some embodiments, the human patient has chronic ITP. In some embodiments, the human patient has recurrent ITP. In some embodiments, the human patient has refractory ITP.

[0344] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least one characteristic selected from the following:

[0345] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least two characteristics selected from the following:

[0346] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least three characteristics selected from the following:

[0347] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy The present invention has at least four characteristics selected from the following:

[0348] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy The present invention has at least five characteristics selected from the following:

[0349] In some embodiments, the human patient has the following characteristics prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has all of the above.

[0350] In some embodiments, the human patient is between 21 and 74 years of age prior to the start of the treatment period.

[0351] In some embodiments, the human patient has two platelet counts below 30,000 / μL prior to the start of the treatment period. In some embodiments, the human patient has two platelet counts below 30,000 / μL prior to the start of the treatment period, wherein the two counts are taken seven or more days apart. In some embodiments, the human patient has two platelet counts below 30,000 / μL prior to the start of the treatment period, wherein the two counts are taken seven or more days apart within 15 days prior to the start of the treatment period.

[0352] In some embodiments, the human patient has a platelet count of less than 30,000 / μL for at least two consecutive platelet counts prior to the start of the treatment period. In some embodiments, the human patient has a platelet count of less than 30,000 / μL for at least two consecutive platelet counts prior to the start of the treatment period, wherein the two counts are taken seven or more days apart. In some embodiments, the human patient has a platelet count of less than 30,000 / μL for at least two consecutive platelet counts prior to the start of the treatment period, wherein the two counts are taken seven or more days apart within 15 days prior to the start of the treatment period.

[0353] In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 28,000 / μL. In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 28,000 / μL, where the two counts are measured seven or more days apart. In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 28,000 / μL, where the two counts are measured seven or more days apart and within 15 days prior to initiation of a treatment period.

[0354] In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 33,000 / μL. In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 33,000 / μL, where the two counts are measured seven or more days apart. In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 33,000 / μL, where the two counts are measured seven or more days apart and within 15 days prior to initiation of a treatment period.

[0355] In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 28,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, is between 3,000 / μL and 28,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, within 15 days before the start of the treatment period, is between 3,000 / μL and 28,000 / μL.

[0356] In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 15,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, is between 3,000 / μL and 15,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, within 15 days before the start of the treatment period, is between 3,000 / μL and 15,000 / μL.

[0357] In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 33,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, is between 3,000 / μL and 33,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, within 15 days before the start of the treatment period, is between 3,000 / μL and 33,000 / μL.

[0358] In some embodiments, the human patient has had ITP for at least 2 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 3 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 4 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 5 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 6 months before the start of the treatment period.

[0359] In some embodiments, the human patient has had ITP for at least one year before the start of the treatment period. In some embodiments, the human patient has had ITP for at least two years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least three years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least four years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least five years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least six years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least seven years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least eight years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least nine years before the start of the treatment period.

[0360] In some embodiments, the human patient has had ITP for at least 10 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 20 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 30 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 40 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 50 years before the start of the treatment period.

[0361] In some embodiments, the human patient has a history of 1 to 41 prior ITP treatments prior to the start of the treatment period. In some embodiments, the human patient has a history of 1 to 54 prior ITP treatments prior to the start of the treatment period.

[0362] In some embodiments, the human patient has a history of at least one prior ITP treatment before the start of the treatment period. In some embodiments, the human patient has a history of at least two prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least three prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least four prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least five prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least six prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least seven prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least eight prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least nine prior ITP treatments before the start of the treatment period.

[0363] In some embodiments, the human patient has a medical history of at least 10 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 15 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 20 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 25 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 30 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 35 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 40 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 45 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 50 prior ITP treatments before the start of the treatment period.

[0364] In some embodiments, the at least one prior ITP treatment is selected from corticosteroids, thrombopoietin receptor agonists, intravenous immunoglobulin, anti-D immunoglobulin, and rituximab.

[0365] In some embodiments, the human patient underwent a splenectomy prior to the start of the treatment period.

[0366] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered as monotherapy.

[0367] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered in combination with at least one concurrent ITP treatment.

[0368] In some embodiments, the at least one concurrent ITP therapy is selected from a corticosteroid and a thrombopoietin receptor agonist, hi some embodiments, the at least one concurrent ITP therapy is selected from a corticosteroid, eltrombopag, and romiplostim.

[0369] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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.

[0370] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 pharmaceutically acceptable salts thereof.

[0371] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is (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 (E) and (Z). This includes mixtures of isomers or pharmaceutically acceptable salts of the above.

[0372] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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.

[0373] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 pharmaceutically acceptable salts thereof.

[0374] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 a pharmaceutically acceptable salt thereof.

[0375] Some embodiments of the present disclosure relate to methods for achieving a platelet count of at least 30,000 / μL in a human patient with immune thrombocytopenia (ITP), comprising administering to the human patient once daily or twice daily for 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 (PRN1008) and pharmaceutically acceptable salts thereof.

[0376] In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL for at least 30% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL for at least 35% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL for at least 40% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL for at least 45% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL for at least 50% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL for at least 55% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL for at least 60% of the platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL for at least 65% of the platelet counts measured during the treatment period, hi some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL for at least 70% of the platelet counts measured during the treatment period.

[0377] In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL in at least two of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL in at least three of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL in at least four of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL in at least five of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL in at least six of the final eight platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL in at least seven of the final eight platelet counts measured during the treatment period.

[0378] In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL for at least two of the final six platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL for at least three of the final six platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL for at least four of the final six platelet counts measured during the treatment period. In some embodiments, the method comprises achieving a platelet count of at least 30,000 / μL for at least five of the final six platelet counts measured during the treatment period.

[0379] In some embodiments, the treatment period is 8 days. In some embodiments, the treatment period is 28 days. In some embodiments, the treatment period is 84 days. In some embodiments, the treatment period is 168 days.

[0380] 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 168 days.

[0381] In some embodiments, the treatment period is 8 to 28 days. In some embodiments, the treatment period is 8 to 84 days. In some embodiments, the treatment period is 8 to 168 days. In some embodiments, the treatment period is 28 to 84 days. In some embodiments, the treatment period is 28 to 168 days. In some embodiments, the treatment period is 84 to 168 days.

[0382] In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily or twice daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient once daily. In some embodiments, the method comprises administering 400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to the human patient twice daily.

[0383] In some embodiments, the method comprises administering 300 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof to a human patient twice daily.

[0384] In some embodiments, the human patient has primary ITP. In some embodiments, the human patient has secondary ITP. In some embodiments, the human patient has chronic ITP. In some embodiments, the human patient has recurrent ITP. In some embodiments, the human patient has refractory ITP.

[0385] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least one characteristic selected from the following:

[0386] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least two characteristics selected from the following:

[0387] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has at least three characteristics selected from the following:

[0388] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy The present invention has at least four characteristics selected from the following:

[0389] In some embodiments, the human patient receives, prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy The present invention has at least five characteristics selected from the following:

[0390] In some embodiments, the human patient has the following characteristics prior to the start of the treatment period: Age 18-80 years; no approved therapeutic options available; platelet count less than 30,000 / μL; ITP duration of at least 1 month; A history of at least one prior treatment for ITP; and Splenectomy It has all of the above.

[0391] In some embodiments, the human patient is between 21 and 74 years of age prior to the start of the treatment period.

[0392] In some embodiments, the human patient has two platelet counts below 30,000 / μL prior to the start of the treatment period. In some embodiments, the human patient has two platelet counts below 30,000 / μL prior to the start of the treatment period, wherein the two counts are taken seven or more days apart. In some embodiments, the human patient has two platelet counts below 30,000 / μL prior to the start of the treatment period, wherein the two counts are taken seven or more days apart within 15 days prior to the start of the treatment period.

[0393] In some embodiments, the human patient has a platelet count of less than 30,000 / μL for at least two consecutive platelet counts prior to the start of the treatment period. In some embodiments, the human patient has a platelet count of less than 30,000 / μL for at least two consecutive platelet counts prior to the start of the treatment period, wherein the two counts are taken seven or more days apart. In some embodiments, the human patient has a platelet count of less than 30,000 / μL for at least two consecutive platelet counts prior to the start of the treatment period, wherein the two counts are taken seven or more days apart within 15 days prior to the start of the treatment period.

[0394] In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 28,000 / μL. In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 28,000 / μL, where the two counts are measured seven or more days apart. In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 28,000 / μL, where the two counts are measured seven or more days apart and within 15 days prior to initiation of a treatment period.

[0395] In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 33,000 / μL. In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 33,000 / μL, where the two counts are measured seven or more days apart. In some embodiments, the average of the two most recent platelet counts for a human patient prior to initiation of a treatment period is between 3,000 / μL and 33,000 / μL, where the two counts are measured seven or more days apart and within 15 days prior to initiation of a treatment period.

[0396] In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 28,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, is between 3,000 / μL and 28,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, within 15 days before the start of the treatment period, is between 3,000 / μL and 28,000 / μL.

