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WO2024124113A1 - Méthodes de traitement de la thrombocytopénie immunitaire chez des sujets présentant un déficit cognitif par administration de rilzabrutinib - Google Patents

Méthodes de traitement de la thrombocytopénie immunitaire chez des sujets présentant un déficit cognitif par administration de rilzabrutinib Download PDF

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WO2024124113A1
WO2024124113A1 PCT/US2023/083090 US2023083090W WO2024124113A1 WO 2024124113 A1 WO2024124113 A1 WO 2024124113A1 US 2023083090 W US2023083090 W US 2023083090W WO 2024124113 A1 WO2024124113 A1 WO 2024124113A1
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patient
need
score
age
itp
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Ahmed DAAK
Umer Khan
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Principia Biopharma Inc
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Principia Biopharma Inc
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Priority to IL321322A priority Critical patent/IL321322A/en
Priority to AU2023390489A priority patent/AU2023390489A1/en
Priority to CN202380084246.9A priority patent/CN120322235A/zh
Priority to EP23844562.1A priority patent/EP4630003A1/fr
Priority to KR1020257022618A priority patent/KR20250114128A/ko
Publication of WO2024124113A1 publication Critical patent/WO2024124113A1/fr
Priority to MX2025006665A priority patent/MX2025006665A/es
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/196—Thrombopoietin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • BTK inhibitors and pharmaceutical compositions comprising the same are also disclosed.
  • Immune thrombocytopenia is a rare autoimmune disease that causes high risk for bleeding, excessive bruising, and fatigue, as well as the potential for life threatening intracranial bleeding due to destruction of platelets. ITP is characterized by immune-mediated (e.g., autoantibody-mediated) platelet destruction and impaired platelet production, resulting in thrombocytopenia, a predisposition to bleeding associated with morbidity and mortality, and an adverse impact on patient quality of life (QOL).
  • immune-mediated e.g., autoantibody-mediated
  • ITP intravenous immunoglobulin
  • corticosteroids intravenous immunoglobulin
  • TPO-RAs thrombopoietin receptor agonists
  • rituximab thrombopoietin receptor agonists
  • MMF mycophenolate mofetil
  • pharmacotherapy e.g., corticosteroids, IVIG, or anti-D immunoglobulin therapy
  • pharmacotherapy is used for symptomatic patients with low platelet counts for reducing platelet destruction. While most patients respond initially to corticosteroids, the rate of continued remission is low.
  • Second line therapies for ITP include rituximab and splenectomy, which are associated with risk of sepsis and immune suppression. Additionally, thrombopoietin (TPO) mimetics (Bussel 2007) are approved for the treatment of patients with chronic ITP who have not had sufficient responses to corticosteroids, IVIG, or splenectomy. [0005] Novel, safe, and effective oral treatments to maintain platelet counts in ITP patients would represent a significant therapeutic advantage over current standard of care.
  • unmet needs in relapsed and refractory ITP include: improving remission rates and durability; avoiding rapid increase of platelet counts/thrombosis risk; steroid-free regimens; and a tolerable and safe therapy that ensures good patient QOL.
  • novel oral therapies for treating ITP including relapsed and refractory ITP, that address some or all of these limitations of existing therapeutic modalities.
  • BTK agammaglobulinemia tyrosine kinase
  • BCR B-cell receptor
  • Fc ⁇ R Fc-gamma receptor
  • Fc ⁇ R Fc- epsilon receptor
  • BTK is a non-receptor tyrosine kinase and a member of the TEC family of kinases. BTK is essential to B cell lineage maturation, and inhibition of BTK activity in cells produces phenotypic changes consistent with blockade of the BCR.
  • BTK inhibition results in the down-regulation of various B-cell activities, including cell proliferation, differentiation, maturation, and survival, and the up-regulation of apoptosis.
  • 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.
  • XLA X-linked agammaglobulinemia
  • 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.
  • 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).
  • a selective BTK inhibitor has the potential to target multiple pathways involved in inflammation and autoimmunity, including, but not limited to: blocking BCR signaling; inhibiting plasma cell differentiation and antibody production; blocking IgG- mediated Fc ⁇ R activation, phagocytosis, and inflammatory mediators in monocytes or macrophages; blocking IgE-mediated Fc ⁇ R activation 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.
  • BTKi BTK inhibitors
  • PCI- 32765 ibrutinib
  • spebrutinib CC-292
  • ibrutinib has provided further clinical validation of the BTK target and was recently approved for human use in mantle cell lymphoma, Waldenström’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 2013, Imbruvica 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).
  • 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).
  • BTKi covalent BTKi
  • ibrutinib and acalabrutinib improved on the selectivity issues that plagued many first-generation kinase inhibitors
  • these inhibitors are typically 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).
  • 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.
  • Rilzabrutinib is a novel, highly selective, and potent small molecule inhibitor of non-T cell white blood cell signaling via B-cell receptor, Fc ⁇ R, and/or Fc ⁇ R signaling of the BTK pathway.
  • rilzabrutinib has the potential to (1) inhibit B cell activation and (2) interrupt antibody-coated cell phagocytosis by FC ⁇ R in the spleen and liver (Bradshaw et al.2021, Langrish et al.2021, Owens et al.2022).
  • Rilzabrutinib functions as a reversible covalent BTK inhibitor and is capable of both non-covalently and covalently binding to 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).
  • 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.
  • Rilzabrutinib’s IC50 values were 1.3 nM for BTK, 0.8 nM for tyrosine protein kinase TEC, 1.0 nM for bone marrow tyrosine kinase on chromosome X (BMX), 1.2 nM for receptor-like kinase (RLK), 6.3 nM for B cell lymphocyte kinase (BLK), and 11 nM for ERBB4. Further preclinical assays with rilzabrutinib showed that binding to BTK persisted while that for other TEC family members decayed rapidly over time. [0016] Rilzabrutinib has shown encouraging results for the treatment of immune- mediated diseases.
  • rilzabrutinib is rapidly absorbed following oral administration, with a fast half-life (3-4 h) and variable pharmacokinetics (Smith PF et al., 2017).
  • target BTK occupancy levels were safely and consistently exceeded, suggesting rilzabrutinib may be highly effective in treating autoimmune diseases.
  • 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 hours) (Smith PF et al., 2015).
  • rilzabrutinib demonstrated blockade of the rat Arthus reaction, full disease reversal in a rat collagen-induced arthritis model, and reduction in platelet loss in a mouse model of immune thrombocytopenia.
  • the therapeutic effects of rilzabrutinib in pemphigus was studied in dogs with newly diagnosed, naturally occurring pemphigus foliaceus (PF).
  • rilzabrutinib The drug safely controlled disease without the need for corticosteroid (CS) in 4 of 4 cases.
  • the clinical efficacy of rilzabrutinib was further demonstrated in an open-label, Phase 1/2 study in immune thrombocytopenic purpura (ITP). In this trial, 40% of participants achieved the primary response endpoint after treatment with rilzabrutinib for at least 12 weeks. Furthermore, there were no related treatment-emergent serious adverse events (TESAEs) observed. Collectively, these and other studies have shown rilzabrutinib to be a safe and effective inhibitor of BTK.
  • rilzabrutinib demonstrates a significant dose dependent reduction of platelet-loss (consumption) in a mouse model of ITP.
