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WO2025068958A1 - Inhibiteur de nlrp3 destiné à être utilisé dans la réduction du risque de maladies cardiovasculaires - Google Patents

Inhibiteur de nlrp3 destiné à être utilisé dans la réduction du risque de maladies cardiovasculaires Download PDF

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Publication number
WO2025068958A1
WO2025068958A1 PCT/IB2024/059449 IB2024059449W WO2025068958A1 WO 2025068958 A1 WO2025068958 A1 WO 2025068958A1 IB 2024059449 W IB2024059449 W IB 2024059449W WO 2025068958 A1 WO2025068958 A1 WO 2025068958A1
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Prior art keywords
compound
subject
dose
nlrp3
nlrp3 inhibitor
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Inventor
Timothy Joseph Clough
Ewa GATLIK
Katy Hayes
Michael Mendelson
Christopher Joseph O'donnell
Nikolaos Patsopoulos
Marianna ROWLANDS
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Novartis AG
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Novartis AG
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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
    • A61K31/425—Thiazoles
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present disclosure relates to the field of pharmacy, particularly to a NLRP3 inhibitor, or a pharmaceutical combination comprising a NLRP3 inhibitor and at least one further therapeutic agent, for use in lowering the risk of cardiovascular disease events in subjects with a known heart disease, particularly in subjects known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations.
  • the disclosure also relates to a method for lowering the risk of cardiovascular disease events in subjects with a known heart disease, particularly in subjects known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations, which involves administering a NLRP3 inhibitor or the combination; and to the use of a NLRP3 inhibitor or the combination for the manufacture of a medicament for lowering the risk of cardiovascular disease events in subjects with a known heart disease, particularly in subjects known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations.
  • CVD Cardiovascular diseases
  • Atherosclerotic CVD is a condition commonly characterized by an elevated inflammatory state. Arterial inflammation and endothelial dysfunction play key roles at all stages of the atherothrombotic process.
  • phagocytes PAT059585-WO-PCT induces phagolysosomal damage and subsequent leakage of contents into cytosol to activate inflammasomes and caspase 1, and consequently the generation of interleukin-1 ⁇ (IL-1 ⁇ ) from pro-interleukin-1 ⁇ .
  • Interleukins are key mediators in the chronic vascular inflammatory response in CVD and have been demonstrated in animal models and in humans to be potent modulators of pro- inflammatory processes.
  • IL- 1 ⁇ is a potent smooth muscle cell mitogen, an activator of endothelial cells and increases extra cellular matrix and collagen deposition, which plays a role in plaque burden and arterial thickening.
  • lack of IL-1 ⁇ or ablation of IL-1 receptor has been shown to decrease severity of atherosclerosis in apoE deficient mice.
  • CANTOS Canakinumab Anti-Inflammatory Thrombosis Outcome Study
  • IL-1 ⁇ neutralization with canakinumab can reduce cardiovascular risk by approximately 15% in patients who have had a prior myocardial infarction (MI) and elevated high-sensitivity C-reactive protein (hsCRP).
  • MI myocardial infarction
  • hsCRP high-sensitivity C-reactive protein
  • IL-1 ⁇ signalling promotes the release of IL-6 and hsCRP, and lower on-treatment levels may identify post-MI patients with the greatest potential CVD benefit.
  • PAT059585-WO-PCT CHIP refers to the presence of clonal populations of hematopoietic stem cells that occur in absence of diagnostic criteria for hematologic malignancy, in absence of morphological variation in blood cells, and with candidate driver gene mutations at variant allele frequency (VAF) of at least 2% in peripheral blood (Steensma DP, Bejar R, Jaiswal S et al (2015) Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood; 126(1):9–16). CHIP is a disorder of aging with about 15% of people affected by 75 years of age.
  • CHIP likely contributes to CVD risk through enhanced inflammation, including increased NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) activation.
  • CHIP epigenetic regulators
  • NLRP3 inflammasome has been implicated as a major driver of inflammation associated with chronic inflammatory diseases.
  • PAT059585-WO-PCT Mechanistically, NLRP3 senses a diverse range of danger signals, and reacts by forming an inflammasome protein complex that drives an ensuing inflammatory response. Via genetic knockouts (Duewell P., Kono H, Rayner KJ, et al.
  • NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals”, Nature, 464 (7293): 1357- 61) or pharmacological inhibition (Hettwer J. et al., “Interleukin-1 ⁇ suppression dampens inflammatory leucocyte production and uptake in atherosclerosis”, Cardiovascular Research, 118(13), 2778-2791), abrogation of NLRP3 function is protective in mouse models of atherosclerosis, exerting a beneficial effect on both peripheral inflammatory leukocytes and cytokines, and local anti-inflammatory effects in the atherosclerotic plaque.
  • Compound I is a potent, small molecule inhibitor of the NLRP3 inflammasome pathway.
  • Compound I blocks IL-1 ⁇ secretion, IL-18 secretion and pyroptotic cell death in response to a wide variety of NLRP3-dependent danger signals in vitro and in mechanistic mouse models in vivo, suggesting that NLRP3 inhibition could have improved efficacy over canakinumab in diseases where IL-1 ⁇ and IL-18 both drive pathology.
  • NLRP3 inhibitors particular compound I, more particularly compound IA, have the potential to significantly reduce cardiovascular risk in patients.
  • NLRP3 inhibitors which may be used to prevent or reduce the NLRP3 inflammasome response and thus address an unmet medical need in subjects with a known heart disease, particularly in subjects known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations.
  • a NLRP3 inhibitor disclosed herein can be developed as a drug for reducing the risk of or preventing cardiovascular events (CVE) or cardiovascular diseases (CVD), which can be recurrent CVEs or CVDs, in a subject with a known heart disease, particularly in a subject known to be a carrier of clonal expansion of hematopoietic cell lines (CHIP) with somatic mutations in either of the genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2.
  • CVE cardiovascular events
  • CVD cardiovascular diseases
  • the present invention relates to a NLRP3 inhibitor for use in reducing the risk of or preventing cardiovascular events (CVE) or cardiovascular diseases (CVD), which can be recurrent CVEs or CVDs, in a subject with a known heart disease, e.g.
  • CVE cardiovascular events
  • CVD cardiovascular diseases
  • coronary heart disease particularly in a subject known to be a carrier of clonal expansion of hematopoietic cell lines (CHIP) with somatic mutations in either of the genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2; or the invention relates to a method for reducing the risk of or preventing cardiovascular events (CVE) or cardiovascular diseases (CVD), which can be a recurrent CVEs or CVDs, in a subject with a known heart disease, particularly in a subject known to be a carrier of clonal expansion of PAT059585-WO-PCT hematopoietic cell lines (CHIP) with somatic mutations in either of the genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2, comprising for a) and b) administering to said subject a therapeutically effective amount a NLRP3 inhibitor.
  • the treated subject has at least one mutation in one of the CHIP driver genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2 or more than one mutation in one of the CHIP driver genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2, wherein at least one unique mutation must be present at a variant allele frequency (VAF) ⁇ 2%.
  • the treated subject has at least one mutation in one of the CHIP driver genes TET2 or DNMT3A, wherein at least one unique mutation must be present at a variant allele frequency ⁇ 2%.
  • the treated subject has a coronary heart disease.
  • the subject had a documented spontaneous myocardial infarction.
  • the subject had a documented spontaneous myocardial infarction and wherein the NLRP3 inhibitor is administered at the earliest 30 days after the myocardial infarction (MI).
  • MI myocardial infarction
  • the cardiovascular events (CVE) or cardiovascular diseases (CVD), which can be recurrent CVEs or CVDs, are selected from non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, and hospitalization for unstable angina requiring unplanned revascularization, or non-fatal myocardial infarction, non- fatal stroke, and cardiovascular death, or unstable angina requiring unplanned revascularization, or non-fatal myocardial infarction or cardiovascular death, or non-fatal myocardial infarction.
  • the NLRP3 inhibitor is administered to a subject orally, particularly as a tablet or capsule.
  • a subject is administered a NLRP3 inhibitor at a total daily dose of about 10 mg to about 100 mg in a single dose or divided doses. In a different embodiment of the first aspect, a subject is administered a NLRP3 inhibitor at a total daily dose of about 10 mg to about 50 mg in a single dose or divided doses. In another embodiment of the first aspect, a subject is administered a NLRP3 inhibitor at a total daily dose of about 25 PAT059585-WO-PCT mg in a single dose or divided doses. In another embodiment of the first aspect, a subject is administered a NLRP3 inhibitor at a total daily dose of about 50 mg in a single dose or divided doses.
  • subjects are administered a NLRP3 inhibitor at a total daily dose of about 10 mg for 3 weeks. In another embodiment of the first aspect, subjects are administered a NLRP3 inhibitor at a total daily dose of about 25 mg for 3 weeks. In another embodiment of the first aspect, subjects are administered a NLRP3 inhibitor at a total daily dose of about 50 mg for 3 weeks. In another embodiment of the first aspect, subjects are administered a NLRP3 inhibitor at a total daily dose of about 100 mg for 3 weeks.
  • the subject has a high sensitivity C-reactive protein (hsCRP) level of ⁇ 2 mg/L before first administration of the NLRP3 inhibitor; particularly, the NLRP3 inhibitor is administered at the earliest 30 days after MI, and wherein said subject has a reduced hsCRP level of ⁇ 2 mg/L assessed approximately 3 weeks after first administration of the NLRP3 inhibitor.
  • hsCRP high sensitivity C-reactive protein
  • one embodiment of the first aspect of the invention relates to uses or methods for reducing circulating levels of inflammatory markers in a subject with known coronary heart disease, and particularly in a subject known to be a carrier of a clonal expansion of hematopoietic cell lines with somatic mutations (e.g., like the above described subject carrying at least one mutation in one of the CHIP driver genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2), wherein at least one unique mutation is present at a variant allele frequency (VAF) ⁇ 2%.
  • the NLRP3 inhibitor is administered in combination with at least one further therapeutic agent.
  • the said subject is concomitantly receiving standard of care treatment for reducing the risk of or preventing CVEs or CVDs, which can be recurrent CVEs or CVDs.
  • the subject in need of a treatment for reducing the risk of or preventing CVEs or CVDs, which can be a recurrent CVEs or CVDs has high serum C-reactive protein (CRP) levels as compared to a control population.
  • CRP serum C-reactive protein
  • the subject in need of a treatment for reducing the risk of or preventing CVEs or CVDs which can be a recurrent CVEs or CVDs, has a serum C-reactive protein PAT059585-WO-PCT (CRP) level higher than 2 mg/L.
  • CRP serum C-reactive protein
  • the CRP level is at least 28 days after MI and before first administration of the NLRP3 inhibitor, and wherein the NLRP3 inhibitor is administered at the earliest 30 days after MI.
  • NLRP3 inhibitor for use in reducing the serum C- reactive protein (CRP) level in a subject with known coronary heart disease, and particularly in a (CHIP) subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2, wherein at least one unique mutation is present, with variant allele frequency (VAF) ⁇ 2%.
  • CCP serum C- reactive protein
  • NLRP3 inhibitor for the manufacture of a medicament for reducing the serum C-reactive protein (CRP) level in a subject with known coronary heart disease, and particularly in a (CHIP) subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2, wherein at least one unique mutation is present with variant allele frequency (VAF) ⁇ 2%.
  • VAF variant allele frequency
  • the serum CRP level in the a subject decreases, as a consequence of the herein described methods and treatments, by at least 1 mg/l, at least 2 mg/l, at least 3 mg/l, at least 4 mg/l or at least 5 mg/l.
  • the serum CRP level in a subject having received a NLRP3 inhibitor as described herein decreases by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% from baseline compared to the patient population not having received the same treatment, e.g. subjects having received standard of care (SOC).
  • the disclosure relates to the use of a NLRP3 inhibitor, for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, which can be recurrent CVEs or CVDs, in a subject with coronary heart disease, in particular in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2, wherein at least one unique mutation is present with variant allele frequency (VAF) ⁇ 2%.
  • VAF variant allele frequency
  • the disclosure relates to pharmaceutical composition
  • a NLRP3 inhibitor for use in reducing the risk of or preventing recurrent cardiovascular events in a subject with coronary heart disease, in particular in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2, wherein at least one unique mutation is present with variant allele frequency (VAF) ⁇ 2%.
  • the NLRP3 inhibitor is compound I.
  • compound I is compound IA.
  • FIG. 1 A schematic overview of the treatment protocol of Example 1.
  • Figure 2 A schematic overview of the treatment protocol of Example 2.
  • the asterisks *, ** and *** have the following meaning: * Bispecific IL-1 ⁇ and IL-18 targeting antibody 600 mg subcutaneous injection + compound IA placebo; ** Bispecific IL-1 ⁇ and IL-18 targeting antibody subcutaneous injection placebo + compound IA placebo; *** Bispecific IL-1 ⁇ and IL-18 targeting antibody subcutaneous injection placebo + compound IA 10 mg QD.
  • inflammation is thought to play an important role in CVDs and the occurrence of CVEs, particularly in subjects with a known heart disease, e.g. coronary heart disease, more particularly in a subject known to be a carrier of clonal expansion of hematopoietic cell lines (CHIP) with somatic mutations in either of the genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2 (CHIP population).