[0397] In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 15,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, is between 3,000 / μL and 15,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, within 15 days before the start of the treatment period, is between 3,000 / μL and 15,000 / μL.

[0398] In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period is between 3,000 / μL and 33,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, is between 3,000 / μL and 33,000 / μL. In some embodiments, the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period, measured at least 7 days apart, within 15 days before the start of the treatment period, is between 3,000 / μL and 33,000 / μL.

[0399] In some embodiments, the human patient has had ITP for at least 2 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 3 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 4 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 5 months before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 6 months before the start of the treatment period.

[0400] In some embodiments, the human patient has had ITP for at least one year before the start of the treatment period. In some embodiments, the human patient has had ITP for at least two years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least three years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least four years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least five years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least six years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least seven years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least eight years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least nine years before the start of the treatment period.

[0401] In some embodiments, the human patient has had ITP for at least 10 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 20 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 30 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 40 years before the start of the treatment period. In some embodiments, the human patient has had ITP for at least 50 years before the start of the treatment period.

[0402] In some embodiments, the human patient has a history of 1 to 41 prior ITP treatments prior to the start of the treatment period. In some embodiments, the human patient has a history of 1 to 54 prior ITP treatments prior to the start of the treatment period.

[0403] In some embodiments, the human patient has a history of at least one prior ITP treatment before the start of the treatment period. In some embodiments, the human patient has a history of at least two prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least three prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least four prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least five prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least six prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least seven prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least eight prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a history of at least nine prior ITP treatments before the start of the treatment period.

[0404] In some embodiments, the human patient has a medical history of at least 10 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 15 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 20 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 25 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 30 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 35 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 40 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 45 prior ITP treatments before the start of the treatment period. In some embodiments, the human patient has a medical history of at least 50 prior ITP treatments before the start of the treatment period.

[0405] In some embodiments, the at least one prior ITP treatment is selected from corticosteroids, thrombopoietin receptor agonists, intravenous immunoglobulin, anti-D immunoglobulin, and rituximab.

[0406] In some embodiments, the human patient underwent a splenectomy prior to the start of the treatment period.

[0407] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered as monotherapy.

[0408] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof is administered in combination with at least one concurrent ITP treatment.

[0409] In some embodiments, the at least one concurrent ITP therapy is selected from a corticosteroid and a thrombopoietin receptor agonist, hi some embodiments, the at least one concurrent ITP therapy is selected from a corticosteroid, eltrombopag, and romiplostim.

[0410] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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.

[0411] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 pharmaceutically acceptable salts thereof.

[0412] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 a pharmaceutically acceptable salt thereof.

[0413] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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.

[0414] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 pharmaceutically acceptable salts thereof.

[0415] In some embodiments, at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof comprises 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 a pharmaceutically acceptable salt thereof.

[0416] In some embodiments, the disclosure relates to a method of treating immune thrombocytopenia in a human patient, comprising administering to the patient a dose selected from 400 mg once daily (QD), 300 mg twice daily (BID), and 400 mg BID of 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 (PRN1008).

[0417] In some embodiments, PRN1008 comprises a mixture of the (E) and (Z) isomers of 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. Furthermore, in some embodiments, PRN1008 is formulated as a pharmaceutical composition, which comprises one or more pharmaceutically acceptable carriers or excipients. For example, in some embodiments, the pharmaceutical composition comprises microcrystalline cellulose, crospovidone, and sodium stearyl fumarate in combination with a film coating.

[0418] In some embodiments of the present disclosure, the method further comprises repeating administration of PRN1008 to the patient throughout the treatment period. Additionally, in some embodiments, the treatment period is at least 8 days or between 8 and 28 days, ranging from 28 to 168 days.

[0419] In some embodiments, the present disclosure provides that the patient's platelet count prior to administration is less than 30,000 / μL for two or more consecutive platelet counts. Further, in some embodiments, after administration throughout the treatment period, the patient achieves two or more consecutive platelet counts of ≥ 50,000 / μL, at least 5 days apart; the treatment period ranges from 28 to 168 days. Additionally, in some embodiments, after administration throughout the treatment period, the patient has a stable response of platelet counts of ≥ 50,000 / μL throughout the treatment period and an increase in platelet count of ≥ 20,000 / μL from baseline.

[0420] In some embodiments, the present disclosure provides that the patient has recurrent or refractory idiopathic thrombocytopenia before administration, which may be primary or secondary to other diseases that the patient suffers from.For example, in some embodiments, the patient has secondary ITP.In some embodiments, the patient is administered a dose of 400 mg QD.

[0421] In some embodiments, the present disclosure relates to situations where the patient is also receiving one or more concurrent medications, for example, in some embodiments, the one or more concurrent medications are selected from corticosteroids, eltrombopag, and romiplostim.

[0422] In some embodiments, the disclosure relates to a method of treating immune thrombocytopenia in a human patient, comprising administering to the patient a dose selected from: 400 mg once daily (QD), 300 mg twice daily (BID), and 400 mg BID 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 (PRN1008), wherein prior to administration, the patient's platelet count is less than 30,000 / μL for two or more consecutive platelet counts, and after administration, the patient has a stable response with a platelet count of 50,000 / μL or greater over the treatment period.

[0423] In some embodiments, the disclosure relates to a method of treating immune thrombocytopenia in a human patient, comprising administering to the patient a dose selected from: 400 mg once daily (QD), 300 mg twice daily (BID), and 400 mg BID 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 (PRN1008), wherein prior to administration, the patient's platelet count is less than 30,000 / μL for two or more consecutive platelet counts, and after administration throughout the treatment period, the patient achieves two or more consecutive platelet counts of ≧50,000 / μL at least 5 days apart, and an increase in platelet count of ≧20,000 / μL from baseline.

[0424] Pharmaceutical Composition: In some embodiments of the present disclosure, PRN1008 is administered as part of a pharmaceutical composition comprising: at least one compound selected from PRN1008 and a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is at least one tablet.

[0425] In some embodiments of the present disclosure, PRN1008 is orally administered as part of a pharmaceutical composition comprising: at least one compound selected from PRN1008 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 comprising 100 mg or 300 mg of PRN1008. In some embodiments, the pharmaceutical composition is in the form of at least one tablet comprising 100 mg of PRN1008. In some embodiments, the pharmaceutical composition is in the form of at least one tablet comprising 300 mg of PRN1008.

[0426] In some embodiments, PRN1008 is administered in the form of a film-coated tablet.

[0427] In some embodiments of the present disclosure, PRN1008 is administered in the form of at least one tablet comprising: at least one compound selected from PRN1008 and its pharmaceutically acceptable salts; and at least one pharmaceutically acceptable excipient. In some embodiments, PRN1008 is administered in the form of at least one tablet comprising: at least one compound selected from PRN1008 and its pharmaceutically acceptable salts; 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 crospovidone. In some embodiments, the at least one lubricant is sodium stearyl fumarate.

[0428] In some embodiments of the present disclosure, PRN1008 is administered in the form of at least one tablet comprising: 100 mg of at least one compound selected from PRN1008 and its pharmaceutically acceptable salts; and at least one pharmaceutically acceptable excipient. In some embodiments, PRN1008 is administered in the form of at least one tablet comprising: 100 mg of at least one compound selected from PRN1008 and its pharmaceutically acceptable salts; 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 crospovidone. In some embodiments, the at least one lubricant is sodium stearyl fumarate.

[0429] In some embodiments of the present disclosure, PRN1008 is administered in the form of at least one tablet comprising: 300 mg of at least one compound selected from PRN1008 and its pharmaceutically acceptable salts; and at least one pharmaceutically acceptable excipient. In some embodiments, PRN1008 is administered in the form of at least one tablet comprising: 300 mg of at least one compound selected from PRN1008 and its pharmaceutically acceptable salts; 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 crospovidone. In some embodiments, the at least one lubricant is sodium stearyl fumarate.

[0430] In some embodiments, PRN1008 is administered with a glass of water.

[0431] In some embodiments, PRN1008 is administered with food.

[0432] In some embodiments, PRN1008 is administered without food.

[0433] The proportion and type of any pharmaceutically acceptable excipient can be determined by the chosen route of administration and standard pharmaceutical practice. Except insofar as any conventionally pharmaceutically acceptable excipient is incompatible with PRN1008, e.g., produces any undesirable biological effect or otherwise interacts deleteriously with any other component of the pharmaceutical composition, its use is deemed to be within the scope of this disclosure.

[0434] Some non-limiting examples of materials that can serve 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 wax; and (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, and corn oil. (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, 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) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic, compatible substances used in pharmaceutical formulations.

[0435] Remington: The Science and Practice of Pharmacy, 21st ed., 2005, edited by D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, also disclose additional non-limiting examples of pharmaceutically acceptable excipients, as well as known techniques for making and using them.

[0436] Those skilled in the art can readily select an appropriate form and route of administration depending on the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. [Example]

[0437] The following examples are intended to be illustrative and are not meant to limit the scope of the disclosure in any way.

