WO2025068958A1

WO2025068958A1 - Nlrp3 inhibitor for use in lowering the risk of cardiovascular diseases

Info

Publication number: WO2025068958A1
Application number: PCT/IB2024/059449
Authority: WO
Inventors: Timothy Joseph Clough; Ewa GATLIK; Katy Hayes; Michael Mendelson; Christopher Joseph O'donnell; Nikolaos Patsopoulos; Marianna ROWLANDS
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2023-09-29
Filing date: 2024-09-27
Publication date: 2025-04-03
Anticipated expiration: 2026-03-29
Also published as: TW202513060A

Abstract

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 or preventing cardiovascular events (CVE) or cardiovascular diseases (CVD) 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 or preventing cardiovascular events (CVE) or cardiovascular diseases (CVD) 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 or preventing cardiovascular events (CVE) or cardiovascular diseases (CVD) in subjects with a known heart disease 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.

Description

PAT059585-WO-PCT NLRP3 INHIBITOR FOR USE IN LOWERING THE RISK OF CARDIOVASCULAR DISEASES TECHNICAL FIELD 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. BACKGROUND OF THE INVENTION Cardiovascular diseases (CVD) remain the leading cause of disease burden in the world. The estimated global prevalence of CVD doubled from 271 million in 1990 to 523 million in 2019 (Roth GA, Mensah GA, Johnson CO, et al (2020) Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update from the GBD 2019 Study. J Am Coll Cardiol; 76(25):2982-3021). A substantial residual risk for CVD events related to chronic inflammation remains despite standard of care (SoC) management of classic risk factors (diabetes, hypertension, lipids, etc.)). 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. Inflammatory mediators are intimately implicated with the cascade of events leading to atherosclerotic plaque initiation, progression and rupture. Vascular endothelial cells express a variety of adhesion molecules that recruit monocytes when chronically exposed to noxious stimuli or pathological conditions. Adverse conditions such as hyperlipidemia are associated with enrichment of a pro-inflammatory subset of monocytes. These monocytes apparently enter the intima under the influence of chemotactic stimuli and engulf modified low density lipoprotein (LDL) and cholesterol crystals (Duewell P, Kono H, Rayner KJ, et al (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature; 464(7293):1357-61). The material internalized by 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-1β (IL-1β) from pro-interleukin-1β. 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. The fact that these cytokines and their receptors are highly expressed and are functional in almost all cell types implicated in the pathogenesis of atherosclerosis including smooth muscle cells, certain subset of macrophages and T cells, as well as endothelium, support the role of interleukins in vascular disease. For example, IL- 1β 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. Furthermore, lack of IL-1β or ablation of IL-1 receptor has been shown to decrease severity of atherosclerosis in apoE deficient mice. Clinical evidence from the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) clinical trial demonstrated that IL-1β 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). Patients in the CANTOS trial that had lower on-treatment levels of IL-6 and hsCRP had even greater CVD benefit (approximately 25-35%). IL-1β 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. In post-hoc subgroup analyses in CANTOS, two populations demonstrated substantially increased residual risk of CVD that was not completely addressed by IL-1β neutralization. First, patients with increased IL-18 levels at baseline in CANTOS had an increased risk of major adverse cardiovascular event (MACE) (15% increase in risk [95% confidence interval (CI) 3-29%, p=0.02] for each tertile increase in baseline IL-18), corroborating other preclinical findings implicating IL-18 in CVD pathogenesis (Ridker PM, MacFadyen JG, Thuren T, et al (2020) Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1β inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis. Eur Heart J; 41(23):2153-63). Second, patients in CANTOS with evidence at baseline of CHIP were found to have higher risk of MACE during the trial follow-up as compared to patients without CHIP (Svensson EC, Madar A, Campbell CD, et al (2022) TET2-driven clonal hematopoiesis and response to canakinumab: an exploratory analysis of the CANTOS randomized clinical trial. JAMA Cardiol; 7(5):521-28). 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. The risk of coronary heart disease for individuals with CHIP is approximately 2-times greater than in non-carriers matched for CVD factors including age, sex, type 2 diabetes and smoking history (Jaiswal S, Natarajan P, Silver A et al (2017) Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med; 377:111-121). In murine models, there is data suggesting a causative role of CHIP in development of both atherosclerosis and cardiac dysfunction (Fuster JJ, Maclauchlan S, Zuriaga MA et al (2017) Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science; 355:6327; Sano S, Oshima K, Wang Y et al (2018) CRISPR-Mediated Gene Editing to Assess the Roles of Tet2 and Dnmt3a in Clonal Hematopoiesis and Cardiovascular Disease. Circulation Research; 123:335–341). CHIP likely contributes to CVD risk through enhanced inflammation, including increased NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) activation. Analysis of the CANTOS data revealed that patients with CHIP, particularly CHIP due to somatic mutations in the TET2 gene, were found to have over 60% higher risk of MACE during the trial follow-up as compared to patients without CHIP (Svensson EC, Madar A, Campbell CD, et al (2022) TET2-driven clonal hematopoiesis and response to canakinumab: an exploratory analysis of the CANTOS randomized clinical trial. JAMA Cardiol; 7(5):521-28). Mutations in epigenetic regulators (DNMT3A and TET2) account for approximately 80% of CHIP and are linked to a pro-inflammatory state (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 is a heterogenous disorder, and the presence of CHIP may mark individuals with a greater inflammatory driven contribution to CVD pathogenesis and potentially greater response to targeted anti-inflammatory therapies. Therapeutic approaches that target additional inflammatory pathways and selecting populations with the potential for greater response to anti-inflammatory therapy (i.e., CHIP) may further attenuate the residual CVD risk seen in CANTOS. Through the production of IL-1β and IL-18, the 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. (2010), “NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals”, Nature, 464 (7293): 1357- 61) or pharmacological inhibition (Hettwer J. et al., “Interleukin-1β 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-1β 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-1β and IL-18 both drive pathology. Through the inhibition of IL-1β and IL- 18, NLRP3 inhibitors, particular compound I, more particularly compound IA, have the potential to significantly reduce cardiovascular risk in patients. SUMMARY OF THE INVENTION Provided herein are 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. For example, 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. Thus, in a first aspect, 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. 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. In one embodiment of the first aspect of the disclosure, 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%. In another embodiment of the disclosure, 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%. In another embodiment of the first aspect of the disclosure, the treated subject has a coronary heart disease. In another embodiment, the subject had a documented spontaneous myocardial infarction. In another embodiment, 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). In an additional embodiment of the first aspect, 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. In another embodiment of the first aspect, the NLRP3 inhibitor is administered to a subject orally, particularly as a tablet or capsule. 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 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. In another embodiment of the first aspect, 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. Additionally, in one embodiment of the first aspect, 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. Accordingly, 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%. In another embodiment of the first aspects of the disclosure, the NLRP3 inhibitor is administered in combination with at least one further therapeutic agent. In another embodiment of the first aspect of the disclosure, 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. In some cases, 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. In one embodiment, 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. In case the subject had a documented myocardial infarction, 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. In one embodiment, provided herein is a 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%. In some embodiments, provided herein is the use of a 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%. In some embodiments, 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. In some embodiments, 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). In another aspect, 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%. In another aspect, the disclosure relates to pharmaceutical composition comprising a 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%. PAT059585-WO-PCT In a particular embodiment, the NLRP3 inhibitor is compound I. In a more particular embodiment, compound I is compound IA. Further features and advantages of the described methods and uses will become apparent from the following detailed description. DESCRIPTION OF THE DRAWINGS Figure 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-1β and IL-18 targeting antibody 600 mg subcutaneous injection + compound IA placebo; ** Bispecific IL-1β and IL-18 targeting antibody subcutaneous injection placebo + compound IA placebo; *** Bispecific IL-1β and IL-18 targeting antibody subcutaneous injection placebo + compound IA 10 mg QD. DETAILED DESCRIPTION OF THE INVENTION Without wishing to be bound by theory, 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). 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-1β 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-1β 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. 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). Clonal hematopoiesis of indeterminate potential (CHIP) 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. The most prominent mutations resulting in CHIP have been identified in DNA damage repair genes (e.g., PPM1D, TP53), the tyrosine kinase JAK2, mRNA spliceosome components (e.g., SF3B1, and SRSF2) and epigenetic regulators (e.g., DNMT3A, TET2, ASXL1). As used herein, the umbrella terms cardiovascular disease (CVD) or cardiovascular event (CVE) will be used as they best reflect the underlying etiology of the disease and are used to describe coronary heart diseases, also simply known as heart disease, or known and called as myocardial ischemia, ischemic heart disease or coronary artery disease. All these indications involve a reduction of blood flow to the heart due to e.g., atherosclerotic plaques in the arteries of the heart. Such 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). Different types of MI are known, like: i) spontaneous MI related to ischemia due to a primary coronary event such as plaque erosion and/or rupture, fissuring or dissection, ii) MI secondary to ischemia due to either increased oxygen demand or decreased supply, e.g., coronary artery spasm, anemia, hypotension, coronary embolism, arrhythmias, hypertension or hypotension, iii) Sudden unexpected cardiac death including cardiac arrest, often with symptoms suggestive of myocardial ischemia, iv) MI associated with PCI (Percutaneous Coronary Intervention), v) MI associated with stent thrombosis as documented by autopsy or angiography, vi) MI associated with CABG (Coronary artery bypass grafting), vii) stable angina and unstable angina. In one embodiment, the CVEs or CVDs treated according to the methods and uses disclosed herein is a recurrent CVE or CVD. Herein are described methods or uses 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 by administering to a subject in need PAT059585-WO-PCT thereof an effective amount of a NLRP3 inhibitor, particularly Compound I, Compound IA or Compound IB, more particularly Compound IA. Accordingly, in one aspect provided is 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. In one embodiment, 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. In one embodiment, 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. In one embodiment, 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. In one embodiment, 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. In one embodiment, 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-1β 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. In one aspect of the invention, 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. In one aspect of the invention, 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. In one aspect of the invention, 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. In one aspect of the invention, 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-1β such as interleukin-6 (IL-6). IL-6 is a known marker of cardiovascular disease associated with obesity, type 2 diabetes and myocardial infarction. It is known that administration of an IL-1 antibody (e.g., canakinumab) to stabilize post-MI patients resulted in lowering of levels of IL-6, a marker for inflammation. Accordingly, in another embodiment of any use or method according to the invention, 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. In one embodiment 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. In one embodiment of the method or use of the invention, 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. In one embodiment of the method or use of the invention, 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. In one embodiment of the method or use of the invention, 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. In one embodiment of the method or use of the invention, 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. Accordingly, 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. 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. PAT059585-WO-PCT Accordingly, 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 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. Furthermore, 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. 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. Accordingly, 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. 