  • a known heart disease e.g. coronary heart disease
  • a subject known to be a carrier of clonal expansion of hematopoietic cell lines (CHIP) with somatic mutations in either of the genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2 (CHIP population).
  • the present disclosure is inter alia based on the unexpected finding that certain NLRP3 inhibitors, in particular Compound I, Compound IA or Compound IB, which block IL-1 ⁇ secretion, IL-18 secretion in response to a wide variety of NLRP3-dependent danger signals more potently attenuate pro-inflammatory cytokine production compared to single IL-1 ⁇ or IL-18 neutralization alone, which is considered by the inventors to be an efficacious treatment for reducing the risk of or preventing cardiovascular events and recurring cardiovascular events in subjects with a known heart disease, e.g.
  • hematopoietic cell lines hematopoietic cell lines
  • Clonal hematopoiesis of indeterminate potential is the results of clonally expanded hematopoietic stem cell caused by a mutation.
  • CHIP populations have a two-fold higher cardiovascular risk compared to non-CHIP individuals, because CHIP results in a pro- PAT059585-WO-PCT inflammatory state that seems to be linked to CVEs like thromboembolic events, myocardial infarction, and coronary artery disease (Marnell C, Bick A, Natarajan P (2021) Clonal hematopoiesis of indeterminate potential (CHIP): Linking somatic mutations, hematopoiesis, chronic inflammation and cardiovascular disease. J Mol Cell Cardiol; 161:98-105.
  • CVD cardiovascular disease
  • CVE cardiovascular event
  • a cardiovascular event can be recurrent and one embodiment of the herein disclosed uses or methods relates to reducing the risk of recurrent cardiovascular events.
  • a cardiovascular event can be a Myocardial Infarction (MI).
  • MI myocardial ischemia
  • PCI Percutaneous Coronary Intervention
  • MI associated with stent thrombosis as documented by autopsy or angiography
  • CABG Coronary artery bypass grafting
  • the CVEs or CVDs treated according to the methods and uses disclosed herein is a recurrent CVE or CVD.
  • a recurrent CVE or CVD is described.
  • a NLRP3 inhibitor particularly Compound I, Compound IA or Compound IB, more particularly Compound IA.
  • a method for reducing the risk of or preventing CVEs or CVDs which can be a recurrent CVE or CVD, in subjects with a known heart disease, e.g. coronary heart disease, more particularly in a CHIP population, comprising administering to a subject in need thereof an effective amount of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA.
  • a NLRP3 inhibitor particularly Compound I, Compound IA or Compound IB, more particularly Compound IA.
  • the disclosure relates to uses or methods of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA, for reducing the risk of or preventing CVEs or CVDs, wherein said events or diseases are selected from non- fatal myocardial infarction, non-fatal stroke, cardiovascular death, and hospitalization for unstable angina requiring unplanned revascularization.
  • the disclosure relates to uses or methods of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA for reducing the risk of or preventing a cardiovascular event, wherein said event is non-fatal myocardial infarction.
  • the disclosure relates to uses or methods of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA, for reducing the risk of or preventing a cardiovascular event, wherein said event non-fatal stroke.
  • the disclosure relates to uses or methods of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA, for reducing the risk of or preventing a cardiovascular event, wherein said event cardiovascular death.
  • the disclosure relates to uses or methods of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA, for reducing the risk of or preventing a cardiovascular event, wherein said event is unstable angina requiring unplanned revascularization.
  • the disclosure relates to NLRP3 inhibitors, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA for the use in reducing the risk of or preventing CVEs or CVDs, which can be a recurrent CVE or CVD, in disease patients having hyper elevated IL-1 ⁇ and/or IL-18.
  • the disclosure also relates to methods, treatment regimens, uses, kits and therapies for reducing the risk of or preventing CVEs or CVDs, which can be a PAT059585-WO-PCT recurrent CVE or CVD, by employing a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA.
  • a NLRP3 inhibitor particularly Compound I, Compound IA or Compound IB, more particularly Compound IA.
  • the hsCRP levels of ⁇ 2 mg/L assessed at least 28 days after MI is reduced by 20% or 21% or 22% or 23% or 24% or 25% or 26% or 27% or 28% or 29% or 30% or more after daily administration for 3 weeks of about 10 mg or 25 mg or 50 mg or 100 mg of Compound IA as measured at 3 weeks after the first administration of Compound IA.
  • the hsCRP levels of ⁇ 2 mg/L assessed at least 28 days after MI is reduced by 20% or 21% or 22% or 23% or 24% or 25% or 26% or 27% or 28% or 29% or 30% or more after daily administration for 3 weeks of about 25 mg of Compound IA as measured at 3 weeks after the first administration of Compound IA.
  • the hsCRP levels of ⁇ 2 mg/L assessed at least 28 days after MI is reduced by 20% or 21% or 22% or 23% or 24% or 25% or 26% or 27% or 28% or 29% or 30% or more after daily administration for 3 weeks of about 50 mg of Compound IA as measured at 3 weeks after the first administration of Compound IA.
  • the hsCRP levels of ⁇ 2 mg/L assessed at least 28 days after MI is reduced by 20% or 21% or 22% or 23% or 24% or 25% or 26% or 27% or 28% or 29% or 30% or more after daily administration for 3 weeks of about 100 mg of Compound IA as measured at 3 weeks after the first administration of Compound IA.
  • Another biomarker that is useful in assessing residual inflammatory risk include downstream mediators of IL-1 ⁇ such as interleukin-6 (IL-6).
  • IL-6 is a known marker of cardiovascular disease associated with obesity, type 2 diabetes and myocardial infarction.
  • IL-6 is used as a biomarker for assessing the response of the stable MI patient to administration for 3 weeks of about 10 mg or 25 mg or 50 mg or 100 mg of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA.
  • the serum level of IL-6 is used as a biomarker for assessing the response of the stable MI patient after daily administration for 3 weeks of about 10 mg or 25 mg or 50 mg or 100 mg of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, PAT059585-WO-PCT more particularly Compound IA, as measured at 3 weeks after the first administration of Compound IA.
  • a NLRP3 inhibitor particularly Compound I, Compound IA or Compound IB, PAT059585-WO-PCT more particularly Compound IA, as measured at 3 weeks after the first administration of Compound IA.
  • the level of IL-6 assessed approximately after daily administration for 3 weeks of about 10 mg of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA is reduced in by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200% or more.
  • the level of IL-6 assessed approximately after daily administration for 3 weeks of about 25 mg of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA is reduced in by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200% or more.
  • the level of IL-6 assessed approximately after daily administration for 3 weeks of about 50 mg of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA is reduced in by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200% or more.
  • the level of IL-6 assessed approximately after daily administration for 3 weeks of about 100 mg of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA is reduced in by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200% or more.
  • the present invention is also directed to the use of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA, for reducing the risk of or preventing a CVE or CVD, which can be a recurrent CVE or CVD, in a CHIP patient that has suffered myocardial infarction (MI), wherein i. said patient has a high sensitivity C-reactive protein (hsCRP) level of ⁇ 2 mg/L assessed at least 28 days after MI and before first administration of a NLRP3 inhibitor, and ii.
  • MI myocardial infarction
  • a NLRP3 inhibitor particularly Compound I, Compound IA or Compound IB, more particularly Compound IA
  • a NLRP3 inhibitor particularly Compound I, Compound IA or Compound IB, more particularly Compound IA
  • the present invention is also directed to the use of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA, for reducing the risk of or preventing a CVE or CVD, which can be a recurrent CVE or CVD, in a CHIP patient that has suffered myocardial infarction (MI), wherein i.
  • MI myocardial infarction
  • said patient is a CHIP patient with somatic mutations in either of the genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2, and ii. said patient has a high sensitivity C-reactive protein (hsCRP) level of ⁇ 2 mg/L assessed at least 28 days after MI and before first administration of a NLRP3 inhibitor, iii. about 10 mg or 25 mg or 50 mg or 100 mg of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA, is administered daily to the patient at the earliest 30 days after MI.
  • hsCRP high sensitivity C-reactive protein
  • the present invention also relates to the use of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA, for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, which can be a recurrent CVEs or CVDs, in a CHIP patient that has suffered myocardial infarction (MI), wherein i. said patient has a high sensitivity C-reactive protein (hsCRP) level of ⁇ 2 mg/L assessed at least 28 days after MI and before first administration of a NLRP3 inhibitor, and ii.
  • MI myocardial infarction
  • a NLRP3 inhibitor particularly Compound I, Compound IA or Compound IB, more particularly Compound IA
  • the present invention is also directed to the use of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA, for the manufacture of a medicament for reducing the risk of or preventing a CVE or CVD, which can be a recurrent CVE or CVD, in a CHIP patient that has suffered myocardial infarction (MI), wherein i.
  • MI myocardial infarction
  • said patient is a CHIP patient with somatic mutations in either of the genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2, and ii.
  • said patient has a high sensitivity C-reactive protein (hsCRP) level of ⁇ 2 mg/L assessed at least 28 days after MI and before first administration of a NLRP3 inhibitor, iii. wherein about 10 mg or 25 mg or 50 mg or 100 mg of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA, is administered daily to the patient at the earliest 30 days after MI.
  • hsCRP high sensitivity C-reactive protein
  • said patient has high sensitivity C-reactive protein (hsCRP) levels of ⁇ 3 mg/L assessed at least 28 days after MI and before first administration of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA.
  • hsCRP high sensitivity C-reactive protein
  • said patient has high sensitivity C-reactive protein (hsCRP) levels of ⁇ 4 mg/L assessed at least 28 days after MI and before first administration of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA.
  • said patient has high sensitivity C- reactive protein (hsCRP) levels of ⁇ 5 mg/L assessed at least 28 days after MI and before first administration of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA.
  • hsCRP high sensitivity C-reactive protein
  • said patient has high sensitivity C-reactive protein (hsCRP) levels of ⁇ 6 mg/L assessed at least 28 days after MI and before first administration of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA.
  • said patient has high sensitivity C- reactive protein (hsCRP) levels of ⁇ 7 mg/L assessed at least 28 days after MI and before first administration of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA.
  • hsCRP high sensitivity C-reactive protein
  • said patient has high sensitivity C-reactive protein (hsCRP) levels of ⁇ 8 mg/L assessed at least 28 days after MI and before first administration of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA.
  • said patient has high sensitivity C- reactive protein (hsCRP) levels of ⁇ 9 mg/L assessed at least 28 days after MI and before first administration of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA.
  • hsCRP high sensitivity C-reactive protein
  • said patient has high sensitivity C-reactive protein (hsCRP) levels of ⁇ 10 mg/L assessed at least 28 days after MI and before first administration of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA.
  • the reduced level of hsCRP in the patient assessed approximately 3 weeks after first administration of a NLRP3 inhibitor as described herein, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA, is ⁇ 1.8 mg/L.
  • the reduced level of hsCRP assessed approximately 3 weeks after first administration of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA is ⁇ 1.5 mg/L.
  • the level of hsCRP in the patient assessed approximately 3 weeks after first administration of a NLRP3 inhibitor as described herein, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA, is reduced in by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200% or more.
  • the patient has reduced hsCRP level of ⁇ 2 mg/L, e.g., 1.9, ⁇ 1.8, ⁇ 1.7, ⁇ 1.6, ⁇ 1.5, ⁇ 1.4, ⁇ 1.3, ⁇ 1.2, ⁇ 1.1, ⁇ 1.0, ⁇ 0.9, ⁇ 0.8, ⁇ 0.7, ⁇ 0.6, or ⁇ 0.5 mg/L, assessed approximately 3 weeks, approximately 6 weeks, approximately 3 months, approximately 6 months or approximately 9 months after first administration of a NLRP3 inhibitor as described herein, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA.
  • a NLRP3 inhibitor as described herein, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA.
  • one embodiment provides the use of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA, for reducing the risk of or preventing a CVE or CVD, which can be a recurrent CVE or CVD, in a patient, in particular a CHIP patient, that has suffered myocardial infarction (MI), i. wherein said patient has a high sensitivity C-reactive protein (hsCRP) level of ⁇ 2 mg/L assessed at least 28 days after MI and before first administration of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA, ii.
  • MI myocardial infarction
  • the reduction in one or more elevated serum inflammatory marker by administration of a NLRP3 inhibitor as described herein, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA can be a reduction of at least about 20%, 30%, 40% or 50% from baseline compared to patients not having received the same treatment, e.g., patients having received standard of care (SOC).
  • SOC standard of care
  • the reduction in one or more elevated serum inflammatory marker by administration of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA can be a reduction of at least about 60%, 70%, 80%, 90% from baseline PAT059585-WO-PCT compared to patients not having received the same treatment, e.g., patients having received standard of care (SOC).
  • SOC standard of care
  • the reduction in one or more elevated serum inflammatory marker by administration of a NLRP3 inhibitor as described herein, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA can be a reduction of at least about 100%, 200%, 300% or more from baseline compared to patients not having received the same treatment, e.g., patients having received standard of care (SOC).
  • SOC standard of care
  • said recurrent CV event is hospitalization for unstable angina requiring unplanned revascularization.