[0438] Abbreviation: [Table 1-1] [Table 1-2] [Table 1-3]

[0439] Example 1: An Adaptive, Open-Label, Dose-Ranging Phase 1 / 2 Study Examining the Safety, Pharmacokinetics, and Clinical Activity of the Oral BTK Inhibitor PRN1008 in Patients with Relapsed / Refractory Immune Thrombocytopenia An ongoing Phase 1 / 2 clinical trial (NCT03395210) investigating the safety, pharmacokinetics, and clinical activity of the oral BTK inhibitor PRN1008 in patients with relapsed / refractory immune thrombocytopenia (ITP) began enrolling patients on March 22, 2018. As of October 6, 2020, the study's estimated primary completion date was September 2022, with an estimated study completion date of September 2023. To date, PRN1008 has been well tolerated in patients with ITP, with no treatment-related bleeding or thrombotic events reported. Positive preliminary results have also been observed in highly treatment-resistant and refractory patient populations.

[0440] Key inclusion criteria for the Phase 1 / 2 study were: adults aged 18–80 years with relapsed / refractory ITP; primary or secondary ITP to other diseases (e.g., systemic lupus erythematosus, chronic lymphocytic leukemia); no other available / approved treatment options; platelet counts of ≥2 <30,000 / μL at study entry; and adequate hematological, liver, 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, had relapsed or were refractory to prior treatment with no available approved therapeutic options, and could continue corticosteroids and / or thrombopoietin mimetics during the study. For example, stable concurrent corticosteroid (CS) or thrombopoietin receptor agonist (TPO-RA) treatment was permitted during the study.

[0441] The sample size used in the study was based on clinical considerations, using conventional approximations to obtain a sufficiently high level of confidence in the study results.

[0442] The completed PRN1008 intrapatient dose escalation portion of the study used a 3 + 3 design. Specifically, if a response was observed in one of three patients, three additional patients were added to that dose level. However, if no response was observed in three patients for 28 days, that dose was stopped, the patient was escalated to a higher dose, and all subsequently enrolled patients began treatment at that higher dose. During the dose escalation portion, patients received PRN1008 orally at doses of 200 and 400 mg qd and 300 and 400 mg bid for the 24-week active treatment period. If a patient responded to the initial dose, they continued on that dose (Figure 2). If a patient did not respond to the initial dose, the dose was escalated to a higher dose. Patients were monitored frequently with weekly platelet counts and complete blood counts (CBCs) throughout the active treatment period. PK samples were collected centrally on the first day of each new, higher dose level and at each follow-up visit at irregular intervals after dosing to assess dose response. Standard clinical and laboratory assessments of other ITP patients were also used in the dose escalation study, including the bleeding assessment used in previous ITP trials (ITP-BAT; Rodeghiero 2013 ).

[0443] The safety objective of the Phase 1 / 2 study was to characterize the safety and tolerability of up to four dose levels of PRN1008 in patients with ITP. In the study, safety was assessed by the occurrence, severity, and relevance of TEAEs, including clinically significant changes in physical examination, laboratory tests, and vital signs. Adverse events were classified as treatment-emergent and emerged after receiving the first dose of PRN1008. TEAEs within the post-treatment follow-up period were also assessed and examined for possible relevance to prior PRN1008 treatment. TEAEs included all AEs beginning at or after the first dose of study drug, or AEs that were present prior to the first dose of study drug but whose severity or relevance increased up to and including the date of the last dose of study drug after the first dose of study drug. If a patient reported more than one event during their treatment period, they were counted only once within each preferred period.

[0444] The pharmacokinetic objective of the study was to characterize the pharmacokinetics of PRN1008 in patients with ITP. max , T max , AUC, t 1 / 2 PK parameters (V / F, CL / F) were assessed in each patient based on frequent sampling on Day 1 of the new, higher dose level and reported by dose and overall, if relevant. Noncompartmental analysis was used to derive PK parameters for each individual. Results are reported using descriptive statistics, and exploratory analyses may pool these data with data from other studies of PRN1008.

[0445] The efficacy objectives of the study included: (1) studying the clinical activity of PRN1008 at up to four dose levels (200 and 400 mg qd; 300 and 400 mg bid) in patients with relapsed / refractory ITP; and (2) identifying potential dosing regimens for use in future studies of PRN1008 in patients with ITP. The dose-finding / dose-escalation portion of the study has been completed, and all enrolled patients are currently being treated at 400 mg bid.

[0446] In Part A of the study, the primary efficacy outcome measure was consecutive elevated platelet counts, i.e., two or more consecutive platelet counts ≥ 50,000 / μL without the need for rescue medication. Specifically, Part A examined the proportion of patients able to achieve two or more consecutive platelet counts ≥ 50,000 / μL at least 5 days apart within the 4 weeks preceding the most recent elevated platelet count without the use of rescue medication, and an increase in platelet count ≥ 20,000 / μL from baseline. Analysis of the primary efficacy endpoint was weighted logistic regression with a binary index of platelet response as the dependent variable, total mg / day dose level as the covariate, and weighted by the number of days patients were dosed.

[0447] Additional efficacy endpoints included: any two platelet counts ≥ 50,000 / μL; platelet response over time with duration of treatment, and clinical benefit (≥ 30,000 / μL); and stable response (platelet counts ≥ 50,000 / μL at 50% of visits for 4 weeks of the last 8 weeks of active treatment). For example, secondary efficacy endpoints of the study were: (1) the proportion of patients able to achieve two or more platelet counts of ≥ 50,000 / μL at any time (either during treatment or follow-up visit) without the use of rescue medication within the four weeks preceding the most recent elevated platelet count and an increase in platelet count of ≥ 20,000 / μL from baseline; (2) the proportion of patients by dose level able to achieve two or more platelet counts at least five days apart representing an increase in platelet count of ≥ 20,000 / μL from baseline without the use of rescue medication within the four weeks preceding the most recent elevated platelet count; (3) the proportion of patients at least five days apart achieving an increase in platelet count of ≥ 100,000 / μL without the use of rescue medication within the four weeks preceding the most recent elevated platelet count. (4) the proportion of patients by dose level achieving two or more platelet counts at least 5 days apart; (5) the change from baseline to the mean of the last two platelet counts at each dose level; (6) the proportion of patients receiving rescue medication at each dose level and overall; (7) the proportion of patients with grade 2 or greater bleeding events at each dose level and overall; (8) the end-of-treatment bleeding scale (ITP-BAT scale) for each dose level; and (9) the proportion of patients completing 24 weeks of treatment and demonstrating a platelet response defined as platelet counts ≥ 50,000 / μL at ≥ 50% of visits during the last 8 weeks of the active treatment period.

[0448] Preliminary objectives of the study included the effect of PRN1008 on platelet autoantibody levels; the effect of PRN1008 on hemolytic markers; the effect of PRN1008 on thrombopoietin (TPO) levels; the effect of PRN1008 on quality of life (QoL) using the Euro-QoL 5-Dimension visual analogue scale (EQ-5D VAS); and plasma metabolite analysis / identification of PRN1008.

[0449] Rationale for doses used and duration of study: An adaptive, open-label, dose-ranging study with rule-based intrapatient dose escalation was an appropriate phase 1 / 2 design to evaluate the safety and efficacy of PRN1008 in patients with ITP, a relatively uncommon autoimmune disease. The study design was similar to that used to study the initial efficacy and safety of the orally available tyrosine kinase inhibitor fostamatinib in ITP (Podolanczuk et al., 2009).

[0450] The doses and exposures investigated in this study were well tolerated in previous human studies, and their interrelationships were well characterized. Platelets express high levels of BTK; however, alternative signaling pathways exist that bypass BTK signaling and preserve normal platelet function. PRN1008 showed no effect on platelet aggregation from the blood of healthy volunteers or ITP patients tested ex vivo (≤1 μM) using a standard panel of platelet agonists (Figures 3A and 3B). For example, ex vivo treatment with PRN1008 at clinically relevant concentrations did not affect collagen-induced platelet aggregation in normal or ITP patient platelet samples or interfere with responses to all other platelet agonists tested. In contrast, the BTK inhibitor ibrutinib had a significant effect on platelet aggregation in healthy volunteers (Figure 4).

[0451] Based on BTK occupancy in a mouse model of antiplatelet-induced immune thrombocytopenia, a human starting dose of 200 mg qd was expected to show minimal improvement in platelet counts. In that model, a 10 mg / kg / d dose was associated with a mean 51% BTK occupancy 1 h post-dose, accompanied by a very small increase in platelet counts relative to vehicle control (71.9% platelet reduction with 10 mg / kg / d PRN1008 compared to a mean 83.1% platelet reduction from baseline relative to vehicle with antiplatelet). The highest dose of 40 mg / kg / d in that model resulted in a peak BTK occupancy of 91%, consistent with the peak occupancy expected for doses up to 400 mg QD and 400 mg BID. The 400 mg BID dose was expected to produce a higher trough, or approximately 70% pre-dose BTK occupancy, compared to 50% for QD dosing, while having a similar peak value. Dosing above 400 mg BID was thought unlikely to result in greater target inhibition.

[0452] In previous studies, no accumulation of exposure was observed with PRN1008 when administered once daily, but a small amount of accumulation was observed with twice-daily dosing.

