Rilzabrutinib for treating warm antibody autoimmune hemolytic anemia

Abstract

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

Description

RILZABRUTINIB FOR TREATING WARM ANTIBODY AUTOIMMUNE HEMOLYTIC ANEMIACROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Application No. 63 / 675,136, filed July 24, 2024, and U.S. Application No. 63 / 804,986, filed May 13, 2025, the entire contents of which are incorporated herein by reference.

[0002] Disclosed herein are methods for treating warm autoimmune hemolytic anemia (wAIHA). BTK inhibitors and pharmaceutical compositions comprising the same are also disclosed.

[0003] Autoimmune hemolytic anemia (AIHA) is a decompensated acquired hemolysis caused by the host’s immune system acting against its own red cell antigens. AIHA can affect both children and adults, with an estimated prevalence of 17 / 100,000 persons and incidence of 0.8 / 100,000 person years. Among adults, the mean age at time of diagnosis is about 55 years, and the peak incidence occurs around the seventh decade, with a slight predominance of females (sex ratio 1.5 to 2). AIHA may occur in 10% of patients with systemic lupus erythematosus (SLE) and 5% to 10% of patients with chronic lymphocytic leukemia (CLL). Serologically, AIHAs are usually classified into warm AIHA (wAIHA), cold antibody mediated AIHA (cAIHA) or mixed AIHA.

[0004] Warm autoimmune hemolytic anemia is the most common type of AIHA. representing 60% to 70% of all AIHA cases in adults. wAIHA is characterized by the presence of autoantibodies directed toward red blood cell membrane antigens that lead to their accelerated destruction. These autoantibodies optimally react with their antigens at 37°C (warm agglutinin), thus the designation ‘‘warm.’’ The warm agglutinins are almost always immunoglobulin G (IgG) antibodies. IgG-coated red cells are recognized by splenic macrophages, which carry Fey receptors for the IgG heavy chain, leading to phagocytosis of the red cell. Extracellular hemolysis in the spleen may also be due to antibody-dependent cell-mediated cytotoxicity from T cells that also possess Fc receptors. IgG subtypes can activate complement, leading to deposition of C3 fragments on the red cell that are then removed by liver macrophages. Approximately half of wAIHA cases are primary, without an apparent underlying disorder, and approximately half are secondary, typically associated withSLE or lymphomas. wAIHA can be quite severe, requiring frequent blood transfusion, and has a reported mortality rate of 11%.

[0005] Currently, there are no approved therapies for wAIHA. Corticosteroids (prednisone or prednisolone) are empirically used as first-line treatment with an initial clinically significant response (i.e., increase in Hb level >10 g / dL with at least a 2g increase from baseline) achieved in 75% to 80% of patients. However, approximately 60% of patients achieving an initial response become corticosteroid dependent. In addition, some patients may show no response to steroid. The commonly used alterative option to steroid is rituximab, which is associated with risk of sepsis and immune suppression. While approximately 85% of patients with wAIHA respond to rituximab, 50% relapse within 2 years. Other options include splenectomy or treatment with immunosuppressive and cytotoxic agents, many of which have significant adverse effects.

[0006] Therefore, there is a real need for safe and efficacious treatments for patients with wAIHA.

[0007] Bruton's agammaglobulinemia tyrosine kinase (BTK), an essential signaling element in B cells and innate immune cells, is expressed downstream of the B cell receptor (BCR), Fc-gamma receptor (FcyR), and Fc-epsilon receptor (FCER) and serves a direct regulator of the NLRP3 inflammasome. BTK is a non-receptor tyrosine kinase and a member of the TEC family of kinases. BTK is essential to B cell differentiation, development, and antibody production. Illustratively, inhibition of BTK activity produces phenotypic changes consistent with blockade of the BCR, including the down-regulation of cell proliferation, differentiation, maturation, and survival, as well as the up-regulation of apoptosis.

[0008] Rather than acting in an “on / off switch” manner, BTK may be best viewed as an immune function "modulator” (Crofford LJ et al., 2016; Pal Singh S et al., 2018). Important insights into BTK function 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), characterized by a complete absence of circulating B cells and plasma cells, and very low levels of immunoglobulins of all classes (Tsukada 1993, Vetrie 1993). This indicates the potential for BTK inhibition to suppress immune cell activation and maturation in a number of diseases, including inflammatory disease, autoimmune disease, heteroimmune disease, or cancer. It indicates the potential for BTK inhibition to suppress production of autoantibodies thought to be important in the development of autoimmune diseases, such as warm AIHA and ITP.

[0009] While BTK is not expressed in T cells, natural killer cells, or plasma cells and has no traceable direct functions in T cells or plasma cells (Sideras and Smith 1995;Mohamed et al., 2009), the enzyme regulates the activation of other hematopoietic cells, such as B cells, monocytes, basophils, mast cells, macrophages, neutrophils, and platelets. For example, BTK plays a role in the activation of neutrophils, which are key players in the inflammatory response that contributes to wound healing but may also cause tissue damage (Volmering S et al., 2016).

[0010] Accordingly, a selective BTK inhibitor has the potential to target multiple pathways involved in inflammation and autoimmunity, including, but not limited to: blocking BCR signaling, B cell activation, and autoantibody production; inhibiting plasma cell differentiation; blocking IgG-mediated FcyR activation, phagocytosis, and inflammatory mediators in monocytes or macrophages; blocking IgE-mediated FCER activation, migration, and degranulation in mast cells or basophils; and inhibiting activation, adhesion, recruitment, and oxidative burst in neutrophils. Based on these effects, a selective BTK inhibitor may block the initiation and progression of various inflammatory diseases and mitigate tissue damage resulting from these diseases. Although individuals with loss of function mutations in the BTK gene have decreased humoral immunity and are susceptible to pyogenic bacterial and enterovirus infections, requiring treatment with intravenous immunoglobulin, inhibition of BTK in individuals with an intact immune system is not predicted to produce similar susceptibility' to infection.

[0011] Several orally administered BTK inhibitors (BTKi), including ibrutinib (PCI- 32765) and spebrutinib (CC-292), are currently marketed or are in clinical development for a range of indications (Lee A et al., 2017). For example, ibrutinib has provided further clinical validation of the BTK target and was recently approved for human use in mantle cell lymphoma, Waldenstrom’s macroglobulinemia, and chronic lymphocytic leukemia by the U.S. Food and Drug Administration (FDA). Ibrutinib has also demonstrated activity in other hematological malignancies (Wang 2013;_Byrd 2013Mmbruvica Package Insert, 2015). In addition, CC-292 has been reported to be well tolerated in a healthy volunteer population at doses which provide 100% occupancy of the BTK enzyme (Evans 2013). Furthermore, evobrutinib recently demonstrated efficacy for 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 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).

[0012] While covalent BTKi, such as ibrutinib and acalabrutinib, improved on the selectivity issues that plagued many first-generation kinase inhibitors, these inhibitors are ty pically irreversible, causing permanent modification 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 treatment modalities for immune-mediated diseases such as wAIHA, based on BTKi with reduced side effects.

[0013] Compound (I) is a BTK inhibitor of the following structure:wherein *C is a stereochemical center. See PCT Publication No. WO 2014 / 039899, which is incorporated herein by reference, e.g., Example 31.

[0014] (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile, has the following structure:is also known as rilzabrutinib. This compound has been disclosed in several patent publications, such as, e.g., PCT Publication Nos. WO 2014 / 039899, WO 2015 / 127310,WO 2016 / 100914, WO 2016 / 105531, WO 2018 / 005849, and WO 2021 / 150723, the contents of each of which are incorporated by reference herein.

[0015] Rilzabrutinib is a novel, highly selective, and potent small molecule inhibitor of non-T cell white blood cell signaling via B-cell receptor, FcyR, and / or FceR signaling of the BTK pathway. In the context of ITP, rilzabrutinib has the potential to (1) inhibit B cell activation and (2) interrupt antibody-coated cell phagocytosis by FCyR in the spleen and liver (Bradshaw et al. 2021, Langrish et al. 2021, Owens et al. 2022).

[0016] Rilzabrutinib functions as a reversible covalent BTK inhibitor and forms both anon-covalent and a covalent bond with its target; in particular, its reversible cysteine binding enables high selectivity and precise BTK inhibition without a permanent modification of proteins and peptides (Langrish et al. 2021, Owens et al. 2022, Smith PF et al. 2017). Taken together, these properties allow for enhanced selectivity and extended inhibition with low systemic exposure. In comparison to first and second generation BTKi, rilzabrutinib has shown minimal cross-reactivity with other molecules and is low risk for off- target effects (Smith PF et al. 2017). Importantly, rilzabrutinib ’s reversible binding minimizes the likelihood of permanently modified peptides (Serafimova IM 2012). In addition, rilzabrutinib shows improved kinase selectivity relative to the covalent BTK inhibitor ibrutinib. Preclinical studies in a broad kinase enzyme inhibition panel showed that 1 pM rilzabrutinib achieved >90% inhibition of just 6 of 251 kinases sharing a common cysteine in their active site. By contrast, 1 pM ibrutinib inhibited 21 kinases. Rilzabrutinib’ s IC50 values were 1.3 nM for BTK, 0.8 nM for ty rosine protein kinase TEC, 1.0 nM for bone marrow ty rosine kinase on chromosome X (BMX), 1.2 nM for receptor-like kinase (RLK), 6.3 nM for B cell lymphocyte kinase (BLK), and 11 nM for ERBB4. Further preclinical assays with rilzabrutinib showed that binding to BTK persisted while that for other TEC family members decayed rapidly over time.

[0017] Rilzabrutinib has shown encouraging results for the treatment of immune- mediated diseases. In humans, rilzabrutinib is rapidly absorbed following oral administration, with a fast half-life (3-4 h) and variable pharmacokinetics (Smith PF et al., 2017).

[0018] In Phase 1 studies of rilzabrutinib with 114 healthy volunteers, target BTK occupancy levels were safely and consistently exceeded, suggesting rilzabrutinib may be highly effective in treating autoimmune diseases. Moreover, preclinical and clinical pharmacokinetic and pharmacodynamic data showed that treatment effects endured even after the compound was cleared from circulation, consistent with an extended target residence time(Hill R et al., 2015) and high target occupancy rate (> 90% within four hours and high sustained occupancy over 24 h) (Smith PF et al., 2015).

[0019] Rilzabrutinib has also demonstrated a favorable safety profile in clinical studies. In contrast with non-selective, irreversible BTK inhibitors, rilzabrutinib does not alter platelet aggregation in healthy volunteers or patients with ITP and thus does not lead to bleeding problems (Langrish et al. 2021, von Hundelshausen and Seiss 2021). As an additional point of contrast with irreversible BTK inhibitors, rilzabrutinib treatment does not exert clinically relevant effects on cardiac repolarization (electrocardiogram parameters including corrected QT interv al) in healthy volunteers (N=51), even when administered at supratherapeutic doses (Lipsky and Lamanna 2020). Indeed, the most commonly reported adverse events in healthy volunteers were gastrointestinal adverse events, including nausea / vomiting and diarrhea. No serious adverse events or deaths were reported, and no participants discontinued treatment due to an adverse event (Smith PF 2017). Moreover, based on preclinical reproductive toxicity studies, rilzabrutinib is not expected to harm fetal development or male fertility.

[0020] There is preliminary evidence to support the role of BTK inhibition in patients with autoimmune cytopenias (Rogers 2016, Montillo 2017), where sequential episodes of severe autoimmune hemolytic anemia and ITP ceased after initiation of treatment with ibrutinib, a BTK / EGFR / ITK inhibitor, in patients with chronic lymphatic leukemia. Additionally, and pertinent to the treatment of ITP, rilzabrutinib treatment in vitro profoundly inhibits human B cell activation and blocks antibody (IgG, IgE) mediated activation of immune cells via Fc receptor signaling. In nonclinical studies, rilzabrutinib demonstrates a significant dose dependent reduction of platelet-loss (consumption) in a mouse model of ITP.

[0021] The present disclosure is therefore directed to the treatment of autoimmune hemolytic anemia (AIHA). In some embodiments, the AIHA is warm AIHA.

[0022] Disclosed herein are methods for treating warm autoimmune hemolytic anemia (wAIHA) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3- (2-fluoro-4-phenoxy-phenyl)pyrazolo[3.4-d]pyrimidin-l-yl]piperidine-I-carbonyl]-4-methyl- 4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof.