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. PAT059585-WO-PCT In one embodiment of any method or use described herein, 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. In one embodiment of any method or use described herein, 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. In one embodiment of any method or use described herein, 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. In one embodiment of any method or use described herein, 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. In one embodiment of any method or use described herein, 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. In one embodiment of any method or use described herein, 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. In one embodiment of any method or use described herein, 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. In one embodiment of any method or use described herein, 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. In one embodiment, 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. In another embodiment, 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. PAT059585-WO-PCT In one embodiment of the method or use of the invention, 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. In another embodiment of any use or method provided herein, 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. Accordingly, 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. wherein about 10 mg, or about 25 mg, or about 50 mg, or about 100 mg of Compound IA is administered daily to the patient at the earliest 30 days after MI, and iii. wherein the hsCRP level assessed approximately 3 weeks after first administration of said antibody in the patient is reduced 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. In some embodiments, 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). In some embodiments, 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). In some embodiments, 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). In another embodiment of any method or use of the invention, said recurrent CV event is hospitalization for unstable angina requiring unplanned revascularization. In other embodiments of the method or use of the invention, 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. 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, diltiazem, nifedipine, nicardipine, verapamil) or beta-adrenergic blocking drugs such as esmolol, metoprolol, nadolol, penbutolol or anti-hypertensives such as labetalol, metoprolol, hydralazine, nitroglycerin, nicardipine, sodium nitroprusside, clevidipine or a diuretic such as a thiazide diuretic, chlorthalidone, furosemide, hydrochlorothiazide, indapamide, metolazone, amiloride hydrochloride, spironolactone, triamterene, or an angiotensin-converting enzyme (ACE) inhibitor such as ramipril, ramiprilat, captopril, lisinopril or an angiotensin II receptor blocker such as losartan, valsartan, olmesartan, irbesartan, candesartan, telmisartan, eprosartan or an angiotensin receptor-neprilysin inhibitor (ARNI) such as sacubitril/valsartan (Entresto®), or an anticoagulant such as acenocoumarol, coumatetralyl, dicoumarol, ethyl biscoumacetate, phenprocoumon, warfarin heparin, low molecular weight heparin such as bemiparin, certoparin, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin, tinzaparin or an inhibitor of platelet aggregation such clopidogrel, elinogrel, prasugrel, cangrelor, ticagrelor, ticlopidine, cilostazol, dipyridamole, picotamide, abciximab, eptifibatide, tirofiban or terutroban or a Prostaglandin analogue (PGI2) such as beraprost, prostacyclin, iloprost or treprostinil, or PAT059585-WO-PCT COX inhibitors such as aspirin, aloxiprin or carbasalate calcium, indobufen or triflusal or cloricromen or ditazole or 1,3-indandiones such as clorindione, diphenadione or phenindion, or tioclomarol, or direct thrombin (II) inhibitors such as hirudin, bivalirudin, lepirudin, desirudin (bivalent) or argatroban or dabigatran (monovalent) or oligosaccharides such as fondaparinux, idraparinux, or heparinoids such as danaparoid, sulodexide, dermatan sulfate or direct Xa inhibitors xabans such as apixaban, betrixaban, edoxaban, otamixaban, rivaroxaban or REG1 or defibrotide or ramatroban or antithrombin III or protein C (drotrecogin alfa) or fibrinolytics plasminogen activators: r-tPA such as alteplase, reteplase, tenecteplase or UPA such as urokinase or saruplase or streptokinase or anistreplase or monteplase or other serine endopeptidases or ancrod or fibrinolysin; or brinase or citrate or EDTA or oxalate or digitalis, or digoxin, or nesiritide, or oxygen, or a nitrate such as glyceryl trinitrate (GTN)/nitroglycerin, isosorbide dinitrate, isosorbide mononitrate or an analgesic such as morphine sulfate or a renin inhibitor such as aliskiren or an endothelin A receptor inhibitor or an aldosterone inhibitor. In another embodiment the disclosure relates to 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. All patents, published patent applications, publications, references and other material referred to herein are incorporated by reference herein in their entirety for the described purpose. As used herein, the articles “a”,“an”, and “the” in both the description and claims are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising”, “having”, “including”, and “containing” are to be construed as open terms (i.e., meaning “including but not limited to”) unless otherwise noted. Additionally, whenever “comprising” or another open-ended term is used in an embodiment, it is to be understood that the same embodiment can be more narrowly claimed using the intermediate term “consisting essentially of” or the closed term “consisting of”. PAT059585-WO-PCT The term “or” is used herein to mean, and is used interchangeably with, the term “and/or”, unless context clearly indicates otherwise. The term “about” or “approximate” in relation to a reference numerical value and its grammatical equivalents as used herein can include the numerical value itself and a range of values plus or minus 20% (preferably ± 15%, more preferably ± 10%, even more preferably ± 5%) from that numerical value. For example, the amount “about 10” includes 10 and any amounts from 8 to 12 or from 9 to 11. For example, 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. In some cases, the numerical value described throughout can be “about” that numerical value even without specifically mentioning the term “about.” As used herein, 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. As used herein, the term “administering” in relation to a compound, e.g., Compound I, Compound IA or Compound IB, optionally in combination with at least one further therapeutic agent, is used to refer to delivery of that compound by any route of delivery. Such delivery may be, for example, an intravenous administration or oral administration. Such delivery may also be, for example, a subcutaneous administration. As used herein, the word “substantially” does not exclude “completely,” e.g., a composition which is “substantially free” from Y may be completely free from Y. Where necessary, the word “substantially” may be omitted from the definition. As used herein, 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). As used herein, 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. In a specific embodiment, the compositions, methods, and uses described herein are in reference to a human patient or subject. As used herein, 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. The term “approximately” when used in the context of a time period refers to a given time point (e.g.90 days or 3 month) including a time period before or after that given time point. The term approximately 3 months includes a time period of 90 days +/- 10 days. As used herein, the term approximately “6 months” refers to a time period of 180 days that includes +/- 15 days. As used herein, the term approximately “9 months” includes a time period of 270 days that includes +/- 20 days. The term "IL-18" is synonym to IL-18 polypeptide, Interleukin-18 polypeptide, IFN-gamma inducing factor or Interferon-gamma-inducing-factor or INF-γ inducing factor. The term "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. Throughout this specification, the term 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. The term “IL-1β” or “IL-1b” is synonym to IL-1β polypeptide and Interleukin-1β polypeptide. The term “IL-1β” refers to human IL-1β unless another species is indicated. IL-1β 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-1β can be measured using a commercially available ELISA kit (88-7261-88, eBioscience) used in accordance with manufacturer’s instructions. PAT059585-WO-PCT The term "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 (κ) chains and lambda (λ) 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). Each VH and VL is composed of three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. As used herein, term “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. In one embodiment, 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. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. As used herein, the terms “C-reactive protein” and “CRP” refers to serum C-reactive protein, which is used as an indicator of the acute phase response to inflammation. In certain embodiments of the uses and methods described herein, 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. As used herein, the term “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. As used herein, the term “cardiovascular 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. As used herein, “sudden cardiac death” is a sudden death that occurs in a previously stable patient who does not have a prior terminal condition, such as malignancy not in remission or end-stage chronic lung disease. Death due to acute myocardial infarction (AMI): 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. 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. As used herein, “death due to other cardiovascular causes” refers to death due to a cardiovascular cause not included in the above categories (e.g. dysrhythmia, pulmonary embolism, cardiovascular intervention, aortic aneurysm rupture, or peripheral arterial disease). Mortal complications of cardiac surgery or non-surgical revascularization, even if “non-cardiovascular” in nature, should be classified as cardiovascular deaths. As used herein, the term “myocardial infarction (MI)” refers to “acute myocardial infarction”: the term myocardial infarction (MI) is used when there is evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. The term MI includes an ST-elevated MI (STEMI) or a non-ST-elevated MI (NSTEMI). Under these conditions any one of the following criteria meets the diagnosis for MI: The term “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., development of pathological Q waves in the ECG (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 an any two leads of a contiguous lead grouping (I, aVL, V6, V4-V6, II, III, aVF), imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. The term “percutaneous coronary intervention (PCI) related myocardial infarct” refers to PCI in patients with normal baseline troponin values elevations of cardiac biomarkers above the 99th percentile URL within 24 hours of the procedure are indicative of peri-procedural PAT059585-WO-PCT myocardial necrosis. By convention increases of biomarkers greater than 3 x 99th percentile URL are consistent with PCI related myocardial infarction. If the cardiac biomarker is elevated prior to PCI a ≥ 20% increase of the value in that second cardiac biomarker within 24 hours of the PCI and documentation that cardiac biomarkers were decreasing (two samples at least 6 hours apart) prior to the suspected recurrent MI is also consistent with PCI related MI. Symptoms of cardiac ischemia are not required. 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 positive T- wave in the absence of a conduction defect Criterion for Reinfarction: In patients where recurrent MI is suspected from clinical signs or symptoms following the initial infarction, an immediate measurement of the employed cardiac biomarker is recommended. 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. Clinical Classification of different types of Myocardial Infarction: • Type 1 – Spontaneous MI related to ischemia due to a primary coronary event such as plaque erosion and/or rupture, fissuring or dissection. • Type 2 – MI secondary to ischemia due to either increased oxygen demand or decreased supply, e.g., coronary artery spasm, anemia, hypotension, coronary embolism, arrhythmias, hypertension, or hypotension. • 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 4a –MI associated with PCI (Percutaneous Coronary Intervention). • 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. When pathologic Q waves (i.e., myocardial infarction) are present, ST elevation or T wave inversion may be used to classify the infraction as New or Acute. However, ST elevation or T wave inversion in the absence of pathologic Q waves are not sufficient criteria for diagnosis of myocardial infarction. • Anterolateral MI - Pathologic Q waves in leads V3-V6. PAT059585-WO-PCT • Anterior MI - Pathologic Q waves in V3 and V4. • Anteroseptal MI - Pathologic Q waves or QS in leads V1-V4. • Extensive Anterior MI - Pathologic Q waves in leads I, aVL, and V1-V6. • High lateral MI - Pathologic Q waves in leads I and aVL. • Inferior MI - Pathologic Q waves or QS in at least two of the inferior leads: aVF, III, II. • Lateral MI - Pathologic Q waves in leads I, aVL, and V5-V6. • Septal MI - Pathologic Q waves or QS in leads V1-V2, (V3). In the presence of LAHB or LVH a Q or QS in V3 is required. • Posterior MI - Initial R wave duration 40 ms in V1 or V2, and R > S and upright T wave; Inferior or Lateral MI are usually also present. The term “new MI” as used herein 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. As used herein, the term “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. As used herein, 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 contiguous leads with the cut-off points: ≥ 0.2 mV in men (> 0.25 mV in men < 40 years) or ≥ PAT059585-WO-PCT 0.15 mV in women in leads V2-V3 and/or ≥ 0.1 mV in other leads), ST depression and T- wave Evidence of ischemia on stress testing with cardiac imaging, evidence of ischemia on stress testing without cardiac imaging but with angiographic evidence of ≥ 70% lesion, and/or thrombus in the epicardial coronary artery or initiation/increased dosing of anti-anginal therapy, angiographic evidence of ≥ 70% lesion and/or thrombus in an epicardial coronary artery. As used herein, “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. As used herein, 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. As used herein, 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. PAT059585-WO-PCT As used herein, the term “prevent”, “preventing”, or “prevention” in connection to a disease, condition, disorder, or syndrome also refers to prophylactic treatment of a subject who is at risk of developing a condition (e.g., risk of a cardiovascular events in a subject) resulting in a decrease in the probability that the subject will develop the condition. Also “treating” may refer to slow the progress of, halt, or reverse disease, condition, disorder, or syndrome progression and improve clinical outcomes. As used herein, the term “therapeutically effective amount” of the NLRP3 inhibitor described herein refers to an amount of said inhibitor that will elicit the biological or medical response of a subject, for example, reducing the risk of or preventing cardiovascular events, ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, condition, disorder, or syndrome, etc. In one non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the NLRP3 inhibitor, that, when administered to a subject, is effectively reducing the risk of or preventing cardiovascular events in a CHIP population. As used herein, the term “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. In yet another embodiment of any method or use of the invention, said recurrent CV event is non-fatal MI or cardiovascular (CV) death. In another embodiment of any method or use of the invention, said recurrent CV event is non- fatal MI. As used herein, the term “NLRP3 inhibitor” is a compound that inhibits the ability of NLRP3 to induce the production of IL-1β and/or IL-18 by directly binding to NLRP3, or by PAT059585-WO-PCT inactivating, destabilizing, altering distribution, of NLRP3 or otherwise. Typically, a NLRP3 inhibitor has an IC50 of <1 µM of IL-1β secretion in the hTHP-1 assay containing 2% fetal bovine serum defined herein. Preferably, the NLRP3 inhibitor is a compound of Compound I, Compound IA, or Compound IB, or a pharmaceutically acceptable salt thereof. More preferably, the NLRP3 inhibitor is Compound IA, or a pharmaceutically acceptable salt thereof. As used herein, “Compound of formula I,” or “Compound I,” are used interchangeably and mean a compound that has the structure shown below, and can be synthesized using procedures known in the art and described in WO2019/023147, incorporated by reference in its entirety. H₂ ^N _O O