  • ITP platelet-loss
  • CBB Cogstate Brief Battery
  • ITP immune thrombocytopenia
  • a therapeutically effective amount of rilzabrutinib wherein the patient in need thereof has at least one characteristic chosen from: a Z-score of ⁇ -1 on the Cogstate Brief Battery (CBB) detection test (DET) relative to age-matched normative data; a Z-score of ⁇ -1 on the CBB identification test (IDN) relative to age-matched normative data; a Z-score of ⁇ -1 for composite DET and IDN scores relative to age-matched normative data; a Z-score of ⁇ -1 on the CBB one card learning test (OCL) relative to age-matched normative data; a Z-score of ⁇ -1 on the CBB one back test (ONB) relative to age-matched normative data; and a Z-score of ⁇ -1 for composite OCL and ONB scores relative to age-
  • Also disclosed herein are methods of treating immune thrombocytopenia (ITP) in a patient in need thereof comprising administering to the patient in need thereof a therapeutically effective amount of rilzabrutinib, wherein the patient in need thereof has at least two characteristics chosen from: a Z-score of ⁇ -1 on the Cogstate Brief Battery (CBB) detection test (DET) relative to age-matched normative data; a Z-score of ⁇ -1 on the CBB identification test (IDN) relative to age-matched normative data; a Z-score of ⁇ -1 for composite DET and IDN scores relative to age-matched normative data; a Z-score of ⁇ -1 on the CBB one card learning test (OCL) relative to age-matched normative data; a Z-score of ⁇ -1 on the CBB one back test (ONB) relative to age-matched normative data; and a Z-score of ⁇ -1 for composite OCL and ONB scores relative to age-matched normative data
  • Fig.1 shows the number of patients initiating rilzabrutinib at each dose, the number of patients who completed the main study, and the number of patients who entered the long-term extension.
  • Fig.2 shows a summary of intrapatient dose-escalation levels with rilzabrutinib.
  • Fig.8 shows rilzabrutinib dose and platelet response over time.
  • Fig.9 shows the percentage of patients in each subgroup who achieved ⁇ 2 consecutive platelet counts, separated by at least 5 days, of ⁇ 50,000/ ⁇ L, and increased ⁇ 20,000/ ⁇ L from baseline, without requiring rescue medication in the 4 weeks prior to the latest elevated platelet count.
  • Fig.10 shows a summary of Z-scores for ITP patients evaluated using the Cogstate Brief Battery (CBB). Z-scores of ⁇ -1 (the double line) were categorized as having an impairment.
  • Fig.11 shows the percentage of ITP patients exhibiting each degree of clinically important cognitive impairment on each of the individual and composite tests of the Cogstate Brief Battery (CBB).
  • Fig.12 shows the percentage of ITP patients exhibiting psychomotor function/attention, learning/memory, or clinically important cognitive impairment.
  • Fig.13A shows the percentage of ITP patients exhibiting psychomotor function/attention or learning/memory cognitive impairment.
  • Fig.13B shows mean Z-scores for psychomotor function/attention and learning/memory in ITP patients.
  • Figs.13C and D show the mean difference between demographic and clinical characteristic factors for clinical impairment (Z-score of ⁇ -1) in (C) the psychomotor function/attention composite score and (D) the learning/working memory composite score.
  • Group 1 refers to the left subgroup and Group 2 refers to the right subgroup listed in parentheses for each characteristic. Analyses were based on two-sample t-test assuming unequal variances. Note: Only 1 patient had a stroke/central nervous system bleeding, so this category was excluded.
  • CI confidence interval
  • CS corticosteroids
  • ITP immune thrombocytopenia
  • TPO-RA thrombopoietin receptor agonist
  • the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably 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 below 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.
  • the term “active pharmaceutical ingredient” or “therapeutic agent” (“API”) refers to a biologically active compound.
  • the term “approved treatment” refers to a medication that has received regulatory authorization, in any country, for its intended use.
  • 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.
  • “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 self- administration and administration by another.
  • the terms “baseline platelet count” or “baseline” refer to an average platelet count obtained by determining the mean of two platelet counts taken on two occasions no less than 7 days apart in the 15 days prior to beginning treatment and a third count taken on the first day of the study. If any of these three counts is missing, the “baseline platelet count” or “baseline” is the average of the other counts.
  • “BID” and “bid” are used interchangeably to refer to twice a day.
  • CBB Cognitive impairment
  • IDN the identification test
  • OCL the one card learning test
  • ONB working memory
  • ITP immune thrombocytopenia
  • ITP encompasses or at least also refers to other terms commonly used such as idiopathic thrombocytopenia and idiopathic thrombocytopenic purpura.
  • ITP acute (short term), persistent, and chronic (long term). Acute ITP lasts less than three months, persistent ITP lasts 3-12 months, and chronic ITP lasts for at least one year.
  • 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.
  • an amount expressed in terms of “mg of [X]” refers to the total amount in milligrams of [X], i.e., the free base.
  • 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 weight of free base therein.
  • “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.
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, and neither biologically nor otherwise undesirable, such as, e.g., a carrier or an excipient that is acceptable for mammalian pharmaceutical use.
  • 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic
  • 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.
  • An 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 impurity in less than about 1% by weight.
  • rilzabrutinib or a pharmaceutically acceptable salt thereof may also be referred to herein as a “drug,” “active agent,” “a therapeutically active agent,” or “API.”
  • QD and “qd” are used interchangeably to refer to once a day.
  • the term “therapeutically effective amount” refers to that an of a compound that produces the desired effect for which it is administered (e.g., improvement in ITP or a symptom of ITP, or lessening the severity of ITP or a symptom of ITP).
  • 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.
  • Some embodiments of the present disclosure relate to methods of treating immune thrombocytopenia (ITP) in a patient in need thereof comprising administering to the patient in need thereof a therapeutically effective amount of rilzabrutinib, wherein the patient in need thereof has at least one characteristic chosen from: a Z-score of ⁇ -1 on the Cogstate Brief Battery (CBB) detection test (DET) relative to age-matched normative data; a Z-score of ⁇ -1 on the CBB identification test (IDN) relative to age-matched normative data; a Z- score of ⁇ -1 for composite DET and IDN scores relative to age-matched normative data; a Z- score of ⁇ -1 on the CBB one card learning test (OCL) relative to age-matched normative data; a Z-score of ⁇ -1 on the CBB one back test (ONB) relative to age-matched normative data; and a Z-score of ⁇ -1 for composite OCL and ONB scores relative to age-matched norm
  • the patient has a Z-score of ⁇ -1 on the DET relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -2 on the DET relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -3 on the DET relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -1 on the IDN relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -2 on the IDN relative to age-matched normative data.
  • the patient has a Z-score of ⁇ -3 on the IDN relative to age- matched normative data. In some embodiments, the patient has a Z-score of ⁇ -1 for composite DET and IDN relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -2 for composite DET and IDN relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -3 for composite DET and IDN relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -1 on the OCL relative to age-matched normative data.
  • the patient has a Z-score of ⁇ -2 on the OCL relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -3 on the OCL relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -1 on the ONB relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -2 on the ONB relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -3 on the ONB relative to age-matched normative data.
  • the patient has a Z- score of ⁇ -1 for composite OCL and ONB relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -2 for composite OCL and ONB relative to age- matched normative data. In some embodiments, the patient has a Z-score of ⁇ -3 for composite OCL and ONB relative to age-matched normative data. [0061] In some embodiments, the patient has a platelet count of ⁇ 33,000/ ⁇ L on two occasions no less than 7 days apart in the 15 days prior to beginning study treatment.