[0023] In some embodiments, the compound as disclosed herein is administered twice a day for a treatment period.

[0024] Disclosed herein is a method for treating primary' yvAIHA. In some embodiments, a patient An need thereof’ comprises a patient having wAIHA, diagnosed with wAIHA and / or suffering from wAIHA.

[0025] In some embodiments, a patient that is treated by a method disclosed herein has a secondary' autoimmune disease. In some embodiments, the secondary' autoimmune disease is systemic lupus erythematosus (SLE).

[0026] In some embodiments, a patient has been identified as having a hemoglobin level of <10 g / dl. In some embodiments, a patient has been identified as having a haptoglobin level of < 25 mg / dl, a bilirubin level above the upper limit of normal, and / or an LDH level above the upper limit of normal. In some embodiments, a patient has been identified as having a positive direct antiglobulin test (DAT).

[0027] Disclosed herein are methods for treating warm autoimmune hemolytic anemia (wAIHA) in a human patient in need thereof comprising administering to the human patient in need thereof a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]piperidine-I-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-I-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof twice a day for a treatment period, wherein the human patient in need thereof has at least one characteristic prior to the treatment period chosen from: an initial hemoglobin level < 10 g / dL, haptoglobin < 25 mg / dL, total bilimbin above the upper limit of normal, or LDH above the upper limit of normal; positive direct antibl oglobulin test; and / or and the human patient has failed to maintain a sustained response after treatment with corticosteroids

[0028] Disclosed herein is the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-l-yl]piperidine-I-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2- enenitrile and pharmaceutically acceptable salts thereof, for treating yvarm autoimmune hemolytic anemia (wAIHA) in a human patient in need thereof.

[0029] Disclosed herein is a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-l-yl]piperidine-I-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof, for use as a medicament for treating warm autoimmune hemolytic anemia (wAIHA) in a human patient in need thereof.

[0030] Disclosed herein is a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2- enenitrile and pharmaceutically acceptable salts thereof, for use for treating warm autoimmune hemolytic anemia (wAIHA) in a human patient in need thereof.

[0031] Disclosed herein is the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2- enenitrile and pharmaceutically acceptable salts thereof, as a medicament for treating warm autoimmune hemolytic anemia (wAIHA) in a human patient in need thereof.

[0032] Brief Description of the Drawings:

[0033] Fig. 1 shows percentage of responders (y-axis) for response (R), complete response (CR). overall hemoglobin response (OR) and durable response (DR) as shown on the x-axis.

[0034] Fig. 2 shows median hemoglobin (g / dL)(y-axis) by visit in responder and nonresponder by week 24.

[0035] Figs. 3A-3C show patient response as measured by changes in hemoglobin and hemolytic markers. Fig. 3A shows changes in hemoglobin from baseline at 12 weeks and 24 weeks. Fig. 3B shows change in reticulocytes from baseline at 12 weeks and 24 weeks. Fig. 3C shows changes in LDH from baseline at 12 weeks and 24 weeks.

[0036] Fig. 4 shows time to hemoglobin response (plot of Kaplan Meier estimates).

[0037] Fig. 5 shows change in FACIT-fatigue scale score from baseline at 12 weeks and 24 weeks.

[0038] Fig. 6A-6F show median change from baseline in analyzed proteins and C4a levels after rilzabrutinib treatment. Fig. 6A shows median change of IL-lb from baseline.Fig. 6b shows median change of IL- 18 from baseline. Fig. 6C shows median change of MPO from baseline. Fig. 6D shows median change of neutrophil elastase from baseline. Fig. 6E shows median change of ICAM1 from baseline. The adjusted p-value for all > 0.05. Fig. 6F shows median change in C4a levels.

[0039] Fig. 7A-7B show median hemoglobin levels and median changes from baseline for FACIT-fatigue scale scores after administration of rilzabrutinib in wAIHA patients in Part B period leading up to week 50. Fig. 7A shows median hemoglobin levels and Fig. 7B shows median change from baseline in fatigue according to FACIT-fatigue scale.Definitions:

[0040] 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 as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0041] As used herein, “a’' or “an’' entity' refers to one or more of that entity'; for example, a compound refers to one or more compounds or at least one compound unless stated otherwise. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.

[0042] As used herein, the term “about” is used herein to mean approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and beloyv the stated value by a variance of 5%. With regard to specific values, it should be understood that specific values described herein for subject populations (e.g., the subject of the described clinical trial) represent median, mean, or statistical numbers, unless otherwise provided. Accordingly, aspects of the present disclosure requiring a particular value in a subj ect are supported herein by population data in which the relevant value is assessed to be a meaningful delimitation on the subject population.

[0043] “Warm autoimmune hemolytic anemia” ( AIHA) is the most common type of autoimmune hemolytic anemia, a condition caused by the host’s immune system acting against its o vn red cell antigens. wAIHA is characterized by the presence of autoantibodies directed toward red blood cell membrane antigens that lead to their accelerated destruction. These autoantibodies optimally react yvith their antigens at 37°C (warm agglutinin), thus the designation “warm.” Some of wAIHA cases are primary, without an apparent underlying disorder, and some are secondary, typically associated yvith systemic lupus erythematosus (SLE) or lymphomas.

[0044] As used herein, the term ‘‘active pharmaceutical ingredient’' or “therapeutic agent” (“API”) refers to a biologically active compound.

[0045] As used herein, the term “approved treatment” refers to a medication that has received regulator}’ authorization, in any country, for its intended use.

[0046] As used herein, the terms “administer,” “administering,” or “administration” herein refer to providing, giving, dosing, and / or prescribing by either a health practitioner or an authorized agent and / or putting into, taking, or consuming by the patient or person himself or herself. For example, “administration” of an API to a patient refers to any route (e.g., oral delivery) of introducing or delivering the API to the patient. Administration includes selfadministration and administration by another.

[0047] As used herein. “BID” and “bid” are used interchangeably to refer to twice a day.

[0048] As used herein, the term “in combination with,” when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means the administration of two or more compounds, agents, or active pharmaceutical ingredients to the patient prior to, concurrent with, or subsequent to each other during a treatment period. Unless specified otherwise, the two or more compounds, agents, or active pharmaceutical ingredients may be administered on different schedules during the treatment period, such as, e.g., with one or more compounds, agents, or active pharmaceutical ingredients being administered once a day and one or more other compounds, agents, or active pharmaceutical ingredients being administered twice a day.

[0049] As used herein, an amount expressed in terms of “mg of [X]” refers to the total amount in milligrams of [X], i.e., the free base. In some embodiments, rilzabrutinib may be administered as a pharmaceutically acceptable salt of rilzabrutinib, in which case an amount expressed in terms of “mg of rilzabrutinib” refers to the total amount in milligrams of rilzabrutinib, i.e., the free base, plus the equivalent amount of one or more pharmaceutically acceptable salts of rilzabrutinib based on the w eight of free base therein. For example, “400 mg of at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof’ includes 400 mg of rilzabrutinib and a concentration of one or more pharmaceutically acceptable salts of rilzabrutinib equivalent to 400 mg of rilzabrutinib.

[0050] As used herein, a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that isgenerally safe, and neither biologically nor otherwise undesirable, such as, e.g., a carrier or an excipient that is acceptable for mammalian pharmaceutical use.

[0051] As used herein, the term “pharmaceutically acceptable salt” refers to a salt form, e.g., an acid addition salt, of an active pharmaceutical agent that is pharmaceutically acceptable and that possesses the desired pharmacological activity' of the API of 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, and the like; or 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, and the like. S. M. Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0052] As used herein, the terms “rilzabrutinib.” “(R)-2-[3-[4-amino-3-(2-fluoro-4- phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile;” “the compound of Formula (I);” and “2-[(3R)- 3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]-pyrimidin-l-yl]piperidine-l- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile” are used interchangeably to refer to a compound having the structure:which is also referred to as 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d] py rimidin- 1 -y 1] piperdine- 1 -carbonyl] -4-methy l-4[4-(oxetan-3 -yl)piperazin- 1 -y 1] -(E and Z)- pent-2-enenitrile; (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2- enenitrile; 1 -piperidinepropanenitrile, 3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl]-a-[2-methyl-2-[4-(3-oxetanyl)-l-piperazinyl]propylidene]-P- oxo-, (3R)-; (EZ)-2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4- d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-yl]pent-2- enenitrile; and also by the International Nonproprietary Names for Pharmaceutical Substances (INN) as published by the World Health Organization(https : Z / cdn, who, i n t / medi a / docs / defaul t-source / internalional -nonpropri elarv -names- (inn) / pl 121, pdf?sfyrsn=69617906 15&download=true) having the following structure:The compound of Formula (I) includes E and Z isomers, as indicated by the wavy bond in the structure shown above. The compound of Formula (I) may be present as a salt form.

[0053] A dose of the (E) isomer of rilzabrutinib may contain the corresponding (Z) isomer as an impurity in less than about 1% by weight; a dose of the (Z) isomer of rilzabrutinib may contain the corresponding (E) isomer as an impuri ty in less than about 1 % by weight. When rilzabrutinib is denoted as a mixture of (E) and (Z) isomers of (R)-2-[3-[4- amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l -carbonyl]- 4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile, it means that the amount of (E) or (Z) isomer in the mixture is greater than about 1% by weight. In some embodiments, the molar ratio of (E) to (Z) isomer is 9: 1. rilzabrutinib or a pharmaceutically acceptable salt thereof may also be referred to herein as a “drug,” “active agent,” “a therapeutically active agent,” or “API.”

[0054] As used herein, “QD” and “qd” are used interchangeably to refer to once a day.

[0055] As used herein, the term “therapeutically effective amount” refers to that of a compound that produces the desired effect for which it is administered (e.g., improvement in wAIHA or a symptom of wAIHA, or lessening the severity of wAIHA or a symptom of wAIHA). The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0056] As used herein, the term ‘‘treat,” “treating,” or “treatment,” when used in connection with a disorder or condition, includes any effect, e.g., lessening, reducing, modulating, ameliorating, or eliminating, that results in the improvement of the disorder or condition. Improvements in or lessening the severity of any symptom of the disorder or condition can be readily assessed according to standard methods and techniques known in the art.

[0057] As used herein, the term “response” refers to an increase in a hemoglobin level of a patient, a decrease in an LDH level of a patient, a decrease in a median reticulocyte level and / or an increase in a FACIT-fatigue scale score following the administration of any appropriate wAIHA therapy.

[0058] Some embodiments of the present disclosure relate to a method for treating warm autoimmune hemolytic anemia (wAIHA) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitnle and pharmaceutically acceptable salts thereof.

[0059] Some embodiments of the present disclosure relate to a method for treating w AIHA in a human patient in need thereof comprising administering to the human patient a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3- (2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l -carbonyl]-4-methyl- 4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof twice a day for a treatment period.

[0060] In some embodiments, a method disclosed herein is for treating warm AIHA (wAIHA). In some embodiments, the method is for treating primary wAIHA. A patient “in need thereof’ is often a patient having w AIHA. diagnosed with w AIHA and / or suffering from wAIHA.

[0061] In some embodiments, the method is for treating secondary wAIHA. In some embodiments, a patient that is treated by a method herein has one or more secondary diseases. In some embodiments, a patient that is treated by a method herein has a secondary autoimmune disease. In some embodiments, the secondary7autoimmune disease is systemic lupus erythematosus (SLE).

[0062] In some embodiments, the patient has or has been identified as having wAIHA for a duration of < 1 year. In some embodiments, the patient has or has been identified as having wAIHA for a duration of 1 to <3 years. In some embodiments, the patient has or has been identified as having wAIHA for a duration of > 3 years. In some embodiments, the patient has or has been identified as having wAIHA for a duration of > 4 years. In some embodiments, the patient has or has been identified as having wAIHA for a duration of > 5 years. In some embodiments, the human patient has or has been identified as having had wAIHA for a duration of >10 years. In some embodiments, the human patient has or has been identified as having had wAIHA for a duration of >15 years. In some embodiments, the human patient has or has been identified as having had wAIHA for a duration of >20 years. In some embodiments, the human patient has or has been identified as having had wAIHA for a duration of >25 years. In some embodiments, the human patient has or has been identified as having had wAIHA for a duration of >30 years. In some embodiments, the human patient has or has been identified as having had wAIHA for a duration of >35 years. In some embodiments, the human patient has or has been identified as having had wAIHA for a duration of >40 years. In some embodiments, the human patient has or has been identified as having had wAIHA for a duration of >45 years. In some embodiments, the human patient has or has been identified as having had wAIHA for a duration of >50 years.