[0453] The blistering disease pemphigus, like ITP, is an autoantibody-induced disease. In Study PRN1008-005, most pemphigus patients experienced a rapid onset of clinical response within 4 weeks, with continued improvement in very low levels of skin inflammation through the end of 12 weeks of treatment. Therefore, a 28-day cycle, which assesses early platelet responses and induces intrapatient dose escalation, seemed appropriate for studying ITP. In addition, a 24-week total treatment period was favorable for a dose-finding study, allowing all patients to potentially be escalated to higher doses and fully evaluated at those doses.

[0454] Dose Escalation Study Design: Patients in the dose-escalation portion of the study were assigned to four cohorts as shown in Table 1. Starting dose levels were 200 mg QD; 400 mg QD; 600 mg / day (300 mg BID); and 800 mg / day (400 mg BID). Due to the study design, not all patients received all dose levels shown in Table 1. The "sentinel cohort" for each dose level consisted of the first three patients, or six if three additional patients were added due to dose-limiting toxicity (DLT) events or platelet responses (defined by the primary endpoint and sustained in at least three of four consecutive platelet counts at either dose level). To be evaluable in the sentinel cohort, patients must have ≥75% compliance over the 28-day dosing period.

[0455] The following dose escalation rules were applied to the study. Individual patients were escalated to the next subsequent dose level unless they were withdrawn from the study, had a platelet response at the current dose level, or the next dose level was determined to be ineligible for further enrollment due to safety concerns. Patients experiencing a platelet response (as defined for the primary endpoint) did not have their dose escalated for the next cycle. If they did not experience a platelet response during the second cycle at the same dose level, their dose was escalated for the next cycle. If the platelet response was merely transient and subsequently required rescue medication, these patients were discontinued from the study. Patients experiencing DLT were discontinued. In addition, pregnant patients and patients with abnormal liver function tests suggestive of DILI as CTCAE ≥ grade 3 were discontinued: elevated ALT and / or AST (i.e., ALT or ALT > 5 × ULN) or ALT or AST > 3 × ULN with total bilirubin > 2 × ULN and no ALP > 2 × ULN without another cause.

[0456] The DLT assessment period for any patient was defined as the duration of PRN1008 dosing. Dose-limiting toxicities in the Phase 1 / 2 studies, including the completed dose-escalation study, were defined as follows: hematologic DLTs were: ANC <500 / μL for ≥5 days; Grade 3 or greater decreased hemoglobin in the absence of prior Grade 2 decreased hemoglobin; febrile neutropenia, absolute neutrophil count (ANC) <1000 / mm 3 DLTs were determined based on a single temperature >38.3°C (101°F) or a sustained temperature ≥38°C (100.4°F) for >1 hour (CTCAE, version 4.0); and a grade 3 or higher bleeding event requiring a platelet transfusion. Nonhematopoietic DLTs were considered nonhematopoietic toxicities >grade 3 according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, with the following exceptions: laboratory TEAEs that were asymptomatic and returned to baseline or grade 1 within 7 days; fatigue; nausea, vomiting, or diarrhea that returned to baseline or grade 1 within 7 days; and systemic reactions (e.g., fever, headache) that returned to baseline or grade 1 within 7 days. Toxicities that, at the investigator's discretion, warranted withholding the study drug for longer than 7 days were also considered DLTs.

[0457] In Table 1, n indicates expected enrollment or DLT in each cohort unless a sustained platelet response was observed, and in each case, three additional patients were added to that group. The starting dose level could be stopped for futility after three or six patients were evaluated, or maintained if efficacy was observed. Notably, individual patients in each cohort would not be dose-escalated if they experienced a platelet response at a lower dose level or toxicity. If some dose levels were therapeutic, some or all patients would not reach higher dose levels.

[0458] [Table 2]

[0459] Each patient enrolled in the dose escalation portion of the study had their dose escalated after 28 days of PRN1008 treatment at each dose level if they had not experienced a platelet response or DLT (as defined by the primary endpoint) at the last dose level. If a patient experienced a platelet response in the first cycle at any one dose level but not in the second cycle at that dose, the dose could be escalated at the end of the second cycle. Patients experiencing a platelet response (as defined by the primary endpoint) did not have their dose escalated in the next cycle.

[0460] Patients were treated with PRN1008 for up to 24 weeks, starting on Day 1 and ending on study Day 169, followed by four weeks of post-treatment safety follow-up. However, patients who were escalated to 400 mg BID were able to continue their effective treatment period until they completed 24 weeks of treatment at the 400 mg BID dose.

[0461] Patients were monitored weekly for platelet counts and CBCs during the dose-escalation study. In addition, PK samples were collected centrally on the first day of each new, higher dose level and irregularly at each follow-up visit after dosing.

[0462] Long-Term Extension Study (LTE): After completion of the active treatment period in a Phase 1 / 2 study (e.g., a dose-escalation study), patients who demonstrated a platelet response, defined as a platelet count ≥ 50,000 / μL in ≥ 50% of the final 8-week visits of the active treatment period, were entered into a long-term extension study (LTE) and received the investigational drug at a dose of 400 mg BID. Patients could continue until they: no longer responded to the LTE-defined platelet response and / or experienced dose-limiting toxicity; the drug was no longer being developed by the sponsor; the program was discontinued for safety reasons; or the drug became commercially available in their country.

[0463] Patients continuing on LTE had platelet counts and CBC monitored weekly for the first 6 months, then monthly for an additional 6 months, and once every 3 months thereafter.

[0464] Patients who had already completed the study, were responders to the LTE requirements, and had not experienced a DLT were eligible to enroll in the LTE.

[0465] Concurrent medications: All patients were eligible to receive concurrent corticosteroids but were not required to do so. Doses had to be fixed (±10%) for at least 2 weeks by Day 1 and remained unchanged throughout the study unless rescue criteria were triggered. If a patient required rescue therapy or their concurrent ITP medication increased by more than 10% of the Day 1 dose, they were discontinued from the study and received rescue therapy according to standard of care. These medications were not increased in dose as part of the "rescue" medication.

[0466] All patients were eligible to receive eltrombopag or romiplostim, but were not required to do so. Doses had to be fixed for at least 2 weeks by Day 1 and remained constant throughout the study unless there were safety concerns with the drug (a 10% variation from the Day 1 dose was allowed). These drugs were not increased in dose as part of "rescue" medication.

[0467] In vitro, PRN1008 was a substrate of P-gp and CYP3A and an inhibitor of CYP3A. When coadministered with midazolam to healthy volunteers, PRN1008 acted as a moderate CYP3A inhibitor, increasing midazolam exposure by approximately threefold. Moderate to strong inducers and inhibitors of cytochrome P450 3A (CYP3A) must be avoided during the study because coadministration may reduce or increase PRN1008 exposure. In addition, because PRN1008 is a weak to moderate CYP3A inhibitor, clinically relevant CYP3A substrate drugs with narrow therapeutic windows are not permitted. Other "sensitive substrates" may increase blood levels of sensitive substrate drugs when used concomitantly with PRN1008, and patients should be monitored if medically indicated.

[0468] Proton pump inhibitors are not permitted during Phase 1 / 2 studies because they may decrease the bioavailability of PRN1008 tablets. Concomitant administration of esomeprazole reduced the exposure of PRN1008 tablet formulations by 48% in a previous study, demonstrating the effect of gastric pH on absorption. Patients could be switched to an alternative H2-receptor blocker. PRN1008 should be administered at least 2 hours before an acceptable gastric acid suppressant.

[0469] Patient selection criteria: The following patient inclusion criteria were used to inform patient enrollment in Phase 1 / 2 studies, including, for example, dose escalation studies. 1. Male and female patients, aged 18-80 years (Czech Republic and Norway only: aged 18-65 years) 2. Immune-related ITP (both primary and secondary) 3. Refractory or relapsed patients with no available approved therapeutic options and platelet counts <30,000 / μL on two occasions >7 days apart within 15 days prior to initiation of study treatment 4. History of response (two or more increases in platelet counts ≥ 50,000 / μL, ≥ 20,000 / μL) to at least one prior line of treatment (splenectomy is considered a line of treatment) 5. Adequate hematological, liver, and renal function (absolute neutrophil count ≥ 1.5 x 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) (pre-dose C1D1 can be checked within 3 days before C1D1) 6. Female patients of reproductive potential must agree to use highly effective contraception (hormonal sterilization methods that suppress ovulation, intrauterine devices, intrauterine hormone-releasing systems, tubal ligation, partner vasectomy, or sexual abstinence) for the duration of active study treatment. Postmenopausal women should have menopause confirmed by FSH testing unless surgically sterile. 7. Able to provide written informed consent and agree to the scheduled evaluation.

[0470] Furthermore, participants cannot begin the enrollment process until all inclusion criteria have been met. If the clinical significance of an abnormal screening test result (laboratory or any other test) is unclear, the test may be repeated.