  • the patient has a history of response (two or more platelet counts ⁇ 50,000/ ⁇ L with an increase of ⁇ 20,000/ ⁇ L) to at least one prior line of therapy.
  • at least one prior line of therapy is chosen from a splenectomy, intravenous immunoglobin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressive drugs.
  • IVIG intravenous immunoglobin
  • the patient achieves at least one platelet count of at least 20,000/ ⁇ L above a baseline platelet count, wherein the baseline platelet count is the mean of two platelet counts taken on two occasions no less than 7 days apart in the 15 days prior to beginning treatment and a third count taken on the first day of the study.
  • the patient achieves at least two platelet counts of at least 20,000/ ⁇ L above the baseline platelet count. In some embodiments, the patient achieves at least two consecutive platelet counts of at least 20,000/ ⁇ L above the baseline platelet count, for example at least 30,000/ ⁇ L above the baseline platelet count. [0064] In some embodiments, the at least two consecutive platelet counts of at least 20,000/ ⁇ L above the baseline platelet count are separated by at least five days, for example at least seven days. In some embodiments, at least two consecutive platelet counts of at least 20,000/ ⁇ L above the baseline platelet count are separated by at least five days. In some embodiments, at least two consecutive platelet counts of at least 20,000/ ⁇ L above the baseline platelet count are separated by at least seven days.
  • the patient achieves a platelet count of at least 50,000/ ⁇ L. In some embodiments, the patient achieves at least two platelet counts of at least 50,000/ ⁇ L. In some embodiments, the patient achieves at least two consecutive platelet counts of at least 50,000/ ⁇ L. [0066] In some embodiments, the at least two consecutive platelet counts of at least 50,000/ ⁇ L are separated by at least five days, for example at least seven days. In some embodiments, the at least two consecutive platelet counts of at least 50,000/ ⁇ L are separated by at least five days. In some embodiments, the at least two consecutive platelet counts of at least 50,000/ ⁇ L are separated by at least seven days.
  • the patient achieves at least one platelet count of at least 50,000/ ⁇ L within eight days of initiating treatment. [0068] In some embodiments, the patient does not receive rescue medication during the four weeks prior to the most recent platelet count of at least 50,000/ ⁇ L. [0069] In some embodiments, the patient has had ITP for less than a year. In some embodiments, the patient has had ITP for one or more years. In some embodiments, the patient has had ITP for two or more years. In some embodiments, the patient has had ITP for three or more years. In some embodiments, the patient has had ITP for one or more years. In some embodiments, the patient has had ITP for four or more years.
  • the patient has had ITP for one or more years. In some embodiments, the patient has had ITP for five or more years. In some embodiments, the patient has had ITP for one or more years. In some embodiments, the patient has had ITP for six or more years. In some embodiments, the patient has had ITP for one or more years. In some embodiments, the patient has had ITP for seven or more years. In some embodiments, the patient has had ITP for one or more years. In some embodiments, the patient has had ITP for eight or more years. In some embodiments, the patient has had ITP for one or more years. In some embodiments, the patient has had ITP for nine or more years. [0070] In some embodiments, the patient has had ITP for more than one decade.
  • the patient has had ITP for more than two decades. In some embodiments, the patient has had ITP for more than three decades. In some embodiments, the patient has had ITP for more than four decades. In some embodiments, the patient has had ITP for more than five decades. [0071] In some embodiments, the patient has a history of taking at least one prior ITP therapy prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least two prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least three prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least four prior ITP therapies prior to the start of the treatment period.
  • the patient has a history of taking at least five prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least six prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least seven prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least eight prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least nine prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least ten prior ITP therapies prior to the start of the treatment period.
  • the patient has a history of taking at least 11 prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least 12 prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least 13 prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least 14 prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least 15 prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least 16 prior ITP therapies prior to the start of the treatment period.
  • the patient has a history of taking at least 17 prior ITP therapies prior to the start of the treatment period.
  • the patient has platelet counts between 2,000/ ⁇ L and 33,000/ ⁇ L on two occasions no less than 7 days apart and within 15 days prior to the start of the treatment period.
  • the patient has platelet counts ⁇ 15,000/ ⁇ L on two occasions no less than 7 days apart and within 15 days prior to the start of the treatment period.
  • the patient in need thereof has platelet counts >15,000/ ⁇ L on two occasions no less than 7 days apart and within 15 days prior to the start of the treatment period.
  • the patient has a history of response to at least one prior line of therapy, wherein at least one prior therapy is chosen from a splenectomy, intravenous immunoglobin (IVIG), corticosteroids, anti-D immunoglobulin therapy, immunosuppressive drugs, thrombopoietic receptor agonists (TPO-RAs), and rituximab.
  • IVIG intravenous immunoglobin
  • corticosteroids corticosteroids
  • anti-D immunoglobulin therapy immunosuppressive drugs
  • TPO-RAs thrombopoietic receptor agonists
  • rituximab rituximab.
  • the patient has a history of response to splenectomy.
  • the patient has a history of response to IVIG.
  • the patient has a history of response to corticosteroids.
  • the patient has a history of response to anti-D immunoglobulin therapy.
  • the patient has a history of response to immunosuppressive drugs. In some embodiments, the patient has a history of response to TPO-RAs. In some embodiments, the patient has a history of response to rituximab. [0074] In some embodiments, the patient had a splenectomy prior to the start of the treatment period. In some embodiments, the patient has a history of taking intravenous immunoglobin (IVIG) prior to the start of the treatment period. In some embodiments, the patient has a history of taking corticosteroids prior to the start of the treatment period. In some embodiments, the patient has a history of taking anti-D immunoglobulin therapy prior to the start of the treatment period.
  • IVIG intravenous immunoglobin
  • the patient has a history of taking at least one immunosuppressive drug prior to the start of the treatment period.
  • the patient has a history of taking at least one immunosuppressive drug is selected from fostamatinib, mycophenolate mofetil (MMF), and cyclosporine.
  • the patient has a history of taking fostamatinib prior to the start of the treatment period.
  • the patient has a history of taking MMF prior to the start of the treatment period.
  • the patient has a history of taking cyclosporine prior to the start of the treatment period.
  • the patient has a history of taking at least one TPO-RA prior to the start of the treatment period.
  • the patient has a history of taking at least one TPO-RA selected from recombinant TPO (rTPO), romiplostim, eltrombopag, and avatrombopag. In some embodiments, the patient has a history of taking rituximab prior to the start of the treatment period.
  • the response to the prior ITP therapy comprised a platelet count of ⁇ 50,000/ ⁇ L.
  • the patient in need thereof receives treatment with at least one TPO-RA.
  • the patient in need thereof receives treatment with at least one TPO-RA selected from rTPO, romiplostim, eltrombopag, and avatrombopag.
  • the patient has primary ITP. In some embodiments, the patient has secondary ITP. In some embodiments, the patient does not have chronic ITP. In some embodiments, the patient has persistent ITP. In some embodiments, the patient has chronic ITP. In some embodiments, the patient has relapsing ITP. In some embodiments, the patient has refractory ITP.
  • the treatment period is at least 8 days. In some embodiments, the treatment period is at least 28 days.
  • the treatment period is at least 84 days. In some embodiments, the treatment period is at least 169 days. [0079] In some embodiments, the method comprises 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-1-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.
  • 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-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof.
  • 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-1- yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof.
  • the at least one compound consists of a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-1-yl]pent-2-enenitrile or a pharmaceutically acceptable salt of the foregoing.