[0063] In some embodiments, a patient has or has been identified as having one or more of the below pre-administration levels before treatment:

[0064] In certain embodiments, a patient has or has been identified as having a hemoglobin level of <10 g / dl. In some embodiments, a patient has or has been identified as having a hemoglobin level of 8 - < 10 g / dl. In some embodiments, a patient has or has been identified as having a hemoglobin level of < 8 g / dl. In some embodiments, a patient has or has been identified as having a hemoglobin level of about 6.5 - < 8 g / dl. In some embodiments, a patient has or has been identified as having a hemoglobin level of < 6.5 g / dl. In some embodiments, a patient has or has been identified as having a hemoglobin level of > 10 g / dl.

[0065] In some embodiments, a patient has or has been identified as having hemolysis. In some embodiments, the patient has or has been identified as having > 1 abnormal hemolytic marker. In some embodiments, the abnormal hemolytic marker comprises at least one of the following: increased lactate dehydrogenase (LDH), elevated bilirubin, decreased haptoglobin, and increased reticulocytes. In some embodiments, thepatient has or has been identified as having at least one abnormal hemolytic marker. In some embodiments, the patient has or has been identified as having at least two abnormal hemolytic markers. In some embodiments, the patient has or has been identified as having at least three abnormal hemolytic markers.

[0066] In some embodiments, a patient has or has been identified as having a haptoglobin level of < 25 mg / dl.

[0067] In some embodiments, a patient has or has been identified as having a bilirubin level above the upper limit of normal.

[0068] In some embodiments, a patient has or has been identified as having an LDH level above the upper limit of normal.

[0069] In some embodiments, a patient has or has been identified as having increased median reticulocyte level.

[0070] In some embodiments, a patient has or has been identified as having a positive direct antiglobulin test (DAT). In some embodiments, DAT is positive dual DAT, IgG or IgG + complement C3d pattern or IgM warm autoantibodies.

[0071] In some embodiments, a patient is a mammal. In some embodiments, a patient is a human. In some embodiments, a patient is a male or a female patient. In some embodiments, the human patient is an adult. In some embodiment, the patient is > 18 years. In some embodiments, a patient is not a pregnant female and / or is not lactating.

[0072] In some embodiments, a patient that is treated by a method herein has a history of taking at least one therapy for treatment of wAIHA prior to the start of the treatment period. In some embodiments, a patient that is treated by a method herein has a history of steroid therapy. In some embodiments, a patient that is treated by a method herein is dependent on a steroid therapy.

[0073] In some embodiments, the patient has a history of response to at least one therapy for treatment of wAIHA. In some embodiments, the patient has a history of no response to at least one therapy for treatment of wAIHA.

[0074] In some embodiments, a patient that is treated by a method herein is refractory to treatment for wAIHA. and / or is refractory to a previously administered or prior line of therapy for wAIHA. In some embodiments, the human patient has or has been identified as having become refractory to at least one prior tine of therapy, for example at least two, for example at least three, for example at least four, for example at least five, for example at least six. for example at least seven, for example at least eight, for example at least nine, forexample at least 10, for example at least 11, for example at least 12, for example at least 13, for example at least 14, for example at least 15, for example at least 16. for example at least 17 prior lines of therapy. In some embodiments, the patient has or has been identified as having become refractory to at least one prior line of therapy. In some embodiments, the patient has or has been identified as having become refractory to at least two prior lines of therapy. In some embodiments, the patient has or has been identified as having become refractory to at least three prior lines of therapy. In some embodiments, the patient has or has been identified as having become refractory to at least four prior lines of therapy. In some embodiments, the patient has or has been identified as having become refractory to at least five prior lines of therapy. In some embodiments, the patient has or has been identified as having become refractory to at least six prior lines of therapy. In some embodiments, the patient has or has been identified as having become refractory to at least seven prior lines of therapy. In some embodiments, the patient has or has been identified as having become refractory to at least eight prior lines of therapy. In some embodiments, the patient has or has been identified as having become refractory to at least nine prior lines of therapy. In some embodiments, the patient has or has been identified as having become refractory to at least 10 prior lines of therapy. In some embodiments, the patient has or has been identified as having become refractory to at least 11 prior lines of therapy. In some embodiments, the patient has or has been identified as having become refractory- to at least 12 prior lines of therapy. In some embodiments, the patient has or has been identified as having become refractory to at least 13 prior lines of therapy. In some embodiments, the patient has or has been identified as having become refractory to at least 14 prior lines of therapy. In some embodiments, the patient has or has been identified as having become refractory- to at least 1 prior lines of therapy. In some embodiments, the patient has or has been identified as having become refractory to at least 16 prior lines of therapy. In some embodiments, the patient has or has been identified as having become refract ory to at least 17 prior lines of therapy.

[0075] In some embodiments, a patient that is treated by a method herein has or has been identified as being resistant to at least one previously administered or prior line of therapy. In some embodiments, a patient that is treated by a method herein has or has been identified having a response to at least one previously administered therapy. In some embodiments, the response to the at least one prior line of therapy was not sustained. In some embodiments, a patient that is treated by a method herein has relapsed from at least one previously administered therapy. In some embodiments, the human patient has become or hasbeen identified as resistant, or having not sustained response to at least one previously administered line of therapy, for example at least two. for example at least three, for example at least four, for example at least five, for example at least six, for example at least seven, for example at least eight, for example at least nine, for example at least 10, for example at least 11, for example at least 12, for example at least 13, for example at least 14, for example at least 15, for example at least 16, for example at least 17 previously administered lines of therapy.

[0076] In some embodiments, the at least one previously administered therapy is selected from administration of danazol, rituximab, corticosteroid, intravenous immunoglobin (IVIG), an immunosuppressor and an immunomodulator. In some embodiments, the previously administered therapy is an immunosuppressor or immunomodulator, which is selected from azathioprine, cyclosporine, or my cophenolate. In some embodiments, the previously administered therapy is the immunosuppressor or immunomodulator, which is selected from fostamatinib, my cophenolate mofetil (MMF), or cyclosporine.

[0077] In some embodiments, a patient that is treated by a method herein has or has been identified as having a history of splenectomy. In some embodiments, the previously administered therapy is IVIG. In some embodiments, the previously administered therapy is danazol. In some embodiments, the previously administered therapy is rituximab.

[0078] In some embodiments, a patient has or has been identified as having a history of taking at least one corticosteroid prior to the start of the treatment period. In some embodiments, the human patient has or has been identified as having a history of taking at least one corticosteroid selected from dexamethasone or prednisone / prednisolone prior to the start of the treatment period. In some embodiments, the human patient has or has been identified as having a history of taking prednisone / prednisolone. In some embodiments, a patient that is treated by a method herein is or has been identified as refractory to treatment with corticosteroid therapy, relapsed from corticosteroid therapy, failing to maintain a sustained response after treatment with corticosteroid therapy, resistant to corticosteroid therapy, or having a history of being dependent on a corticosteroid therapy.

[0079] In some embodiments, a patient that is treated by a method herein has or has been identified as having an Eastern Cooperative Oncology Group (ECOG) performance status grade of 2 or lower.

[0080] In some embodiments, the at least one compound disclosed herein is orally administered to the human patient. In some embodiments, the at least one compounddisclosed herein is administered to the human patient in the form of at least one tablet. In some embodiments, the at least one compound disclosed herein is administered with water.

[0081] In some embodiments, a patient is administered an effective amount of the at least one compound disclosed herein at a frequency of once daily, twice daily (BID), or three times daily. In some embodiments, a patient is administered an effective amount of the at least one compound disclosed herein at a frequency of twice daily (BID).

[0082] In some embodiments, a patient is administered the at least one compound disclosed herein for a time period of at least 4 weeks, at least 7 weeks, at least 12 weeks, at least 24 weeks, at least 26 weeks, at least 50 weeks, or at least 52 weeks. In some embodiments, a patient is administered the at least one compound disclosed herein for a time period of 12 to 52 weeks, 12 to 50 weeks, 12 to 48 weeks, 12 to 26 weeks, or 12 to 24 weeks.

[0083] In some embodiments, a patient is administered the at least one compound disclosed herein at an effective amount, where an effective amount is in a range of 100 to 1200 mg. In some embodiments, an effective amount comprises a range of 200 to 800 mg. In some embodiments, an effective amount comprises a range of 200 to 600 mg. In some embodiments, an effective amount comprises a range of 300 to 500mg. In some embodiments, an effective amount is about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg. mg, 1,100 mg, 1,150 mg, or 1.200 mg. In some embodiments, an effect amount is 400 mg.

[0084] In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein has an increase in baseline hemoglobin level during the treatment period. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein achieves a hemoglobin response. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein achieves a complete hemoglobin response. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein achieves an overall hemoglobin response. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein achieves a durable hemoglobin response.

[0085] In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein has at least one hemoglobin level of > 10 g / dL during the treatment period and / or a post-administration hemoglobin level of at least 2 g / dL higherthan a pre-administration baseline measurement of a hemoglobin level. In some embodiments, the patient has at least one hemoglobin level of at least 10 g / dL during the treatment period. In some embodiments, the patient has at least one hemoglobin level of at least 11 g / dL during the treatment period. In some embodiments, the patient has at least one hemoglobin level of at least 12 g / dL during the treatment period. In some embodiments, the patient has at least one hemoglobin level of at least 13 g / dL during the treatment period. In some embodiments, the patient has at least one hemoglobin level of 10-13 g / dL during the treatment period. In some embodiments, the patient has at least one hemoglobin level of 11- 12.5 g / dL during the treatment period. In some embodiments, the patient has at least one hemoglobin level of at least 11 g / dL during the treatment period and there is no evidence of hemolysis at the time the hemoglobin response is achieved.

[0086] In some embodiments, the patient has an increase in hemoglobin by at least 2 g / dL from the baseline hemoglobin during the treatment period. In some embodiments, the patient has an increase in hemoglobin by at least 2.5 g / dL from the baseline hemoglobin during the treatment period. In some embodiments, the patient has an increase in hemoglobin by at least 3 g / dL from the baseline hemoglobin during the treatment period. In some embodiments, the patient has an increase in hemoglobin by at least 3.5 g / dL from the baseline hemoglobin during the treatment period. In some embodiments, the patient has an increase in hemoglobin by at least 4 g / dL from the baseline hemoglobin during the treatment period. In some embodiments, the patient has an increase in hemoglobin by 2 g / dL to 4 g / dL from the baseline during the treatment period. In some embodiments, the patient has an increase in hemoglobin by 2 g / dL to 3 g / dL from the baseline during the treatment period. In some embodiments, the patient has an increase in hemoglobin by at least 2 g / dL from the baseline hemoglobin during the treatment period and there is no biochemical resolution of hemolysis at the time the increase in hemoglobin is achieved.

[0087] In some embodiments, the patient has at least one hemoglobin level of at least 10 g / dL and an increase in hemoglobin by at least 2 g / dL from the baseline during the treatment period. In some embodiments, the patient has at least one hemoglobin level of at least 11 g / dL and an increase in hemoglobin by at least 2 g / dL from the baseline during the treatment period. In some embodiments, the patient has at least one hemoglobin level of at least 12 g / dL and an increase in hemoglobin by at least 2 g / dL from the baseline during the treatment period.

[0088] In some embodiments, a patient achieves the hemoglobin response within 1 week of initiating treatment. In some embodiments, a patient achieves the hemoglobin response within 2 weeks of initiating treatment. In some embodiments, a patient achieves the hemoglobin response within 3 week of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 4 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 5 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 6 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 7 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 8 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 9 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 10 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 11 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 12 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 13 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 14 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 15 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 16 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 17 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 18 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 19 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 20 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 21 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 22 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 23 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 24 weeks of initiating treatment. In some embodiments, a patient achieves the hemoglobin response within 25 weeks of initiating treatment. In some embodiments, a patient achieves the hemoglobin response within 26 weeks of initiating treatment. In some embodiments, a patient achieves the hemoglobin response within 27 weeks of initiating treatment. In some embodiments, a patient achievesthe hemoglobin response within 28 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 29 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 30 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 31 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 32 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 33 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 34 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 35 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 36 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 37 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 38 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of hemolysis markers within 39 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 40 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 41 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 42 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 43 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 44 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 45 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 46 w eeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 47 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 48 w eeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 49 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 50 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 51 weeks of initiating treatment. In some embodiments, the patient achieves the hemoglobin response within 52 weeks of initiating treatment.