[0471] Exclusion criteria: The following exclusion criteria were used to inform patient enrollment in Phase 1 / 2 studies, including, for example, dose escalation studies. 1. Pregnant or breastfeeding women 2. ECG findings of QTcF >450 msec (men) or >470 msec (women), poorly controlled atrial fibrillation (i.e., symptomatic patient or heart rate >100 beats / min on ECG), or other clinically significant abnormalities 3. Past or current active malignancy requiring or likely to require chemotherapy or surgical treatment during the study, with the exception of non-melanoma skin cancer. 4. Blood or blood product transfusion or plasma exchange within 2 weeks prior to Day 1 5. Changes in corticosteroid and / or TPO agonist dose within 2 weeks prior to Day 1 (more than 10% variation from Day 1 dose) 6. Use of rescue medication other than corticosteroids or TPO in exclusion number 5 within 2 weeks prior to Day 1 7. Immunosuppressants other than corticosteroids - these drugs must be discontinued for at least 14 days before Day 1 8. Treatment with rituximab or splenectomy within 3 months prior to Day 1 9. Continued need for the use of proton pump inhibitors such as omeprazole and esomeprazole (tolerance to H2 receptor blockers before Day 1 is acceptable) 10. Concurrent use of a known strong to moderate inducer or inhibitor of CYP3A within 3 days or 5 half-lives (whichever is longer) of Day 1 11. Use of a narrow therapeutic index CYP3A sensitive substrate drug within 3 days or 5 half-lives (whichever is longer) of the investigational drug dose, including but not limited to alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or terfenadine 12. Planned or concurrent use of anticoagulants and platelet aggregation inhibitors, e.g., aspirin, NSAIDs, thienopyridenes (within 14 days of planned dosing until the end of follow-up) 13. Received an investigational drug within 30 days or at least 5 elimination half-lives of the drug (whichever is longer) prior to receiving the first dose of study drug; patient is not using an investigational device at the time of dosing 14. Current drug or alcohol abuse 15. Refractory nausea and vomiting, malabsorption, external bile shunt, or significant bowel resection that would prevent adequate study drug absorption 16. History of solid organ transplant 17. Positive screening for HIV, Hepatitis B (surface and core antibodies unrelated to vaccination), or Hepatitis C (anti-HCV antibodies supported by Hep C RNA) 18. History of serious infection requiring intravenous treatment within the last 3 months prior to Day 1 19. Clinically significant cognitive impairment (≥ Grade 1) or a medical history suggesting an increased risk of cognitive impairment during the study 20. Live vaccine within 28 days prior to Day 1 or planned to receive one during the study 21. Planned surgery during the medication period 22. Any other clinically significant disease, condition, or medical history that, in the investigator's opinion, interferes with patient safety, study assessments, and / or study procedures.

[0472] Additionally, participants must meet all inclusion criteria to enroll in the study. Participants who fail to meet the inclusion criteria may be re-screened at the investigator's discretion after notifying the study medical monitor.

[0473] evaluation: After providing written informed consent, subjects routinely completed the following clinical assessments: physical examination; medical history; concurrent medications; weight; height; vital signs; ITP-BAT bleeding scale; quality of life assessment EQ-5D VAS; online cognitive testing; and safety assessments.

[0474] Subjects routinely completed the following laboratory and ECG evaluations as part of the study: 1. Urinalysis: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrites, urobilinogen and leukocytes measured by dipstick or local requirements 2. Hepatitis B and C, HIV 3. Pregnancy testing for women of childbearing potential only. Serum pregnancy test at screening, urine pregnancy test at other visits 4. FSH: To confirm postmenopausal status in fertile women who are not surgically infertile 5. ABO and Rh blood types 6. Immature platelet fraction and mean platelet volume (if available in local laboratories) 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 excluded) 14.PK sampling at various time points 15. 12-lead ECG (single and triple)

[0475] Laboratory evaluation may be performed in both central and local laboratories, if necessary.

[0476] Safety assessments will include: frequency, severity, and relevance of AEs; changes in clinical examination (laboratory tests); physical examination, ECG, vital signs, and cognitive function.

[0477] In the dose escalation study, patients remained under observation in the clinic for 6 hours after administration of the first dose at the start of each new higher dose level while intensive PK sampling was performed.

[0478] Dosage form: In the study, PRN1008 was administered in the form of film-coated tablets. PRN1008 tablets were packaged in white, high-density polyethylene (HDPE) bottles with child-resistant, induction-seal lids; these bottles were intended for storage at 2-8°C and could be shipped at room temperature without ice. Additionally, the bottles could be kept at room temperature for up to 2 weeks.

[0479] Each PRN1008 film-coated tablet contained 100 mg or 300 mg of PRN1008 drug substance. In addition, the tablets contained microcrystalline cellulose (filler), crospovidone (disintegrant), sodium stearyl fumarate (lubricant), and a non-functional film coating. The 100 mg tablets were round and orange in color. The 300 mg tablets were oval and white in color.

[0480] Based on previous studies, food does not appear to affect the extent of PRN1008 absorption, but does slow the rate (a longer mean T of approximately 2.5 hours). max ). Thus, PRN1008 tablets are taken with a full glass (approximately 8 ounces) of water, but may be taken with or without food; i.e., no fasting period is required.

[0481] Analysis population: The screening population for this study included all participants who provided informed consent and underwent a screening assessment for study participation.

[0482] The safety population included all participants who received at least one dose of PRN1008 and was included in safety analyses. The safety population was used for all safety analyses. For safety evaluation by IDSM, three evaluable patients were required for dose reduction as a no-no, defined as ≥75% compliance with the dose for that dose level. During the study, patients were substituted if necessary to meet this requirement.

[0483] The Intent-to-Treat Exposed (ITT-E) population includes all participants who received at least one dose of PRN1008.

[0484] The pharmacokinetic analysis population included all participants who received at least one dose of PRN1008 and had at least one plasma concentration value and were included in the PK analyses. The pharmacokinetic analysis population was used for all PK analyses. Participants who discontinued the study early for reasons other than TEAEs may be replaced at the sponsor's discretion to ensure an adequate number of evaluable participants.

[0485] Patients who were removed from the study before the scheduled end of a study visit were considered to have been withdrawn early. Participants in this study had the right to withdraw at any time for any reason. In addition, the investigator could remove a participant from the study if there was an intercurrent illness, an AE, failure of treatment after a prescribed procedure, lack of compliance with the study and / or study measures, or any other reason felt to be in the participant's best interest to terminate the study.

[0486] Safety and Toxicity Control: An Independent Data Safety Monitor (IDSM), selected from experienced clinicians in the field of ITP, provided independent monitoring of the Phase 1 / 2 study. A Safety Monitoring Committee (SMC), consisting of the IDSM chair, lead investigator, study medical monitor, and sponsor's medical monitor, also closely oversaw study conduct, meeting approximately every 3 months to recommend study modifications or termination to the sponsor based on reported safety and efficacy information. SMC findings affecting patient safety in this study were reported to the local competent authority (CA) and IRB / EC.

[0487] IDSM conducted a "sentinel cohort" safety evaluation. Data from the "sentinel patients" for each dose level were reviewed by IDSM to select the starting dose for additional new patients. After review, IDSM could determine whether the starting dose for a new patient should be stopped due to futility (lack of platelet response), increased to the next planned dose level, maintained, or decreased. New patients entered into the study were initiated at a dose level determined by IDSM based on: (1) f ≥ 2 / 3 or ≥ 2 / 6 of the sentinel patients with DLT at any dose level, which determined the "maximum dose" and starting dose (for new patients) and subsequent doses (for patients already studied) set to lower dose levels (or the study was paused if the current sentinel dose cohort was 200 mg QD); (2) two or more sustained platelet responses (three of four counts) in the sentinel patient were seen at the current starting dose level, and the starting dose was not increased.

[0488] Clinical Adverse Events The AE collection period began at the time of the initial screening / eligibility assessment and ended at the end of the study for each patient. An AE is any undesirable medical condition in a clinical study for a participant or a participant to whom a medicinal product was administered, and does not necessarily have a causal relationship to the therapeutic intervention. Thus, an AE can be any untoward and unintended sign (e.g., including abnormal laboratory findings), symptom, or illness temporally associated with the use of the investigational product, whether or not considered related to the investigational product. Investigators were instructed to record in detail all AEs encountered during the clinical study, from the date of participant consent through the study follow-up period. Pre-existing conditions that worsened during the study were reported as AEs.

[0489] Relationship of adverse events to the investigational drug Investigators were instructed to use their knowledge of the study participant, the circumstances surrounding the event, and an evaluation of any potential alternative causes to determine whether an AE was considered related to the study drug, including "yes" or "no." Investigators were asked to consider the following information in assessing relevance: (1) the temporal relationship between the onset of the event and the initiation of the study drug; (2) the course of the event, particularly considering the effects of dose reduction, discontinuation of the study drug, or reintroduction of the study drug (if appropriate); (3) any known association of the event with the study drug or similar treatment; (4) any known association of the event with the disease under study; (5) the presence of risk factors in the study participant 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.

[0490] Investigators were instructed to follow for AEs based on the drug's PK profile until stabilization or 4 weeks after the last dose (considered the last visit), especially if grade 3 or greater in severity.