  • the method comprises administering to the patient 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile twice a day.
  • the method comprises administering to the patient the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.
  • the method comprises administering to the patient the (Z) isomer of (R)- 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.
  • the method comprises administering to the patient a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.
  • the at least one compound is orally administered to the patient.
  • the at least one compound is administered to the patient in the form of at least one tablet.
  • the at least one compound is administered with water.
  • Also disclosed herein are methods of treating immune thrombocytopenia (ITP) in a patient in need thereof comprising administering to the patient in need thereof a therapeutically effective amount of rilzabrutinib, wherein the patient in need thereof has at least two characteristics chosen from: a Z-score of ⁇ -1 on the Cogstate Brief Battery (CBB) detection test (DET) relative to age-matched normative data; a Z-score of ⁇ -1 on the CBB identification test (IDN) relative to age-matched normative data; a Z-score of ⁇ -1 for composite DET and IDN scores relative to age-matched normative data; a Z-score of ⁇ -1 on the CBB one card learning test (OCL) relative to age-matched normative data; a Z-score of ⁇ -1 on the CBB one back test (ONB) relative to age-matched normative data; and a Z-score of ⁇ -1 for composite OCL and ONB scores relative to age-matched normative data
  • the patient has at least two characteristics chosen from the following: a Z-score of ⁇ -1 on the DET test relative to age-matched normative data; a Z- score of ⁇ -1 on the IDN test relative to age-matched normative data; a Z-score of ⁇ -1 for composite DET and IDN scores relative to age-matched normative data; a Z-score of ⁇ -1 on the OCL test relative to age-matched normative data; a Z-score of ⁇ -1 on the ONB test relative to age-matched normative data; and a Z-score of ⁇ -1 for composite OCL and ONB scores relative to age-matched normative data.
  • the patient has a Z-score of ⁇ -1 on the DET relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -2 on the DET relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -3 on the DET relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -1 on the IDN relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -2 on the IDN relative to age-matched normative data.
  • the patient has a Z-score of ⁇ -3 on the IDN relative to age- matched normative data. In some embodiments, the patient has a Z-score of ⁇ -1 for composite DET and IDN relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -2 for composite DET and IDN relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -3 for composite DET and IDN relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -1 on the OCL relative to age-matched normative data.
  • the patient has a Z-score of ⁇ -2 on the OCL relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -3 on the OCL relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -1 on the ONB relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -2 on the ONB relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -3 on the ONB relative to age-matched normative data.
  • the patient has a Z- score of ⁇ -1 for composite OCL and ONB relative to age-matched normative data. In some embodiments, the patient has a Z-score of ⁇ -2 for composite OCL and ONB relative to age- matched normative data. In some embodiments, the patient has a Z-score of ⁇ -3 for composite OCL and ONB relative to age-matched normative data. [0086] In some embodiments, the patient has a platelet count of ⁇ 33,000/ ⁇ L on two occasions no less than 7 days apart in the 15 days prior to beginning study treatment.
  • the patient has a history of response (two or more platelet counts ⁇ 50,000/ ⁇ L with an increase of ⁇ 20,000/ ⁇ L) to at least one prior line of therapy.
  • at least one prior line of therapy is chosen from a splenectomy, intravenous immunoglobin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressive drugs.
  • IVIG intravenous immunoglobin
  • the patient achieves at least one platelet count of at least 20,000/ ⁇ L above a baseline platelet count, wherein the baseline platelet count is the mean of two platelet counts taken on two occasions no less than 7 days apart in the 15 days prior to beginning treatment and a third count taken on the first day of the study.
  • the patient achieves at least two platelet counts of at least 20,000/ ⁇ L above the baseline platelet count. In some embodiments, the patient achieves at least two consecutive platelet counts of at least 20,000/ ⁇ L above the baseline platelet count, for example at least 30,000/ ⁇ L above the baseline platelet count. [0089] In some embodiments, the at least two consecutive platelet counts of at least 20,000/ ⁇ L above the baseline platelet count are separated by at least five days, for example at least seven days. In some embodiments, at least two consecutive platelet counts of at least 20,000/ ⁇ L above the baseline platelet count are separated by at least five days. In some embodiments, at least two consecutive platelet counts of at least 20,000/ ⁇ L above the baseline platelet count are separated by at least seven days.
  • the patient achieves a platelet count of at least 50,000/ ⁇ L. In some embodiments, the patient achieves at least two platelet counts of at least 50,000/ ⁇ L. In some embodiments, the patient achieves at least two consecutive platelet counts of at least 50,000/ ⁇ L. [0091] In some embodiments, the at least two consecutive platelet counts of at least 50,000/ ⁇ L are separated by at least five days, for example at least seven days. In some embodiments, the at least two consecutive platelet counts of at least 50,000/ ⁇ L are separated by at least five days. In some embodiments, the at least two consecutive platelet counts of at least 50,000/ ⁇ L are separated by at least seven days.
  • the patient achieves at least one platelet count of at least 50,000/ ⁇ L within eight days of initiating treatment. [0093] In some embodiments, the patient does not receive rescue medication during the four weeks prior to the most recent platelet count of at least 50,000/ ⁇ L. [0094] In some embodiments, the patient has had ITP for less than a year. In some embodiments, the patient has had ITP for one or more years. In some embodiments, the patient has had ITP for two or more years. In some embodiments, the patient has had ITP for three or more years. In some embodiments, the patient has had ITP for one or more years. In some embodiments, the patient has had ITP for four or more years.
  • the patient has had ITP for one or more years. In some embodiments, the patient has had ITP for five or more years. In some embodiments, the patient has had ITP for one or more years. In some embodiments, the patient has had ITP for six or more years. In some embodiments, the patient has had ITP for one or more years. In some embodiments, the patient has had ITP for seven or more years. In some embodiments, the patient has had ITP for one or more years. In some embodiments, the patient has had ITP for eight or more years. In some embodiments, the patient has had ITP for one or more years. In some embodiments, the patient has had ITP for nine or more years. [0095] In some embodiments, the patient has had ITP for more than one decade.
  • the patient has had ITP for more than two decades. In some embodiments, the patient has had ITP for more than three decades. In some embodiments, the patient has had ITP for more than four decades. In some embodiments, the patient has had ITP for more than five decades. [0096] In some embodiments, the patient has a history of taking at least one prior ITP therapy prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least two prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least three prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least four prior ITP therapies prior to the start of the treatment period.
  • the patient has a history of taking at least five prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least six prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least seven prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least eight prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least nine prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least ten prior ITP therapies prior to the start of the treatment period.
  • the patient has a history of taking at least 11 prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least 12 prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least 13 prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least 14 prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least 15 prior ITP therapies prior to the start of the treatment period. In some embodiments, the patient has a history of taking at least 16 prior ITP therapies prior to the start of the treatment period.
  • the patient has a history of taking at least 17 prior ITP therapies prior to the start of the treatment period.
  • the patient has platelet counts between 2,000/ ⁇ L and 33,000/ ⁇ L on two occasions no less than 7 days apart and within 15 days prior to the start of the treatment period.
  • the patient has platelet counts ⁇ 15,000/ ⁇ L on two occasions no less than 7 days apart and within 15 days prior to the start of the treatment period.
  • the patient in need thereof has platelet counts >15,000/ ⁇ L on two occasions no less than 7 days apart and within 15 days prior to the start of the treatment period.