[0089] In some embodiments, the patient has at least one hemoglobin level of at least 10 g / dL or an increase in hemoglobin by at least 2 g / dL from the baseline during the treatment period on at least 2, 3. 4, 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, 15, or 16 consecutivevisits. In some embodiments, the patient has at least one hemoglobin level of at least 10 g / dL and an increase in hemoglobin by at least 2 g / dL from the baseline during the treatment period on at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 consecutive visits. In some embodiments, the patient has at least one hemoglobin level of at least 10 g / dL and an increase in hemoglobin by at least 2 g / dL from the baseline during the treatment period on at least 3 consecutive visits. In some embodiments, the patient has no evidence of hemolysis during the treatment period. In some embodiments, the patient has at least one hemoglobin level of at least 10 g / dL or an increase in hemoglobin by at least 2 g / dL from the baseline during the treatment period with no evidence of hemolysis. In some embodiments, the patient does not require rescue medication during the treatment period. In some embodiments, the patient does not require a blood transfusion during the treatment period. In some embodiments, the patient has at least one hemoglobin level of at least 10 g / dL and an increase in hemoglobin by at least 2 g / dL from the baseline during the treatment period on at least 3 consecutive visits in the absence of rescue therapy or blood transfusion.

[0090] In some embodiments, a patient has a reduction of at least one hemolysis marker during the treatment period. In some embodiments, the at least one hemolysis marker is chosen from the following: LDH level, reticulocytes, and bilirubin. In some embodiments, a patient has a reduction of at least two hemolysis markers during the treatment period. In some embodiments, a patient has a reduction of at least three hemolysis markers during the treatment period.

[0091] In some embodiments, a patient has a reduction of median LDH levels from the baseline LDH level during the treatment period. In some embodiments, the patient has at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% reduction of the baseline median LDH level during the treatment period. In some embodiments, a patient has 30%-45% reduction of the median LDH level compared to baseline. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein has a post-administration LDH level at least 30% less than a pre-administration baseline measurement of an LDH level in the patient. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein has a post-administration LDH level at least 33% less than a preadministration baseline measurement of an LDH level in the patient. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein hasa post-administration LDH level at least 40% less than a pre-administration baseline measurement of an LDH level in the patient. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein has a postadministration LDH level at least 42% less than a pre-administration baseline measurement of an LDH level in the patient. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein has a post-administration LDH level at least 44% less than a pre-administration baseline measurement of an LDH level in the patient.

[0092] In some embodiments, a patient has a reduction of median reticulocyte level from the baseline reticulocyte level during the treatment period. In some embodiments, the patient has at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% reduction of the baseline reticulocyte level during the treatment period. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein has a post-administration median reticulocyte level of about 20% to 70% less than a pre-administration baseline measurement of a median reticulocyte level in the patient. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein has a post-administration median reticulocyte level of about 30% to 65% less than a pre-administration baseline measurement of a median reticulocyte level in the patient. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein has a post-administration median reticulocyte level of about 32% to 62% less than a pre-administration baseline measurement of a median reticulocyte level in the patient. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein has a postadministration median reticulocyte level of about 32% to 51% less than a pre-administration baseline measurement of a median reticulocyte level in the patient.

[0093] In some embodiments, a patient has a reduction of baseline bilirubin level during the treatment period. In some embodiments, a patient has a reduction of baseline total bilirubin level during the treatment period. In some embodiments, the patient has at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% reduction of the baseline bilirubin level during the treatment period. In some embodiments, a patient that is administered an effective amount of at least one compounddisclosed herein has a post-administration total bilirubin level of about 20% to 80% less than a pre-administration baseline measurement of a total bilirubin level in the patient. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein has a post-administration total bilirubin level of about 40% to 70% less than a pre-administration baseline measurement of a total bilirubin level in the patient. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein has a post-administration total bilirubin level of about 45% to 70% less than a pre-administration baseline measurement of a total bilirubin level in the patient. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein has a post-administration total bilirubin level of about 44% to 66% less than a pre-administration baseline measurement of a total bilirubin level in the patient.

[0094] In some embodiments, a patient achieves the reduction of at least one hemolysis marker within 1 week of initiating treatment. In some embodiments, a patient achieves the reduction of at least one hemolysis marker within 2 weeks of initiating treatment. In some embodiments, a patient achieves the reduction of at least one hemolysis marker within 3 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 4 w eeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 5 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 6 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 7 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 8 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 9 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 10 w eeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 11 weeks of initiating treatment. In some embodiments, the patient achieves the reduction at least one hemolysis marker within 12 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 13 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 14 w eeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 15 weeks of initiating treatment. In some embodiments, the patient achieves thereduction of at least one hemolysis marker within 16 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 17 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 18 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 19 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 20 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 21 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 22 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 23 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 24 weeks of initiating treatment. In some embodiments, a patient achieves the reduction of at least one hemolysis marker within 25 weeks of initiating treatment. In some embodiments, a patient achieves a reduction of at least one hemolysis marker within 26 w eeks of initiating treatment. In some embodiments, a patient achieves the reduction of at least one hemolysis marker within 27 weeks of initiating treatment. In some embodiments, a patient achieves the reduction of at least one hemolysis marker within 28 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 29 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 30 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 31 w eeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 32 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 33 w eeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 34 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 35 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 36 w eeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 37 w eeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 38 weeks of initiating treatment. In some embodiments, the patient achievesthe reduction of at least one hemolysis marker within 39 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 40 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 41 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 42 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 43 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 44 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 45 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 46 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 47 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 48 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 49 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 50 weeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 51 eeks of initiating treatment. In some embodiments, the patient achieves the reduction of at least one hemolysis marker within 52 weeks of initiating treatment.

[0095] In some embodiments, the patient has a reduction of expression of at least one protein related to inflammation, neutrophil function, complement activation, and cell adhesion from baseline during the treatment period. In some embodiments, the protein comprises at least one of the following: C1QA, C3, C5, IL-1B, IL-6, IL-10, IL-18, FGA. MPO, ICAML ELANE, SELL, SELP, SELENOP, NEFL, GFAP, IFNG, TNF, and VCAM1. the patient has a reduction of expression of at least tw o, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, or nineteen proteins related to inflammation, neutrophil function, complement activation, and cell adhesion from baseline during the treatment period. In some embodiments, the patient has a reduction of expression of IL-1B, neutrophil elastase (ELANE), myeloperoxidase (MPO), ICAM1, IFNG, and IL- 18 from baseline during the treatment period. In some embodiments, the patient has a reduction of expression of at least one protein related to complement activation from baseline during the treatment period. In some embodiments, the proteincomprises at least one of the following: Bb, C3a, C4a, C5a, and sC5b-9. In some embodiments, the patient has a reduction of expression of at least two, three, four, or five proteins related to complement activation from baseline during the treatment period. In some embodiments, the patient has a reduction of expression of C3a, C4a, and C5a from baseline during the treatment period. In some embodiments, the patient has a reduction of expression of C4a from baseline during the treatment period.

[0096] In some embodiments, a patient achieves the reduced protein expression within 1 week of initiating treatment. In some embodiments, a patient achieves the reduced protein expression within 2 weeks of initiating treatment. In some embodiments, a patient achieves the reduced protein expression within 3 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 4 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 5 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 6 weeks of initiating treatment. In some embodiments, the patent achieves the reduced protein expression within 7 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 8 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 9 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 10 w eeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 11 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 12 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression s within 13 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 14 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 15 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 16 w eeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 17 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 18 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 19 w eeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 20 w eeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 21 weeks ofinitiating treatment. In some embodiments, the patient achieves the reduced protein expression within 22 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 23 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 24 weeks of initiating treatment. In some embodiments, a patient achieves the reduced protein expression within 25 weeks of initiating treatment. In some embodiments, a patient achieves a reduced protein expression within 26 w eeks of initiating treatment. In some embodiments, a patient achieves the reduced protein expression within 27 weeks of initiating treatment. In some embodiments, a patient achieves the reduced protein expression within 28 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 29 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 30 w eeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 31 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 32 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 33 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 34 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 35 weeks of initiating treatment. In some embodiments, the patient achieves reduced protein expression within 36 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 37 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 38 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 39 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 40 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 41 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 42 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 43 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 44 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 45 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 46 weeks of initiating treatment. In some embodiments, the patientachieves the reduced protein expression within 47 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 48 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 49 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 50 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 51 weeks of initiating treatment. In some embodiments, the patient achieves the reduced protein expression within 52 weeks of initiating treatment.

[0097] In some embodiments, the patient experiences a reduction in fatigue from baseline during the treatment period. In some embodiments, the patient experiences a reduction in fatigue from baseline as determined using Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-fatigue scale). In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein has a median increase from baseline of 3-10 as determined by FACIT-fatigue scale. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein has a median increase from baseline of 4-7. In some embodiments, a patient that is administered an effective amount of at least one compound disclosed herein has a postadministration FACIT-fatigue scale score of at least 21% higher than a pre-administration baseline FACIT-fatigue scale score in the patient.

[0098] In some embodiments, wherein the patient experiences a reduction in fatigue from baseline, the human patient experiences a reduction in fatigue within 1 week of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 2 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 3 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 4 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 5 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 6 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 7 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 8 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 9 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 10 weeks ofinitiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 11 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 12 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 13 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 14 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 15 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 16 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 17 w eeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 18 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue w ithin 19 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 20 w eeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 21 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 22 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 23 w eeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 24 w eeks of initiating treatment. In some embodiments, wherein the patient experiences a reduction in fatigue, the human patient experiences a reduction in fatigue within 25 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 26 w eeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 27 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 28 w eeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 29 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 30 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 31 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 32 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 33 w eeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 34 weeks of initiating treatment. In someembodiments, the human patient experiences a reduction in fatigue within 35 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 36 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 37 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 38 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 39 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 40 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 41 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 42 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 43 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 44 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 45 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 46 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 47 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 48 w eeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 49 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 50 weeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 51 w eeks of initiating treatment. In some embodiments, the human patient experiences a reduction in fatigue within 52 weeks of initiating treatment.

[0099] A post-administration level, score or measurement can be determined at a suitable time after administration of at least one compound disclosed herein, non-limiting examples of which include 0.5 to 48 w eeks, 1 to 24 weeks, 8 to 24 weeks, 1 to 12 w eeks, 8 to 12 weeks or 12 to 24 weeks after administration. In some embodiments, a postadministration level, score or measurement is determined at about 12 weeks, at about 24 weeks, at about 26 w eeks, at about 50 w eeks, or at about 52 weeks after the administering. In some embodiments, a post-administration level, score or measurement is determined at about 50 days after administration of a compound disclosed herein. A post-administration level, score or measurement can be an absolute, mean or median measurement taken fromone or more samples. In some embodiments, post-administration level, score or measurement is provided or determined from, for example, a medical record or database.

[0100] A pre-administration baseline level, score or measurement can be measured at a suitable time prior to a first administration of the at least one compound disclosed herein, non-limiting examples of which include 1 to 12 weeks, 1 to 6 weeks, 0.5 to 30 days, or 0.5 to 10 days prior to a first administration of the at least one compound. A pre-administration baseline level, score or measurement can be an absolute, mean or median measurement taken from one or more samples. In some embodiments, a pre-administration baseline level, score or measurement is provided or determined from, for example, a medical record or database.

[0101] In some embodiments, the median duration of the response is at least 5 days, 10, days, 15 days, 20 days. 25 days, 30 days, 35 days. 40 days, 45 days, 50 days, 55 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 105 days, 110 days, 115 days, 120 days, 125 days, 130 days, 135 days, 140 days, 145 days, 150 days, 155 days, 160 days, 165 days, 170 days, 175 days, 180 days, 185 days, 190 days, 195 days, 200 days, 205 days, 210 days, 215 days, 220 days. 225 days, 230 days, 235 days, 240 days. 245 days. 250 days, 255 days, 260 days. 265 days. 270 days, 274 days, 275 days. 280 days. 285 days, 290 days, 295 days, 300 days, 305 days, 310 days, 315 days, 320 days, 325 days, 330 days, 335 days, 340 days, 345 days, 350 days, 355 days, 360 days, 365 days, 370 days, 375 days, 380 days, 385 days, 390 days, 395 days, or 400 days.