[0491] Laboratory and ECG abnormalities Investigators were instructed to record any treatment-emergent abnormal laboratory or ECG result that was clinically significant, i.e., that met one or more of the following criteria, as a single diagnosis on the AE page of the CRF: As a non-limiting example, laboratory and ECG abnormalities accompanied by clinical symptoms that led to a change in investigational product (e.g., dose modification, interruption, or permanent discontinuation) or required a change in concurrent therapy (e.g., addition, interruption, cessation, or any other change in concurrent medication, treatment, or procedure) met the criteria for a serious adverse event (SAE) and therefore must be recorded as an AE, with any abnormal laboratory or ECG result reported in addition to being recorded as an AE.

[0492] Adverse Event Severity Rating Investigators were instructed to report all clinical AEs encountered during the study. AE intensity was graded based on the NCI CTCAE, version 4.0 or higher. For AEs not in the CTCAE, an explanation of intensity grading can be found below:

[0493] Grade 1: Mild; asymptomatic or mildly symptomatic; clinical or diagnostic observation only; no therapeutic intervention indicated.

[0494] Grade 2: Moderate; minimal, partial or non-invasive intervention indicated; limited age-appropriate instrumental activities of daily living.

[0495] Grade 3: Serious or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; incapacitating; limited independent activities of daily living.

[0496] A serious adverse event (SAE) is any experience (clinical AE or abnormal laboratory test) that suggests a significant risk, contraindication, side effect, or precaution. An SAE must meet at least one of the following criteria at any dose level: fatal (resulting in death); life-threatening; requiring patient hospitalization or prolongation of current hospitalization; resulting in persistent or significant disability / incapacity; congenital anomaly / birth defect; or medically significant or requiring therapeutic intervention to prevent one or other of the outcomes listed above. Investigators are instructed to report life-threatening events, or any event with an outcome of death must be reported as an SAE.

[0497] pregnancy All female clinical trial participants who became pregnant during the study were instructed to stop taking the study drug and notify the investigators immediately. Pregnancies up to 90 days after completing the study drug must also be reported to the investigators.

[0498] Code of Ethics: Researchers were tasked with ensuring that the study would be conducted in accordance with the principles of the Declaration of Helsinki or the laws of the country in which the study was conducted, whichever provides greater protection for individuals. In addition, the study would adhere to the principles outlined in the current ICH Tripartite Guideline for Good Clinical Practice or comply with local laws if they provide greater protection for participants.

[0499] Before participating in the study, signed and dated informed consent was obtained from each participant after an appropriate explanation of the study's goals, methods, objectives, and potential risks. The investigator or designee must explain that participants are completely free to refuse or withdraw from the study at any time for any reason.

[0500] Physical Examination Procedure: At screening and follow-up visits in the study, a complete physical examination consisted of checking the following body systems for normality or abnormalities: general appearance, skin, eyes, ears, nose, throat, heart, chest / thorax, abdomen, nervous system, lymph nodes, spine, and limbs (skeleton) and performing online cognitive tests of learning and memory. An abbreviated physical examination consisted of checking the following body systems for normality or abnormalities: general appearance, skin, abdomen, and cardiopulmonary examination. Height was recorded only at screening. Blood pressure (BP), pulse rate, temperature, and respiratory rate were recorded at individual time points.

[0501] A single 12-lead ECG assessment was also obtained at each time point to confirm eligibility and ensure real-time safety assessment of participants in the study. For ECG assessment, participants had to be in a restful position for at least 10 minutes prior to the measurement. Body position had to be maintained consistently for each ECG assessment. In particular, changes in heart rate were to be avoided. There should be no environmental distractions (TV, radio, conversation) during rest before the ECG and during the ECG recording.

[0502] Heart rate (HR), QRS duration and respiratory rate (RR), and QT interval were recorded. Changes in T and U wave morphology and overall ECG interpretation were documented. All ECG recordings were performed using a standard, high-quality, high-fidelity digital electrocardiograph with computer-based interval measurement. For triplicate ECG evaluation, at least three interpretable ECG recordings (artifact-free) per time point were collected within a ±10-minute period per time point.

[0503] Clinical Test Procedures: Laboratory evaluations were performed at a central laboratory, with occasional testing at local laboratories if necessary. Laboratory safety tests were collected at specific time points. If any test results fell outside the reference range or clinical symptoms indicated additional testing was needed to monitor the participant's safety, additional blood or urine samples could be obtained at the investigator's discretion. If the clinical significance of an abnormal laboratory result is considered unclear, the screening laboratory test may be repeated before Day 1 to confirm eligibility. In the case of an unexplained abnormal clinically significant laboratory value, the test should be repeated immediately and the participant followed up until it returns to the normal range, the participant is considered clinically stable, and / or an appropriate explanation for the abnormality is identified.

[0504] Preliminary results: Positive preliminary data have been observed in an ongoing Phase 1 / 2 study of PRN1008 in the treatment of ITP. As an illustration, Figure 5 shows the platelet count response for enrolled patients with secondary ITP, demonstrating responsiveness to treatment at 400 mg qd. During the completed dose-escalation study, PRN1008 was well tolerated at all doses (200 and 400 mg qd, 300 and 400 mg bid) in a highly treatment-resistant and refractory patient population with immune thrombocytopenia (ITP). All TEAEs were mild to moderate, and there were no thrombotic events.

[0505] Initial study data were reported in October 2019. At the time of reporting, the phase 1 / 2 trial of PRN1008 enrolled 26 adult patients who had two platelet counts <30,000 / μL within the 15 days prior to treatment. Oral PRN1008 starting doses were 200 mg qd, 400 mg qd, 300 mg bid, and 400 mg bid, with intrapatient dose escalation permitted every 4 weeks. The median treatment duration in the trial at the time of reporting was 12.7 weeks (range: 0.14-39.71). In early study data reported in October 2019, 39 percent (80% confidence interval (CI) 27.3, 51.0) of the 26 patients enrolled to that point achieved the study's primary endpoint of two consecutive platelet counts of ≥ 50,000 / μL at least 5 days apart and an increase of ≥ 20,000 / μL from baseline without the need for rescue medication (Tables 2 and 3). In addition, 46 percent (80% CI 34.2, 58.5) of enrolled patients achieved two platelet counts of ≥ 50,000 / μL (Table 3). These results were observed despite the limited duration of treatment and the use of multiple escalating dose levels in patients. In preliminary data for 15 patients across all doses who completed at least 12 weeks of treatment, response rates exceeded 50 percent for both endpoints. At the time of initial reporting, PRN1008 was well tolerated at all doses studied, both as monotherapy and with approved concurrent ITP therapies, and no treatment-related bleeding or thrombotic events were reported.

[0506] In Table 2, percentages are based on the number of patients in each dose group and overall. Patients were stratified into different dose levels according to the dose they received prior to the onset of platelet response. 95% confidence intervals are based on the Wilson Score method.

[0507] [Table 3]

[0508] [Table 4]

[0509] As of November 13, 2019, the 31 enrolled patients in the Phase 1 / 2 study were characterized by the demographic information shown in Tables 4 and 5. The median age of enrolled patients was 50 years. 29 of the 31 patients were classified as primary ITP (94%), and 2 of the 31 were classified as secondary ITP (6%). At enrollment, patients had ITP with a median duration of 7.8 years and were heavily pretreated (median 6 prior therapies), with 26% having undergone prior splenectomy. During the study, 10 patients (32%) received PRN1008 monotherapy, and 21 patients (68%) were receiving ≥1 concurrent ITP therapy.

[0510] As of November 13, 2019, study data confirmed that the optimal safety and efficacy dose for PRN1008 in the treatment of ITP is 400 mg bid.

[0511] The primary endpoint, defined as two consecutive platelet counts ≥ 50,000 μL without the need for rescue medication, was met in 39% of all patients, regardless of dose or treatment duration. This patient population was highly treatment-resistant and refractory, characterized by a median of six prior therapies; e.g., 55% had received a prior TPO-RA. Acute onset (platelet count > 30kJ in the first week of treatment) was observed after initiation of PRN1008 treatment, and responses were durable in the majority of patients. Platelet responses further improved with longer treatment and higher doses of PRN1008.

[0512] [Table 5]

[0513] [Table 6]

[0514] Table 6 provides an overview of platelet responses by treatment duration and dose (data cutoff: November 13, 2019). Individual platelet counts by dose level over time for the low starting dose (qd dosing, n=10) and the high starting dose (bid dosing) (n=21) are shown in Figures 6 and 7, respectively (data cutoff: November 13, 2019). In Figures 6 and 7, responders are those who achieved a platelet count of ≥50,000 / μL at least once.

[0515] A subset analysis of primary platelet responses is shown in Figure 8 (data cutoff: November 13, 2019). As of November 13, 2019, 10 of 25 heavily pretreated (≥4 prior treatments) patients (40%) responded to PRN1008 treatment. Similar responses were achieved in patients receiving PRN1008 monotherapy (4 of 10 patients) and concurrent treatment (8 of 21 patients).