  • the patient may concomitantly receive a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA, and a standard of care (SOC) treatment for reducing the risk of or preventing CV events, which can be a recurrent CVEs or CVDs.
  • a NLRP3 inhibitor particularly Compound I, Compound IA or Compound IB, more particularly Compound IA
  • SOC standard of care
  • Said standard of care treatment includes, but is not limited to, lipid lowering agents such as a HMG-CoA reductase inhibitor, e.g., a statin such as lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, mevastatin, pitavastatin, rosuvastatin or mixtures thereof or mixtures with ezetimibe, niacin, amlodipine besylate, inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9i) such as alirocumab (Praluent®), evolocumab (Repatha®), bococizumab, inhibitors of cholesterylester transfer protein (CETP) such as anacetrapib, torcetrapib, dalcetrapib, anti-hypertensives such as a calcium channel blocker (e.g., amlodipine,
  • the disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA, for use in reducing the risk of or preventing cardiovascular events in a subject with coronary heart disease, in particular in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2. Definitions: In order that the present document may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout this document.
  • the amount “about 10” includes 10 and any amounts from 8 to 12 or from 9 to 11.
  • the term “about” in relation to a reference numerical value can also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value.
  • the numerical value described throughout can be “about” that numerical value even without specifically mentioning the term “about.”
  • the term “baseline” refers to a subject’s state or the degree of a condition, e.g., a disease, or one or more parameters associated with the state of a patient, observed before treatment, e.g., before administration of a compound, e.g., before administration of Compound I, or a pharmaceutically acceptable salt thereof, optionally in combination with at least one further therapeutic agent, according to the described methods and uses.
  • the term “pharmaceutically acceptable” means a nontoxic material that does not substantially interfere with the effectiveness of the biological activity of the active ingredient(s).
  • the term “patient” is used interchangeably with the term “subject” and includes any human or nonhuman animal.
  • the term “nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, PAT059585-WO-PCT cats, horses, cows, chickens, amphibians, reptiles, etc.
  • the compositions, methods, and uses described herein are in reference to a human patient or subject.
  • a subject is “in need of” a treatment if such subject who is afflicted with the condition (i.e., disease, disorder, or syndrome) of interest and who would benefit biologically, medically, or in quality of life from such treatment.
  • condition i.e., disease, disorder, or syndrome
  • approximately 3 months includes a time period of 90 days +/- 10 days.
  • approximately 6 months refers to a time period of 180 days that includes +/- 15 days.
  • IL-18 is synonym to IL-18 polypeptide, Interleukin-18 polypeptide, IFN-gamma inducing factor or Interferon-gamma-inducing-factor or INF- ⁇ inducing factor.
  • IL-18 refers to human IL-18, unless another species is indicated. IL-18 is well known to a person skilled in the art, and for example obtainable from MBL® International Corporation under product reference #B001-5.
  • IL-18 encompasses both pro-IL-18 (precursor of mature IL-18 prior protease cleavage) and mature IL-18 (post protease cleavage) interchangeably unless it is specified that the pro- or mature form is meant.
  • IL-1 ⁇ or “IL-1b” is synonym to IL-1 ⁇ polypeptide and Interleukin-1 ⁇ polypeptide.
  • IL-1 ⁇ refers to human IL-1 ⁇ unless another species is indicated.
  • IL-1 ⁇ is well known to a person skilled in the art, and commercially available (e.g., Sino Biological under product reference #10139-HNAE-5).
  • Total IL-18 in serum can be measured by conjugating anti-human IL-18 antibody (e.g., clone 125-2H, MBL International) to Bio-plex Magnetic COOH beads (Bio- Rad, Inc.), detected using biotinylated anti-human IL-18 (clone 159-12B, MBL), and concentrations calculated using the IL-18 contained in the Group II cytokine standard curve (Bio-Rad, Inc.).
  • Free IL-18 can be measured as described in Girard et al. Rheumatology (Oxford).2016 Dec;55(12):2237-2247.
  • Serum IL-1 ⁇ can be measured using a commercially available ELISA kit (88-7261-88, eBioscience) used in accordance with manufacturer’s instructions.
  • antibody refers to an intact immunoglobulin or a functional fragment thereof.
  • Naturally occurring antibodies typically comprise a tetramer which is usually composed of at least two heavy (H) chains and at least two light (L) chains.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region, usually comprised of three domains (CH1, CH2 ad CH3).
  • Heavy chains can be of any isotype, including IgG (IgG1, IgG2, IgG3 and IgG4 subtypes), IgA (IgA1 and IgA2 subtypes), IgM and IgE.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region (CL).
  • Light chain includes kappa ( ⁇ ) chains and lambda ( ⁇ ) chains.
  • the heavy and light chain variable region is typically responsible for antigen recognition, whilst the heavy and light chain constant region may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • excipient or “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • C-reactive protein and “CRP” refers to serum C-reactive protein, which is used as an indicator of the acute phase response to inflammation.
  • hsCRP levels are assessed in a PAT059585-WO-PCT biological sample, e.g., blood, obtained from the patient.
  • a biological sample from the patient is assayed for the level of hsCRP.
  • hsCRP refers to the level of CRP in the blood as measured by high sensitivity CRP testing.
  • the level of CRP or hsCRP in plasma may be given in any concentration, e.g., mg/dl, mg/L, nmol/L.
  • Levels of CRP or hsCRP may be measured by a variety of well-known methods, e.g., radial immunodiffusion, electroimmunoassay, immunoturbidimetry, ELISA, turbidimetric methods, fluorescence polarization immunoassay, and laser nephelometry.
  • Testing for CRP may employ a standard CRP test or a high sensitivity CRP (hsCRP) test (i.e., a high sensitivity test that is capable of measuring low levels of CRP in a sample, e.g., using laser nephelometry).
  • Kits for detecting levels of CRP or hsCRP may be purchased from various companies, e.g., Calbiotech, Inc, Cayman Chemical, Roche Diagnostics Corporation, Abazyme, DADE Behring, Abnova Corporation, Aniara Corporation, Bio-Quant Inc., Siemens Healthcare Diagnostics, etc.
  • the term “high sensitivity C-reactive protein (hsCRP) level” in the context of a method for reducing the risk of or preventing cardiovascular events in a subject refers to: • a 60 % increase from normalized levels in treated patients of C-reactive protein (CRP), wherein normalized levels indicate minimal or absent inflammation or disease activity (e.g., CRP ⁇ 2 mg/L); or • an elevation of CRP of > 2 mg/L.
  • cardiac death includes sudden cardiac death, death due to acute myocardial infarction (AMI), death due to heart failure, death due to stroke, and death due to other cardiovascular causes.
  • AMD acute myocardial infarction
  • death due to heart failure refers to a death within 30 days after a myocardial infarction (MI) related to consequences seen immediately after the myocardial infarction, such as progressive congestive heart failure (CHF), inadequate cardiac output, or recalcitrant arrhythmia.
  • MI myocardial infarction
  • Death due to heart failure or cardiogenic shock refers to death occurring in the context of clinically worsening symptoms and/or signs of heart without evidence of another cause of death and includes sudden death occurring during an admission for worsening heart failure PAT059585-WO-PCT as well as death from progressive heart failure or cardiogenic shock following implantation of a mechanical assist device.
  • Death due to stroke intracranial hemorrhage or non-hemorrhagic stroke refers to death occurring up to 30 days after a suspected stroke based on clinical signs and symptoms as well as neuroimaging and/or autopsy, and where there is no conclusive evidence of another cause of death.
  • “death due to other cardiovascular causes” refers to death due to a cardiovascular cause not included in the above categories (e.g.
  • MI myocardial infarction
  • MI acute myocardial infarction
  • spontaneous MI refers to the detection of rise and/or fall of cardiac biomarkers with at least one value above the 99th percentile of the upper reference limit (URL) together with evidence of myocardial ischemia with at least one of the following: symptoms of ischemia, ECG changes indicative of new ischemia (ST Elevation - New ST elevation at the J-point in two contiguous leads with the cut-off points: ⁇ 0.2 mV in men or ⁇ 0.15 mV in women in leads V2-V3 and/or ⁇ 0.1 mV in other leads, ST depression and T-wave changes – New horizontal or down-sloping ST depression ⁇ 0.05 mV in two contiguous leads; and/or T inversion ⁇ 0.1 mV in two contiguous leads with prominent R waves or R/S ratio >1.
  • PCI percutaneous coronary intervention
  • Criteria for Prior Myocardial Infarction Any of the following criteria meets the diagnosis for prior myocardial infarction: development of new pathological Q waves with or without symptoms, imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract in the absence of a non-ischemic cause, pathological findings of a healed or healing myocardial infarction: ECG changes associated with prior Myocardial Infarction: • Any Q wave in leads V2-V3 ⁇ 0.02 seconds or QS complex in leads V2 and V3 • Q-wave ⁇ 0.03 seconds and ⁇ 0.1 mV deep or QS complex in leads I, II, aVL, aVF, or V4-V6 in any two leads of a contiguous lead grouping (I, aVL, V6, V4-V6, II, III, and aVF) • R-wave ⁇ 0.04 seconds in V1-V2 and R/S ⁇ 1 with a concordant
  • a second sample should be obtained 3-6 hours later. Recurrent infarction is diagnosed if there is a ⁇ 20% increase of the value in the second sample. This value should exceed the 99th percentile URL. However if cardiac biomarkers are elevated prior to the suspected new MI, there must also be documentation of decreasing values (two samples at least 6 hours apart) prior to the suspected new MI. If the values are falling criteria for reinfarction by further measurement of biomarkers together with features of the ECG or imaging can be applied. ECG diagnosis of reinfarction following the initial infarction: may be confounded by the initial evolutionary ECG changes.
  • Reinfarction should be considered when the ST elevation ⁇ 0.1 mV reoccurs in an inpatient having a lesser degree of ST elevation or new pathognomonic Q- waves, in at least two contiguous leads, particularly when associated with ischemic symptoms for 10 minutes or longer.
  • the re-evaluation of the ST segment can, however, also be seen in threatening myocardial rupture and should lead to additional diagnostic work-up.
  • ST PAT059585-WO-PCT depression or LBBB on their own should not be considered valid criteria for Myocardial Infarction. If biomarkers are increasing or peak is not reached, then there is insufficient data to diagnose recurrent MI.
  • Type 3 Sudden unexpected cardiac death including cardiac arrest, often with symptoms suggestive of myocardial ischemia accompanied by presumably new ST elevation, or new LBBB, or evidence of fresh thrombus in a coronary artery by angiography and/or at autopsy, but death occurring before blood samples could be obtained or at a time before the appearance of cardiac biomarkers in the blood.
  • Type 4b –MI associated with stent thrombosis as documented by autopsy or angiography.
  • Type 5 –MI associated with CABG Coronary artery bypass grafting
  • the term “silent MI”: the following criteria will be used by the central ECG reading vendor to define interval “silent” (no clinical symptoms or signs) MI between baseline and yearly ECGs (Surawicz B et al, Chou's electrocardiography in clinical practice: adult and pediatric. Philadelphia: Saunders; 2001): Myocardial infarctions are reported only on the basis of pathologic Q waves. Pathologic Q waves are defined as Q wave duration > 40ms and Q/R ratio 1/3. Any Q wave in V1 or V2 that is followed by an R wave should be considered abnormal.
  • ST elevation or T wave inversion may be used to classify the infraction as New or Acute.
  • ST elevation or T wave inversion in the absence of pathologic Q waves are not sufficient criteria for diagnosis of myocardial infarction.
  • PAT059585-WO-PCT • Anterior MI - Pathologic Q waves in V3 and V4.
  • new MI is based on criteria for MI more stringent than the Expert Consensus Document criteria, requiring Q waves to be > 0.04 sec in duration and an R/S ratio > 1/3. These criteria (drawn from the cardiology literature) are designed to minimize the false positive detection of MIs due to very small physiologic Q waves in the inferior and anterolateral leads.
  • stroke is defined as the rapid onset of a new persistent neurological deficit attributed to an obstruction in cerebral blood flow and/or cerebral hemorrhage with no apparent non-vascular cause (e.g. tumor, trauma, infection). Available neuroimaging studies will be considered to support the clinical impression and to determine if there is a demonstrable lesion compatible with an acute stroke.
  • Non-fatal strokes will be classified as ischemic, hemorrhagic, or unknown.
  • the term “unstable angina requiring unplanned revascularization” is defined as no elevation in cardiac biomarkers and clinical presentation (one of the following) with cardiac symptoms lasting ⁇ 10 minutes and considered to be myocardial ischemia on final diagnosis (rest angina or new onset ( ⁇ 2 months) severe angina (CCS classification severity ⁇ III; Grading of Angina Pectoris According to Canadian Cardiovascular Society Classification) or increasing angina (in intensity, duration and/or frequency) and severe recurrent ischemia requiring urgent revascularization: as defined by an episode of angina prompting the performance of coronary revascularization on the index hospitalization or an episode of recurrent angina after discharge that resulted in re-hospitalization during which coronary revascularization was performed; and at least one of the following: new or worsening ST or T segment changes on ECG, ST Elevation (new ST elevation at the J point in two anatomically con
  • coronary revascularization“ is defined as an invasive procedure, which usually follows coronary angiography, wherein either percutaneous transluminal intervention, followed by Stent Placement, Balloon Angioplasty, or CABG is performed to relieve obstructed coronary arteries.