(R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide) or Compound IB (i.e., (S)-N'- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide) may be used in crystalline or amorphous form, as a solvate, e.g., a hydrate, or an unsolvated form. O H₂N O O

Tautomers: The scope of the compounds disclosed herein includes tautomeric form of the compounds. Thus, by way of example, a compound that is represented as containing the moiety H₂N O O

form containing the moiety PAT059585-WO-PCT H^N _O O

Stereoisomers: Non-limiting exemplified compounds of the formulae described herein include a stereogenic sulfur atom. This disclosure provides examples of stereoisomer mixtures (e.g. racemic mixture of enantiomers). This disclosure also describes and exemplifies methods for separating individual components of said stereoisomer mixtures (e.g. resolving the enantiomers of a racemic mixture). 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. As used herein, “Compound I” is also intended to include enantiomeric excesses of either Compound IA or Compound IB. For example, 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%. Alternatively, 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 ³H, ¹¹C, ¹³C, ¹⁴C, and ¹⁵N. 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 ³H and ¹⁴C, or those into which non-radioactive isotopes, such as ²H and ¹³C are present. Such isotopically labelled compounds are useful in metabolic studies (with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), 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. As used 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. Examples of 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. Generally, 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 . 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. For example, pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines. For example, the salt can be a hydrochloride salt. The phrase “pharmaceutically acceptable” as employed herein 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. Unless otherwise indicated, as used here, the “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. For salt forms of the NLRP3 inhibitor, the actual amount will be adjusted based on the salt form used. An “effective amount” refers to an amount sufficient to effect beneficial or desired results. For example, 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. The 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. The skilled artisan will appreciate that certain factors may influence the 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. Moreover, 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. As herein defined, “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. The terms “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. The term “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. The term “fixed combination” means that the active ingredients are administered to a subject simultaneously in the form of a single entity or dosage. The term “free combination” (non-fixed 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. In particular, reference to the combination comprising a) Compound I and b) at least one additional therapeutic agent as used herein (e.g., in any of the embodiments or in any of the claims herein), refers to a “non-fixed combination” and may be administered independently at the same time or separately within time intervals. By “simultaneous 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). The term “sequential 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. By “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. By “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. The term “dose” refers to a specified amount of a drug administered at one time. The dose could, for example, be declared on a product package or in a product information leaflet. As used herein, the term “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 The methods of treatment of the present invention comprise administering a NLRP3 inhibitor according to a dosing regimen. PAT059585-WO-PCT In an embodiment 1, 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. In an embodiment 2, 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. In an embodiment 3, 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. In an embodiment 4, 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. In another embodiment 5, the doses are administered to a subject during or after consuming food. In an embodiment 6, the time interval between the administration of two subsequent doses is about 22-26 hours. In an embodiment 7, 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. In another embodiment 7.1, 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-1β, CXL9, CXCL10, hsIFNg, von- Willebrand-Factor (vWF), myeloid/lymphoid cell activation/enumeration by flow cytometry (whole blood/PBMC) and lipid parameters (e.g. LDL, Lp(a), apolipoproteins), more particularly, the method of treatment relates to reducing circulating levels of inflammatory markers selected from IL-6 serum levels, IL-18 serum levels and hsCRP. In another embodiment 8, the subject in the methods of treatment is a human subject. In another embodiment 8.1, 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. In another embodiment 8.3, 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%. In another embodiment 9, 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. In another embodiment 10, the cardiovascular diseases or cardiovascular event is non-fatal myocardial infarction. In another embodiment 11, the cardiovascular diseases or cardiovascular event is non-fatal stroke. In another embodiment 12, the cardiovascular diseases or cardiovascular event is cardiovascular death. In another embodiment 13, the cardiovascular diseases or cardiovascular event is cardiovascular death. In another embodiment 14, the cardiovascular diseases or cardiovascular event is hospitalization for unstable angina requiring unplanned revascularization. In another embodiment 15 according to any one of embodiments 1-14, 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. In another embodiment 16 according to any one of embodiments 1-15, 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. In another embodiment 17 according to any one of embodiments 1-16, 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. In another embodiment 18, the subject does not exhibit any skin rash. In another embodiment 19, the NLRP3 inhibitor is administered to the subject orally. In another embodiment 20, the NLRP3 inhibitor is comprised in a tablet formulation. In another embodiment 21, at least one further therapeutic agent is administered. In another embodiment 22, the NLRP3 inhibitor is Compound I, or a pharmaceutically acceptable salt thereof: H₂ ^N _O O .

inhibitor is Compound IA, or a pharmaceutically acceptable salt thereof. PAT059585-WO-PCT In another embodiment 24, 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%. In another embodiment 25, the NLRP3 inhibitor is Compound IB, or a pharmaceutically acceptable salt thereof. In another embodiment 26, 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%. As is understood by a person skilled in the art, the above embodiments of the present invention may be combined with other embodiments disclosed herein. Further embodiments of the present invention: In embodiment 27, 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, or the use of a NLRP3 inhibitor in the manufacture of a medicine for reducing the risk of or preventing cardiovascular events (CVE) or cardiovascular diseases (CVD), which can be recurrent CVEs or CVDs, wherein the NLRP3 inhibitor is administered to a subject at a total daily dose of about 10 mg to about 100 mg in a single dose or divided doses. In an embodiment 27.1, the NLRP3 inhibitor for use according to embodiment 27, wherein the NLRP3 inhibitor is administered to a subject at a total daily dose of about 10 mg to about 50 mg in a single dose or divided doses. In another embodiment 27.2, the NLRP3 inhibitor for use according to embodiment 27 or 27.1, wherein the NLRP3 inhibitor is administered to a subject at a total daily dose of about 20 mg in a single dose or divided doses. In another embodiment 27.3, 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. PAT059585-WO-PCT In another embodiment 27.4, 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. In another embodiment 27.5, 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. In an embodiment 27.6, 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. In an embodiment 27.7, the NLRP3 inhibitor for use according to any one of embodiments 27-27.6, wherein there is about a 22-26 hour time interval between the administration of two subsequent doses of the NLRP3 inhibitor to a subject. In an embodiment 27.8, the NLRP3 inhibitor for use according to any one of embodiments 27-27.7, wherein said reducing 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. In another embodiment 27.9, 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. In another embodiment 27.10, the NLRP3 inhibitor for use according to any one of embodiments 27-27.9, the subject 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. PAT059585-WO-PCT In another embodiment 27.11, 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. In another embodiment 27.12, the NLRP3 inhibitor for use according to any one of embodiments 27-27.11, wherein the subject does not exhibit any skin rash. In another embodiment 27.13, the NLRP3 inhibitor for use according to any one of embodiments 27-27.12, wherein the NLRP3 inhibitor is administered to the subject orally. In another embodiment 27.14, the NLRP3 inhibitor for use according to any one of embodiments 27-27.13, wherein the NLRP3 inhibitor is comprised in a tablet formulation. In another embodiment 27.15, the NLRP3 inhibitor for use according to any one of embodiments 27-26.14, comprising administering at least one further therapeutic agent. In another embodiment 27.16, the NLRP3 inhibitor for use according to any one of embodiments 27-27.15, wherein the NLRP3 inhibitor is Compound I, or a pharmaceutically acceptable salt thereof: H₂ ^N _O O .