  • the patient has a history of response to at least one prior line of therapy, wherein at least one prior therapy is chosen from a splenectomy, intravenous immunoglobin (IVIG), corticosteroids, anti-D immunoglobulin therapy, immunosuppressive drugs, thrombopoietic receptor agonists (TPO-RAs), and rituximab.
  • IVIG intravenous immunoglobin
  • corticosteroids corticosteroids
  • anti-D immunoglobulin therapy immunosuppressive drugs
  • TPO-RAs thrombopoietic receptor agonists
  • rituximab rituximab.
  • the patient has a history of response to splenectomy.
  • the patient has a history of response to IVIG.
  • the patient has a history of response to corticosteroids.
  • the patient has a history of response to anti-D immunoglobulin therapy.
  • the patient has a history of response to immunosuppressive drugs. In some embodiments, the patient has a history of response to TPO-RAs. In some embodiments, the patient has a history of response to rituximab. [0099] In some embodiments, the patient had a splenectomy prior to the start of the treatment period. In some embodiments, the patient has a history of taking intravenous immunoglobin (IVIG) prior to the start of the treatment period. In some embodiments, the patient has a history of taking corticosteroids prior to the start of the treatment period. In some embodiments, the patient has a history of taking anti-D immunoglobulin therapy prior to the start of the treatment period.
  • IVIG intravenous immunoglobin
  • the patient has a history of taking at least one immunosuppressive drug prior to the start of the treatment period.
  • the patient has a history of taking at least one immunosuppressive drug is selected from fostamatinib, mycophenolate mofetil (MMF), and cyclosporine.
  • the patient has a history of taking fostamatinib prior to the start of the treatment period.
  • the patient has a history of taking MMF prior to the start of the treatment period.
  • the patient has a history of taking cyclosporine prior to the start of the treatment period.
  • the patient has a history of taking at least one TPO-RA prior to the start of the treatment period.
  • the patient has a history of taking at least one TPO-RA selected from recombinant TPO (rTPO), romiplostim, eltrombopag, and avatrombopag. In some embodiments, the patient has a history of taking rituximab prior to the start of the treatment period.
  • the response to the prior ITP therapy comprised a platelet count of ⁇ 50,000/ ⁇ L.
  • the patient has primary ITP. In some embodiments, the patient has secondary ITP. In some embodiments, the patient does not have chronic ITP. In some embodiments, the patient has persistent ITP. In some embodiments, the patient has chronic ITP.
  • the patient has relapsing ITP. In some embodiments, the patient has refractory ITP. [0102] In some embodiments, the treatment period is at least 8 days. In some embodiments, the treatment period is at least 28 days. In some embodiments, the treatment period is at least 84 days. In some embodiments, the treatment period is at least 169 days.
  • the method comprises 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-1-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.
  • 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-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof.
  • 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-1- yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile and pharmaceutically acceptable salts thereof.
  • the at least one compound consists of a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-1-yl]pent-2-enenitrile or a pharmaceutically acceptable salt of the foregoing.
  • the method comprises administering to the patient 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile twice a day.
  • the method comprises administering to the patient the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.
  • the method comprises administering to the patient the (Z) isomer of (R)- 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.
  • the method comprises administering to the patient a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.
  • the at least one compound is orally administered to the patient.
  • the at least one compound is administered to the patient in the form of at least one tablet.
  • the at least one compound is administered with water.
  • 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.
  • the pharmaceutical composition is in the form of at least one tablet.
  • 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.
  • the pharmaceutical composition is in the form of at least one tablet.
  • rilzabrutinib is administered in the form of a film- coated tablet.
  • 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.
  • 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.
  • rilzabrutinib is administered with a glass of water.
  • 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 incompatible with 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.
  • 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., corn 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, corn oil, and soybean oil; (10) glycols, such as, e.g., propylene glycol; (11) polyols, such as, e.g., glycerin, sorbitol,
  • rilzabrutinib has been well-tolerated in ITP patients, with no reported treatment-related bleeding or thrombotic events. Moreover, positive preliminary results have been observed in a highly treatment-resistant and refractory patient population.
  • the key inclusion criteria for the phase 1/2 study are: adults aged 18-80 years old with relapsed/refractory ITP; ITP primary or secondary to other diseases (e.g., systemic lupus erythematosus, chronic lymphocytic leukemia); no other available/approved treatment options; ⁇ 2 platelet counts ⁇ 30,000/ ⁇ L at study entry 1 ; and adequate hematologic, hepatic, and renal function.
  • Enrolled patients have low platelet counts, having relapsed on or been refractory to prior therapies with no available and approved therapeutic options and may continue corticosteroids and/or thrombopoietin mimetics during the study. For example, stable concomitant corticosteroid (CS) or thrombopoietin receptor agonist (TPO-RA) treatment is permitted during the study.
  • CS corticosteroid
  • TPO-RA thrombopoietin receptor agonist
  • the margin of error for platelet counts can be, for example, ⁇ 3,000/ ⁇ L, depending on the equipment and methods used by the central lab. Therefore, a platelet count of 33,000/ ⁇ L would be considered a protocol deviation but may not automatically disqualify a patient from the study.
  • Participants [0120] Eligible immune thrombocytopenia patients were aged 18-80 years (upper age 65 years in Norway/Czech Republic) and platelet counts of ⁇ 30 ⁇ 10 9 /L on 2 occasions no less than 7 days apart within 15 days prior to study entry. Patients were required to respond to ⁇ 1 prior immune thrombocytopenia therapy (including splenectomy), but at baseline were unable to maintain response to prior/concomitant therapy.
  • Inclusion Criteria [0121] The following inclusion criteria were used to inform the enrollment of patients in the phase 1/2 study, including, e.g., the dose escalation study. 1. Male and female patients, aged 18 to 80 years old (Czech Republic and Norway only: aged 18 to 65 years old) 2. Immune-related ITP (both primary and secondary) 3. Refractory or relapsed patients with no available and approved therapeutic options with a platelet count of count ⁇ 30,000/ ⁇ L on two occasions no less than 7 days apart in the 15 days prior to beginning study treatment 4. A history of response (two or more platelet counts ⁇ 50,000/ ⁇ L with an increase of ⁇ 20,000/ ⁇ L) to at least one prior line of therapy (with splenectomy being considered a line of therapy) 5.
  • Adequate hematologic, hepatic, and renal function (absolute neutrophil count ⁇ 1.5 X 10 9 /L, Hgb > 9 g/dL, AST/ALT ⁇ 1.5 x ULN, albumin ⁇ 3 g/dL, total bilirubin ⁇ 1.5 x ULN, estimated GFR > 60 (Cockcroft and Gault method) (C1D1 pre dose may be checked up to Day -3 prior to C1D1) 6.
  • Female patients who are of reproductive potential must agree for the duration of active treatment in the study to use a highly effective means of contraception (hormonal contraception methods that inhibits ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized partner, sexual abstinence). Unless surgically sterile, postmenopausal females should have menopause confirmed by FSH testing. 7. Able to provide written informed consent and agreeable to the schedule of assessment [0122] Additionally, participants could not commence enrollment procedures until all entry criteria had been fulfilled. Where the clinical significance of an abnormal screening test result (lab or any other tests) was uncertain, the test may have been repeated.