  • a team of medical professionals lead by either an invasive cardiologist (percutaneous transluminal intervention, followed by stent placement, balloon angioplasty) or a thoracic surgeon (CABG), who performs the described procedures.
  • the term ”non-coronary revascularization“ is defined as vascular surgery or percutaneous intervention.
  • Vascular surgery is defined as the placement of a conduit with or without proximal and/or distal anastamoses.
  • Percutaneous intervention is defined as balloon inflation with or without stenting.
  • the term “atherosclerosis” occurs when fatty material and a substance called plaque builds up on the walls of the arteries. This causes their lumen to get narrow.
  • the term “treat”, “treating”, “treatment”, “prevent”, “preventing” or “prevention” includes therapeutic treatments, prophylactic treatments and applications in which one reduces the risk that a subject will develop a disorder or other risk factor. Treatment does not require the complete curing of a disorder and encompasses the reduction of the symptoms or underlying risk factors.
  • the term “treating or preventing” includes the administration of a compound, e.g.
  • a NLRP3 inhibitor optionally in combination with at least one further therapeutic agent, to prevent or delay the onset of the symptoms, complications, or biochemical indicia of a disease, condition, disorder, or syndrome (e.g., for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations.
  • Treatment may be prophylactic (to prevent or delay the onset of the disease, condition, disorder, or syndrome, or to prevent the manifestation of clinical or subclinical symptoms thereof) or therapeutic suppression or alleviation of symptoms after the manifestation of the disease, condition, disorder, or syndrome.
  • recurrent CV event is a repeated CV event taking place after the myocardial infarction and comprises non-fatal MI, non-fatal stroke, cardiovascular (CV) death and hospitalization for unstable angina requiring unplanned revascularization. Accordingly, in one embodiment of any method or use of the invention, said recurrent CV event is selected from non-fatal MI, non-fatal stroke, cardiovascular (CV) death and hospitalization for unstable angina requiring unplanned revascularization. In another embodiment of any method or use of the invention, said recurrent CV event is selected from non-fatal MI, non-fatal stroke and cardiovascular (CV) death.
  • said recurrent CV event is non-fatal MI or cardiovascular (CV) death.
  • said recurrent CV event is non- fatal MI.
  • the term “NLRP3 inhibitor” is a compound that inhibits the ability of NLRP3 to induce the production of IL-1 ⁇ and/or IL-18 by directly binding to NLRP3, or by PAT059585-WO-PCT inactivating, destabilizing, altering distribution, of NLRP3 or otherwise.
  • a NLRP3 inhibitor has an IC50 of ⁇ 1 ⁇ M of IL-1 ⁇ secretion in the hTHP-1 assay containing 2% fetal bovine serum defined herein.
  • Compound I for example, represents each of a non- racemic mixture of Compound IA or Compound IB, a racemic mixture of Compound IA or Compound IB; Compound IA in enantiomerically pure form; or Compound IB in enantiomerically pure form.
  • “Compound I” is also intended to include enantiomeric excesses of either Compound IA or Compound IB.
  • Compound IA may be present in an enantiomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5%.
  • Compound IB may be present in an enantiomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5%.
  • Any chemical formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Isotopes that can be incorporated into compounds of the disclosure include, for example, isotopes of hydrogen, carbon, nitrogen, and oxygen, such as 3 H, 11 C, 13 C, 14 C, and 15 N. Accordingly, it should be understood that methods of the present invention can or may involve compounds that incorporate one or more of any of the aforementioned isotopes, including for example, radioactive isotopes, such as 3 H and 14 C, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • Such isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, e.g., using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • PAT059585-WO-PCT The present invention encompasses embodiments that include all pharmaceutically acceptable salts of the compounds useful according to the invention provided herein.
  • pharmaceutically acceptable salt refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are .
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are .
  • Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines.
  • the salt can be a hydrochloride salt.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • dose or amount of NLRP3 inhibitor, e.g. Compound I, or a pharmaceutically acceptable salt thereof, refers to the amount of the free base or free acid form of the compound.
  • an “effective amount” refers to an amount sufficient to effect beneficial or desired results.
  • a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease, condition, disorder, or syndrome or related symptoms.
  • An effective amount can be administered in one or more administrations, PAT059585-WO-PCT applications or dosages.
  • a “therapeutically effective amount” of a therapeutic compound i.e., an effective dosage) depends on the therapeutic compounds selected.
  • compositions can be administered from one or more times per day to one or more times per week, and also include less frequent administration, e.g., as described herein.
  • dosage and timing required to effectively treat a subject including but not limited to the severity of the disease, condition, disorder, or syndrome, previous treatments, the general health and/or age of the subject, and other concurrent diseases, conditions, disorders, or syndromes.
  • treatment of a subject with a therapeutically effective amount of the therapeutic compounds described herein can include a single treatment or a series of treatments.
  • “combination” refers to either a fixed combination in one unit dosage form (e.g., capsule, tablet, sachet or vial), free (i.e., non-fixed) combination, or a kit of parts for the combined administration where Compound I, or a pharmaceutically acceptable salt thereof, and the one or more additional therapeutic agents may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g., synergistic effect.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of an additional therapeutic agent to a single subject in need thereof (e.g., a subject), and the additional therapeutic agent are intended to include treatment regimens in which Compound I and additional therapeutic agent are not necessarily administered by the same route of administration and/or at the same time.
  • Each of the components of the presently described combination may be administered simultaneously or sequentially and in any order.
  • Co-administration comprises simultaneous, sequential, overlapping, interval, and/or continuous administrations and any combination thereof.
  • pharmaceutical combination as used herein means a pharmaceutical composition that results from the combining (e.g., mixing) of more than one active ingredient and includes both fixed and free combinations of the active ingredients.
  • fixed combination means that the active ingredients are administered to a subject simultaneously in the form of a single entity or dosage.
  • free combination means that the active ingredients as defined herein are administered to a subject as separate entities either simultaneously, PAT059585-WO-PCT concurrently or sequentially with no specific time limits, and in any order, wherein such administration provides therapeutically effective levels of the compounds in the subject’s body.
  • reference to the combination comprising a) Compound I and b) at least one additional therapeutic agent as used herein refers to a “non-fixed combination” and may be administered independently at the same time or separately within time intervals.
  • spontaneous administration it is meant that the active ingredients as defined herein, are administered on the same day.
  • the active ingredients can be administered at the same time (for fixed or free combinations), or one at a time (for free combinations).
  • simultaneous administration may mean that during a period of two or more days of continuous co-administration only one of active ingredients as herein defined, is administered on any given day.
  • overlapping administration it is meant that during a period of two or more days of continuous co-administration, there is at least one day of simultaneous administration and at least one day when only one of active ingredients as herein defined, is administered.
  • continuous administration it is meant a period of co-administration without any void day.
  • the continuous administration may be simultaneous, sequential, or overlapping, as described above.
  • NLRP3 is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous NLRP3 molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.
  • Doses and Dosing Regimens comprise administering a NLRP3 inhibitor according to a dosing regimen.
  • the dosing regimen comprises administering a NLRP3 inhibitor at a total daily dose of about 10 mg to about 100 mg in a single dose or divided doses to a subject as defined herein.
  • the dosing regimen comprises administering a NLRP3 inhibitor at a total daily dose of about 10 mg to about 50 mg in a single dose or divided doses to a subject as defined herein.
  • the dosing regimen comprises administering a NLRP3 inhibitor at a total daily dose of about 25 mg in a single dose or divided doses to a subject as defined herein.
  • the dosing regimen comprises administering a NLRP3 inhibitor at a total daily dose of about 50 mg in a single dose or divided doses to a subject as defined herein.
  • the doses are administered to a subject during or after consuming food.
  • the time interval between the administration of two subsequent doses is about 22-26 hours.
  • the methods of treatment relates to reducing the risk of or preventing cardiovascular events (CVE) or cardiovascular diseases (CVD), which can be recurrent CVEs or CVDs.
  • CVE cardiovascular events
  • CVD cardiovascular diseases
  • the method of treatment relates reducing circulating levels of inflammatory markers, as determined by change from baseline; particularly, the method of treatment relates to reducing circulating levels of inflammatory markers selected from IL-6 serum levels, IL-18 serum levels, hsCRP, soluble ASC, IL-1 ⁇ , CXL9, CXCL10, hsIFNg, von- Willebrand-Factor (vWF), myeloid/lymphoid cell activation/enumeration by flow cytometry (whole blood/PBMC) and lipid parameters (e.g.
  • the method of treatment relates to reducing circulating levels of inflammatory markers selected from IL-6 serum levels, IL-18 serum levels and hsCRP.
  • the subject in the methods of treatment is a human subject.
  • the subject has a high hsCRP level of ⁇ 2 mg/L before first administration of the NLRP3 inhibitor.
  • PAT059585-WO-PCT In another embodiment 8.2, the NLRP3 inhibitor is administered at the earliest 30 days after MI, and wherein said subject has a reduced hsCRP level of ⁇ 2 mg/L assessed approximately 3 weeks after first administration of the NLRP3 inhibitor.
  • the subject in the methods of treatment has a known coronary heart disease, and particularly the subject is known to be a carrier of a clonal expansion of hematopoietic cell lines with somatic mutations (e.g., like the above described subject carrying at least one mutation in one of the CHIP driver genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2), wherein at least one unique mutation is present at a variant allele frequency (VAF) ⁇ 2%.
  • somatic mutations e.g., like the above described subject carrying at least one mutation in one of the CHIP driver genes TET2, DNMT3A, ASXL1, PPM1D, TP53, SF3B1, SRSF2 or JAK2
  • VAF variant allele frequency
  • the administration of the NLRP3 inhibitor reduces the risk of or preventing cardiovascular events (CVE) or cardiovascular diseases (CVD), wherein the cardiovascular diseases or cardiovascular event are selected from non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, and hospitalization for unstable angina requiring unplanned revascularization.
  • the cardiovascular diseases or cardiovascular event is non-fatal myocardial infarction.
  • the cardiovascular diseases or cardiovascular event is non-fatal stroke.
  • the cardiovascular diseases or cardiovascular event is cardiovascular death.
  • the cardiovascular diseases or cardiovascular event is cardiovascular death.
  • the cardiovascular diseases or cardiovascular event is hospitalization for unstable angina requiring unplanned revascularization.
  • the level of hsCRP in the subject assessed approximately 3 weeks after first administration of a NLRP3 inhibitor as described herein, is reduced in by at least about 20%, about 30%, about 40%, about 50%, PAT059585-WO-PCT about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200% or more, as determined by change from baseline.
  • the patient has a reduced hsCRP level of ⁇ 2 mg/L, e.g., 1.9, ⁇ 1.8, ⁇ 1.7, ⁇ 1.6, ⁇ 1.5, ⁇ 1.4, ⁇ 1.3, ⁇ 1.2, ⁇ 1.1, ⁇ 1.0, ⁇ 0.9, ⁇ 0.8, ⁇ 0.7, ⁇ 0.6, or ⁇ 0.5 mg/L, assessed approximately 3 weeks, approximately 6 weeks, approximately 3 months, approximately 6 months or approximately 9 months after first administration of a NLRP3 inhibitor as described herein, as determined by change from baseline.
  • a reduced hsCRP level of ⁇ 2 mg/L, e.g., 1.9, ⁇ 1.8, ⁇ 1.7, ⁇ 1.6, ⁇ 1.5, ⁇ 1.4, ⁇ 1.3, ⁇ 1.2, ⁇ 1.1, ⁇ 1.0, ⁇ 0.9, ⁇ 0.8, ⁇ 0.7, ⁇ 0.6, or ⁇ 0.5 mg/L, assessed approximately 3 weeks, approximately 6 weeks, approximately 3 months, approximately 6 months or approximately 9 months after first administration of a NLRP3 inhibitor as
  • the level of IL-6 assessed approximately after daily administration for 3 weeks of a NLRP3 inhibitor is reduced in by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200% or more, as determined by change from baseline.
  • the subject does not exhibit any skin rash.
  • the NLRP3 inhibitor is administered to the subject orally.
  • the NLRP3 inhibitor is comprised in a tablet formulation.
  • at least one further therapeutic agent is administered.
  • the NLRP3 inhibitor is Compound I, or a pharmaceutically acceptable salt thereof: H 2 N O O .
  • inhibitor is Compound IA, or a pharmaceutically acceptable salt thereof.
  • PAT059585-WO-PCT Compound IA has an enantiomeric excess of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5%.
  • the NLRP3 inhibitor is Compound IB, or a pharmaceutically acceptable salt thereof.
  • Compound IB has an enantiomeric excess of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5%.
  • the above embodiments of the present invention may be combined with other embodiments disclosed herein.
  • the NLRP3 inhibitor for use according to embodiments 27 or 27.1 wherein the NLRP3 inhibitor is administered to a subject at a total daily dose of about 50 mg in a single dose or divided doses.
  • the NLRP3 inhibitor for use according to embodiments 27 or 27.1 wherein the NLRP3 inhibitor is administered to a subject at a dose of about 10 mg twice daily.