[0102] In some embodiments, the patient does not require rescue therapy during the treatment period. In some embodiments, the patient does not require a blood transfusion during the treatment period. In some embodiments, the patient does not require a blood transfusion for > 7 days and / or a rescue medication > 4 weeks prior to achieving the at least three consecutive hemoglobin level of > 10 g / dl and increase of hemoglobin of > 2 g / dl during the treatment period.

[0103] In some embodiments, a method or treatment disclosed herein further comprises administering a corticosteroid to a patient during the treatment period. In some embodiments, a corticosteroid comprises prednisone or prednisolone. In some embodiments, a corticosteroid is administered at a dose of at least 5 mg / day. at least 7.5 mg / day, at least 10 mg / day, at least 15 mg / day.

[0104] In some embodiments, a method or treatment disclosed herein does not further comprise administering of a corticosteroid to a patient during the treatment period.

[0105] In some embodiments, the patient is administered rescue therapy during the treatment period. In some embodiments, the patient is administered a blood transfusion during the treatment period. In some embodiments, a method or treatment disclosed herein further comprises administering rituximab to a patient. In some embodiments, a method or treatment disclosed herein further comprises administering danazol to a patient. In some embodiments, a method or treatment disclosed herein further comprises a splenectomy. In some embodiments, a method or treatment disclosed herein further comprises administering IVIG to a patient during the treatment period. In some embodiments, a method or treatment disclosed herein further comprises administering an immunomodulator or immunosuppressant to a patient during the treatment period. In some embodiments, a method or treatment disclosed herein further comprises administering other wAIHA medications to a patient during the treatment period. In some embodiments, a method or treatment disclosed herein does not comprise further administering of rituximab to a patient. In some embodiments, a method or treatment disclosed herein does not comprise administering danazol to a patient. In some embodiments, a method or treatment disclosed herein does not comprise a splenectomy. In some embodiments, a method or treatment disclosed herein does not comprise further administering of IVIG to a patient. In some embodiments, a method or treatment disclosed herein does not comprise further administering of immunomodulators or immunosuppressants to a patient. In some embodiments, a method or treatment disclosed herein does not further comprise administering of other wAIHA medications to a patient.

[0106] In some embodiments, a method disclosed herein comprises administering one or more compounds disclosed herein to a patient having a body mass index (BMI) of >17.5 to <40 kg / m2A BMI can be determined using a suitable method.

[0107] In some embodiments, a method disclosed herein comprises administering the at least one compound disclosed herein to a patient, wherein the patient has been prescreened to not have a certain disease or disorder. In some embodiments, a method disclosed herein comprises administering the at least one compound disclosed herein to a patient, wherein the patient does not have a lymphoproliferative disorder. In some embodiments, a patient does not have a lymphoma, leukemia, or a malignancy. In some embodiments, a patient does not have myelodysplastic syndrome. In some embodiments, a patient does not have poor or uncontrolled atrial fibrillation. In some embodiments, a patient does not have a coagulation or bleeding disorder. In some embodiments, a patient does not have an active or chronic infection, non-limiting examples of which include HBV, HIV, and TB.

[0108] In some embodiments, a method disclosed herein comprises administering to the human patient 400 mg of at least one compound chosen from (R)-2-[3-[4-amino-3-(2- fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4- [4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof twice a day. In some embodiments, the at least one compound consists of at least one compound chosen from the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3.4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof. In some embodiments, the at least one compound consists of at least one compound chosen from the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof. In some embodiments, the at least one compound consists of a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3.4-d]pyrimidin-l-yl]piperidine-I-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]pent-2-enenitrile or a pharmaceutically acceptable salt of the foregoing.

[0109] In some embodiments, the method comprises administering to the human patient 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2- enenitrile twice a day. In some embodiments, the at least one compound is the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3.4-d]pyrimidin-l-yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l -yl]pent-2-enenitrile. In some embodiments, the at least one compound is the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro- 4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-I-carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile. In some embodiments, the at least one compound consists of a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4- phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile.

[0110] In some embodiments, a method disclosed herein comprises administering to the human patient in need thereof a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl] piperidine- 1 -carbonyl] -4-methyl-4-[4-(oxetan-3-yl)piperazin- 1 -yl] pent-2-enenitrile and pharmaceutically acceptable salts thereof twice a day for a treatment period, wherein the human patient in need thereof has at least one characteristic prior to the treatment periodchosen from: an initial hemoglobin level < 10 g / dL; aptoglobin < 25 mg / dL, total bilirubin above the upper limit of normal, and / or LDH above the upper limit of normal; positive direct antibloglobuhn test; and / or and the human patient has failed to maintain a sustained response after treatment with corticosteroid therapy.[OHl] In some embodiments, the at least one compound is orally administered to a patient, e.g., a human patient. In some embodiments, the at least one compound is administered to the human patient in the form of at least one tablet. In some embodiments, the at least one compound is administered with water.

[0112] Pharmaceutical Compositions:

[0113] In some embodiments of the present disclosure, rilzabrutinib is administered as part of a pharmaceutical composition comprising: at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is in the form of at least one tablet.

[0114] In some embodiments of the present disclosure, rilzabrutinib is orally administered as part of a pharmaceutical composition comprising: at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is in the form of at least one tablet.

[0115] In some embodiments, rilzabrutinib is administered in the form of a film- coated tablet.

[0116] In some embodiments of the present disclosure, rilzabrutinib is administered in the form of at least one tablet comprising: at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, rilzabrutinib is administered in the form of at least one tablet comprising: at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof; at least one filler; at least one disintegrant; at least one lubricant; and at least one film coating.

[0117] In some embodiments, rilzabrutinib is administered with a glass of water.

[0118] The proportion and nature of any pharmaceutically acceptable excipient may be determined by the chosen route of administration and standard pharmaceutical practice. Except insofar as any conventional pharmaceutically acceptable excipient is incompatiblewith rilzabrutinib, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically composition, its use is contemplated to be within the scope of this disclosure.

[0119] Some non-limiting examples of materials which may serve as pharmaceutically acceptable excipients include: (1) sugars, such as, e.g., lactose, glucose, and sucrose; (2) starches, such as, e.g.. com starch and potato starch; (3) cellulose and its derivatives, such as, e.g.. sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as, e.g., cocoa butter and suppository' waxes; (9) oils, such as, e.g., peanut oil, cottonseed oil, safflower oil. sesame oil, olive oil. com oil, and soybean oil; (10) glycols, such as, e.g., propylene glycol; (11) polyols, such as, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as, e.g., ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as, e.g., 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 solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0120] One skilled in the art can readily select the proper form and route of administration depending upon the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances.EXAMPLES

[0121] The following example is intended to be illustrative and is not meant in any w ay to limit the scope of the disclosure.Abbreviations:API Active pharmaceutical ingredientALT Alanine aminotransferaseAST Aspartate aminotransferase bid / BID Twice daily (morning and evening)BTK Bruton’s Tyrosine KinaseCS CorticosteroidsECG ElectrocardiogramHRQOL Health-related quality of lifeICH International Conference on HarmonizationIgG Immunoglobulin GIV IntravenousIVIG Intravenous immunoglobulinIWG International Working GroupLTE Long term extensionMID Minimal important differenceNE Not estimablePO Oral qd / QD Once a dayQ2d / Q2D Every other dayQOL Quality of LifeSysteme international d’unites (InternationalSI system of units)TPO ThrombopoietinTPO-RA Thrombopoietin receptor agonistULN Upper limit of normalWHODD World Health Organization Drug Dictionary'Hb or Hgb HemoglobinOR Overall hemoglobin responseDR Durable hemoglobin responseR Hemoglobin responseCR Hemoglobin complete responseExample 1: A multicenter, open-label, Phase Hb study to evaluate the efficacy, safety, and pharmacokinetics of rilzabrutinib in patients with warm autoimmune hemolytic anemiaStudy Overview

[0122] This open-label, single-arm, multicenter study is designed to evaluate the efficacy, safety, tolerability', pharmacokinetics, and pharmacodynamics of rilzabrutinib in adult patients with primary wAIHA and wAIHA secondary to autoimmune diseases who areeither relapsed / refractory to, or dependent on steroid therapy. The study will be conducted in 2 parts:

[0123] Part A to evaluate efficacy and safety and Part B, a long-term extension, for assessment of long-term safety and maintenance of effect.Study Rationale

[0124] In Part A. after providing informed consent, participants will enter a 4-week Screening period.

[0125] Eligible participants will receive oral rilzabrutinib twice daily (BID) for 24 weeks. Participants will be evaluated for a hemoglobin response (defined as response [R]) or hemoglobin complete response (defined as complete response [CR]). Overall, there are 16 planned study visits for efficacy, safety and pharmacokinetic / pharmacodynamic (PK / PD) assessments in Part A.

[0126] Participants who achieve a hemoglobin response (R or CR) will be provided the option to proceed directly to Part B after the End-of-Treatment (EOT) visit Part A (EOT- Part A / W24). Participants who fail to achieve a hemoglobin response (R or CR) during the 24-week treatment period, or who receive any therapy (other than predniso[lo]ne and transfusions) known to be active in wAIHA (danazol, rituximab, immunosuppressor or immunomodulator such as azathioprine, cyclosporine, and my cophenol ate), or splenectomy will not be eligible to enter Part B. These participants will undergo a 7-day safety follow-up period and the End-of-Study visit (EOS-Part A) after receiving the last dose of study drug. The long-term extension study (Part B) will run for 52 weeks following the LPI-Part B. Each participant will be asked to attend a safety follow-up visit 7 days after their last dose of study intervention. The End-of-Study (EOS) visit will be 7 days after the last dose or early termination visit (ED). In Part B, participants will be monitored bi-weekly for Weeks 26 to 30 then every 4 weeks (Weeks 34 to 50) and every 8 weeks thereafter through EOS.

[0127] In Part B, if the participant maintains durable response through W50, the Investigator may consider withholding treatment with rilzabrutinib for up to 24 weeks (W50- W74). The participant should continue and return to the site for all scheduled visits, as per the SoA (Part B), and complete all required assessments that are not contingent to receiving the study drug at these visits. In such cases, the Hb levels and hemolytic biomarkers assessment may be repeated during an unscheduled visit (on-site or at home), as needed at the discretion of the Investigator for participant safety and to evaluate whether the participant needs to beretreated with rilzabrutinib, due to low Hb (Hb level <10 g / dL in tw o consecutive visits at least 2 weeks apart).Patient Eligibility and RecruitmentINCLUSION CRITERIAAge

[0128] Participant must be >18 to years of age, inclusive, at the time of signing the informed consent.Type of participant and disease characteristics

[0129] Male and female patients with a confirmed diagnosis of primary wAIHA or systemic lupus erythematosus (SLE)-associated wAIHA (without other SLE-related manifestations apart from cutaneous and musculoskeletal manifestations) w ho meet the following criteria: a) Hemoglobin level <10 g / dL at Screening and Day 1 b) Hemolysis (haptoglobin <25 mg / dL OR total bilirubin above the upper limit of normal OR LDH above the upper limit of normal) c) Positive direct antiglobulin test (DAT) (IgG or IgG + complement C3d pattern or IgM warm autoantibodies [positive dual DAT]).

[0130] Participants who have previously failed to maintain a sustained response after treatment with corticosteroids (corticosteroid-resistance [failure to obtain hematologic response within 3 weeks on at least 1 mg / kg predniso{lo)ne per day], corticosteroiddependent wAIHA [need to continue on predniso{lo}ne at a dose of >10 mg / day to maintain a response]).

[0131] Eastern Cooperative Oncology Group (ECOG) performance status grade 2 or lower.

[0132] Up-to-date vaccination status as per local guidelines.Weight

[0133] Body mass index (BMI) >17.5 and <40 kg / m2.EXCLUSION CRITERIA

[0134] Participants are excluded from the study if any of the following criteria apply:Medical conditions

[0135] -Clinically significant medical history or ongoing chronic illness that would jeopardize the safety of the participant or compromise the quality of the data derived from his or her participation in the study as determined by the Investigator.