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. In another embodiment 27.18, the NLRP3 inhibitor for use according to any one of embodiments 27-27.17, wherein 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%. PAT059585-WO-PCT In another embodiment 27.19, the NLRP3 inhibitor for use according to any one of embodiments 27-27.18, wherein the NLRP3 inhibitor is Compound IB, or a pharmaceutically acceptable salt thereof. In another embodiment 27.20, the NLRP3 inhibitor for use according to any one of embodiments 27-27.19, the NLRP3 inhibitor for use according to embodiment 26.23, wherein 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%. In another embodiment 27.21, the NLRP3 inhibitor for use according to any one of embodiments 27-27.20, the NLRP3 inhibitor for use according to any one of embodiments 26.1-26.24, wherein the subject is a human subject. In another embodiment 27.22, 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. Various embodiments of the methods and uses described herein are included below and elsewhere in the document. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments. It is taught herein that the below embodiments relate to the use of any NLRP3 inhibitor, and is not limited to Compound I. Preferably, 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%. Preferably, Compound IA is in enantiomeric excess of at least 90%. More preferably, Compound IA is in enantiomeric excess of at least 95%. In some embodiments, provided herein is a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In particular embodiments, the pharmaceutical composition is a tablet. In yet particular embodiments, the pharmaceutical composition is administered as a whole or crushed tablet. In some embodiments, 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. In any of embodiments described herein, Compound I, or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof orally. In some embodiments, Compound I, or a pharmaceutically acceptable salt thereof, is in the form of a tablet that is administered either whole or subdivided, i.e., crushed prior to administration. In particular embodiments, for example when patients are unable to swallow, 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). Scheme 1: PAT059585-WO-PCT O C

Compound I: H₂N O O

s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimidamide Step 1: N-(tert-butyldimethylsilyl)-N'-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide: Into a 50-mL round-bottom flask was placed a solution of N'-(tert-butyldimethylsilyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide (Intermediate I) (336 mg, 1.0 mmol) in THF (10 mL). To this solution was added NaH (60% wt, 80 mg, 2.0 mmol) in portions at 0oC. The solution was stirred at 0oC for 15 minutes, and this was followed by the addition of a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (209 mg, 1.1 mmol) in THF (5 mL) dropwise with stirring at RT. The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 10 mL of NH4Cl (sat.). The resulting solution was extracted with 3x10 mL of DCM and the combined organic layers were concentrated under vacuum. This resulted in 535 mg (crude) of the title compound as a brown oil. MS-ESI: 535.0 (M+1). 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). To this solution was added HF/Py (70% wt, 143 mg, 5.0 mmol) dropwise at 0oC. The solution was stirred at RT for 4 h. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x10 mL of ethyl acetate and the combined organic layers were concentrated under vacuum. The crude product was purified by Prep-HPLC using Method B with ACN/water (20% to 60% in 10 minutes). This resulted in 189 mg (45%, 2 steps) of Compound I as a white solid. Compound I: MS-ESI: 421.0 (M+1).1H NMR (400 MHz, DMSO-d6) δ 8.46 (br s, 1H), 8.04 (s, 1H), 7.80 (br s, 2H), 6.86 (s, 1H) 6.28 (s, 1H), 2.88 – 2.71 (m, 4H), 2.71 – 2.56 (m, 4H), 2.02 – 1.80 (m, 4H), 1.49 (s, 6H). Compound IA and Compound IB: H₂ ^N _O H O ₂N O O

Compounds IA and IB: (R) and (S)-N'-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide: Step 3: Chiral separation. The Compound I product obtained as described in the previous step (189 mg) 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. Compound IB: MS-ESI: 421.0 (M+1).1H NMR (400 MHz, DMSO-d6) δ 8.43 (br s, 1H), 8.05 (s, 1H), 7.83 (br s, 2H), 6.87 (s, 1H) 6.29 (s, 1H), 2.82 – 2.71 (m, 4H), 2.71 – 2.56 (m, 4H), 2.02 – 1.80 (m, 4H), 1.50 (s, 6H). Compound IA: MS-ESI: 421.0 (M+1).1H NMR (400 MHz, DMSO-d6) δ 8.41 (br s, 1H), 8.05 (s, 1H), 7.83 (s, 2H), 6.87 (s, 1H) 6.27 (s, 1H), 2.82 – 2.71 (m, 4H), 2.71 – 2.56 (m, 4H), 2.02 – 1.80 (m, 4H), 1.50 (s, 6H). PAT059585-WO-PCT Intermediate I of scheme 1 was synthesized in accordance with the synthesis set out in WO2019/023147, and as provided in scheme 2, below. Scheme 2: N OH ^O S O _H2N ^O HCl

Intermediate I: TBS

-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide: Step 1: 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole: Into a 500-mL round-bottom flask was placed a solution of 1-(thiazol-2-yl)ethanone (20 g, 157.0 mmol) in toluene (300 mL) and ethane-1,2-diol (19.5 g, 314 mmol). To the solution was added TsOH (2.7 g, 15.7 mmol). The resulting solution was refluxed overnight and water was separated from the solution during the reflux. The resulting solution was diluted with 200 mL of water and extracted with 2x100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under vacuum. This resulted in 26.6 g (99%) of the title compound as light yellow oil. MS-ESI: 172.0 (M+1). 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^oC. The resulting solution was stirred for 0.5 h at -78^oC and then SO₂ was introduced into the above reaction mixture. The reaction was slowly warmed to RT and then NCS (12.8 g, 95.86 mmol) was added. The resulting solution was stirred for 1 h at PAT059585-WO-PCT RT. The solids were filtered out. The resulting filtrate was concentrated under vacuum and then was diluted in DCM (160 mL). To the above was added a saturated solution of ammonia in DCM (300 mL). The resulting solution was stirred for 3 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:20 to 1:5). This resulted in 12.5 g (61%) of the title compound as a yellow solid. MS-ESI: 251.0 (M+1). 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^oC. The resulting solution was diluted with 100 mL of water and extracted with 2x200 mL of ethyl acetate. The organic layers were combined, dried over anhydrous Na₂SO₄, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:2 to 1:1). This resulted in 9.3 g (90%) of the title compound as a yellow solid. MS-ESI: 207.0 (M+1). Steps 4-6 used the same procedures as those specified for converting compound Z to compound Y shown in Scheme 3, to afford Intermediate I from compound I-d. MS-ESI: 336.1 (M+1). Scheme 3: O O O