  • the NLRP3 inhibitor for use according to any one of embodiments 27 to 27.4 wherein the NLRP3 inhibitor is administered to a subject for about 21 consecutive days.
  • the NLRP3 inhibitor for use according to any one of embodiments 27-27.5 wherein the NLRP3 inhibitor is administered to a subject during or after consuming food.
  • CVE cardiovascular events
  • CVD cardiovascular diseases
  • the NLRP3 inhibitor for use according to any one of embodiments 27-27.8, the level of hsCRP in the subject, assessed approximately 3 weeks after first administration of a NLRP3 inhibitor as described herein, is reduced in by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200% or more, as determined by change from baseline.
  • the NLRP3 inhibitor for use according to any one of embodiments 27-27.10, the level of IL-6 assessed approximately after daily administration for 3 weeks of a NLRP3 inhibitor is reduced in by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200% or more, as determined by change from baseline.
  • NLRP3 inhibitor for use according to any one of embodiments 27-27.16, wherein the NLRP3 inhibitor is Compound IA, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a NLRP3 inhibitor of embodiments 27 to 27.21, for use according to any one of embodiments 27 to 27.21.
  • Compound I of the below embodiments is Compound IA (i.e. the R enantiomer) in an enantiomeric excess of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5%.
  • Compound IA is in enantiomeric excess of at least 90%. More preferably, Compound IA is in enantiomeric excess of at least 95%.
  • a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is a tablet.
  • the pharmaceutical composition is administered as a whole or crushed tablet.
  • the pharmaceutical composition includes about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg in each unit dose.
  • PAT059585-WO-PCT Provided herein is a pharmaceutical composition comprising Compound I, or a pharmaceutically acceptable salt thereof, for use in any of the embodiments described herein.
  • Compound I, or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof orally.
  • Compound I is in the form of a tablet that is administered either whole or subdivided, i.e., crushed prior to administration.
  • Compound I may be administered via a nasogastric tube.
  • Synthesis of Compound I Compounds I, IA and IB were synthesized in accordance with the synthesis defined in WO2019/023147 for examples 4, 5 and 6, and as detailed below. The compounds, however, may be assembled in various ways, building up the final molecules using related reaction procedures in a modular fashion which allows for different reaction orders and/or different reagents. The progress of reactions was often monitored by TLC or LC-MS.
  • the identity of the products was often confirmed by LC-MS.
  • the LC-MS was recorded using the following method: Method A: Shim-pack XR-ODS, C18, 3x50 mm, 2.5 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 5-100% (1.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA) and water (0.05% TFA), 2 minute total run time.
  • the final targets were purified by Prep-HPLC.
  • the Prep-HPLC was carried out using the following method: Method B: Prep-HPLC: Column, XBridge Shield RP18 OBD (19x250 mm, 10 um); mobile phase, Water (10mmol/L NH4HCO3) and ACN, UV detection 254/210 nm. NMR was recorded on BRUKER NMR 300.03 MHz, DUL-C-H, ULTRASHIELDTM300, AVANCE II 300 B-ACSTM120 or BRUKER NMR 400.13 MHz, BBFO, ULTRASHIELDTM400, AVANCE III 400, B-ACSTM120 or BRUKER AC 250 NMR instrument with TMS as reference measured in ppm (part per million).
  • Step 2 N'-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimidamide: PAT059585-WO-PCT Into a 50-mL round-bottom flask was placed a solution of N-(tert-butyldimethylsilyl)-N'- (1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide (535 mg, crude, 1.0 mmol) in THF (10 mL).
  • Compound IA and Compound IB H 2 N O H O 2 N O O
  • the Compound I product obtained as described in the previous step was resolved by Chiral-Prep-HPLC using the following conditions: Column, CHIRAL Cellulose-SB, 2*25 cm, 5 um; mobile phase, Hex (0.1%DEA) and EtOH (hold 20% EtOH over 16 min); Flow rate, 20 mL/min; Detector, UV 254/220 nm. This resulted in 70 mg of Compound IB (front peak, 99% ee) as a white solid and 65 mg of Compound IA (second peak, 97.5% ee) as a white solid.
  • Step 2 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole-5-sulfonamide: Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-(2-methyl-1,3-dioxolan-2-yl)thiazole (14 g, 81.6 mmol) in THF (200 mL). This was followed by the addition of n-BuLi (2.5 M in THF, 35.2 mL, 88.0 mmol) dropwise with stirring at -78 o C. The resulting solution was stirred for 0.5 h at -78 o C and then SO 2 was introduced into the above reaction mixture.
  • 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole-5-sulfonamide Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-(2-methyl
  • Step 3 2-Acetylthiazole-5-sulfonamide: Into a 250-mL round-bottom flask was placed a solution of 2-(2-methyl-1,3-dioxolan-2- yl)thiazole-5-sulfonamide (12.5 g, 50.0 mmol) in THF (125 mL). To the above was added aq. HCl (4 N, 50.0 mL). The resulting solution was stirred for 6 h at 70 o C.
  • Step 2 Methyl 2-(chlorosulfonyl)thiazole-5-carboxylate: Into a 1-L round-bottom flask was placed methyl 2-mercaptothiazole-5-carboxylate (30 g, 170 mmol) and acetic acid (300 mL). This was followed by the addition of sodium hypochlorite (300 mL, 8%-10% wt.) in portions at 0oC. The resulting solution was stirred for 2 h at RT and then was diluted with 500 mL of water.
  • Step 3 Methyl 2-sulfamoylthiazole-5-carboxylate: Into a 2-L round-bottom flask was placed methyl 2-(chlorosulfonyl)thiazole-5-carboxylate as a crude solution in DCM (900 mL). To the solution was introduced NH3 (g) below 0oC for 20 minutes. The resulting solution was stirred for 1 h at RT and then concentrated under vacuum.
  • Step 5 N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide: Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide (5 g, 22.5 mmol) in THF (100 mL). Then to the above was added NaH (60% wt, 1.8 g, 45.0 mmol) in portions in an ice/water bath.
  • Step 6 N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide: Into a 100-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of PPh 3 Cl 2 (3 g, 9.0 mmol) in CHCl 3 (100 mL). This was followed by the addition of DIEA (1.54 g, 11.9 mmol) dropwise with stirring at RT. The resulting solution was stirred for 10 min at RT.
  • TBS tert-butyldimethylsilyl
  • TBSCl tert-butyldimethylsilyl chloride
  • TBDPSCl tert-butyldiphenylsilyl chloride
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • TLC thin layer chromatography
  • Example 1 Therapeutic use in adults with coronary heart disease and elevated hsCRP (high-sensitivity C-reactive protein) A randomized, placebo-controlled, parallel-group, investigator- and participant-blinded Phase 2a study to investigate the efficacy, safety, and tolerability of compound IA for inflammatory marker reduction in adult participants with coronary heart disease and elevated high-sensitivity C-reactive protein (hsCRP).
  • hsCRP high-sensitivity C-reactive protein
  • the justification for the estimand is that it will capture the effect of the investigational treatment versus placebo under research-like conditions, where participants adhere to their assigned treatment regimen and there is no impact of other intercurrent events on the primary endpoints (aside from potential changes in standard of care cardiovascular disease prevention medication).
  • the estimand is defined by the following attributes: Population: patients with known coronary heart disease, elevated hsCRP, and background cardiovascular disease prevention medication. Endpoints: Serum IL-6 and IL-18 levels at 3 weeks after the start of a dosing period.
  • Treatment of interest COMPOUND IA once daily (QD) or placebo QD. Handling of intercurrent events: see Table 1 Summary measure: the model-based difference in variable means between treatments.
  • Participants who don't meet hsCRP levels at Screening 1 visit will be considered screen failures. Participants meeting all eligibility criteria will be randomized in a 5:5:1:1 ratio to one of four treatment sequences (three COMPOUND IA treatment sequences or a placebo-only sequence). Within each COMPOUND IA sequence, participants will start on either oral placebo or COMPOUND IA 10 mg QD. On Day 1, participants will receive the first oral dose of COMPOUND IA or placebo. After initial dosing, assessments will be conducted at site. Participants will then be provided with a sufficient amount of study medication for daily dosing until their next scheduled visit.
  • COMPOUND IA The dose of COMPOUND IA will be uptitrated (according to the specific treatment sequence that the participant is assigned to) approximately every three weeks at the scheduled visits on Days 22, 43 and 64, as shown in the study design figure ( Figure 1). At these visits, efficacy, safety, and tolerability assessments will be performed. Participants will take oral daily doses of COMPOUND IA for a total of approximately 12 weeks. Participants will return for an end of treatment (EoT) period visit on Day 85. After the EoT visit, participants will return approximately 1 week later (Day 92) for an EoS. 1.2.2 Scientific rationale for study design
  • Treatment Sequence 1 and Treatment Sequence 2 participants begin with placebo treatment and are followed with increasing doses of COMPOUND IA.
  • Treatment Sequence 3 and Treatment Sequence 4 were primarily included to maintain the blind in each dosing period so that there is both active and placebo within each dosing period.
  • Treatment Sequence 4 in addition, will generate more placebo data, which is useful for the primary analysis. More participants are allocated to Treatment Sequence 1 and Treatment Sequence 2 as they will contribute intra- individual placebo data, thereby making analyses more efficient. Randomization Participants will be randomized in a 5:5:1:1 ratio to the 4 treatment sequences.
  • Randomization is used to limit selection bias and decrease the chance of an imbalance in participant characteristics between sequences, thereby facilitating an unbiased assessment of the effect of treatment.
  • baseline clinical characteristic imbalances may occur across the sequences. This has limited consequence in this study design as most of the participants serve as their own placebo controls with intra- individual dose-response modeling rather than comparison between two equal active and placebo treatment arms. Blinding Blinding of participants and investigators during the study allows for an unbiased assessment of study endpoints.
  • the follow-up period up to Day 114 allows for adequate safety monitoring over a period of approximately 5 half-lives.
  • P lacebo comparator The use of placebo provides a comparison group for an unbiased collection and assessment of safety, tolerability, efficacy, and PD parameters.
  • the study design includes both inter- and intra-individual placebo comparators. Justification for dose In this study, film-coated tablets with 10 or 25 mg COMPOUND IA will be administered orally to achieve doses of 10 mg, 25 mg, 50 mg, and 100 mg. Within each COMPOUND IA treatment sequence, participants will start with either placebo or COMPOUND IA 10 mg dose given QD for approximately three weeks.
  • COMPOUND IA mean Ctrough at steady state for 10 mg suspension QD (fasted) was 183 ng/mL (CV% 64.4%), thus exceeded IC50.
  • Dosing of single 100 mg tablet under fasted and PAT059585-WO-PCT fed conditions resulted in 24 h-plasma levels of 1260 ng/mL (CV% 46.6) and 1670 ng/mL (CV% 49.0%), respectively. Trough levels at steady state are roughly 20% higher based on accumulation ratio. Assuming plasma levels above IC90 for a 24 h-period are needed to maintain complete target occupancy, the highest dose of 100 mg COMPOUND IA given once daily is proposed in this study.
  • COMPOUND IA was, in general, well tolerated in healthy participants and patients when dosed for up to 2 weeks in completed clinical studies. Skin reactions were reported when dosed with 30 mg, 100 mg, or 200 mg suspension QD, or with 50 mg tablet twice a day (BID). Skin reactions were not reported when dosed as 10 mg suspension QD or 25 mg tablet BID. All skin-related events were graded to be of mild or moderate intensity, started 5 to 17 days after treatment initiation and resolved following treatment discontinuation within 1 to 18 days after onset. Skin-related events were not reported in any animal toxicology studies and the mechanism causing rash is likely T-cell driven.
  • cytochrome P4502C9 CYP2C9
  • cytochrome P4503A4 CYP3A4
  • the systemic COMPOUND IA exposure in participants who are poor CYP2C9 metabolizers is likely to be approximately 3-fold higher compared to normal (extensive) metabolizers (*1*1) due to decreased or no CYP2C9 activity.
  • the safety for the COMPOUND IA doses and treatment duration is supported by GLP toxicology studies in rat and cynomolgus monkey. Overall, on average for 100 mg QD of COMPOUND IA, the safety margins are 3 (26-week rat) and 7 (46-week monkey) based on PK in healthy participants (majority were normal CYP2C9 metabolizers).
  • Study completion is defined as when the last participant finishes their last study visit and any repeat assessments associated with this visit have been documented and followed-up appropriately by the Investigator. All randomized and/or treated participants should have a safety follow-up phone call conducted at least 30 days after last administration of study treatment. The information collected is kept as source documentation. Serious Adverse Event (SAE) reporting continues during this time period as described. Documentation of attempts to contact the participant are required to be recorded in the source documentation. Study population The study population is adults with known coronary heart disease and elevated hsCRP. In this study, approximately 24 participants will be enrolled. Inclusion criteria PAT059585-WO-PCT Participants eligible for inclusion in this study must meet all of the following criteria: 1. Written informed consent must be obtained before any assessment is performed. 2.
  • Diagnosis of the qualifying MI should be based on medical history of clinical symptoms consistent with myocardial ischemia associated with elevation of cardiac biomarkers above the 99th percentile of the upper reference limit (preferably troponin) OR development of new pathological Q waves regardless of symptoms.