  • Exclusion Criteria [0123] The following exclusion criteria were used to inform the enrollment of patients in the phase 1/2 study, including, e.g., the dose escalation study. 1. Pregnant or lactating women 2. ECG findings of QTcF > 450 msec (males) or > 470 msec (females), poorly controlled atrial fibrillation (i.e., symptomatic patients or a ventricular rate above 100 beats/min on ECG), or other clinically significant abnormalities 3. History or current, active malignancy requiring or likely to require chemotherapeutic or surgical treatment during the trial, with the exception of non-melanoma skin cancer 4. Transfusion with blood or blood products or plasmapheresis within 2 weeks before Day 1 5.
  • CYP3A-sensitive substrate drugs with a narrow therapeutic index within 3 days or 5 half-lives (whichever is longer) of study drug dosing including, but not limited to, alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or terfenadine 12.
  • hepatitis B surface and core antibodies unrelated to vaccination
  • hepatitis C anti-HCV antibody confirmed with Hep C RNA
  • Trial Design This was a global phase 1-2 adaptive, open-label, dose-finding study of oral rilzabrutinib (Principia Biopharma Inc, a Sanofi Company, South San Francisco, CA) in 8 countries (NCT03395210; EudraCT 2017-004012-19).
  • Rilzabrutinib was administered with intrapatient dose-escalation utilizing a 3+3 design ( Figure 1).
  • Initial doses could be 200 mg once daily (qd), 400 mg qd, 300 mg twice daily (bid; 600 mg/day), or 400 mg bid (800 mg/day; maximum).
  • Urinalysis pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrites, urobilinogen and leukocytes measured by dip stick or local requirement 2. Hepatitis B and C, HIV 3. Pregnancy test for women of childbearing potential only. Serum pregnancy tests at screening, urine pregnancy tests at other visits 4. FSH: To confirm postmenopausal status for women who are not surgically sterile and of reproductive potential 5. ABO and Rh blood type 6. Immature Platelet Fraction and Mean Platelet Volume (where available at local lab) 7.
  • Serum chemistry Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Total, direct, and indirect bilirubin levels, Alkaline phosphatase (ALP), Albumin, Creatinine, Urea, Total Protein, Sodium, Chloride, Calcium, Phosphate, Potassium, Glucose (random), and creatine phosphokinase (CPK) 8.
  • PT/INR PTT 11.
  • TPO levels Hemolysis panel consisting of Coombs test, haptoglobin levels 13. Platelet autoantibody panel (Australia Only: test excluded) 14. PK sampling at various times 15.
  • Hematologic DLTs included absolute neutrophil counts (ANCs) of ⁇ 500/ ⁇ L for ⁇ 5 days; grade 3 or higher decreased hemoglobin in the absence of a pre-existing grade 2 decreased hemoglobin; febrile neutropenia, with absolute ANC ⁇ 1000/mm 3 and single temperature >38.3°C or a sustained temperature of ⁇ 38°C for more than 1 h; or grade ⁇ 3 or higher bleeding event requiring platelet transfusion.
  • ANCs absolute neutrophil counts
  • Non-hematologic DLTs included any grade ⁇ 3 non-hematologic toxicity per the NCI CTCAE, version 4.0, with the following exceptions: fatigue; laboratory TEAEs, nausea, vomiting, diarrhea, or systemic reactions (such as fever, headache) that returned to baseline or grade 1 within 7 days; or any toxicity that, at the discretion of the investigator warranted withholding the study drug for >7 days.
  • Rescue medication intravenous immunoglobulin (IVIG), high-dose corticosteroids, platelet infusion or anti-D immunoglobulin infusion
  • IVIG intravenous immunoglobulin
  • rilzabrutinib tablets are packaged in white high-density polyethylene (HDPE) bottles with child-resistant induction-sealed caps; these bottles are intended to be stored at 2–8 °C and can be transported without ice at room temperature. Additionally, the bottles can be kept at room temperature conditions for up to 2 weeks.
  • Analysis Populations [0134] The Screening Population for this study included all participants who provided informed consent and had screening assessments evaluated for study participation. [0135] The Safety Population included all participants who received at least one dose of rilzabrutinib. The Safety Population was used for all safety analyses.
  • the Intent-to-Treat Exposed (ITT-E) Population included all participants who received at least one dose of rilzabrutinib.
  • the Pharmacokinetic Analysis Population included all participants who received at least one dose of rilzabrutinib and had at least one plasma concentration value that was included in the PK analysis. The Pharmacokinetic Analysis Population was used for all PK analyses.
  • IDSM Independent Data Safety Monitor
  • SMC Safety Monitoring Committee
  • CA Competent Authority
  • IRB/EC IRB/EC
  • the IDSM could determine that a starting dose for new patients should be dropped for futility (lack of platelet response), increased to the next planned dosing level, kept the same, or reduced.
  • New patients entering the study commenced at the dose level determined by the IDSM based on: (1) if ⁇ 2/3 or ⁇ 2/6 of those sentinel patients have a DLT at any dose level, that level was determined to be the “Maximally Administered Dose” and starting doses (new patients) and continuing doses (patients already on study) were set at lower dosing levels (or study suspended if the current sentinel dose cohort was 200 mg QD); (2) if two or more sustained platelet responses (3 of 4 counts) in the sentinel patients were seen at the current starting dose level the starting dose would not be escalated.
  • the AE Collection Period began at the time of the first screening/eligibility assessment and will end at the end of the study for each patient.
  • An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with the intervention.
  • An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of an investigational product, whether or not considered related to the product.
  • Investigators were instructed to record all AEs encountered during the clinical study in detail from the date of participant consent throughout the study follow-up period. Pre- existing conditions that worsened during a study were reported as AEs.
  • laboratory and ECG abnormalities accompanied by clinical symptoms, leading to a change in study drug (e.g., dose modification, interruption or permanent discontinuation), or requiring a change in concomitant therapy (e.g., addition of, interruption of, discontinuation of, or any other change in a concomitant medication, therapy or treatment) should have been recorded as an AE, with any laboratory or ECG result abnormality fulfilling the criteria for a serious adverse event (SAE) reported as such, in addition to being recorded as an AE.
  • SAE serious adverse event
  • Adverse Event Intensity Grading [0146] Investigators were instructed to report all clinical AEs encountered during the study. The intensity of AEs is graded based on the NCI CTCAE, Version 4.0 or higher.
  • Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
  • Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living.
  • Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living.
  • SAE serious adverse event
  • An SAE must have fulfilled at least one of the following criteria at any dose level: was fatal (results in the outcome death); was life-threatening; required in-patient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; or was medically significant or requires intervention to prevent one or other of the outcomes listed above.
  • Investigators were instructed to report life-threatening events or any event with an outcome of death should be reported as an SAE.
  • Pregnancy [0151] Any female clinical trial participant who became pregnant during the study was to be instructed to stop taking the study drug and immediately inform the Investigator. Pregnancies occurring up to 90 days after the completion of the study drug were also to be reported to the Investigator.
  • ECG recordings were performed using a standard high- quality, high-fidelity digital electrocardiograph machine equipped with computer-based interval measurements. For triplicate ECG assessments, at least three interpretable ECG recordings (without artifacts) were collected per time point within a ⁇ 10 minute period per time point.
  • Laboratory Test Procedures [0157] Laboratory assessments were performed at a central laboratory, with the provision for occasional local laboratory testing, if required. Laboratory safety tests were collected at specific time points. Additional blood or urine samples may have been taken at an investigator’s discretion if the results of any test fell outside the reference ranges, or clinical symptoms necessitated additional testing to monitor participant safety. Where the clinical significance of abnormal lab results was considered uncertain, screening lab tests may have been repeated before Day 1 to confirm eligibility.