Compound Y: PAT059585-WO-PCT TBS

-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide: Step 1: Methyl 2-mercaptothiazole-5-carboxylate: Into a 2-L round-bottom flask was placed methyl 2-bromothiazole-5-carboxylate (100 g, 450 mmol), EtOH (1000 mL), sodium hydrogensulfide (50 g, 890 mmol). The resulting solution was stirred for 2 h at 80oC and then was cooled to 0oC with a water/ice bath. The pH value of the solution was adjusted to 3 with hydrogen chloride (1 N). The solids were collected by filtration. This resulted in 63.2 g (80%) of the title compound as a light yellow solid. MS-ESI: 176.0 (M+1). 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. The solution was extracted with 3x300 mL of DCM and the combined organic layers were washed with 2x300 mL of brine and dried over anhydrous Na2SO4. The crude product as a yellow solution in DCM was used in the next step. 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. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 23 g (75%, 2 steps) of the title compound as a white solid. MS-ESI: 223.0 (M+1). Step 4: 5-(2-Hydroxypropan-2-yl)thiazole-2-sulfonamide: Into a 500-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of methyl 2-sulfamoylthiazole-5-carboxylate (15 g, 67.5 mmol) in THF (150 mL). This was followed by the addition of MeMgBr/THF (3 M, 90 mL) dropwise with stirring at 0oC. The resulting solution was stirred for 14 h at RT and then was quenched by the addition of 100 mL of NH4Cl (sat.). The resulting solution was extracted with 3x150 mL of DCM. The organic layers were combined and dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 11.5 g (78%) of the title PAT059585-WO-PCT compound as a white solid. MS-ESI: 223.0 (M+1), 221.0 (M-1) in positive and negative ion mode, respectively. 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. After stirring for 20 minutes in a water/ice bath, this was followed by the addition of a solution of TBSCl (4.1 g, 27.2 mmol) in THF (10 mL) dropwise with stirring at 0oC. The resulting solution was stirred for 4 h at RT. The reaction was quenched with sat. NH₄Cl (100 mL). The resulting solution was extracted with 3 x 100 mL of ethyl acetate and the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude solid was washed with ethyl acetate/hexane (1:5) (2x100 mL). This resulted in 6.81 g (90%) of the title compound as a yellow solid. MS-ESI: 337.1 (M+1), 335.1 (M-1) in positive and negative ion mode, respectively. 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 PPh₃Cl₂ (3 g, 9.0 mmol) in CHCl₃ (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. This was followed by the addition of a solution of N-(tert- butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide (2.0 g, 5.9 mmol) in CHCl₃ (30 mL) dropwise with stirring in an ice/water bath. The resulting solution was stirred for 30 min in an ice/water bath. To the above was introduced NH₃ (g) below 0oC for 15 minutes. The resulting solution was stirred for 20 minutes at RT. The solids were filtered out and the filtrate was concentrated and the residue was dissolved in 300 mL of ethyl acetate. The solution was washed with brine (2x100 mL), dried over Na₂SO₄ and concentrated under vacuum. The crude solid was washed with CHCl₃ (100 mL). Then the filtrate was concentrated under vacuum and the residue was further purified by a silica gel column with ethyl acetate/petroleum ether (1:10 to 1:3). The original washed solid and solid from silica gel purification were combined. This resulted in 1.2 g (60%) of the title compound as a white solid. MS-ESI: 336.1 (M+1).1H-NMR (300 MHz, DMSO-d6) δ 7.66 (s, 1H), 7.12 (s, 2H), 5.78 (s, 1H), 1.51 (s, 6H), 0.86 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H). The following abbreviations have the indicated meanings: ACN = acetonitrile BTC = trichloromethyl chloroformate Boc = t-butyloxy carbonyl Davephos = 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl PAT059585-WO-PCT DCM = dichloromethane DEA = diethylamine DMF = N,N-dimethylformamide DMSO = dimethyl sulfoxide DIEA = N,N-diisopropylethylamine DPPA = diphenylphosphoryl azide dppf = 1,1'-Bis(diphenylphosphino)ferrocene EtOH = ethanol HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate Hex = hexane HPLC = high performance liquid chromatography LC-MS = liquid chromatography – mass spectrometry LiHMDS = lithium bis(trimethylsilyl)amide LDA = lithium diisopropylamide M = mol/L Me = methyl MeOH = methanol MSA = methanesulfonic acid NBS = N-bromosuccinimide NCS = N-chlorosuccinimide NMR = nuclear magnetic resonance Pd(dppf)Cl₂ = dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium Ph = phenyl PPh₃Cl₂ = dichlorotriphenylphosphorane Py = pyridine RT = room temperature Rt = Retention time Rf = Retardation factor Sat. = saturated TBAF = tetrabutylammonium fluoride TBS = tert-butyldimethylsilyl TBSCl = tert-butyldimethylsilyl chloride TBDPSCl = tert-butyldiphenylsilyl chloride TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran PAT059585-WO-PCT TLC = thin layer chromatography TsOH = 4-methylbenzenesulfonic acid UV = ultraviolet b.i.d. = twice daily WCC = White Cell Count EP = End Point y = year y/n = yes/no EXAMPLES The following Examples illustrate the methods and uses described herein. They are not, however, intended to limit the scope of the described methods and uses in any way. Other variants of the embodiment will be readily apparent to one of ordinary skill in the art and are encompassed by the appended claims. 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). 1.1 Objectives, endpoints, estimands Objective(s) Endpoint(s) Primary objective(s) Endpoint(s) for primary objective(s) To evaluate the effect of various dose levels of Serum levels of IL-6 and IL-18 at 3 COMPOUND IA versus placebo to reduce weeks after the start of a dosing period circulating levels of inflammatory markers in participants with coronary heart disease and elevated hsCRP Secondary objective(s) Endpoint(s) for secondary objective(s) To evaluate the safety and tolerability of Adverse events, and parameters from COMPOUND IA in participants with coronary safety assessments, including vital heart disease and elevated hsCRP signs, electrocardiograms, and laboratory assessments (urine and blood) PAT059585-WO-PCT Objective(s) Endpoint(s) To assess the pharmacokinetics of Plasma trough concentrations (Ctrough) COMPOUND IA in participants with coronary of COMPOUND IA at steady state heart disease and elevated hsCRP Exploratory objective(s) Endpoint(s) for exploratory objective(s) To explore whether individual variation in genes Plasma Ctrough of COMPOUND IA and related to drug metabolism confer differential its metabolite, KEY METABOLITE, by pharmacokinetic response to COMPOUND IA CYP2C9 genotype To assess pharmacokinetics of key metabolite Plasma Ctrough of KEY METABOLITE of COMPOUND IA in plasma at various doses of COMPOUND IA To assess the effect of COMPOUND IA on Pharmacodynamic and inflammation- pharmacodynamic (PD), inflammation-related, related markers may include but are not and cardiovascular disease-related biomarkers limited to hsCRP, soluble ASC, IL-1β, (including pharmacokinetic/pharmacodynamic CXCL9, CXCL10, hsIFNg, von- relationships) Willebrand-Factor (vWF), myeloid/lymphoid cell activation/enumeration by flow cytometry (whole blood/PBMC) Cardiovascular disease-related biomarkers may include but are not limited to lipid parameters (e.g., LDL, Lp(a), apolipoproteins) To explore genetic and proteomic drug-related Exploratory genetic and proteomic response mechanisms, understand the disease endpoints may include but are not and/or the safety and efficacy of COMPOUND limited to: IA Presence of genetic polymorphisms Presence of somatic mutations (Clonal Hematopoeisis of Indeterminate Potential (CHIP)) and their change from baseline) Serum or plasma proteins and their change from baseline Primary estimands The primary clinical question of interest is: What is the effect of COMPOUND IA in addition to standard of care cardiovascular disease prevention medication in patients with known coronary heart disease and elevated hsCRP on the inflammatory markers IL-6 and IL-18, PAT059585-WO-PCT assuming patients continue treatment with reasonable adherence and there are no new major cardiovascular events, initiations of prohibited medication, or febrile infections, but without regard to changes in standard of care cardiovascular disease prevention medication? 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. Table 1: Intercurrent events for the primary estimand Intercurrent event Details (if necessary) Handling of event Permanent discontinuation N/A Data collected after this of study treatment intercurrent event will not be used for this estimand Incidence of a new major N/A Data collected after this cardiovascular disease intercurrent event will not be event (e.g., MI, stroke, etc.) used for this estimand Change in standard of N/A All data collected after this care CVD prevention intercurrent event will be medication used for this estimand Unforeseen use of any Data collected after this medication expected to intercurrent event will not be have a sustained effect on used for this estimand Initiation of a prohibited the primary endpoints (i.e., medication for a comorbid any systemic condition corticosteroids) Unforeseen use of Only the assessment medication expected to immediately following the PAT059585-WO-PCT Intercurrent event Details (if necessary) Handling of event have a limited effect on the event will be excluded for primary endpoints (i.e., any the purpose of this estimand other prohibited medications) New-onset febrile infection Febrile infection around time Only the assessment of assessment (details to be immediately following the provided in the statistical event will be excluded for analysis plan (SAP)) the purpose of this estimand Greater than 20% of missed Only the assessment daily doses within 3 weeks immediately following the prior to an assessment event will be excluded for Nonadherence to study the purpose of this estimand treatment Any missed dose within the Only the assessment 2 days prior to an immediately following the assessment event will be excluded for the purpose of this estimand The handling of each intercurrent event specified in Table 1, with the exception of changes in standard of care cardiovascular disease prevention medication, reflects what is referred to as the hypothetical strategy, which aims to mimic a scenario in which the intercurrent event did not actually occur and all participants had adhered to the randomized treatment throughout the course of the study. To enable this strategy, data from various assessments taking place after the event will be excluded from the primary analysis, as described in the table. The exception to this is changes to standard of care cardiovascular disease prevention medication, which will be handled by a treatment policy strategy, in which any occurrence of the event is ignored and the subsequent data are included in the analysis. 1.2 Study design 1.2.1 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 elevated hsCRP. The study consists of a screening period of up to 60 days, a treatment period of approximately 12 weeks, an end of treatment (EOT) visit on Day 85, which is one day after the last dose on Day 84, a follow-up period of approximately 1 week PAT059585-WO-PCT and a standard safety-follow-up call approximately 30 days following the last dose. The overall study duration is approximately 24 weeks and approximately 24 participants will be enrolled into the trial. The screening period includes 2 visits. During Screening 1, hsCRP levels will be measured. If hsCRP levels at Screening 1 meet the eligibility criteria, participants will complete Screening 2 (at least 8 days after Screening 1), where other eligibility assessments will be performed. 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. 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

PAT059585-WO-PCT _{Study Design Aspect} ^Rationale _Overall ^{In this study, participants will be randomized to one of four} treatment sequences comprised of placebo and/or various uptitrating doses of COMPOUND IA. The rationale behind the uptitration of doses within sequences is the efficiency for evaluating cytokine reductions that result from intra- individual measurements. Uptitration also may improve tolerability by decreasing the risk for rash; however, this has yet to be demonstrated. Clinical experience from prior clinical trial data with COMPOUND IA suggests that most adverse events (AEs), especially the emergence of rash, should occur within the first 17 days of dosing and therefore limited carry-over of the initiation of AEs into subsequent dosing periods is expected to occur. The uptitration of doses and progressive further inhibition of the NLRP3 inflammasome is expected to result in a peak cytokine reduction similar to what would be seen regardless of prior dose exposures. _{Primary Endpoints} ^{Serum levels of IL-6 and IL-18 at 3 weeks after the start of} a dosing period were chosen as the primary endpoints because both cytokines are linked to increased risk of CVD in numerous clinical populations. In addition, preclinical models implicated IL-6 and IL-18 in CVD pathogenesis. In the CANTOS trial of IL-1β inhibition, participants that had the lowest on-treatment IL-6 levels had the greatest CVD benefit. While IL-18 is associated with CVD risk in human populations and preclinical evidence supports a causal role, no pharmacologic intervention trials have yet demonstrated that IL-18 inhibition reduced CVD risk. PAT059585-WO-PCT _{Study Design Aspect} ^Rationale _{Analysis of primary endpoints} ^{Each participant will contribute data on levels of IL-6 and} IL-18 after 3 weeks of oral daily treatment with COMPOUND IA at up to 3 different dose levels and/or placebo, depending on treatment sequence assignment. A dose-response modeling approach, which integrates the IL-6 or IL-18 levels across all dose levels to fit a dose- response relationship, will be utilized to quantify placebo- adjusted reductions at the highest tested dose level, 100 mg. The rationale for analyzing all of the IL-6 and IL- 18 data from the end of each 3-week dosing period together in a dose-response model is to take advantage of the efficiencies introduced by the uptitration design. The model treats each dosing period as independent of the prior period, which is justified because cytokine levels are expected to reach a maximum reduction within 7-14 days, and therefore the 3-week timepoint is expected to be at steady state reduction. The fact that dosing occurs in a monotonically increasing manner ensures that no washout between doses is required, as the effect is only expected to be greater with higher doses. It is possible that subsequent dose levels may reach steady state cytokine reduction sooner than if drug had not already been on board, but this will not impact the analysis as only the 3-week measurement is collected and used in the analysis.