  • the upper reference limit preferably troponin
  • Documentation in the medical history to support evidence of prior MI may include: • Evidence of an acute MI in hospitalization or medical records: • requires documentation of a rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit or above criteria diagnostic for MI AND • Evidence of myocardial ischemia as demonstrated by at least one of the following: • Symptoms of ischemia • ECG changes indicative of new ischemia (new ST-T changes or new LBBB) • Development of pathologic Q waves • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality If no documented evidence of an acute MI in the medical record, then evidence of a prior MI may include: • Development of pathological Q waves with or without symptoms • Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract in the absence of a non-ischemic cause PAT059585-WO-PCT • Pathologic findings of a healed or healing MI 6.
  • Participants must have hsCRP levels ⁇ 2 mg/L at two timepoints during screening. Screening values must be separated by a minimum of 8 days. The initial hsCRP value must be a minimum of 30 days after the qualifying MI or after any percutaneous coronary intervention (PCI) performed separately from the qualifying MI. 7.
  • PCI percutaneous coronary intervention
  • Patients receiving concomitant medications that are known to be: • strong or moderate inducers of cytochrome CYP2C9 enzyme, or • strong inducers of CYP3A, or • strong inhibitors of CYP2C9, or • strong or moderate inhibitors of CYP3A • and the treatment cannot be discontinued or switched to a different medication within 5 half-lives or 1 week (whichever is longer) prior to Day 1 and for the duration of the study. 2.
  • Use of other investigational drugs within 5 half-lives of Day 1, or until the expected pharmacodynamic effect has returned to baseline, whichever is longer. 3. History of hypersensitivity to any of the study treatments or excipients or to drugs of similar chemical classes. 4.
  • Unhealthy alcohol use may be considered with a history of, or current, alcohol misuse/abuse or “Five or more drinks on the same occasion on each of 5 or more days in the past 30 days.” However unhealthy alcohol use may be considered at lower level per investigator judgement based on the participant's history. 5. Pregnant or nursing (lactating) women. 6. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception for at least 3 months prior to first dose administration (Day 1), during dosing and for 7 days after stopping of investigational drug.
  • Highly effective contraception methods include: PAT059585-WO-PCT • Total abstinence from heterosexual intercourse (when this is in line with the and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. • Male sterilization (at least 6 months prior to screening).
  • the vasectomized male partner should be the sole partner for that subject.
  • oral hormonal contraception must be supplemented with a barrier method, preferable a male condom.
  • women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Women are considered post- menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential.
  • ICF Informed Consent Form
  • Any diagnosed psychiatric condition that includes, but is not limited to, a history of mania, bipolar disorder, psychotic disorder, schizophrenia, or schizoaffective disorder, depression or anxiety, which may jeopardize patient safety or compliance with study procedures, as judged by the investigator 10.
  • any immune modulating agent in doses with systemic effects e.g., high dose oral or intravenous (i.v.) steroids (> 20 mg prednisone orally daily for > 14 days, > 5 mg prednisone orally daily or equivalent dose of i.v. steroid) or high dose methotrexate (> 15 mg weekly).
  • Topical, inhaled, local steroid use in doses that are not considered to cause systemic effects are permitted.
  • any biologic drugs targeting the immune system for example, but not limited to: TNF blockers, anakinra, rituximab, abatacept, tocilizumab, or canakinumab) within 26 weeks of Day 1. 14.
  • a systemic auto-immune disease eg. systemic lupus erythematosus, etc.
  • Current use or within 5 half-lives of colchicine at the start of screening. 16. Participants with a MI resulting from PCI or CABG procedures. 17. Major non-cardiac surgical or major endoscopic procedure within the past 6 months prior to the start of screening. 18. Multi-vessel CABG surgery within the past 3 years prior to the start of screening. 19. Planned coronary revascularization (PCI or CABG) or any other major surgical procedure during the study (until EOS). PAT059585-WO-PCT 20. Symptomatic Class IV heart failure (New York Heart Association) at the start of screening. 21.
  • PCI or CABG Planned coronary revascularization
  • PAT059585-WO-PCT 20. Symptomatic Class IV heart failure (New York Heart Association) at the start of screening. 21.
  • Clinical and laboratory evidence of uncontrolled diabetes may include but are not limited to hemoglobin A1C >9%, recurrent fasting glucose >200mg/dL, frequent urination/thirst not explained by other causes, etc. 24.
  • liver disease or liver injury at screening as indicated by abnormal liver enzymes or function tests (as defined below) including but not limited to Alanine Aminotransferase (ALT), Aspartate Transaminase (AST), Serum Glutamic Oxaloacetic Transaminase (SGOT), Serum Glutamic Pyruvic Transaminase (SGPT), alkaline phosphatase (ALP), serum bilirubin, albumin, and prothrombin time (PT).
  • ALT Alanine Aminotransferase
  • AST Aspartate Transaminase
  • SGOT Serum Glutamic Oxaloacetic Transaminase
  • SGPT Serum Glutamic Pyruvic Transaminase
  • ALP alkaline phosphatase
  • serum bilirubin albumin
  • prothrombin time PT
  • the demographic information, informed consent, and Inclusion/Exclusion pages must also be completed for screen failure participants. No other data will be entered into the clinical database for participants who are screen failures, unless the participant experienced a SAE during the screening period. If the participant fails to be randomized, the Interactive Response Technology (IRT) must be notified within 2 days of the screen fail that the participant was not randomized. Data and samples collected from participants prior to screen failure may still be analyzed. Participants who are randomized and fail to start treatment, e.g., participants randomized in error, will be considered an early terminator. The reason should be recorded on the appropriate Case Report Form. Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened once.
  • IRT Interactive Response Technology
  • Participant numbering Each participant is identified in the study by a Participant Number (Participant No.), that is assigned when the participant is enrolled for screening and is retained for the participant throughout his/her participation in the trial. A new Participant No. will be assigned at every subsequent enrollment if the participant is rescreened.
  • the Participant No. consists of the Site Number (Site No.) (as assigned by Novartis to the investigative site) with a sequential participant number suffixed to it, so that each participant’s participation is numbered uniquely across the entire database. Upon signing the ICF, the participant is assigned to the next sequential Participant number available.
  • COMPOUND IA The investigational drug, COMPOUND IA, will be prepared by the sponsor (Novartis) as indicated in Table 2. COMPOUND IA will be administered orally with food once a day (QD).
  • Table 2 Investigational and control drug Investigational/ Treatment Form Route of Presentation Sponsor (global Control Drug or Administration or local) (Name and Pharmaceutical Strength) Dosage Form COMPOUND IA Tablet Oral use Blinded Supplies Sponsor (global) 10 mg in HDPE Bottle of 35 tablets COMPOUND IA Tablet Oral use Blinded Supplies Sponsor (global) 25 mg in HDPE Bottle of 35 tablets COMPOUND IA Tablet Oral use Blinded Supplies Sponsor (global) 10 mg Placebo in HDPE Bottle of 35 tablets COMPOUND IA Tablet Oral use Blinded Supplies Sponsor (global) 25 mg Placebo in HDPE Bottle of 35 tablets Additional study treatments No other treatment beyond investigational drug and control drug are included in this trial.
  • cardiovascular disease events eg. lipid lowering therapy, anti-hypertensives, etc..
  • Each 3-week dosing period (i.e., Day 1-21, Day 22-42, Day 43-63, and Day 64-84) is approximately 21 days in duration but must be at least 17 days in duration.
  • the following/next PAT059585-WO-PCT visit should be scheduled the day after the last dose of that current dosing period.
  • the participants In the event that an uptitration visit cannot be scheduled within the allowed visit windows, the participants should continue to take their dose up to a maximum of 35 days (maximum number of tablets dispensed for a given dosing period) and every effort should be made to schedule the visit before the participant's supply of tablets for the given period runs out.
  • a visit should be scheduled as soon as possible to only perform safety assessments (Safety/Tolerability Assessments). Other non-safety assessments (Efficacy assessments) must not be performed. Participants will then start the next dosing period as applicable. The last dose will be taken on Day 84 prior to the EOT visit on Day 85. To achieve the target doses for each time period, please refer to Table below. Participants are to take COMPOUND IA or placebo once daily at approximately the same time each day. On days of study visits with dose administration, the participants should not take their daily dose until they are on-site and instructed to do so by the site staff.
  • the participant On days that pre-dose PK samples are obtained, the participant should take COMPOUND IA or placebo after the pre- dose PK samples, as instructed by site staff. In the event that the participants have taken their daily dose on the visit day prior to arriving for their on-site visit, the visit and associated assessments should be rescheduled as soon as possible (e.g., next day or after the weekend). Participants should take COMPOUND IA or placebo at home with food or no later than 5 minutes after completion of the meal with a glass of water or any non-alcoholic beverage. Participants should be instructed to swallow whole tablets and not to chew or break them. On days of study visits with dose administration, COMPOUND IA or placebo does not need to be taken with food.
  • a missed dose is defined as a case when the full dose is not taken within 12h after the approximate time of the usual daily dosing. That day's dose should be omitted, and the participant should continue treatment with the next scheduled dose.
  • Example 2 Therapeutic use in adult participants with coronary heart disease and clonal hematopoiesis of indeterminate potential (CHIP) A randomized, placebo-controlled, parallel-group, investigator- and participant-blinded Phase 2a study to investigate the efficacy, safety, and tolerability of COMPOUND IA for inflammatory marker reduction in an adult population with coronary heart disease and Clonal Hematopoiesis of Indeterminate Potential (CHIP).
  • CHIP indeterminate potential
  • PAT059585-WO-PCT Overall design This is a multi-center, randomized, placebo-controlled, participant- and investigator-blinded study to evaluate the efficacy, safety, and tolerability of intra-individual dose escalation of COMPOUND IA for inflammatory marker reduction in participants with coronary heart disease and TET2 or DNMT3A CHIP (VAF ⁇ 2%).
  • the study consists of a screening period up to 30 days; a treatment period of approximately 12 weeks with an end of treatment (EOT) visit on Day 85, which is one day after the last dose of COMPOUND IA or placebo; a follow- up period of approximately 1 week; and a standard safety follow-up call approximately 30 days following the last dose.
  • the overall study duration is approximately 21 weeks.
  • patients with TET2 or DNMT3A CHIP will be determined based on their most common mutation (e.g., patients with mutations in both DNMT3A + TET2 will be allocated to the subgroup based on the mutation with the highest VAF).
  • Participants meeting all eligibility criteria will be randomized in a 4:4:4:1:1 ratio to one of the five treatment sequences as shown in Figure 2 (1 bispecific antibody (antibody binding to two different targets, such as IL-18 and IL-1 ⁇ )+-placebo sequence, 3 COMPOUND IA+placebo sequences, and 1 placebo-only sequence).
  • COMPOUND IA+placebo sequence participants will start on either oral placebo or COMPOUND IA 10 mg QD. On Day 1, participants will receive the first oral dose of COMPOUND IA or placebo. None of the treatment sequences include a combination of both active COMPOUND IA and bispecific antibody (antibody binding to two different targets, such as IL-18 and IL-1 ⁇ ). After initial dosing, assessments will be conducted at site. Participants will then be provided with a sufficient amount of study medication for daily dosing until their next scheduled visit. If applicable, the dose of COMPOUND IA will be uptitrated (according to the specific treatment sequence to which the participant is assigned) approximately every three weeks at the scheduled visits on Days 22, 43 and 64 as shown in the study design figure ( Figure 1).
  • Treatment Sequence 2 and Treatment Sequence 3 participants begin with placebo treatment and are followed with increasing doses of COMPOUND IA.
  • Treatment Sequence 4 and Treatment Sequence 5 are primarily included to maintain the blind in each dosing period so that there is both active and placebo within each dosing period.
  • Treatment Sequence 5 in addition, will generate more placebo data, which is useful for the primary analysis. More participants are allocated to Treatment Sequence 2 and Treatment Sequence 3 as they will contribute intra-individual placebo data, thereby making analyses more efficient.
  • Randomization Participants will be randomized in a 4:4:4:1:1 ratio to the 5 treatment sequences. Randomization is used to limit selection bias and decrease the chance of an imbalance in participant characteristics between sequences, thereby facilitating an unbiased assessment of the effect of treatment. However, with a modest sample size and 5 treatment sequences, baseline clinical characteristic imbalances may occur across the sequences. This has limited consequence in this study design as most of the participants serve as their own placebo controls with intra-individual dose-response modeling rather than comparison between two equal active and placebo treatment arms. Blinding Blinding of participants and investigators during the study allows for an unbiased assessment of study endpoints.
  • film-coated tablets with 10 or 25 mg COMPOUND IA will be administered orally to achieve doses of 10 mg, 25 mg, 50 mg, and 100 mg.
  • participants will start with either placebo or COMPOUND IA 10 mg dose given QD for approximately three weeks. Participants will then receive three up- titrating COMPOUND IA doses up to 100 mg (or placebo), each for approximately three weeks as shown in the study design figure ( Figure 2).
  • the dose range 10-100 mg was selected based on data from the FIH study in healthy volunteers (Example 3).