[0516] [Table 7]

[0517] PRN1008 was well tolerated across all doses in ITP patients as of November 13, 2019 (Table 7). The median treatment duration at the November 13, 2019 cutoff was 12.0 weeks (range: 0.1 to -41.9). Related TEAEs were reported in 11 (35%) patients, and all reported TEAEs were grade 1 or 2 (mild to moderate). No treatment-related bleeding or thrombotic events were reported, and there was no significant change from baseline in the ITP-BAT bleeding scale through the final visit. No dose-limiting toxicities were observed by the data cutoff. The observed safety profile was consistent with that observed in the pemphigus study (Murrell D. et al., AAD 2018).

[0518] [Table 8]

[0519] As of April 22, 2020, 47 patients were enrolled in the study, and 32 patients initiated the 400 mg bid dose. Demographic information for enrolled patients as of April 22, 2020, is shown in Table 8. ITP patient characteristics were similar across all treatment arms in this difficult-to-treat population. Similar to the November 13, 2019 cutoff data, patients had a median ITP age of 7+ years at enrollment, were heavily pretreated (median 6 prior medications), and 28% had undergone prior splenectomy. In addition, 31 patients (66%) were receiving ≥1 concurrent ITP medication (CS and / or TPO) and were considered inadequate responders.

[0520] [Table 9]

[0521] As of April 22, 2020, platelet responses had a rapid onset and were sustained in the majority of patients who initiated a 400 mg bid dose of PRN1008 (Figure 9). By Day 8 (first platelet count taken after treatment initiation), platelets ≥ 30 x 10 9 Clinically significant platelet counts of ≥ 50,000 / μL (clinically significant platelet counts) were observed in 53% of patients starting at 400 mg bid and in 79% of primary endpoint responders, where the primary endpoint was defined as two consecutive platelet counts ≥ 50,000 / μL without the need for rescue medication. By week 4, 57% of responders achieved the primary endpoint. In addition, 50% of patients started at 400 mg bid of PRN1008 and achieved a primary endpoint response when treated for ≥ 12 weeks. Furthermore, responses were durable, with responders maintaining platelet counts ≥ 50 x 10 71% of the time (weeks). 9 / L; and 88% of the time (weeks) ≥ 20 × 10 above baseline 9 / L.

[0522] A subset analysis of platelet responses is shown in Figure 10 (data cutoff: April 22, 2020). Overall, 43% of patients met the primary endpoint augmented by PRN1008 at ≥12 weeks. As of April 22, 2020, 15 of 38 heavily pretreated (≥4 prior therapies) patients (40%) responded to PRN1008 treatment. Similar responses were achieved in patients receiving PRN1008 monotherapy (7 of 16 patients) and inadequate responders to concurrent treatment (13 of 31 patients).

[0523] PRN1008 was well tolerated across all doses in ITP patients as of April 22, 2020 (Table 9). At the data cutoff on April 22, 2020, the median treatment duration was 17.7 weeks (range: 0.6–41.9) for all patients and 18 weeks (range: 1.4–24.6) for patients who initiated 400 mg bid. Related TEAEs were reported in 21 patients (45%); all reported TEAEs were transient and grade 1 or 2 (mild to moderate). No related serious adverse events were reported. Additionally, no treatment-related bleeding or thrombotic events were reported, and there were no significant changes from baseline in the ITP-BAT bleeding scale through the final visit. The observed safety profile was consistent with that observed in the pemphigus study (Murrell D. et al., AAD 2018).

[0524] [Table 10]

[0525] As of May 5, 2020, oral PRN1008 met its primary endpoint in 50% of patients treated for ≥12 weeks (n=26) with rapid onset and durable response. ≥12 weeks of PRN1008 treatment further improved platelet responses. The primary endpoint was defined as two consecutive platelet counts ≥50,000 μL without the need for rescue medication, with a data cutoff of November 13, 2019. Table 10 shows a summary of platelet responses by treatment duration and dose (data cutoff: May 5, 2020).

[0526] [Table 11]

[0527] References: Several documents are referred to in this application in abbreviated citation form. Details regarding some of the documents referred to are provided below. Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med, 357:2237-47, 2007. Cataland SR, Scully MA, Paskavitz J, Maruff P, Witkoff L, Jin M, Wu, HM. Evidence of persistent neurologic injury following thrombotic thrombocytopenic purpura. American Journal of Hematology. 2011; 86(1): 87-89. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. U.S. Food and Drug Administration. https: / / www.fda.gov / Drugs / DevelopmentApprovalProcess / DevelopmentResources / DrugInteractionsLabeling / ucm093664.htm Montillo M, O’Brien SO, Tedeschi A, Byrd JC, Dearden C, et al. Ibrutinib in previously treated chronic lymphocytic leukemia patients with autoimmune cytopenias in the RESONATE study. Blood Cancer Journal 7, e524, (Letter to the editor) 2017. Murrell DF, Stavropoulos P., Patsatsi A et al. Final results of the Believe-PV proof of concept study of PRN1008 in pemphigus. The 77 th Annual Meeting of the American Academy of Dermatology; 2019 Mar 1-5; Washington, DC: AAD; 2019. Session S034: Late-breaking research-clinical trials. Podolanczuk A, Lazarus AH, Crow AR, Grossbard E, Bussel JB. Of mice and men: an open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk. Blood 2009;113:3154-3160. PRN1008 Investigator Brochure, Principia Biopharma. RodeghieroF, Michel M, Gernsheimer T, Ruggeri M, Blanchette V, et. al. Standardization of bleeding assessment in immune thrombocytopenia: report from the International Working Group. Blood 2013 121: 2596-2606. Rogers KA, Ruppert AS, Bingman A, Andritsos LA, Awan FT, Blum KA, Flynn JM, Jaglowski S. Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia. Leukemia 2016; 30:346-350. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, Sharman JP, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Sukbuntherng J, Chang BY, Clow F, Hedrick E, Buggy JJ, James DF, O'Brien S. Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med., 369(1):32-42, 2013. Evans EK, Tester R, Aslanian S, Karp R, Sheets M, Labenski MT, Witowski SR, Lounsbury H, Chaturvedi P, Mazdiyasni H, Zhu Z, Nacht M, Freed MI, Petter RC, Dubrovskiy A, Singh J, Westlin WF. Inhibition of Btk with CC-292 Provides Early Pharmacodynamic Assessment of Activity in Mice and Humans. J Pharmacol Exp Ther, 346(2):219-28, 2013. Imbruvica [package insert]. Pharmacyclics, Inc., Sunnyvale, CA; 2015. Mohamed AJ, Yu L, Backesjo CM, Vargas L, Faryal R, et al. Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev 228, 58-73, 2009. P and Smith Ciders CI. Molecular and cellular aspects of X-linked agammaglobulinemia. Adv Immunol, 59:135-223; Tsukada , S. , Saffran , DC , Rawlings , DJ , Parolini , O. , Allen , RC , Klisak , I. , Sparkes , RS , Kubagawa , H. , Mohandas , T. , Quan , S. , et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell, 72: 279–290; Vetrie , D. , Vorechovsky , I. , Sideras , P. , Holland , J. , Davies , A. , Flinter , F. , Hammarstrom , L. , Kinnon , C. , Levinsky , R. , Bobrow , M. , et al. The gene involved in X-linked agammaglobulinemia is a member of the src family of protein-tyrosine kinases. Nature, 361: 226-233; Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, Jurczak W, Advani RH, Romaguera JE, Williams ME, Barrientos JC, Chmielowska E, Radford J, Stilgenbauer S, Dreyling M, Jedrzejczak WW, Johnson P, Spurgeon SE, Li L, Zhang L, Newberry K, Ou Z, Cheng N, Fang B, McGreivy J, Clow F, Buggy JJ, Chang BY, Beaupre DM, Kunkel LA, Blum KA. Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med. 2013 Jun 19. [Epub ahead of print]. RITUXAN (rituximab) Highlights of Prescribing Information. 2018. at https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2018 / 103705s5450lbl.pdf.) Crofford LJ, Nyhoff LE, Sheehan JH, Kendall PL. The role of Bruton's tyrosine kinase in autoimmunity and implications for therapy. Expert Rev Clin Immunol 2016;12:763-73. Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton's tyrosine kinase in B cells and malignancies. Mol Cancer 2018;17:57. Volmering S, Block H, Boras M, Lowell CA, Zarbock A. The Neutrophil Btk Signalosome Regulates Integrin Activation during Sterile Inflammation. Immunity 2016;44:73-87. Montalban X, Arnold DL, Weber MS, et al. Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. N Engl J Med 2019;380:2406-17. Norman P. Investigational Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Expert Opin Investig Drugs 2016;25:891-9. Tam CS, LeBlond V, Novotny W, et al. A head-to-head Phase III study comparing zanubrutinib versus ibrutinib in patients with Waldenstrom macroglobulinemia. Future Oncol 2018;14:2229-37. Crawford JJ, Johnson AR, Misner DL, et al. Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development. J Med Chem 2018;61:2227-45. Min TK, Saini SS. Emerging Therapies in Chronic Spontaneous Urticaria. Allergy Asthma Immunol Res 2019;11:470-81. Gillooly KM, Pulicicchio C, Pattoli MA, et al. Bruton's tyrosine kinase inhibitor BMS-986142 in experimental models of rheumatoid arthritis enhances efficacy of agents representing clinical standard-of-care. PLoS One 2017;12:e0181782. Nadeem A, Ahmad SF, Al-Harbi NO, et al. Inhibition of Bruton's tyrosine kinase and IL-2 inducible T-cell kinase suppresses both neutrophilic and eosinophilic airway inflammation in a cockroach allergen extract-induced mixed granulocytic mouse model of asthma using preventative and therapeutic strategy. Pharmacol Res 2019;148:104441 Drug Record Kinase Inhibitors. In: Services NIoHUSDoHH, ed.2019. Khan Y, O'Brien S. Acalabrutinib and its use in treatment of chronic lymphocytic leukemia. Future Oncol 2019;15:579-89. Paydas S. Management of adverse effects / toxicity of ibrutinib. Crit Rev Oncol Hematol 2019;136:56-63. IMBRUVICA (ibrutinib) Highlights of Prescribing Information. US Food and Drug Administration, 2013. at https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2015 / 205552s002lbl.pdf.) Rigg RA, Aslan JE, Healy LD, et al. Oral administration of Bruton's tyrosine kinase inhibitors impairs GPVI-mediated platelet function. Am J Physiol Cell Physiol 2016;310:C373-80. Tang CPS, McMullen J, Tam C. Cardiac side effects of bruton tyrosine kinase (BTK) inhibitors. Leuk Lymphoma 2018;59:1554-64. Smith PF, Krishnarajah J, Nunn PA, et al. A phase I trial of PRN1008, a novel reversible covalent inhibitor of Bruton's tyrosine kinase, in healthy volunteers. Br J Clin Pharmacol 2017;83:2367-76. Hill R BJ, Bisconte A, Tam D, Owens T, Brameld K, et al. Preclinical Characterization of PRN1008, a Novel Reversible Covalent Inhibitor of BTK that Shows Efficacy in a RAT Model of Collagen-Induced Arthritis. EULAR. Rome2015. Serafimova IM, Pufall MA, Krishnan S, et al. Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles. Nat Chem Biol 2012;8:471-6.