PAT059585-WO-PCT _{Study Design Aspect} ^Rationale _{Treatment Sequences} ^{In 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. However, with a modest sample size and 4 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.

PAT059585-WO-PCT S_{tudy Design Aspect} ^Rationale D_{uration of study periods} ^{The duration and frequency of screening was chosen to} ensure hsCRP values obtained in this time period are representative of the participant's true sustained baseline value to capture a study population with sustained markers of chronic inflammation. The treatment period of approximately 12 weeks allows for a gradual uptitration (uptitration occurs approximately every 3 weeks) to the maximal dose of 100 mg of COMPOUND IA. From prior clinical trials with COMPOUND IA, the expected peak reduction of cytokines occurs within 7-14 days, and, therefore, approximately three weeks for each dosing period should allow adequate assessment of cytokine reduction efficacy and tolerability at each dose level. 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. Participants will then receive three uptitrating COMPOUND IA doses up to 100 mg, each for approximately three weeks as shown in the study design figure (Figure 1). The dose range 10-100 mg was selected based on data from the phase 1 FIH study in healthy volunteers (Example 3). In the FIH study, an ex vivo whole blood assay of lipopolysaccharide-stimulated IL-1β secretion was used as a PD readout to estimate pharmacological activity. Based on the results of this analysis, the mean COMPOUND IA Ctrough required to inhibit 50% (IC₅₀) and 90% (IC₉₀) of stimulated IL-1β release in healthy subjects were respectively 61.8 ng/ milliliter (mL) and 1330 ng/mL. 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. As indicated above, a positive food effect on PK (2.05-fold increase in Cmax and 1.49-fold increase in AUClast) was demonstrated with a 100 mg tablet after a high-fat / high-calorie meal in the FIH study. A less pronounced effect, especially on Cmax is expected for the 10 and 25 mg doses due to a better solubility; however, to maximize the effect and to limit variability, all tablets should be taken with a meal. The type of food should not have any impact on COMPOUND IA exposure based on physiology-based PK simulation. The apparent terminal elimination half-life of COMPOUND IA tablet under fed conditions is approximately 10 hours (h) and the steady state is anticipated the next day after starting each dose treatment. With the exception of maculopapular skin rash and/or pruritus, 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. The response-exposure is not yet well understood, however skin reactions, especially for 50 and 100 mg QD doses cannot be ruled out. Metabolism by cytochrome P4502C9 (CYP2C9) and cytochrome P4503A4 (CYP3A4) is considered to be the major clearance mechanism for COMPOUND IA with fractional hepatic contributions of 64% and 29%, respectively. 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 (*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 PAT059585-WO-PCT (for further details refer to the IB). Supported by sufficient safety margins, all eligible patients irrespective of CYP2C9 genotype are allowed to participate in the study. Rationale for choice of control drugs (comparator/placebo) or combination drugs Placebo treatment will be used as a comparator to provide objective control for the evaluation of efficacy, safety, and tolerability during the 12-week treatment with COMPOUND IA. The oral tablet formulation will contain either active drug or placebo and will be indistinguishable in appearance and taste. Rationale for public health emergency mitigation procedures In the event of a public health emergency as declared by local or regional authorities (i.e., pandemic, epidemic or natural disaster), mitigation procedures may be required to ensure participant safety and trial integrity and are listed in relevant sections of the study protocol. Notification of the public health emergency should be discussed with Novartis prior to implementation of mitigation procedures and permitted/approved by local or regional health authorities and ethics committees as appropriate. Purpose and timing of interim analyses/design adaptations No interim analysis is planned for this study, but ad-hoc interim analyses may be conducted to support decision making concerning the current clinical study, the sponsor's clinical development projects in general, or in case of any safety concerns. End of study definition The end of the study is defined as the date of the last visit of the last participant in the study. 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. Able to communicate well with the investigator, to understand and comply with the requirements of the study. 3. Male and female participants aged between 18 - 80 years (inclusive) at the start of screening will be included. 4. Subjects must have a body mass index (BMI) within the range of 18 - 40 kg/m². BMI = Body weight (kg) / [Height (m)]² 5. Documented spontaneous myocardial infarction (MI) (diagnosed according to the universal MI criteria with or without evidence of ST segment elevation) at least 30 days before the start of screening (Thygesen K, Alpert JS, White HD et al (2007) Universal Definition of Myocardial Infarction. 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: • 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. For participants on statin therapy (HMG-CoA reductase inhibitor) as clinically indicated, 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. Exclusion criteria Participants meeting any of the following criteria are not eligible for inclusion in this study. 1. 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. History of drug abuse or unhealthy alcohol use within the 12 months prior to the start of screening, per investigator judgement. 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). For female subjects on the study the vasectomized male partner should be the sole partner for that subject. • Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device or intrauterine system or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. Based on an in vitro induction of CYP3A4, there is a slight potential risk for a DDI of COMPOUND IA with hormonal contraception at high exposures, therefore oral hormonal contraception must be supplemented with a barrier method, preferable a male condom. In case of use of oral contraception 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. If local regulations deviate from the contraception methods listed above and require more extensive measures to prevent pregnancy, local regulations apply and will be described in the Informed Consent Form (ICF). 7. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 7 days after stopping 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. 8. 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 PAT059585-WO-PCT 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). 9. 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. History of ongoing, chronic, or major recurrent infectious disease, at the discretion of the investigator, at the start of screening. 11. Live vaccinations within 1 month prior to Day 1 or live vaccinations planned during the trial. 12. Patients with suspected or proven immunocompromised state at screening, including: a. known clinical diagnosis of Human Immunodeficiency Virus (HIV) infection. Patients on systemic anti-retroviral therapy are also excluded from the trial; b. those with any other medical condition which in the opinion of the investigator places the patient at unacceptable risk for participation in immunomodulatory therapy; c. absolute neutrophil count ≤ 1000/mm3; d. those requiring systemic or local treatment with 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. • Use of 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. Known diagnosis of a systemic auto-immune disease (eg. systemic lupus erythematosus, etc.) 15. 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. 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 22. Uncontrolled hypertension (defined as systolic blood pressure (SBP) >160 mmHg or diastolic blood pressure (DBP) >100 mmHg) at screening. 23. 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 >200mg/dL, frequent urination/thirst not explained by other causes, etc. 24. Known nephrotic syndrome diagnosis, or eGFR < 30 mL/min calculated using the CKD-EPI formula (https://www.kidney.org/professionals/KDOQI/gfr_calculator), or ≥2+ protein on urine dipstick testing at screening 25. History of clinically significant 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). The Investigator should be guided by the following criteria: • Any single parameter may not exceed 2 x upper limit of normal (ULN). 26. Uncontrolled asthma at the start of screening, as defined by the investigator, with high likelihood of requiring systemic corticosteroids during treatment period. Lifestyle considerations For the duration of the study, participants should be informed and reminded of the restrictions outlined in this section. Meals and dietary restrictions Participants are to take COMPOUND IA or placebo once daily at approximately the same time each day. No grapefruit or grapefruit juice is to be consumed from first day of dosing until 7 days following the last dose. No St. John’s wort (Hypericum perforatum) is to be consumed 14 days before start of treatment until 7 days following the last dose. PAT059585-WO-PCT Screen failures Participants who sign an ICF and are subsequently found to be ineligible prior to randomization will be considered as screen failures. The reason for screen failure should be recorded on the appropriate 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 Case Report Form. Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened once. Each case of re-screening must be discussed and agreed with Novartis on a case-by-case basis. Participants who failed their initial screening due to elevated blood pressure (BP) may be re-screened if anti-hypertensive therapy has been started or increased as a result of initial screening BP above these limits. Genotyping will not need to be repeated in case of re-screening. Participants who are re-screened will be assigned a new participant number and will be reconsented. Replacement policy The proposed sample size accounts for dropouts at rates depending on the dose level of COMPOUND IA or placebo, therefore discontinued patients will not be replaced. 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. A new ICF will need to be signed if the Investigator chooses to rescreen the participant after a participant has screen failed, and the participant will be assigned a new Participant number. PAT059585-WO-PCT 1.3 Study treatments 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. As this is a population with known coronary heart disease, participants would be expected to be on standard of care therapies to reduce risk of recurrence of cardiovascular disease events (eg. lipid lowering therapy, anti-hypertensives, etc..), if clinically indicated. Treatment arms/group Participants will be assigned at Day 1 to one of the following 4 treatment arms/groups in a ratio of 5:5:1:1: PAT059585-WO-PCT