  • COMPOUND IA was, in general, well tolerated in healthy participants and patients when dosed for up to 2 weeks in completed clinical studies (refer to IB for further details). Skin reactions were reported when dosed with 30 mg, 100 mg, or 200 mg suspension QD, or 50 mg tablet b.i.d. Skin reactions were not reported when dosed as 10 mg suspension QD or 25 mg tablet b.i.d. All skin-related events were graded to be of mild or moderate intensity, started 5 to 17 days after treatment initiation and resolved following treatment discontinuation within 1 to 18 days after onset. Skin- related events were not reported in any animal toxicology studies and the mechanism causing rash is likely T-cell driven.
  • CYP2C9 is a polymorphic enzyme. Based on the physiology-based PK prediction, the systemic COMPOUND IA exposure in participants who are poor CYP2C9 metabolizers (e.g., *3*3) is likely to be approximately 3-fold higher compared to normal (extensive) metabolizers (e.g., *1*1) due to decreased or no CYP2C9 activity.
  • the safety for the COMPOUND IA doses and treatment duration is supported by GLP toxicology studies in rat and cynomolgus monkey. Overall, on average for 100 mg QD of COMPOUND IA, the safety margins are 3 (26-week rat) and 7 (46-week monkey) based on PK in healthy participants (majority were normal CYP2C9 metabolizers). Up to 3-fold lower safety margins are expected in patients who are intermediate or poor CYP2C9 metabolizers (for further details see IB). Supported by sufficient safety margins, all eligible participants irrespective of CYP2C9 genotype are allowed to participate in the study.
  • Objectives, endpoints, and estimands PAT059585-WO-PCT Table 5 Objectives and related endpoints O bjective(s) Endpoint(s) P rimary objective(s) Endpoint(s) for primary objective(s) • To evaluate the effect of • Serum levels of IL-6 and IL-18 at 3 weeks after various dose levels of the start of a COMPOUND IA dosing period COMPOUND IA versus placebo to reduce circulating levels of inflammatory markers in participants with coronary heart disease and CHIP S econdary objective(s) Endpoint(s) for secondary objective(s) • To evaluate the safety and • Adverse events, and parameters from safety tolerability of COMPOUND IA assessments, including vital signs, in participants with coronary electrocardiograms (ECGs), and laboratory heart disease and CHIP assessments (urine and blood) • To assess the PK of • Plasma trough concentrations (C trough ) of COMPOUND IA in COMPOUND IA at steady-state participants with coronary heart disease and CHIP E
  • PD and inflammation-related markers may include COMPOUND IA on PD and but are not limited to hsCRP, soluble ASC, total inflammation-related, and IL-1 ⁇ , CXCL9, CXCL10, hsIFN- ⁇ , vWF, CVD-related biomarkers myeloid/lymphoid cell activation/enumeration by flow cytometry (whole blood/peripheral blood PAT059585-WO-PCT O bjective(s) Endpoint(s) (including PK/PD mononuclear cells (PBMC)), CVD-related relationships) biomarkers may include but are not limited to lipid parameters (e.g., LDL, Lp(a), apolipoproteins) 3.
  • lipid parameters e.g., LDL, Lp(a), apolipoproteins
  • proteomic drug-related include but are not limited to: response mechanisms, to 5. Presence of genetic polymorphisms understand the disease 6. Presence of somatic mutations (CHIP) and and/or the safety and efficacy their change from baseline of COMPOUND IA 7. Serum or plasma proteins and their change from baseline 6.
  • the justification for the estimand is that it will capture the effect of the investigational treatments versus placebo under research-like conditions, where participants adhere to their assigned treatment regimen and there is no impact of other intercurrent events on the primary endpoints (aside from potential changes in SoC CVD prevention medication).
  • the estimand is defined by the following attributes: • Population: participants with known coronary heart disease and TET2 or DNMT3A CHIP (VAF ⁇ 2%) and potential SoC CVD prevention medication • Endpoints: Serum levels of IL-6 and IL-18 at 3 weeks after the start of a dosing period for COMPOUND IA • Treatment of interest: COMPOUND IA QD or COMPOUND IA placebo QD • Handling of intercurrent events: see Table 6 • Summary measure: the model-based difference in variable means between treatments.
  • Circulation; 116:2634-53 Diagnosis of the qualifying MI should be based on medical history of clinical symptoms consistent with myocardial ischemia associated with elevation of cardiac biomarkers above the 99th percentile of the upper reference limit (preferably troponin) OR development of new pathological Q waves regardless of symptoms (for details, refer to the Universal Definition of MI (Thygesen K, Alpert JS, White HD et al (2007) Universal Definition of Myocardial Infarction. Circulation; 116:2634-53). Documentation in the medical history to support evidence of prior MI may include: 8. Evidence of an acute MI in hospitalization or medical records: 2.
  • TET2 or DNMT3A with somatic mutations in either of two genes, TET2 or DNMT3A, with VAF ⁇ 2%.
  • Participants may have a second or additional mutation in a different CHIP driver gene (e.g., DNMT3A + JAK2); however, the most common mutation (highest VAF) must be in either TET2 or DNMT3A.
  • Patients may have more than one different CHIP-driver mutation in the same gene (e.g., two unique known CHIP mutations in TET2) but at least one unique mutation must be present at VAF ⁇ 2%.
  • statin therapy HMG-CoA reductase inhibitor
  • participants must be on a stable regimen (at least 4 weeks before randomization), with no planned statin dose changes over the course of the trial treatment period. Unplanned statin dose changes during the trial treatment period may occur but must be documented.
  • 7. Able to communicate well with the investigator, to understand and comply with the requirements of the study. Exclusion criteria 1. Participants meeting any of the following criteria are not eligible for inclusion in this study.
  • Unhealthy alcohol use may be considered with a history of, or current, alcohol misuse/abuse or “Five or more drinks on the same occasion on each of 5 or more days in the past 30 days.” However unhealthy alcohol use may be considered at lower level per investigator judgement based on participant's history. 5. Any diagnosed psychiatric condition that includes, but is not limited to, a history of mania, bipolar disorder, psychotic disorder, schizophrenia, or schizoaffective disorder, depression or anxiety, which may jeopardize patient safety or compliance with study procedures, as judged by the Investigator. 6.
  • WOCBP defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception for at least 3 months prior to first drug administration (Day 1), during dosing and for 5 months of the placebo dose.
  • Highly effective contraception methods include: • Total abstinence from heterosexual intercourse (when this is in line with the and usual lifestyle of the participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
  • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug.
  • hormonal contraceptives must be supplemented by a barrier method, preferably a male condom.
  • a barrier method preferably a male condom.
  • women should be stable on the same pill for a minimum of 3 months before taking study treatment.
  • a condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above. 9. History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system within the past 5 years of the start of screening (except for basal cell carcinoma or actinic keratoses that have been treated with no evidence of recurrence in the past 3 months, or carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been removed). 10. At screening, pre-malignant clonal cytopenias or clonal cytopenia of unknown significance (CCUS).
  • Cytopenia in the context of clonal abnormalities is defined as an acquired and persistent anemia (hemoglobin ⁇ 12 g/dL in females and ⁇ 13 g/dL in males), neutropenia (ANC ⁇ 1.8 ⁇ 10 9 /L), and/or thrombocytopenia (platelets ⁇ 150 ⁇ 10 9 /L) that is not explained by another known or identifiable condition.
  • hemoglobin ⁇ 12 g/dL in females and ⁇ 13 g/dL in males neutropenia
  • thrombocytopenia platelets ⁇ 150 ⁇ 10 9 /L
  • any biologic drugs targeting the immune system for example, but not limited to: tumour necrosis factor (TNF) blockers, anakinra, rituximab, abatacept, tocilizumab, or canakinumab
  • TNF tumour necrosis factor
  • rituximab rituximab
  • abatacept tocilizumab
  • canakinumab a systemic auto-immune disease
  • Participants with a MI resulting from percutaneous coronary interventions (PCI) or coronary artery bypass graft (CABG) procedures.
  • PCI percutaneous coronary interventions
  • CABG coronary artery bypass graft
  • 20. Planned coronary revascularization (PCI or CABG) or any other major surgical procedure during the study (until EOS).
  • 21. Symptomatic Class IV heart failure (New York Heart Association [NYHA]) at the start of screening.
  • 22. History or current diagnosis of ECG abnormalities indicating significant risk of safety for participants participating in the study such as: • Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker • History of familial long QT syndrome or known family history of Torsades de Pointe 23.
  • Uncontrolled hypertension defined as systolic blood pressure (SBP) >160 mmHg or diastolic blood pressure (DBP) >100 mmHg
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • Uncontrolled diabetes as defined by the Investigator, at screening.
  • Clinical and laboratory evidence of uncontrolled diabetes may include but are not limited to: hemoglobin A1C >9%, recurrent fasting glucose >200 mg/dL, frequent urination/thirst not explained by other causes, etc.
  • liver disease or liver injury at screening as indicated by abnormal liver enzymes or function tests (as defined below) including but not limited to Alanine Aminotransferase (ALT), Aspartate Transaminase (AST), Serum Glutamic PAT059585-WO-PCT Oxaloacetic Transaminase (SGOT), Serum Glutamic Pyruvic Transaminase (SGPT), alkaline phosphatase (ALP), serum bilirubin, albumin and prothrombin time.
  • ALT Alanine Aminotransferase
  • AST Aspartate Transaminase
  • SGOT Serum Glutamic PAT059585-WO-PCT Oxaloacetic Transaminase
  • SGPT Serum Glutamic Pyruvic Transaminase
  • ALP alkaline phosphatase
  • serum bilirubin albumin and prothrombin time.
  • UPN upper limit of normal
  • the reason for screen failure should be recorded on the appropriate Case Report Form (CRF).
  • CRF Case Report Form
  • the demographic information, informed consent, and Inclusion/Exclusion pages must also be completed for screen failure participants. No other data will be entered into the clinical database for participants who are screen failures, unless the participant experienced a SAE during the screening period. If the participant fails to be randomized, the Interactive Response Technology (IRT) must be notified within 2 days of the screen fail that the participant was not randomized. Data and samples collected from participants prior to screen failure may still be analyzed. Participants who are randomized and fail to start treatment, e.g., participants randomized in error, will be considered an early terminator. The reason should be recorded on the appropriate CRF. Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened once.
  • Table 7 Investigational and control drug Treatment COMPOUN COMPOUN COMPOUN COMPOUN Bispecific Bispecific IL- Title D IA 10 mg D IA 25 mg D IA 10 mg D IA 25mg IL-1 ⁇ and 1 ⁇ and IL-18 Placebo Placebo IL-18 targeting targeting antibody antibody placebo Treatment 10 mg tablet 25 mg tablet 0 mg tablet 0 mg tablet 600 mg 0 mg single Description QD QD QD QD single injection injection T ype Drug Drug Drug Biologic Biologic Dose Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Solution for Solution for Formulation injection injection Unit Dose 10 mg 25 mg 0 mg 0 mg 100 mg/mL 0 mg/mL Strength(s) Dosage 10 mg QD 25 mg QD 0 mg QD 0 mg QD 600 mg 0 mg single Level(s) single dose dose Route of Oral Oral Oral Oral Injection Injection Administratio n U se Experimental Experimental Placebo Placebo Experiment Placebo al I MP Yes Yes Yes Yes Yes Yes Yes Yes Yes Sourcing Provide
  • Participants will be randomized to one of five treatment sequences ( Figure 2). Based on the treatment sequence assignments, participants will start on either a combination of COMPOUND IA and placebo, or placebo and placebo on Day 1, and then, within each COMPOUND IA treatment sequence, participants will receive up-titrating doses of COMPOUND IA or placebo at the corresponding study visits. Participants will be dispensed with COMPOUND IA double-blind high density polyethylene (HDPE) bottle packs for each 3-week dosing period to ensure the appropriate dosage is being taken while maintaining the blind.
  • HDPE high density polyethylene
  • Table 8 COMPOUND IA dose and treatment schedule D osing period Dose/strength Investigational / Frequency and/or Control Drug regimen (Name and Strength) + Number of Tablets Dosing Period 1 COMPOUND IA 10 1 tablet of QD with food for 3 (Day 1 to 21)* mg COMPOUND IA 10 weeks mg COMPOUND IA 0 1 tablet of 10 mg mg matching placebo PAT059585-WO-PCT Dosing Period 2 COMPOUND IA 10 1 tablet of QD with food for 3 (Day 22 to 42) mg COMPOUND IA 10 weeks mg + 1 tablet of 25 mg matching placebo COMPOUND IA 25 1 tablet of mg COMPOUND IA 25 mg +1 tablet of 10 mg matching placebo COMPOUND IA 0 1 tablet of 10 mg mg mg matching placebo + 1 tablet of 25 mg matching placebo Dosing Period 3 COMPOUND IA 50 2 tablets of QD with food for 3 (Day 43 to 62) mg COMPOUND IA 25 weeks mg COMPOUND IA 25 1 tablet of mg COMPOUND IA 25 mg
  • the following/next visit should be scheduled the day after the last dose of that current dosing period.
  • the participants should continue to take their dose up to a maximum of 35 days (i.e., the maximum number of tablets dispensed for a given dosing period) and every effort should be made to schedule the visit before the participant's supply of tables for the given period runs out.