[0528] Any claim or description including "or" or "and / or" between at least one member of a group is considered to be satisfied if one, more than one, or all of the members of the group are present in, employed in, or otherwise relevant to a given product or process, unless indicated to the contrary or otherwise clear from context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the members of the group are present in, employed in, or otherwise relevant to a given product or process.

[0529] Where ranges are given, endpoints are included. Also, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume that a specific value or subrange within the stated range in different embodiments of the present disclosure can be assumed to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0530] The foregoing disclosure has been described in some detail by way of example for purposes of clarity and understanding. It is therefore to be understood that the foregoing description is intended to be illustrative and not limiting. The scope of the present disclosure should, therefore, be determined not with reference to the foregoing description, but should instead be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

1. 1. A pharmaceutical composition comprising 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 for use in the treatment of immune thrombocytopenia (ITP) in a human patient in need thereof, wherein the human patient has refractory ITP and is a platelet count less than 30,000 / μL on at least two consecutive counts before the start of the treatment period; A history of at least four prior ITP treatments prior to the start of the treatment period; and Splenectomy before the start of the treatment period A pharmaceutical composition having at least one characteristic selected from the following:

2. 1. A pharmaceutical composition comprising 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 (PRN1008) and a pharmaceutically acceptable salt thereof for use in increasing platelet count in a human patient with immune thrombocytopenia (ITP), wherein the human patient has refractory ITP and is: a platelet count less than 30,000 / μL on at least two consecutive counts before the start of the treatment period; A history of at least four prior ITP treatments prior to the start of the treatment period; and Splenectomy before the start of the treatment period A pharmaceutical composition having at least one characteristic selected from the following:

3. 3. The pharmaceutical composition for use according to claim 2, wherein increasing the platelet count comprises increasing the platelet count by at least 20,000 / μL compared to the pre-administration baseline platelet count.

4. 4. The pharmaceutical composition for use according to claim 2 or 3, wherein increasing the platelet count comprises increasing the platelet count measured during the treatment period by at least 50% by at least 20,000 / μL compared to the pre-administration baseline platelet count.

5. 5. The pharmaceutical composition for use according to any one of claims 2 to 4, wherein increasing platelet count comprises increasing platelet count on at least two consecutive occasions compared to the pre-administration baseline platelet count.

6. 6. The pharmaceutical composition for use according to any one of claims 3 to 5, wherein the pre-administration baseline platelet count is the average of the human patient's two most recent platelet counts before the start of the treatment period and the human patient's platelet count on the first day of the treatment period.

7. 1. A pharmaceutical composition comprising 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 (PRN1008) and a pharmaceutically acceptable salt thereof for use in achieving a platelet count of at least 50,000 / μL in a human patient with immune thrombocytopenia (ITP), wherein the human patient has refractory ITP and is: a platelet count less than 30,000 / μL on at least two consecutive counts before the start of the treatment period; A history of at least four prior ITP treatments prior to the start of the treatment period; and Splenectomy before the start of the treatment period A pharmaceutical composition having at least one characteristic selected from the following:

8. 8. The pharmaceutical composition for use according to claim 7, wherein achieving a platelet count comprises achieving a platelet count of at least 50,000 / μL at least twice.

9. 9. The pharmaceutical composition for use according to claim 7 or 8, wherein achieving a platelet count comprises achieving a platelet count of at least 50,000 / μL on at least two consecutive occasions.

10. 10. The pharmaceutical composition for use according to any one of claims 7 to 9, wherein achieving a platelet count comprises achieving a platelet count of at least 50,000 / μL in at least 50% of the platelet counts measured during the treatment period.

11. 11. The pharmaceutical composition for use according to any one of claims 7 to 10, wherein achieving a platelet count comprises achieving a platelet count of at least 50,000 / μL in at least four of the last eight platelet counts measured during the treatment period.

12. 12. The pharmaceutical composition for use according to any one of claims 7 to 11, wherein achieving a platelet count comprises achieving a platelet count of at least 50,000 / μL in at least four of the last six platelet counts measured during the treatment period.

13. The pharmaceutical composition for use according to any one of claims 1 to 12, wherein successive platelet counts are measured at least 5 days apart.

14. The pharmaceutical composition for use according to any one of claims 1 to 13, wherein the human patient has primary ITP, secondary ITP, chronic ITP, or recurrent ITP.

15. The pharmaceutical composition for use according to any one of claims 1 to 14, wherein the human patient has no approved therapeutic options available.

16. The pharmaceutical composition for use according to any one of claims 1 to 15, wherein the human patient has a platelet count below 30,000 / µL on two occasions prior to the start of the treatment period.

17. 17. The pharmaceutical composition for use according to any one of claims 1 to 16, wherein the human patient has two platelet counts below 30,000 / μL prior to the start of the treatment period, wherein the two counts are taken no more than seven days apart and within 15 days prior to the start of the treatment period.

18. 18. The pharmaceutical composition for use according to any one of claims 1 to 17, wherein the at least four prior ITP treatments are selected from corticosteroids, thrombopoietin receptor agonists, intravenous immunoglobulin, anti-D immunoglobulin, and rituximab.

19. The pharmaceutical composition for use according to any one of claims 1 to 18, wherein the treatment period is at least 8 days, at least 28 days, at least 84 days, or at least 168 days.

20. 20. The pharmaceutical composition for use according to any one of claims 1 to 19, comprising administering to a human patient once daily or twice daily 400 mg 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.

21. 20. The pharmaceutical composition for use according to any one of claims 1 to 19, comprising administering to a human patient 300 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.

22. The pharmaceutical composition for use according to any one of claims 1 to 21, wherein at least one compound is administered as monotherapy.

23. The pharmaceutical composition for use according to any one of claims 1 to 21, wherein at least one compound is administered in combination with at least one concurrent ITP treatment.

24. 24. The pharmaceutical composition for use according to claim 23, wherein at least one concurrent ITP therapy is selected from a corticosteroid and a thrombopoietin receptor agonist.

25. 25. The pharmaceutical composition for use according to claim 23 or 24, wherein at least one concurrent ITP therapy is selected from corticosteroids, eltrombopag, and romiplostim.

26. 26. The pharmaceutical composition for use according to any one of claims 1 to 25, wherein the at least one compound comprises at least one compound selected from the (E)-isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-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.

27. 26. The pharmaceutical composition for use according to any one of claims 1 to 25, wherein the at least one compound comprises at least one compound selected from the (Z)-isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-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.

28. 26. The pharmaceutical composition for use according to any one of claims 1 to 25, wherein at least one compound comprises 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 a pharmaceutically acceptable salt thereof.

29. The pharmaceutical composition for use according to any one of claims 1 to 28, wherein at least one compound is administered orally to a human patient.

30. The pharmaceutical composition for use according to any one of claims 1 to 28, wherein the at least one compound is administered to a human patient in the form of at least one tablet.

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