[0136] -Participants with medical history of lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for the past 3 years.

[0137] - History of recurring (2 or more) serious infections requiring intravenous antibiotic therapy within the last 3 months before Study Day 1 or active serious or moderate infection ongoing at Day 1. Participants with symptomatic herpes zoster within 3 months prior to screening will be excluded.

[0138] - Secondary wAIHA from any cause including drugs, lymphoproliferative disorders (low count monoclonal B-cell lymphocytosis is allowed), infectious or autoimmune disease (systemic lupus erythematosus [SLE] without other SLE-related manifestations apart from cutaneous and musculoskeletal manifestations is allowed), or active hematologic malignancies. Participants with positive antinuclear antibodies but without a definitive diagnosis of an autoimmune disease are allow ed.

[0139] - Myelodysplastic syndrome.

[0140] - ECG findings:• QTcF >450 msec (males) or >470 msec (females), poorly controlled atrial fibrillation (z.e., symptomatic patients or a ventricular rate above 100 beats / min on ECG), or other clinically significant abnormalities.

[0141] - History of coagulation or bleeding disorders.

[0142] -Uncontrolled or active HBV infection: Patients with positive HBsAg and / or HBV DNA.

[0143] - HIV infection.

[0144] - Refractory nausea and vomiting, malabsorption, external biliary shunt, significant bowel resection, or any other condition that would preclude adequate study drug absorption.

[0145] - History of solid organ transplant.

[0146] - A history of active or latent tuberculosis (TB) (unless the participant has completed a full course of anti-tuberculosis therapy or it is documented by a specialist that the participant has been adequately treated and can begin treatment with animmunosuppressive agent); A positive test for TB (PPD or QuantiFERON-TB-Gold [QFT]) performed at the screening visit or within the 3 months prior to screening.

[0147] - Positive COVID-19 molecular test (if COVID-19 testing required per local guidelines to be determined for each site).

[0148] - Any of laboratory abnormalities at the screening visit

[0149] - Ferritin levels below the lower limit of normal.

[0150] - Prothrombin time (PT / INR) or activated partial thromboplastin time (aPTT) above the ULN and deemed to be clinically significant by the Investigator.

[0151] - If female, pregnancy (defined as positive (3-HCG blood test) or lactating.

[0152] - Recent history' of substance, alcohol abuse or mental illness.Endpoints and AssessmentsPart A: Overall hemoglobin response (response [R] or complete response [CR] by week 24 of treatment

[0153] R is defined as an increase in hgb by >2 g / dL from baseline without biochemical resolution of hemolysis at the time response is achieved

[0154] CR is defined as hgb >11 g / dL (women) or >12 g / dL (men) with no evidence of hemolysisPart B: Durable hemoglobin response

[0155] Defined as hgb level >10 g / dL with an increase from baseline of >2 g / dL on three consecutive scheduled visits by Week 50 in the absence of rescue therapy or blood transfusion

[0156] Secondary endpoints:Durable hemoglobin response in Part ATime to hemoglobin response (TTR)Effect on rescue medicationImpact on fatigueSafety and tolerability of Rilzabrutinib

[0157] Secondary safety endpoints include an evaluation of the frequency and severity of treatment-emergent adverse events and bleeding events. Safety will be assessed by the incidence, severity, and causal relationship of treatment-emergent adverse events,including clinically significant changes in physical examination, vital signs, electrocardiogram, and laboratory parameters.Example 2: Basic characteristics of adult patients enrolled in phase 2 placebo- controlled study of rilzabrutinib, an oral Bruton’s tyrosine kinase inhibitor

[0158] The purpose of this study was to examine the basic patient characteristics of adult patients in the study.

[0159] Table 1. Baseline Patient Demographics, Disease Characteristics

[0160] Table 2 - Disease characteristics

[0161] Table 3: Prior and concomitant wAIHA medications* Use of different types of corticosteroids was counted as one prior wAIHA medication; Splenectomy not included.

[0162] Table 3 (Cont.)Example 3: Results of a multicenter, open-label, Phase lib study to evaluate the efficacy, safety, and pharmacokinetics of rilzabrutinib in patients with warm autoimmune hemolytic anemiaPart A

[0163] 22 patients were enrolled, including 21 with primary wAIHA and 1 erroneously enrolled with cold agglutinin disease. 21 patients completed part A, 1 withdrew due to the patient decision within the first 12 weeks, and 15 have entered part B LTE. At baseline, median age was 65 y (range, 33-87; 23% >75 y) and 59% were female. For 21 wAIHA patients, median time since diagnosis was 4.9 y (maximum 47 y ; 55% >3 y). 11 (50%) patients had >3 prior medications. Rilzabrutinib monotherapy was given in 9 (41%) patients, and with concomitant corticosteroids (CS) in 13 (59%) patients.

[0164] Overall Hb response was achieved in 14 (64%) patients (13 [59%] patients met criteria for response and 3 [ 14%] for complete response), and 9 (41%) patients achieved durable response (Figure 1 and Table 4)

[0165] Table 4:

[0167] Median time to Hb response in 14 responders was 50 days (range, 28-169).Increased Hb levels were associated with reduced hemolysis markers (Figure 3). At weeks 12 and 24 relative to baseline, median LDH levels were reduced by 33% for both, and median reticulocytes reduced by 32% and 51% respectively. Mean (SD) baseline FACIT-fatigue scale score of 30.0 (11.1) improved with clinically meaningful increases to 36.4 (10.5) at week 12 and 37.0 (11.5) at week 24 (Figure 5).

[0168] Rescue medication was used in 1 patient from weeks 1-12 and 3 patients from weeks >12-24. 5 (23%) patients (3 responders, 2 non-responders) received blood transfusions during the first 12 weeks of treatment. 1 (7%) responder who received frequent blood transfusions pre-study, received them 6x in weeks 1-12, and 2x in weeks >12-24.

[0169] Table 5 : Rescue Medication* Dose of prednisone was transiently increased from baseline 7.5 mg per day to 15 mg per day for 7 days and then returned to baseline line level.

[0170] Table 6: Blood transfusion* The subject has been receiving weekly blood transfusion prior to study. The subject received six blood transfusions in the first 12 weeks, and two blood transfusions after 12 weeks and up to Week 24.

[0171] Rilzabrutinib was given for a median duration of 24 weeks (range, 9-25). 20 (91%) patients had on-treatment adverse events (AEs) due to any cause; 10 (45%) patients had treatment-related AEs. The most common any-cause AEs were nausea (32%), diarrhea (23%), and upper abdominal pain (18%); all mild grade. Four (18%) patients had serious AEs; none were treatment related.

[0172] Therefore, rilzabrutinib demonstrated sustained and rapid hemoglobin (Hb) response and favorable safety profile in part A of the phase 2B study (NCT05002777) in adult patients with wAIHA.

[0173] The impact of rilzabrutinib on inflammatory and complement biomarkers in patients with wAIHA was also evaluated.

[0174] In a post-hoc analysis, protein expression in patients with wAIHA was compared to that in healthy volunteers (HV). A targeted inflammatory biomarker analysis was performed at baseline and weeks 4, 12, and 24 that focused on 19 proteins related to inflammation, neutrophil function, complement activation, and cell adhesion (C1QA, C3, C5, IL-1B, IL-6, IL-10, IL-18, FGA. MPO, ICAM1, ELANE. SELL, SELP, SELENOP, NEFL, GFAP, IFNG, TNF, VCAM1) using data from Olink Explore HT profiling. Additionally, complement analyses were performed at baseline and week 24 to test Bb, C3a, C4a, C5a, sC5b-9 levels using the Quansys multiplex kit.

[0175] Samples for inflammatory biomarker assessments were available in 14 wAIHA patients at baseline and in 9, 11, and 10 patients at weeks 4, 12, and 24, respectively and in 20 HV. There was a significantly higher expression of VC AMI, IL 10, IL 18, NEFL, ICAM1, C3, and ELANE in patients with wAIHA compared to HV (adjusted -value <0.05). C1QA and TNF expression were significantly higher in wAIHA patients, while expression of SELL was significantly higher in HV (P<0.05 for all but adjusted P- value not significant).

[0176] Of the 19 analyzed proteins, there was a decrease from baseline at week 4 (7M).05) in neutrophil elastase (ELANE) and myeloperoxidase (MPO) indicating decreased neutrophil activation and decrease in circulating ICAM1 ( <0.05), suggesting reduction in adhesion and inflammation. FIG. 6D and 6E. Significantly decreased MPO (P=0.003) and increased IFNG (P=0.042) were observed at week 12. FIG. 6C. At week 24, significantly decreased IL-18 was observed ( <0.05; FIG. 6B) indicating reduced inflammasome activity. There was a trending decrease in inflammatory biomarkers from week 12. Paired samples for complement analysis were available in 11 patients and revealed decrease in anaphylatoxin (C3a. C4a. C5a) levels after rilzabrutinib with 9 of 11 patients showing decrease in C4a (FIG. 6F) suggesting that the classical pathway complement activation may be suppressed by rilzabrutinib. C4a decrease also correlated with durable Hb responses.

[0177] In the phase IIB study (NCT05002777), part A patients with wAIHA (N=22) receiving rilzabrutinib showed robust overall and durable hemoglobin (Hb) response, decreased hemolytic markers, improved fatigue, and a well-tolerated safety profile.Part B

[0178] Part B extension (last patient completed 50 weeks of treatment) evaluated long-term efficiency / safety of rilzabrutinib.

[0179] Eligible patients aged >18 years old had primary wAIHA that was relapsed / refractory to or dependent on corticosteroids (CS). At baseline, patients had ECOG PS 0-2, Hb level <10 g / dL, >1 abnormal hemolytic marker, positive direct antiglobulin test, and unsustained CS response. To enter part B. part A patients had to complete 24 weeks of oral rilzabrutinib 400 mg bid and achieved overall Hb response (response / complete response) by week 24. Part B rilzabrutinib was given until the last patient completes 52 weeks in part B. Stable concomitant CS doses and rescue therapy are allowed. Part B primary efficacy endpoint was durable Hb response: Hb >10 g / dL increased from baseline >2 g / dL on 3 consecutive scheduled visits during weeks >24-50, absent blood transfusion for >7 days and rescue medication for 4 weeks prior to / throughout durable Hb response. Fatigue was measured by FACIT-Fatigue scale (Scippa Blood 2023).

[0180] 15 of 22 (68%) part A patients entered part B. At baseline, 15 part B patients(1 with cold agglutinin disease) had median age of 68 y (range. 33-87; 27% >75 y) and 40% were female. For 14 wAIHA patients, median time since diagnosis was 7.1 years (maximum 47 years; 60% >3 years). Nine (60%) patients received >3 prior medications. Rilzabrutinib monotherapy was given in 6 (40%) patients, and with concomitant CS in 9 (60%) patients.

[0181] Durable Hb response was achieved in 12 (80%) patients, with median Hb levels ranging from 11.5-12.1 g / dL through part B up to week 50 (FIG. 7A). Median duration of response (parts A+B) was 274 days (range, 37-323). Increased Hb levels were associated with reduced hemolytic markers. At weeks 26 and 50 relative to baseline, respective reductions were observed in median LDH levels by 42% and 44%, reticulocytes by 57% and 62%. and total bilirubin by 48% and 66%. Rescue medication was used in 3 (20%) patients after week 24 to week 50. Three (20%) patients received blood transfusions by week 50. Clinically meaningful increases in FACIT-fatigue scale scores were observed with median changes from baseline (median: 34.0) of 4.3 and 6.0 at weeks 26 and 50, respectively (FIG. 7B).

[0182] Rilzabrutinib was given for a median duration of 26 weeks (range, 18-27). Nine (60%) patients had any cause adverse events (AEs); 4 (27%) with treatment-related AEs. The most common any-cause AEs in 2 (13%) patients each were back pain, cellulitis, and upper respiratory tract infection; all others occurred in 1 patient each. One patient had an SAE of decreased Hb unrelated to treatment (no treatment-related SAEs). No AEs led to treatment discontinuation, AEs of special interest, or deaths.