  • the secondary efficacy endpoints were the percent of weeks with platelet counts ⁇ 50 ⁇ 10 9 /L, the proportion of patients with 4 out of the final 8 platelet counts ⁇ 50 ⁇ 10 9 /L, change from baseline to the average of the post day 1 platelet counts for patients with >4 weeks of treatment, number of weeks with platelet counts ⁇ 50 ⁇ 10 9 /L, number of weeks with platelet counts ⁇ 30 ⁇ 10 9 /L, and time to first platelet count ⁇ 50 ⁇ 10 9 /L.
  • Secondary safety endpoints included rescue medication use, proportion of patients with grade ⁇ 2 bleeding events, and bleeding scale scores (using the immune thrombocytopenia-specific bleeding assessment tool (ITP-BAT) (Rodeghiero et al., 2013) and/or immune thrombocytopenia bleeding scale (IBLS)) at the end of the treatment period.
  • Post-hoc analyses are included for responders and nonresponders, as well as subgroup analyses of platelet response that evaluated the potential impact of baseline patient and disease characteristics.
  • Statistical Analyses [0160] The safety population included all patients receiving ⁇ 1 dose of rilzabrutinib.
  • the intent-to-treat population included all patients who enrolled into the study.
  • BTK inhibitors i.e., neutropenia, treatment-related infections, bleeding, thrombotic events, fungal infections, or atrial fibrillation.
  • TEAEs Due to Any Cause Treatment-Related TEAEs* Any grad Grad Grad Grad Any Grad Grad Grad Grad Grad e 1 e grad e 2 e 3/4 e e 1 e 2 e 3/4 TEAEs Due to Any Cause Treatment-Related TEAEs* Any Gr Any grad ad Grad Grad Grad Grad Grad Grad Grad Grad e 1 e 2 e 3 grad e /4 e e 1 e 2 e 3/4 TEAEs Due to Any Cause Treatment-Related TEAEs* Any ad Grad Gra Any gr d Grad Grad Grad Grad Grad e e 1 e 2 e 3/4 grad e e 1 e 2 e 3/4 — represents zero events; TEAE, treatment-emergent adverse event.
  • TEAEs leading to study drug discontinuation were of grade 1 or 2 severity, with the exception of grade 3 GI hemorrhage, grade 4 thrombocytopenia, and grade 4 Evans syndrome in 1 patient each.
  • Four of the TEAEs leading to study drug discontinuation were reported as serious adverse events (grade 2 rectal hemorrhage, grade 3 GI hemorrhage, grade 4 thrombocytopenia, and grade 4 Evans syndrome); none were related to rilzabrutinib treatment.
  • Efficacy [0172] All 60 patients were evaluable for efficacy for this 24-week study.
  • the primary endpoint ( ⁇ 2 consecutive platelet counts ⁇ 50 ⁇ 10 9 /L and increased ⁇ 20 ⁇ 10 9 /L from baseline without requiring rescue medication) was achieved in 24 patients (40%; 95% CI, 28%-53%) (Table 5). According to dose level at any time during the study (patients could respond at more than one dose level), 1 of 9 patients (11%) achieved the primary endpoint at 200 mg qd, 2/8 (25%) at 400 mg qd, 4/12 (33%) at 300 mg bid, and 20/52 (38%) at 400 mg bid. In 45 patients who initiated and maintained rilzabrutinib at a dose of 400 mg bid throughout the study, 18 (40%) patients achieved the primary platelet response (Table 5 and Table 6). [0173] Table 5.
  • Efficacy endpoints by initial dose level of rilzabrutinib for the 24-week study (and prior to the long-term extension) are reported in Table 6.
  • CI confidence interval (based on Wilson Score method). The widths of the confidence intervals have not been adjusted for multiplicity and should not be used to definitively infer efficacy.
  • the primary endpoint for platelet response was defined as ⁇ 2 consecutive platelet counts, separated by at least 5 days, of ⁇ 50 ⁇ 10 9 /L and increased ⁇ 20 ⁇ 10 9 /L from baseline without requiring rescue medication in the 4 weeks prior to the latest elevated platelet count.
  • the primary endpoint for platelet response was defined as ⁇ 2 consecutive platelet counts, separated by at least 5 days, of ⁇ 50 ⁇ 10 9 /L and increased ⁇ 20 ⁇ 10 9 /L from baseline without requiring rescue medication in the 4 weeks prior to the latest elevated platelet count.
  • the mean percent of weeks with platelet counts ⁇ 50 ⁇ 10 9 /L was 29% overall; post-hoc analyses showed that the mean percent of weeks was 65% for responder patients meeting the primary endpoint.
  • the minimum effective dose for rilzabrutinib was identified as 400 mg bid. No escalations beyond 400 mg bid were tested.
  • the proportion of patients with ⁇ 4 of final 8 platelet counts ⁇ 50 ⁇ 10 9 /L was 17 (28%) overall and 14 (31%) for patients initiating 400 mg bid (Table 5).
  • Mean changes from baseline to the average of post-day 1 platelet counts in patients completing >4 weeks of treatment were 29 ⁇ 10 9 /L (SD, 40 ⁇ 10 9 /L) for all patients and 31 ⁇ 10 9 /L (SD, 43 ⁇ 10 9 /L) for patients initiating 400 mg bid.
  • Platelet counts of ⁇ 50 ⁇ 10 9 /L and ⁇ 30 ⁇ 10 9 /L were maintained for median 1 and 5 weeks, respectively, in the overall patient population.
  • Immunomodulators for relapsed immune thrombocytopenia include spleen tyrosine kinase inhibitor fostamatinib (Tavalisse (fostamatinib) prescribing information, 2020) and anti-CD20 antibody rituximab (Ghanima W et al., 2015; Deshayes S et al., 2019; Tjonnfjord E et al., 2020).
  • CBB Cogstate Brief Battery
  • DET detection test
  • IDN identification test
  • OCL card learning test
  • ONB one back test
  • the individual and composite scores from these tests have a high sensitivity to cognitive dysfunction in clinical contexts (Hinton-Bayre AD, 2010; Maruff P et al., 2009).
  • the CBB test was presented to all patients by trained and certified raters using a laptop or tablet computer according to standardized administration procedures. At the beginning of each test, written instructions and testing rules were presented on the screen and read aloud to the patient. An interactive demonstration of the CBB followed and practice trials were presented to allow patients to demonstrate their understanding of the rules.
  • Each CBB test was presented in the form of a card game and required patients to respond using a “yes” or “no” button on each trial, with “yes” responses made with the right hand.
  • the identification (IDN) test assessed visual attention and was based on a choice reaction time test paradigm. Patients were to attend to the card in the center of the screen and follow the rule “Is the face-up card red?” as the card turned, pressing the “yes” or “no” buttons. This task continued until 35 correct responses were recorded or the maximum allowed time (2 min) had elapsed. The outcome measure for this test was speed of performance.
  • the one card learning (OCL) test assessed visual learning and was based on a pattern separation paradigm. Patients were to attend to the card in the center of the screen and follow the rule “Have you seen this card before in this task?” as the card turned, pressing “yes” or “no.” Patients were required to learn a series of four cards (target cards) presented in pseudo-random order with 6 distracter cards (i.e., non-repeating) in groups of 10 trials for 80 trials or until the maximum time allowed (3 min) had elapsed. The outcome measure for this test was accuracy of performance.
  • the one back (ONB) test assessed working memory and was based on the n- back (1-back condition) paradigm.