  • PAT059585-WO-PCT If a participant runs out of tablets before the next visit can be scheduled, a visit should be scheduled as soon as possible to only perform safety assessments. Participants will then start the next dosing period as applicable. The last COMPOUND IA dose will be taken on Day 84 prior to the EOT visit on Day 85., SoA.
  • Table 9 Dose and treatment schedule Investigational / Control Dose Number of Frequency and/or Drug (Name and tablets Regimen Strength) COMPOUND IA 10 mg or 10 mg 1 QD with food for 3 matching placebo weeks COMPOUND IA 25 mg or 25 mg 1 QD with food for 3 matching placebo weeks COMPOUND IA 25 mg or 50 mg 2 QD with food for 3 matching placebo weeks COMPOUND IA 25 mg or 100 mg 4 QD with food for 3 matching placebo weeks Participants are to take COMPOUND IA or placebo QD at approximately the same time each day. On days of study visits with dose administration, the participants should not take their daily dose until they are on-site and instructed to do so by the site staff.
  • the participant On days that pre-dose PK samples are obtained, the participant should take COMPOUND IA or placebo after collection of the pre-dose PK samples, as instructed by site staff. In the event that the participants have taken their daily dose on the visit day prior to arriving for their on-site visit, the visit and associated assessments should be rescheduled as soon as possible (e.g., next day or after the weekend). Participants should take COMPOUND IA or placebo with food or no later than 5 minutes after completion of the meal with a glass of water or any non-alcoholic beverage. Participants should be instructed to swallow whole tablets and not to chew or break them. On days of study visits with dose administration, COMPOUND IA or placebo does not need to be taken with food.
  • a missed dose is defined as a case when the full dose is not taken within 12 hours after the approximate time of the usual daily dosing. That day's dose should be omitted, and the participant should continue treatment with the next scheduled dose. All kits of study treatment assigned by the IRT will be recorded in the IRT system.
  • SAD single ascending dose
  • Part B relative bioavailability of tablet formulations
  • MAD multiple ascending dose
  • Part D relative bioavailability and food effect
  • T2 Test Formulation 2 (crystalline tablet)
  • T3 Test Formulation 3 (spray-dried dispersion suspension)
  • Compound IA 3, 10, 30, 100, 300 mg of crystalline suspension and 100, 300, 600 mg of spray-dried dispersion (SDD) under fasted conditions.
  • SDD spray-dried dispersion
  • BMI body mass index
  • Part D Subjects participating in Part D had to be willing and able to consume the entire high-fat breakfast meal in the designated timeframe. Subjects were excluded if they had history of major psychiatric disorders, diagnosis of intellectual disability, clinically significant vital signs abnormality, and using tobacco products within 90 days prior to (the first) drug administration through follow-up. Blinding In Part A and C, active and placebo treatments could not be distinguished based on labelling, were identical in appearance, and were similar in taste and smell. To maintain the blind, the same number of tablet or suspension was given to each subject in respective cohort. The investigator and subjects remained blinded throughout the relevant part of the study, and the blind remained unbroken throughout.
  • the Sponsor IMM Management, Inc.
  • the Sponsor became unblinded with access to all study data and was provided with a copy of the randomization codes to support decision making concerning the study.
  • the Part D was open label, only Compound IA was administered in subjects to 1 of 6 treatment sequences (1 subject per sequence) according to a Williams design.
  • Objectives The primary objective of the study was to evaluate the safety and tolerability of SAD and MAD oral doses of Compound IA in healthy subjects in all parts of the study.
  • Key secondary objectives were to characterize the PK profile following single and multiple doses of Compound IA and to evaluate the effect of food on PK profile of Compound IA.
  • samples were collected at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose; on Days 2, 4, 7, 9, and 11: at pre-dose; after the last dose on Day 14: at 24 and 36 hours (Day 15), and 48 hours (Day 16) post- dose; and at the follow-up visit.
  • PK parameters were calculated using noncompartmental methods using software Phoenix Version 8.1. Concentrations below the lower limit of quantification (LLOQ) were treated as zero in summary statistics for concentration data only. The linear trapezoidal rule was used for AUC calculation. Regression analysis of the terminal plasma elimination phase for the determination of t 1/2 included at least 3 data points after C max . Parameters with an adjusted r2 below 0.80 were flagged but included in the descriptive statistics. The parameters AUC 0-inf , %AUC extra , CL/F, and VZ/F with an %AUC extra above 20% were excluded from the descriptive statistics.
  • LLOQ lower limit of quantification
  • Part A dose proportionality was explored using a regression power model relating logarithmically (log)-transformed C max , AUC 0-last , and AUC 0-inf to the log-transformed dose level. Point estimates for the intercept and the slope and corresponding 90% confidence intervals (CIs) for the slope were calculated. For Part C, dose proportionality was not explored.
  • Part D the relative bioavailability of the Test Formulation (crystalline tablet, SDD and crystalline tablet) versus the Reference Formulation (crystalline suspension), as well as PAT059585-WO-PCT the effect of food, was explored using an analysis of variance (ANOVA) model on the PK data.
  • ANOVA analysis of variance
  • TEAEs The majority of TEAEs reported by 84 (69%) subjects were of mild intensity, whereas 15 subjects (12%) reported moderate TEAEs. The frequently reported system organ class AEs in >20% of the subjects were nervous system disorders (34%), general disorders and administration site conditions (29%), and gastrointestinal disorders (27%). Collectively, 46 related TEAEs reported by 24/122 subjects (20%) were considered to be related to study drug, including 21/94 (22%) who received Compound IA and 3/28 (11%) PAT059585-WO-PCT subjects who received placebo. For 12/122 (10%) subjects, 20 TEAEs of maculopapular skin rash and/or pruritus were considered adverse events of special interest.
  • the mean t 1/2 of Compound IA was comparable between the tablet (18.6 hours) and suspension (17.7 hours) formulations.
  • Pharmacodynamics PAT059585-WO-PCT Dose-dependent decreases in concentrations of IL-1 ⁇ (with mean nadir concentrations of approximately 5% to 20% of the baseline value) were observed with increasing single and multiple oral doses of Compound IA. At most dose levels of Compound IA, the inhibition of IL-1 ⁇ was observed from 1 hour after dosing until the last sampling time point for single (Day 3 or up to 6 hours for the lowest ⁇ 10 mg dose levels) and multiple (Day 15) oral doses of Compound IA.
  • the arithmetic mean ( ⁇ SD) of the observed stimulation effect of IL-1 ⁇ was 1820 ( ⁇ 102) ng/L, and the E max of IL-1 ⁇ was -0.985 ( ⁇ 0.00277).
  • the median potency of Compound IA inhibiting 90% of the ex-vivo stimulated IL-1 ⁇ release (IC 90 ) in the (LPS) challenge was a concentration of 3.18 ⁇ M (90% CI: 2.84; 3.54).
  • the effective concentrations relative to the estimated maximum therapeutic effect and inhibitory concentrations relative to 100% inhibition of Compound IA resulting from ex-vivo stimulated IL-1 ⁇ release were EC 50 : 0.141 ⁇ M (90% CI: 0.114, 0.171), EC 90 : 2.57 ⁇ M (90% CI: 2.24, 2.94), and IC 50 : 0.146 ⁇ M (90% CI: 0.118, 0.179) Discussion
  • SAEs serious adverse events
  • Renal clearance was determined to be about 0.004 L/h (Day 1) or 0.008 L/h (Day 14), PAT059585-WO-PCT approximating to less than 0.8% of oral dose. This shows that direct secretion of the parent drug into urine is not expected to be a major elimination route for this drug in humans.
  • Compound IA as 100 mg crystalline tablet showed a positive food effect with increased C max and AUC by 2.05 and 1.49-fold in the fed (high-fat, high-calorie meal) vs fasted state, respectively. Median T max for 100 mg crystalline tablet was 5 hours, while shorter T max values (0.76–3.0 hours) were reported for suspensions.
  • Compound IA has a very low oral clearance (CLss/F ⁇ 1.0 L/h), which relates to ⁇ 2% of human liver blood flow and a low volume of distribution (Vss/F) of ⁇ 12.6–23.3 L. Slight drug accumulation of about 1.2-fold was observed after once daily dosing and 2-fold after twice daily dosing was observed in reaching steady state consistent with an effective half-life of approximately 10 hours as determined for crystalline tablet when given with food. Nonclinical studies have suggested that Compound IA blocks the release of IL-1 ⁇ using broad range of NLRP3-dependent activators. This has been observed with di-aryl sulfonylurea compounds which are structurally similar to Compound IA [15].
  • IL-1 ⁇ production can be mediated by other inflammasomes or by inflammasome independent pathways; thus, inhibitors aimed at IL-1 ⁇ can result in unintentional immunosuppressive effects. Therefore, pharmacological inhibitors which specifically target the NLRP3 inflammasome only could be a better option for treatment of NLRP3-associated disease.
  • Safety laboratory findings were mild, non-clinically significant decrease in neutrophil and leukocyte counts in 27 subjects.
  • Example 4 The following procedures are suitable for testing the activity of NLRP3 inhibitors, as per those disclosed herein.
  • PAT059585-WO-PCT Procedure 1 IL-1 ⁇ production in PMA-differentiated THP-1 cells stimulated with Gramicidin.
  • THP-1 cells were purchased from the American Type Culture Collection and sub-cultured according to instructions from the supplier. Cells were cultured in complete RPMI 1640 (containing 10% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 ⁇ g/ml)), and maintained in log phase prior to experimental setup.
  • DMSO dimethyl sulfoxide
  • THP-1 cells were treated with PMA (Phorbol 12-myristate 13-acetate) (20 ng/ml) for 16-18 hours. On the day of the experiment the media was removed and adherent cells were detached with trypsin for 5 minutes. Cells were then harvested, washed with complete RPMI 1640, spun down, and resuspended in RPMI 1640 (containing 2% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 ⁇ g/ml). The cells were plated in the 384-well assay plate containing the spotted compounds at a density of 50,000 cells/well (final assay volume 50 ⁇ l).
  • PMA Phorbol 12-myristate 13-acetate
  • RPMI 1640 containing 2% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 ⁇ g/ml).
  • the cells were plated in a 384-well plate at a density of 50,000 cells/well (final assay volume 50 ⁇ l).
  • Compound Preparation Prepare the 3-fold serial dilution of the compounds with DMSO in a 384-well LDV Microplate using TECAN EVO system to generate the compound source plate with 10 concentrations. Top concentration is 30 mM.
  • Cell preparation 1) Centrifuge THP-1 cells at 350g for 5 min. 2) Re-suspend cells with complete RMPI-1640 medium, and count cells. 3) Seed cells in T225 flask, about 2.5x10 7 per flask, treat cells with 20ng/ml PMA (final DMSO concentration ⁇ 1%). 4) Incubate overnight.
  • THP-1 Stimulation Wash adherent THP-1 cells with PBS, and detach cells with 4ml trypsin for T225 flask. Centrifuge cells at 350g for 5 min, re-suspend cells with RPMI-1640 containing 2% FBS and count cells with trypan blue.
  • PAT059585-WO-PCT Transfer 50 nl/well the serial dilution of test compound to 384-well plate by Echo; For the high control and first point of CRID3 (MCC950), transfer 165 nl, then backfill to make the DMSO concentration is consistent in all wells, the plate layout is as below. Seed 50k cells in 40ul RPMI-1640 with 2% FBS per well in 384-well plate.

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Abstract

La présente divulgation concerne le domaine de la pharmacie, en particulier un inhibiteur de NLRP3, ou une combinaison pharmaceutique comprenant un inhibiteur de NLRP3 et au moins un autre agent thérapeutique, pour une utilisation dans la réduction du risque ou la prévention d'événements cardiovasculaires (CVE) ou de maladies cardiovasculaires (CVD) chez des sujets atteints d'une maladie cardiaque connue, en particulier chez des sujets connus comme étant un porteur d'expansion clonale de lignées cellulaires hématopoïétiques avec des mutations somatiques. La divulgation concerne également un procédé de réduction du risque ou de prévention d'événements cardiovasculaires (CVE) ou de maladies cardiovasculaires (CVD) chez des sujets atteints d'une maladie cardiaque connue, en particulier chez des sujets connus comme étant un porteur d'expansion clonale de lignées cellulaires hématopoïétiques avec des mutations somatiques, qui consiste à administrer un inhibiteur de NLRP3 ou la combinaison ; et l'utilisation d'un inhibiteur de NLRP3 ou de la combinaison pour la fabrication d'un médicament pour réduire le risque ou prévenir des événements cardiovasculaires (CVE) ou des maladies cardiovasculaires (CVD) chez des sujets atteints d'une maladie cardiaque connue chez des sujets atteints d'une maladie cardiaque connue, en particulier chez des sujets connus comme étant un porteur d'expansion clonale de lignées cellulaires hématopoïétiques avec des mutations somatiques.
PCT/IB2024/059449 2023-09-29 2024-09-27 Inhibiteur de nlrp3 destiné à être utilisé dans la réduction du risque de maladies cardiovasculaires Pending WO2025068958A1 (fr)

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