[0183] Therefore, long-term rilzabrutinib showed sustained efficacy based on durable hemoglobin (Hb) response, decreased hemolytic markers, and clinically meaningful improvement in fatigue, and had a well-tolerated safety profile in patients with wAIHA.Embodiments:Non-limiting embodiments of the disclosure include:1. A method for treating warm autoimmune hemolytic anemia (wAIHA) in a patient in need thereof comprising administering to the patient in need thereof a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2- fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4- methyl-4-[4-(oxetan-3-yl)piperazin-l -yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof.2. The method of embodiment 1 , wherein the wAIHA is primary wAIHA.3. The method of any one of embodiments 1 to 2, wherein the patient has a secondary autoimmune disease.4. The method of embodiment 3, wherein the secondary autoimmune disease is sy stemic lupus erythematosus (SLE).5. The method of any one of embodiments 1 to 4, wherein the patient has been identified as having a hemoglobin level of <10 g / dl.6. The method of any one of embodiments 1 to 5, wherein the patient has been identified as having a hemoglobin level of 8 to < 10 g / dl.7. The method of any one of embodiments 1 to 5, wherein the patient has been identified as having a hemoglobin level of 6.5 to < 8 g / dl.The method of any one of embodiments 1 to 5, wherein the patient has been identified as having a hemoglobin level of < 6.5 d / dl. The method of any one of embodiments 1 to 4, wherein the patient has been identified as having a hemoglobin level of >10 g / dl. The method of any one of embodiments 1 to 9, wherein the patient has been identified as having hemolysis. The method of any one of embodiments 1 to 10. wherein the patient has been identified as having > 1 abnormal hemolytic marker. The method of any one of embodiments 1 to 11, wherein the patient has been identified as having a haptoglobin level of < 25 mg / dl. The method of any one of embodiments 1 to 12, wherein the patient has been identified as having a bilirubin level above the upper limit of normal. The method of any one of embodiments 1 to 13, wherein the patient has been identified as having an LDH level above the upper limit of normal. The method of any one of embodiments 1 to 14. wherein the patient has been identified as having a positive direct antiglobulin test (DAT). The method of any one of embodiments 1 to 15, wherein the patient has been identified as failing to maintain a sustained response after treatment with corticosteroid, resistant to corticosteroid therapy, or dependent on steroid therapy. The method of any one of embodiments 1 to 15, wherein the patient has a history of taking at least one previously administered therapy for wAIHA. The method of any one of embodiments 1 to 15, wherein the patient has a his ton of response to at least one previously administered therapy for wAIHA. The method of any one of embodiments 1 to 18, wherein the patient has been identified as refractory to treatment, or refractory to at least one previously administered therapy for wAIHA.The method of any one of embodiments 1 to 18, wherein the patient has been identified as relapsed from at least one previously administered therapy for wAIHA, or has a prior response to at least one previously administering therapy for wAIHA that was not sustained. The method of any one of embodiments 1 to 17. wherein the patient has a history of no response to at least one prior line of therapy for wAIHA. The method of any one of embodiments 17 to 21, wherein the at least one previously- administered therapy is selected from a splenectomy, corticosteroid, intravenous immunoglobin (1VIG). danazol, ntuximab, immunosuppressor and immunomodulator. The method of embodiment 22, wherein the immunosuppressor or immunomodulator is selected from azathiopnne, cyclosporine, or my cophenolate. The method of embodiment 22, wherein the corticosteroid is selected from prednisone or prednisolone. The method of any one of embodiments 1 to 24, wherein the patient had a splenectomy prior to the start of the treatment period. The method of any one of embodiments 1 to 25. wherein the patient has a history of taking rituximab prior to the start of the treatment period. The method of any one of embodiments 1 to 25, wherein the patient has not received prior treatment with rituximab. The method of any one of embodiments 1 to 27, wherein the patient has a history7of taking danazol prior to the start of the treatment period. The method of any one of embodiments 1 to 27. wherein the patient has not received prior treatment with danazol.The method of any one of embodiments 1 to 29, wherein the patient has a history of taking at least one immunosuppressor or immunomodulator prior to the start of the treatment period. The method of any one of embodiments 1 to 29, wherein the patient has a history of taking at least one immunosuppressor or immunomodulator selected from azathioprine. cyclosporine, and my cophenolate prior to the start of the treatment period. The method of any one of embodiments 1 to 29, wherein the patient has not received prior treatment with at least one immunosuppressor or immunomodulator. The method of any one of embodiments 1 to 32, wherein the patient has a history of taking intravenous immunoglobin (IVIG) prior to the start of the treatment period. The method of any one of embodiments 1 to 32 wherein the patient has not received prior treatment with intravenous immunoglobin (IVIG). The method of any one of embodiments 1 to 34, wherein the patient has a history of taking at least one corticosteroid prior to the start of the treatment period. The method of any one of embodiments 1 to 34, wherein the patient has a history' of taking at least one corticosteroid selected from prednisone or prednisolone prior to the start of the treatment period. The method of any one of the embodiments 1 to 34, wherein the patient has not received prior treatment of at least one corticosteroid. The method of any one of embodiments 1 to 37. wherein the patient has been identified as having an Eastern Cooperative Oncology7Group (ECOG) performance status grade of 2 or lower. The method of any one of embodiments 1 to 38. wherein the at least one compound is administered twice daily (BID).The method of any one of embodiments 1 to 39, wherein the at least one compound is administered for a treatment period of at least 4 weeks, at least 7 weeks, at least 12 weeks, at least 24 weeks, at least 26 weeks, at least 50 weeks, or at least 52 weeks. The method of any one of embodiments 1 to 40, wherein the at least one compound is administered for a treatment period of 12 to 52 weeks, 12 to 50 weeks, 12 to 48 weeks, 12 to 26 weeks, or or 12 to 24 weeks. The method of any one of embodiments 1 to 41, wherein the effective amount of the at least one compound ranges from 100 to 1200 mg. The method of any one of embodiments 1 to 42, wherein the effective amount of the at least one compound ranges from 200 to 600 mg. The method of any one of embodiments 1 to 43, wherein the effective amount of the at least one compound is 400 mg. The method of any one of embodiments 1 to 44. wherein the patient achieves a hemoglobin response. The method of any one of embodiments 1 to 45, wherein the patient achieves a complete hemoglobin response. The method of any one of embodiments 1 to 46, wherein the patient achieves an overall hemoglobin response. The method of any one of embodiments 1 to 47. wherein the patient achieves a durable hemoglobin response. The method of any one of embodiments 1 to 48, wherein the patient has an increase in hemoglobin level during the treatment period.The method of any one of embodiments 1 to 49, wherein during the treatment period, after the administering, the patient has a post-administration hemoglobin level of at least 2 g / dL higher than a pre-administration baseline measurement of a hemoglobin level in the patient. The method of any one of embodiments 1 to 50. wherein the patient has at least one hemoglobin level of > 10 g / dL during the treatment period. The method of any one of embodiments 1 to 51, wherein the patient has at least one hemoglobin level of > 11 g / dL during the treatment period. The method of any one of embodiments 1 to 52, wherein the patient has at least one hemoglobin level of > 12 g / dL during the treatment period. The method of any one of embodiments 1 to 51, wherein the patient has at least one hemoglobin level of > 10 g / dL and an increase of hemoglobin of > 2 g / dL during the treatment period. The method of any one of embodiments 1 to 52. wherein the patient has at least one hemoglobin level of > 11 g / dL and an increase of hemoglobin of > 2 g / dL during the treatment period. The method of any one of embodiments 45 to 55, wherein the patient has no evidence of hemolysis and / or does not require rescue medication or blood transfusion. The method of any one of embodiments 1 to 56, wherein the patient has at least one hemoglobin level of > 11 g / dL and an increase of hemoglobin of > 2 g / dL from baseline during the treatment period, and wherein the patient has no evidence of hemolysis. The method of any one of embodiments 1 to 51 or 54. wherein the patient has at least three consecutive hemoglobin level of > 10 g / dl and an increase of hemoglobin of > 2 g / dL from baseline during the treatment period, in the absence of rescue medication and / or blood transfusion.The method of any one of embodiments 45-59, wherein the post-administration hemoglobin level has been determined at about 50 days. 12 weeks, 24 weeks. 26 weeks, or 50 weeks after the administering. The method of any one of embodiments 1 to 59, wherein the patient has a reduction of at least one of the following hemolysis markers during the treatment period:1) median LDH levels;2) median reticulocyte level; and3) total bilirubin. The method of any one of embodiments 1 to 60. wherein the patient has a reduction of at least two of the following hemolysis markers during the treatment period: a) median LDH levels; b) median reticulocyte level; and c) total bilimbin. The method of any one of embodiments 1 to 61, wherein the patient has a reduction of all of the following hemolysis markers during the treatment period: a) median LDH levels; b) median reticulocyte level; and c) total bilimbin. The method of any one of embodiments 1 to 59, wherein the patient has at least one of the following during the treatment period: a) at least 30% decrease of median LDH levels; b) at least 30% decrease in median reticulocytes; and c) at least 40% decrease in total bilimbin. The method of any one of embodiments 1 to 59, wherein the patient has at least two of the following during the treatment period: a) at least 30% decrease of median LDH levels; b) at least 30% decrease in median reticulocytes; and c) at least 40% decrease in total bilimbin.The method of any one of embodiments 1 to 59, wherein the patient has all of the following during the treatment period: a) at least 30% decrease of median LDH levels; b) at least 30% decrease in median reticulocytes; and c) at least 40% decrease in total bilirubin. The method of any one of embodiments 1 to 65. wherein the patient has a reduction of expression of at least one protein related to inflammation, neutrophil function, complement activation, and cell adhesion during the treatment period. The method of any one of embodiments 1 to 66. wherein the patient has a reduction of expression of at least one protein related to inflammation, neutrophil function, complement activation, and cell adhesion during the treatment period, and wherein the protein comprises at least one of the following: C1QA, C3, C5, IL-1B, IL-6, IL- 10, IL-18, FGA, MPO, ICAM1, ELANE, SELL, SELP, SELENOP, NEFL. GFAP. IFNG, TNF, and VCAM1. The method of any one of embodiments 1 to 67, wherein the patient has a reduction of expression of at least one protein related to complement activation during the treatment period. The method of any one of embodiments 1 to 68, w herein the patient has a reduction of expression of at least one protein related to complement activation during the treatment period, wherein the protein comprises at least one of the following: Bb. C3a, C4a, C5a, and sC5b-9. The method of any one of embodiments 1 to 69, w herein the patient experiences a reduction in fatigue during the treatment period. The method of any one of embodiments 1 to 70, wherein the patient experiences a reduction in fatigue during the treatment period as determined using FACIT-fatigue scale.The method of any one of embodiments 1 to 71, wherein the patient experiences a median increase of at least 4 from baseline in FACIT-fatigue scale score during the treatment period. The method of any one of embodiments 1 to 72, wherein the treatment period is at least 4 weeks, 7 weeks, 12 weeks, 24 weeks, 26 weeks, 37 weeks. 50 weeks, or 52 weeks. The method of any one of embodiments 1 to 73, wherein the patient has at least three consecutive hemoglobin level of > 10 g / dL and an increase of hemoglobin of > 2 g / dL from baseline, in the absence of rescue medication or blood transfusion during a treatment period of at least 50 weeks. The method of any one of embodiments 1 to 73. wherein the patient has at least three consecutive hemoglobin level of > 10 g / dL and an increase of hemoglobin of > 2 g / dL from baseline during a treatment period of at least 50 weeks, and wherein the patient was not administered blood transfusion for > 7 days and / or rescue medication > 4 weeks prior to achieving the at least three consecutive hemoglobin level of > 11 g / dl and increase of hemoglobin of > 2 g / dL. The method of any one of embodiments 1 to 75, wherein the patient does not require rescue medication and / or blood transfusion during the treatment period. The method of any one of embodiments 1 to 74, wherein the patient is administered rescue medication and / or blood transfusion during the treatment period. The method of any one of embodiments 1 to 75, wherein the patient is not administered blood transfusion for > 7 days and / or rescue medication > 4 weeks prior to achieving at least three consecutive hemoglobin level of > 10 g / dl and / or an increase of hemoglobin of > 2 g / dL. The method of any one of embodiments 1 to 75. wherein the patient is further administered at least one therapy chosen from a splenectomy, corticosteroid, danazol, rituximab, intravenous immunoglobin (IVIG), immunomodulator, and immunosuppressive drug.The method of any one of embodiments 1 to 75 or 77-79, wherein the patient is further administered a corticosteroid. The method of embodiment 80, wherein the corticosteroid is prednisone or prednisolone. The method of embodiment 80 or 81, wherein the corticosteroid is administered at a dose of at least 7.5 mg / day, at least 10 mg / day, or at least 15 mg / day. The method of any one of embodiments 1 to 75 or 77 to 82, wherein the patient is further administered rituximab. The method of any one of embodiments 1 to 75 or 77 to 83, wherein the patient is further administered a blood transfusion. The method of any one of embodiments 1 to 84, wherein the at least one compound is administered orally. The method of any one of embodiments 1 to 85, wherein the at least one compound is administered to the patient in the form of at least one tablet. The method of any one of embodiments 1 to 86. wherein the at least one compound is administered with water. The method of any one of embodiments 1 to 87, wherein the patient is a human. The method of any one of embodiments 1 to 88, wherein the patient has a body mass index (BMI) of >17.5 to <40 kg / m2. The method of any one of embodiments 1 to 89. wherein the patient does not have lymphoma, leukemia, or a malignancy. The method of any one of embodiments 1 to 90, wherein the patient does not have a lymphoproliferative disorder.The method of any one of embodiments 1 to 91, wherein the patient does not have myelodysplastic syndrome. The method of any one of embodiments 1 to 92, wherein the patient does not have poorly or uncontrolled atrial fibrillation. The method of any one of embodiments 1 to 93, wherein the patient does not have a coagulation or bleeding disorder. The method of any one of embodiments 1 to 94. wherein the patient does not have an active or chronic infection. The method of any one of embodiments 1 to 95, wherein the patient has an active or chronic infection selected from HBV, HIV, and TB. The method of any one of embodiments 1 to 96, wherein the patient is a female patient. The method of embodiment 96, wherein the female patient is not pregnant or not lactating. The method of any one of embodiments 1 to 97. wherein after the administering, the patient has a post-administration LDH level of 33% to 50% less than a preadministration baseline measurement of an LDH level in the patient. The method of embodiment 98, wherein the post-administration LDH level has been determined at about 12 weeks, at about 24 weeks, at about 26 weeks, or at about 50 weeks after the administering. The method of any one of embodiments 1 to 99. wherein after the administering, the patient has a post-administration median reticulocyte level of about 32% to 51% less than a pre-administration baseline measurement of a median reticulocyte level in the patient.The method of any one of embodiments 1 to 100, wherein after the administering, the patient has a post-administration median reticulocyte level of about 30% to 65% less than a pre-administration baseline measurement of a median reticulocyte level in the patient. The method of embodiment 100 or 101, wherein the post-administration median reticulocyte level has been determined at about 12 weeks, at about 24 weeks, at about 26 weeks, or at about 50 weeks after the administering. The method of any one of embodiments 1 to 102, wherein after the administering, the patient has a post-administration total bilirubin level of about 40% to 70% less than a pre-administration baseline measurement of a total bilirubin level in the patient. The method of embodiment 103. wherein the post-administration total bilirubin level has been determined at about 12 weeks, at about 24 weeks, at about 26 weeks, or at about 50 weeks after the administering. The method of any one of embodiments 1 to 104, wherein after the administering, the patient has a post-administration FACIT-fatigue scale score of at least 21% higher than a pre-administration baseline FACIT-fatigue scale score in the patient. The method of any one of embodiments 1 to 104, wherein after the administering, the patient has an increase in a post-administration FACIT-fatigue scale score of 4-8 compared to a pre-administration baseline FACIT-fatigue scale score in the patient. The method of embodiment 105 or 106, wherein the post-administration FACIT- fatigue scale score has been determined at about 12 weeks, at about 24 weeks, at about 26 weeks, or at about 50 weeks after the administering. The method of any one of embodiments 1 to 107, wherein the patient is aged >18 years. The method of any one of embodiments 1 to 108, comprising administering to the patient 400 mg of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro- 4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof twice a day. The method of any one of embodiments 1 to 109, wherein the at least one compound consists of at least one compound chosen from the (E) isomer of (R)-2-[3-[4-amino-3- (2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4- methyl-4-[4-(oxetan-3-yl)piperazin-l -yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof. The method of any one of embodiments 1 to 109, wherein the at least one compound consists of at least one compound chosen from the (Z) isomer of (R)-2-[3-[4-amino-3- (2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4- methyl-4-[4-(oxetan-3-yl)piperazin-l -yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof. The method of any one of embodiments 1 to 109, wherein the at least one compound consists of a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4- phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4- [4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile or a pharmaceutically acceptable salt thereof The method of any one of embodiments 1 to 109, comprising administering to the patient 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d] pyrimidin- 1 -y 1] piperidine- 1 -carbonyl] -4-methy 1-4- [4-(oxetan-3 -y l)piperazin- 1 - yl]pent-2-enenitrile twice a day. The method of any one of embodiments 1 to 109 or 113, wherein the at least one compound is the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3.4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan- 3-yl)piperazin-l-yl]pent-2-enenitrile. The method of any one of embodiments 1 to 109 or 113, wherein the at least one compound is the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile. The method of any one of embodiments 1 to 109 or 113, wherein the at least one compound consists of a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2- fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4- methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile. A method for treating warm autoimmune hemolytic anemia (wAIHA) in a human patient in need thereof comprising administering to the human patient in need thereof a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4- amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof twice a day for a treatment period, wherein the human patient in need thereof has at least one characteristic prior to the treatment period chosen from: a) an initial hemoglobin level < 10 g / dL, b) haptoglobin < 25 mg / dL, total bilirubin above the upper limit of normal, or LDH above the upper limit of normal; c) positive direct antibloglobulin test; and the human patient has failed to maintain a sustained response after treatment with corticosteroids. Use of a therapeutically effective amount of at least one compound chosen from (R)- 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-en enitrile and pharmaceutically acceptable salts thereof, for treating warm autoimmune hemolytic anemia (wAIHA) in a human patient in need thereof. A therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4- amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof, for use as a medicament for treating warmautoimmune hemolytic anemia (wAIHA) in a human patient in need thereof.120. A therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4- amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof, for use for treating warm autoimmune hemolytic anemia (wAIHA) in a human patient in need thereof.121. The use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof, as a medicament for treating warm autoimmune hemolytic anemia (wAIHA) in a human patient in need thereof.