Table 3: Dose and treatment schedule D_{osing Period} ^{Dose/Strength Investigational / Control Drug (Name} Frequency and Strength) + Number of Tablets and/or Regimen Dosing Period 1 10 mg 1 tablet of COMPOUND IA 10 mg Once daily with (Day 1 to 21) _{0 mg 1 tablet of 10 mg matching placebo} ^{food for 3 weeks} Dosing Period 2 25 mg 1 tablet of COMPOUND IA 25 mg + 1 Once daily with (Day 22 to 42) tablet of 10 mg matching placebo food for 3 weeks 1_{0 mg} ^{1 tablet of COMPOUND IA 10 mg + 1} tablet of 25 mg matching placebo 0_mg ^{1 tablet of 25 mg matching placebo + 1} tablet of 10 mg matching placebo Dosing Period 3 50 mg 2 tablets of COMPOUND IA 25 mg Once daily with (Day 43 to 62) _{25 mg} ^{1 tablet of COMPOUND IA 25 mg + 1 food for 3 weeks} tablet of 25 mg matching placebo 0_mg ^{2 tablets of 25 mg matching placebo} Dosing Period 4 100 mg 4 tablets of COMPOUND IA 25 mg Once daily with (Day 63 to 84) _{0 mg} ^{4 tablets of 25 mg matching placebo food for 3 weeks} Uptitration will occur at the study visits during the Treatment Period. Schedule of Activities. 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. 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. If participants run out of tablets before the next uptitration visit can be scheduled, 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. 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. If vomiting occurs during the course of treatment, participants should not take the study treatment (COMPOUND IA or placebo) again before the next scheduled dose. Participants should be instructed not to make up missed doses. 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). 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. Approximately 28 participants will be randomized into the trial, of which a minimum of approximately 40% of randomized participants will be CHIP with TET2 somatic mutations. For subgroup allocation, 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-1β)+-placebo sequence, 3 COMPOUND IA+placebo sequences, and 1 placebo-only sequence). Within each 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-1β). 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). 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 EOT period visit on Day 85. After the EOT visit, participants will return approximately 1 week later on Day 92 for an End of Study (EOS) visit. Scientific rationale for study design Table 4: Rationale for study design PAT059585-WO-PCT _{Study Design Aspect} ^Rationale _Overall ^{In this study, participants will be randomized} to one of five treatment sequences comprised of various uptitrating doses of COMPOUND IA and/or placebo. The rationale behind the up-titration of COMPOUND IA doses within sequences is the efficiency for evaluating cytokine reductions that result from intra-individual measurements. Uptitration also may improve tolerability by decreasing the risk for rash; however, this has yet to be demonstrated. Clinical experience from prior clinical trial data with COMPOUND IA suggests that most AEs, especially the emergence of rash, should occur within the first 17 days of dosing and therefore limited carry-over of the initiation of AEs into subsequent dosing periods is expected to occur. The uptitration of COMPOUND IA doses and progressive further inhibition of the NLRP3 inflammasome is expected to result in a peak cytokine reduction similar to what would be seen regardless of prior dose exposures. This could be further evaluated in a subsequent Phase 2b dose-range finding study.

PAT059585-WO-PCT A cross-over design including placebo after active COMPOUND IA was not implemented as this could potentially confound the interpretation of the primary endpoints, as it is not known precisely when cytokine levels return to baseline after COMPOUND IA with the NLRP3 inflammasome activation profile in this population (which may differ from trial populations in prior or ongoing studies). _{Primary Endpoints} ^{Serum levels of IL-6 and IL-18 at 3 weeks} after the start of a dosing period were chosen as the primary endpoints for COMPOUND IA because both cytokines are linked to increased risk of CVD in numerous clinical populations. In addition, preclinical models implicated IL-6 and IL-18 in CVD pathogenesis. In the CANTOS clinical trial of IL-1β inhibition, participants that had the lowest on-treatment IL-6 levels had the greatest CVD benefit. While IL-18 is associated with CVD risk in human populations and preclinical evidence supports a causal role, no pharmacologic intervention trials have yet demonstrated that IL-18 inhibition reduced CVD risk.

PAT059585-WO-PCT _{Analysis of primary endpoints} ^{For participants randomized to receive} active COMPOUND IA treatment, each participant will contribute data on levels of IL- 6 and IL-18 after 3 weeks of oral daily treatment with COMPOUND IA at up to 3 different dose levels, and/or placebo, depending on treatment sequence assignment. A dose-response modeling approach, which integrates the IL-6 and IL- 18 levels across all dose levels and fits a dose-response relationship, will be utilized to quantify placebo-adjusted reductions at the highest tested dose level, 100 mg daily COMPOUND IA. The rationale for analyzing all of the IL-6 and IL-18 data from the end of each 3-week dosing period together in a dose-response model is to take advantage of the efficiencies introduced by the up- titration design. The model treats each dosing period as independent of the prior period, which is justified because cytokine levels are expected to reach a maximum reduction within 7-14 days for COMPOUND IA and therefore the 3-week timepoint is expected to be at steady state reduction. The fact that dosing occurs in a monotonically increasing manner ensures that no washout between doses is required, as the effect is only expected to be greater with higher doses. It is possible that subsequent dose levels may reach steady state cytokine reduction sooner than if drug had not already been on board, but this will not impact the analysis as only the 3-week measurement is collected and used in the analysis. PAT059585-WO-PCT _{Treatment Sequences} ^{In 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. PAT059585-WO-PCT D_{uration of study periods} ^{COMPOUND IA treatment sequences: the} treatment period of approximately 12 weeks allows for a gradual up-titration (up-titration occurs approximately every 3 weeks) to the maximal dose of 100 mg of COMPOUND IA. From prior clinical trials with COMPOUND IA, the expected peak reduction of cytokines occurs within the first 7-14 days, and therefore, approximately three weeks for each dosing period should allow adequate assessment of cytokine reduction efficacy and tolerability at each dose level. 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. Depending on the randomization to one of five treatment sequences, 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). In the FIH study, an ex vivo whole blood assay of lipopolysaccharides (LPS)-stimulated IL-1β secretion was used as a PD readout to estimate pharmacological activity. Based on the results of this analysis, the mean COMPOUND IA plasma C_trough required to inhibit 50% (IC₅₀) and 90% (IC₉₀) of stimulated IL-1β release in healthy subjects were respectively 61.8 ng/mL and 1330 ng/mL. COMPOUND IA mean C_trough at steady-state for 10 mg suspension QD (fasted) was 183 ng/mL (coefficient of variation (CV)% 64.4%), thus exceeded IC50. Dosing of single 100 mg tablet under fasted and 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 (refer to the IB for further details). PAT059585-WO-PCT 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 QD is proposed in this study. As indicated above, a positive food effect on PK (2.05-fold increase in Cmax and 1.49-fold increase in AUClast) was demonstrated with a 100 mg tablet after a high-fat/high-calorie meal in the FIH study. A less pronounced effect, especially on Cmax, is expected for the 10 and 25 mg doses due to a better solubility; however, to maximize the effect and to limit variability, all tablets should be taken with a meal. The type of food should not have any impact on COMPOUND IA exposure based on physiology-based PK simulation. The apparent terminal elimination half-life of COMPOUND IA tablet under fed conditions is approximately 10 hours and the steady state is anticipated the next day after starting each dose treatment. With the exception of maculopapular skin rash and/or pruritus, 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. The response-exposure is not yet well understood, however skin reactions, especially for 50 and 100 mg QD doses cannot be ruled out. Metabolism by CYP2C9 and CYP3A4 is considered to be the major clearance mechanism for COMPOUND IA with fractional hepatic contributions of 64% and 29% respectively. 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_{xploratory objective(s)} ^{Endpoint(s) for exploratory objective(s)} • To assess the PK of KEY • Plasma C_trough of KEY METABOLITE at various METABOLITE a metabolite of dose levels of COMPOUND IA COMPOUND IA in plasma • To explore whether individual • Plasma C_trough of COMPOUND IA and its variation in genes related to metabolite, as well as CYP2C9 genotype drug metabolism confer differential PK response to COMPOUND IA 1. To assess the effect of 2. 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-1β, CXCL9, CXCL10, hsIFN-γ, 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. To explore genetic and 4. Exploratory genetic and proteomic endpoints may 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. To explore the effect of • Change from baseline in skin microbiome at COMPOUND IA on changes various visits to the skin microbiome Primary estimands The primary clinical question of interest is: What is the effect of COMPOUND IA in addition to SoC (standard of care) CVD prevention medication in patients with known coronary heart disease and presence of CHIP on the inflammatory markers IL-6 and IL-18 (IL-18 applicable for COMPOUND IA only), assuming patients continue treatment with reasonable adherence and there are no new major cardiovascular events, initiations of prohibited medication, or febrile infections, but without regard to changes in SoC CVD prevention medication? 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. PAT059585-WO-PCT Table 6: Intercurrent events for the primary estimand Intercurrent event Details (if necessary) Handling of event Permanent discontinuation - Data collected after this of study treatment intercurrent event will not be used for this estimand Incidence of a new major - Data collected after this CVD event (e.g., myocardial intercurrent event will not be infarction, stroke, etc.) used for this estimand Change in SoC CVD - All data collected after this prevention medication intercurrent event will be used for this estimand Initiation of a prohibited Unforeseen use of any Data collected after this medication for a comorbid medication expected to intercurrent event will not be condition have a sustained effect on used for this estimand the primary endpoints (i.e., any systemic corticosteroids) Unforeseen use of Only the assessment medication expected to immediately following the have a limited effect on the event will be excluded for primary endpoints (i.e., any the purpose of this estimand other prohibited medications) New-onset febrile infection Febrile infection around time Only the assessment of assessment (details to be immediately following the provided in the statistical event will be excluded for analysis plan) the purpose of this estimand Nonadherence to study Greater than 20% of missed Only the assessment treatment daily doses within 3 weeks immediately following the prior to an assessment event will be excluded for the purpose of this estimand Any missed dose within the Only the assessment 2 days prior to an immediately following the assessment event will be excluded for the purpose of this estimand PAT059585-WO-PCT Study population The study population is adults with known coronary heart disease and CHIP with somatic mutations in TET2 or DNMT3A (VAF ≥2%). In this study, approximately 28 participants will be randomized. Inclusion criteria Participants eligible for inclusion in this study must meet all of the following criteria: • Written informed consent must be obtained before any assessment is performed. • Male and female participants aged between 18 - 80 years (inclusive) at the start of screening will be included. • Subjects must have a body mass index (BMI) within the range of 18 - 40 kg/m². BMI = Body weight (kg) / [Height (m)]² at screening. 7. Documented spontaneous MI (diagnosed according to the universal MI criteria with or without evidence of ST segment elevation) at least 30 days before the start of screening (Thygesen K, Alpert JS, White HD et al (2007) Universal Definition of Myocardial Infarction. 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. 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: 3. Symptoms of ischemia 4. ECG changes indicative of new ischemia (new ST-T changes or new Left bundle branch block (LBBB)) 5. Development of pathologic Q waves 6. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality PAT059585-WO-PCT If no documented evidence of an acute MI in the medical record, then evidence of a prior MI may include: 4. Development of pathological Q waves with or without symptoms 5. 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 6. Pathologic findings of a healed or healing MI 5. Known to be a carrier of clonal expansion of hematopoietic cell lines 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%. 6. For participants on statin therapy (HMG-CoA reductase inhibitor) as clinically indicated, 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. • Patients receiving concomitant medications that are known to be: • strong or moderate inducers of 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 PD 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. PAT059585-WO-PCT 4. History of drug abuse or unhealthy alcohol use within the 12 months prior to the start of screening, per Investigator judgement. 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. 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). For female participants on the study, the vasectomized male partner should be the sole partner for that participant. • Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an IUD or intrauterine system, or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception. Based on an in vitro induction of CYP3A4, there is a slight potential risk for a DDI of COMPOUND IA with hormonal contraception at high exposures, thus hormonal contraceptives must be supplemented by a barrier method, preferably a male condom. In case of use of oral contraception, women should be stable on the same pill for a minimum of 3 months before taking study treatment. PAT059585-WO-PCT If local regulations deviate from the contraception methods listed above and require more extensive measures to prevent pregnancy, local regulations apply and will be described in the Informed Consent Form (ICF). Women are considered post-menopausal and not of child bearing 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 prior to Day 1. 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. 7. Pregnant or nursing (lactating) women. 8. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 90 days after stopping 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 × 10⁹/L), and/or thrombocytopenia (platelets < 150 × 10⁹/L) that is not explained by another known or identifiable condition. 11. History of ongoing, chronic, or major recurrent infectious disease, at the discretion of the Investigator, at the start of screening. 12. Live vaccinations within 1 month prior to Day 1 or live vaccinations planned during the trial. 13. Patients with suspected or proven immunocompromised state at screening, including: (a) known clinical diagnosis of Human Immunodeficiency Virus (HIV) infection. Patients on systemic anti-retroviral therapy are also excluded from the trial; (b) those with any other medical condition which in the opinion of the Investigator places the patient at unacceptable risk for participation in immunomodulatory therapy or (c) those requiring systemic or local treatment with any immune modulating agent in doses with systemic effects, e.g., high dose oral or i.v. steroids (>20 mg prednisone orally PAT059585-WO-PCT 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. 14. Use of any biologic drugs targeting the immune system (for example, but not limited to: tumour necrosis factor (TNF) blockers, anakinra, rituximab, abatacept, tocilizumab, or canakinumab) within 26 weeks of Day 1. 15. Known diagnosis of a systemic auto-immune disease (e.g., systemic lupus erythematosus, etc.). 16. Current use or within 5 half-lives of use of colchicine at start of screening. 17. Participants with a MI resulting from percutaneous coronary interventions (PCI) or coronary artery bypass graft (CABG) procedures. 18. Major non-cardiac surgical or major endoscopic procedure within the past 6 months prior to the start of screening. 19. Multi-vessel CABG surgery within the past 3 years prior to the start of screening. 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) at screening. 24. 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. 25. Known nephrotic syndrome diagnosis, or eGFR <30 mL/min calculated using the CKD- EPI formula (https://www.kidney.org/professionals/KDOQI/gfr calculator), or ≥2+ protein on urine dipstick testing at screening. 26. History of clinically significant 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. The Investigator should be guided by the following criteria: • Any single parameter may not exceed 2x upper limit of normal (ULN) 27. Uncontrolled asthma at the start of screening, as defined by the Investigator, with high likelihood of requiring systemic corticosteroids during the treatment period. Lifestyle considerations For the duration of the study, participants should be informed and reminded of the restrictions outlined in this section. Meals and dietary restrictions Participants are to take COMPOUND IA or placebo QD at approximately the same time each day. No grapefruit or grapefruit juice is to be consumed from first day of dosing until 7 days following the last dose. No St. John’s wort (Hypericum perforatum) is to be consumed 14 days before start of treatment until 7 days following the last dose. Screen failures Participants who sign an ICF and are subsequently found to be ineligible prior to randomization will be considered as screen failures. The reason for screen failure should be recorded on the appropriate Case Report Form (CRF). 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. Each case of re-screening must be discussed and agreed with Novartis on a case-by-case basis. Participants who failed their initial screening due to elevated blood pressure (BP) may be re-screened if anti-hypertensive therapy has been started or increased as a result of initial screening BP above these limits. Participants who are re- screened will be assigned a new participant number, and will be reconsented. PAT059585-WO-PCT Study treatment(s) The investigational drugs COMPOUND IA or placebo, will be prepared by the Sponsor as indicated in Table 7. COMPOUND IA or placebo will be administered orally with food QD. 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-1β and 1β 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 Drug Biologic Biologic} Dose 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 _Sourcing ^Provided Provided Provided Provided Provided Provided centrally by centrally by centrally by centrally by centrally by centrally by the Sponsor the Sponsor the Sponsor the Sponsor the Sponsor the Sponsor