  • Z-scores were used to measure the distance between an observed value and a reference mean using standard deviation units (SD) and could be positive or negative, indicating that the observed value lay above or below the mean, respectively.
  • Z-scores ⁇ -1 denoted clinically important impairment, and (for tests that used performance speed as the outcome, the sign of standardized scores was reversed, so that all standardized scores with lower values indicated performance worse than normal and vice versa.).
  • SD standard deviation units
  • the magnitude of impairment in cognition in the ITP group was then determined by computing group means and 95% confidence intervals (CI) for each individual and composite score.
  • a clinically important cognitive impairment was defined as performance on either of the composite scores that was less than or equal to -1 (i.e., ⁇ -1). Differences were considered statistically significant if the 95% CIs did not include zero.
  • the second stage of the analysis determined the number and percentage of patients with ITP who showed clinically important impairment on the individual tests and psychomotor function/attention and learning/working memory composite scores. The composite scores were used for these analyses because of greater reliability than the individual participant tests from which they were derived (Maruff et al.2013).
  • the participants were classified into subgroups based on the presence or absence of cognitive impairment on each of the composite scores.
  • data for the demographic and clinical characteristics were compared between subgroups. Analyses were based on two-sample t-test assuming unequal variances. Mean difference values between groups ⁇ 0 signified greater cognitive impairment.
  • Table 8 Baseline Demographics and Characteristics Overall and Comparison of Factors in Patients with or without Cognitive Impairment. *Defined as any cognitive impairment referring to any 2 or more of DET, IDN, OCL, and ONB having a score ⁇ -1. Percentages were calculated as number of patients with cognitive impairment divided by the number of patients within that group at baseline. ⁇ P-values from Fisher exact test comparing between impaired patient groups. Patients were receiving concomitant ITP medication at baseline of the study and prior to treatment initiation [0196] The group mean Z-scores ( ⁇ 95% CI) for the individual CBB tests, and for the composite scores, are shown in Figure 10 and Table 9.
  • the estimated mean provides an index of the magnitude of impairment for each aspect of the cognitive tests.
  • the estimated mean z- scores can be inferred to be statistically significantly different from healthy controls when the associated 95% CI does not include zero (American Psychiatric Association D-TF. Diagnostic and Statistical Manual of Mental Disorders: DSM-5 (5 th ed); Maruff et al.2013).
  • Group mean Z-scores on the detection and identification tests were both negative, large in magnitude, statistically different from healthy control data (i.e., the 95% CI did not include zero), and could be classified as clinically important.
  • the mean Z-score for the psychomotor function/attention composite which is based on these two test scores, was also negative, large in magnitude, statistically different from age-matched normative data, and clinically meaningful.
  • performance was also negative and statistically different from age-matched normative data; however, the magnitude of the impairment was moderate and thus could not be classified as clinically important.
  • performance was slightly positive but not statistically different from age-matched normative data. Accordingly, the learning/working memory composite score, based on the scores from the one card learning and one back tests, was also small, not statistically different from age- matched normative data, and insufficient for classification as clinically important.
  • the performance score for each CBB test was classified as being abnormal if the score was ⁇ -1 (indicating cognitive impairment).
  • the percentage of patients with abnormal scores on each test is shown in Figure 11.
  • the level of individual impairment followed the same pattern as the group mean scores, with top rates for attention (67% of patients), followed by psychomotor function (53% of patients), working memory (39% of patients), and visual learning (16% of patients) tests.
  • the two composite scores were used to classify clinically important cognitive impairment in individual patients, where a score of ⁇ -1 on the psychomotor function/attention composite or the learning/working memory composite was classified as clinically important cognitive impairment.
  • the psychomotor function/attention composite mean difference between groups favored less cognitive impairment (i.e., mean above 0) for patients with ITP who had higher platelet counts (>15 ⁇ 10 9 /L), longer duration of ITP ( ⁇ 3 y), a higher number of prior ITP treatments ( ⁇ 3), and prior splenectomy, although in each case these benefits were not significant (i.e., 95% CI included zero).
  • Non-limiting embodiments of the disclosure include: 1. A method of treating immune thrombocytopenia (ITP) in a patient in need thereof comprising administering to the patient in need thereof a therapeutically effective amount of rilzabrutinib, wherein the patient in need thereof has at least one characteristic chosen from: a. a Z-score of ⁇ -1 on the Cogstate Brief Battery (CBB) detection test (DET) relative to age-matched normative data; b.
  • ITP immune thrombocytopenia
  • CBB Cogstate Brief Battery
  • a method of treating immune thrombocytopenia (ITP) in a patient in need thereof comprising administering to the patient in need thereof a therapeutically effective amount of rilzabrutinib, wherein the patient in need thereof has at least two characteristics chosen from: a. a Z-score of ⁇ -1 on the Cogstate Brief Battery (CBB) detection test (DET) relative to age-matched normative data; b. a Z-score of ⁇ -1 on the CBB identification test (IDN) relative to age-matched normative data; c. a Z-score of ⁇ -1 for composite DET and IDN scores relative to age-matched normative data; d.
  • CBB Cogstate Brief Battery
  • IDN CBB identification test
  • a Z-score of ⁇ -1 on the CBB one card learning test (OCL) relative to age- matched normative data OCL
  • f. a Z-score of ⁇ -1 for composite OCL and ONB scores relative to age-matched normative data OCL and ONB scores relative to age-matched normative data
  • the at least one prior line of therapy is chosen from a splenectomy, intravenous immunoglobin (IVIG), corticosteroids, anti-D immunoglobulin therapy, and immunosuppressive drugs.
  • the at least one immunosuppressive drug is selected from fostamatinib, mycophenolate mofetil (MME), and cyclosporine.
  • TPO-RA is selected from rTPO, romiplostim, eltrombopag, and avatrombopag.
  • TPO-RA is selected from rTPO, romiplostim, eltrombopag, and avatrombopag.
  • 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 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 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 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.

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Abstract

Des méthodes de traitement de la thrombocytopénie immunitaire chez un sujet présentant un déficit cognitif, comprenant l'administration d'au moins un composé choisi parmi le (R)-2-[3-[4-amino-3-(2-fluoro-4-phénoxy-phényl)pyrazolo[3,4-d]pyrimidin-1-yl]pipéridine-1-carbonyl]-4-méthyl-4-[4-(oxétan-3-yl)pipérazin-1yl]pent-2-ènenitrile (rilzabrutinib), ainsi que des sels pharmaceutiquement acceptables de celui-ci sont divulgués.
PCT/US2023/083090 2022-12-09 2023-12-08 Méthodes de traitement de la thrombocytopénie immunitaire chez des sujets présentant un déficit cognitif par administration de rilzabrutinib Ceased WO2024124113A1 (fr)

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IL321322A IL321322A (en) 2022-12-09 2023-12-08 Methods for treating immune thrombocytopenia in people with cognitive impairment by administering rilzabrotinib
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CN202380084246.9A CN120322235A (zh) 2022-12-09 2023-12-08 通过施用利扎鲁替尼治疗患有认知损害的受试者中的免疫性血小板减少症的方法
EP23844562.1A EP4630003A1 (fr) 2022-12-09 2023-12-08 Méthodes de traitement de la thrombocytopénie immunitaire chez des sujets présentant un déficit cognitif par administration de rilzabrutinib
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MX2025006665A MX2025006665A (es) 2022-12-09 2025-06-06 Metodos para tratar la trombocitopenia inmunitaria en sujetos con deterioro cognitivo mediante la administracion de rilzabrutinib

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