[0184] Claims or descriptions that include “or” or “and / or” between at least one members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The 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 disclosure includes embodiments in which more than one, or all the group members are present in, employed in, or otherwise relevant to a given product or process.

[0185] Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0186] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the disclosure should, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

What is claimed is:

1. A method for treating warm autoimmune hemolytic anemia (wAIHA) in a patient in need thereof comprising administering to the patient in need thereof a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2- fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4- methyl-4-[4-(oxetan-3-yl)piperazin-l -yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof.

2. The method of claim 1 , wherein the wAIHA is primary wAIHA.

3. The method of claim 1, wherein the patient has a secondary autoimmune disease, optionally wherein the secondary autoimmune disease is systemic lupus erythematosus (SLE).

4. The method of any one of claims 1 to 3. wherein the patient has been identified as having a hemoglobin level of <10 g / dl.

5. The method of any one of claims 1 to 4, wherein the patient has been identified as having at least one of the following: a) haptoglobin level of < 25 mg / dl; b) bilirubin level above the upper limit of normal; and c) LDH level above the upper limit of normal.

6. The method of any one of claims 1 to 5, wherein the patient has been identified as having a positive direct antiglobulin test (DAT).

7. The method of any one of claims 1 to 6, wherein the patient has been identified as failing to maintain a sustained response after treatment with corticosteroid, resistant to corticosteroid therapy, or dependent on steroid therapy.

8. The method of any one of claims 1 to 7, wherein the patient has ahistory of taking at least one previously administered therapy for wAIHA.

9. The method of any one of claims 1 to 8, wherein the patient has been identified as refractory to at least one previously administered therapy for wAIHA, relapsed from at least one previously administered therapy for wAIHA, or has a prior response to at least one previously administering therapy for wAIHA that was not sustained.

10. The method of claim 8 or 9, wherein the at least one previously administered therapy is selected from a splenectomy, corticosteroid, intravenous immunoglobin (IVIG), danazol, rituximab, immunosuppressor and immunomodulator, optionally wherein the immunosuppressor or immunomodulator is selected from azathioprine, cyclosporine, or my cophenolate, and wherein the corticosteroid is selected from prednisone or prednisolone.

11. The method of any one of claims 1 to 10, wherein the at least one compound is administered twice daily (BID).

12. The method of any one of claims 1 to 11, wherein the at least one compound is administered for a treatment period of at least 4 weeks, at least 7 weeks, at least 12 weeks, at least 24 weeks, at least 26 weeks, at least 50 weeks, or at least 52 weeks.

13. The method of any one of claims 1 to 12, wherein the effective amount of the at least one compound is 400 mg.

14. A method for treating warm autoimmune hemolytic anemia (wAIHA) in a human patient in need thereof comprising administering to the human patient in need thereof a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4- amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof twice a day for a treatment period, wherein the human patient in need thereof has at least one characteristic prior to the treatment period chosen from: a) an initial hemoglobin level < 10 g / dL, b) haptoglobin < 25 mg / dL, total bilirubin above the upper limit of normal, or LDH above the upper limit of normal; andc) positive direct antibloglobulin test; and the human patient has failed to maintain a sustained response after treatment with corticosteroids.

15. The method of any one of claims 1 to 14, wherein after the administering, the patient has a post-administration hemoglobin level of at least 2 g / dL higher than a preadministration baseline measurement of a hemoglobin level in the patient and / or the patient has at least one hemoglobin level of > 10 g / dL during the treatment period.

16. The method of any one of claims 1 to 15, wherein the patient has at least one hemoglobin level of > 11 g / dL during the treatment period.

17. The method of any one of claims 1 to 16, wherein the patient has a reduction of at least one of the following hemolysis markers during the treatment period: a) median LDH levels; b) median reticulocyte level; and c) total bilirubin.

18. The method of any one of claims 1 to 17, wherein during the treatment period, the patient has a reduction of expression of:- at least one protein related to inflammation, neutrophil function, complement activation, and cell adhesion, or- at least one protein related to complement activation; optionally wherein the protein related to inflammation, neutrophil function, complement activation, and cell adhesion comprises at least one of the following: C1QA, C3, C5, IL-1B, IL-6, IL-10, IL-18, FGA, MPO, ICAM1, ELANE, SELL, SELP, SELENOP, NEFL, GFAP, IFNG, TNF, and VCAM1, or wherein the protein related to complement activation comprises at least one of the following: Bb, C3a, C4a, C5a, and sC5b-9.

19. The method of any one of claims 1 to 18, wherein the patient experiences a reduction in fatigue during the treatment period as determined using FACIT-fatigue scale.

20. The method of any one of claims 1 to 19, wherein the patient does not require rescue medication and / or blood transfusion during the treatment period.

21. The method of any one of claims 1 to 19, wherein the patient is administered rescue medication and / or blood transfusion during the treatment period.

22. The method of any one of claims 1 to 21, wherein the patient is further administered at least one therapy chosen from a splenectomy, corticosteroid, danazol, rituximab, intravenous immunoglobin (IVIG), immunomodulator, and immunosuppressive drug.

23. The method of any one of claims 1 to 22, wherein the patient is further administered a corticosteroid, optionally wherein the corticosteroid is prednisone or prednisolone, and further optionally wherein the corticosteroid is administered at a dose of at least 7.5 mg / day, at least 10 mg / day, or at least 15 mg / day.

24. The method of any one of claims 1 to 23, wherein the patient is a human.

25. Use of a therapeutically effective amount of at least one compound chosen from (R)- 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]piperidine-l-carbonyl]-4-methyl-4-f4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof, for treating warm autoimmune hemolytic anemia (wAIHA) in a human patient in need thereof.

26. A therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4- amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof, for use as a medicament for treating warm autoimmune hemolytic anemia (wAIHA) in a human patient in need thereof.

27. A therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4- amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile andpharmaceutically acceptable salts thereof, for use for treating warm autoimmune hemolytic anemia (wAIHA) in a human patient in need thereof.

28. The use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof, as a medicament for treating warm autoimmune hemolytic anemia (wAIHA) in a human patient in need thereof.

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