PAT059585-WO-PCT Packaging Study Study Study Study Study Study and Labeling treatment will treatment will treatment will treatment will treatment treatment will be provided be provided be provided be provided will be be provided in blinded in blinded in blinded in blinded provided in in vials via HDPE HDPE HDPE HDPE vials via open label bottles of 35 bottles of 35 bottles of 35 bottles of 35 open label supply. Each tablets. Each tablets. Each tablets. Each tablets. Each supply. vial will be bottle will be bottle will be bottle will be bottle will be Each vial labeled as labeled as labeled as labeled as labeled as will be required per required per required per required per required per labeled as country country country country country required per requirement. requirement. requirement. requirement. requirement. country requirement Instruction for prescribing and taking study treatment 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. 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 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 + 1 tablet of 25 mg matching placebo COMPOUND IA 0 2 tablets of 25 mg mg matching placebo Dosing Period 4 COMPOUND IA 100 4 tablets of QD with food for 3 (Day 63 to 84) mg COMPOUND IA 25 weeks mg COMPOUND IA 0 4 tablets of 25 mg mg matching placebo 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 visit should be scheduled the day after the last dose of that current dosing period. In the event that an up-titration visit cannot be scheduled within the allowed visit windows, 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. To achieve the target doses for each time period, please refer to Table 9 below. 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. 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. If vomiting occurs during the course of treatment, participants should not take the study treatment (COMPOUND IA or placebo) again before the next scheduled dose. PAT059585-WO-PCT Participants should be instructed not to make up missed doses. 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. Example 3: Clinical first-in-human (FIH) study: Study design The study design comprised of 4 parts: single ascending dose (SAD; Part A), relative bioavailability of tablet formulations (Part B), multiple ascending dose (MAD; Part C), and relative bioavailability and food effect (Part D) (Figure 2; RF=Reference Formulation (crystalline suspension); T2=Test Formulation 2 (crystalline tablet); T3=Test Formulation 3 (spray-dried dispersion suspension); T4=Test Formulation 4 (encapsulated crystalline tablet)). In each group of Parts A and C, 8 subjects were randomized in a 3:1 ratio to receive Compound IA (6 subjects) or matching placebo (2 subjects). For Part A, eight cohorts of eight eligible subjects were enrolled. Each subject received a single oral dose of Compound IA (3, 10, 30, 100, 300 mg of crystalline suspension and 100, 300, 600 mg of spray-dried dispersion (SDD) under fasted conditions. As this was a FIH study, two sentinel subjects were dosed first, at least 24 hours before the rest of the cohort was dosed, to assure maximum safety. Part B was skipped because the data from Part A provided for an adequate comparison of crystalline and SDD formulations. For part C, eligible subjects were enrolled in six different cohorts. Each subject received once daily (QD) multiple doses of Compound IA (10, 30 mg of crystalline suspension and 100, 200 mg of SDD for 14 days) in fasted condition, and (25, 50 mg of encapsulated crystalline tablet for 13 days and single dose on Day 14 or placebo) under fed condition. Subjects were dosed in Part C following review available safety, tolerability and PK data from preceding groups in Part A. Part D had an open-label, randomized, 3-period crossover design consisting of 1 group of 6 subjects. The PK of the crystalline tablet formulation of Compound IA was compared between fed and fasted conditions, and with the PK of the crystalline suspension of Compound IA under fasted conditions. Subjects received 3 doses of Compound IA with washout period of 7-14 days between each dose (Dose 1: 100 mg oral suspension in fasted condition; Dose 2: 100 mg oral tablet in fasted condition; Dose 3: 100 mg oral tablet in fasted condition). Based on these doses, subjects were randomly assigned to 1 of 6 treatment sequences (1 subject per sequence) prepared using Williams design. Subjects PAT059585-WO-PCT Eligible subjects were healthy male, and female aged between 18 to 64 years with body mass index (BMI) ≥18.5 and ≤ 30.0 kg/m². No subject participated in more than 1 part or group. A written informed consent was obtained prior to any study procedure. 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 (IFM Management, Inc.) 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. Assessments Safety assessments in all parts of the study included adverse event (AE) reporting using the Medical Dictionary for Regulatory Activities (version 22.1), clinical laboratory tests (biochemistry, hematology, and urinalysis), vital signs, electrocardiograms (ECGs), physical examination and skin biopsy (as applicable). In single-dose part, blood samples were collected for determining the concentrations of Compound IA at the following time points relative to dosing on Day 1: at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours post-dose, and at the follow-up visit. In multiple-dose part, relative to dosing on Days 1 and 14, 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. Following PK parameters were estimated using PAT059585-WO-PCT noncompartmental analysis maximum concentration in plasma (C_max); time to maximum concentration (t_max); concentration at 24 h post-dose (C_24h) (Part A only); Lag time: time of observation prior to the first quantifiable concentration (t_lag); time of the last quantifiable concentration (t_last); area under the concentration-time curve from time 0 to the last quantifiable concentration (AUC_0-last); area under the plasma concentration-time curve from time 0 to infinity (AUC_0-inf); area under the plasma concentration-time curve from time 0 to 24 hour post-dose (AUC_0-24); terminal phase rate constant (K_el); terminal phase half-life (t_1/2); apparent total body clearance (CL/F); and apparent volume of distribution at terminal phase (V_z/F); and in addition for Part C only: area under the plasma concentration-time curve over the dosing interval from time 0 to 12 hours post-dose (AUC_0-tau); apparent clearance at steady state (CLss/F); accumulation ratio based on AUC_0-tau (R_ac,AUC); and accumulation ratio based on C_max (R_ac,C_max). To determine the PD response to NLRP3 inhibition, whole blood samples were collected for exploratory PD analysis (Part A and Groups 1-3 of Part C). An ex-vivo stimulation by activating the NLRP3 inflammasome with lipopolysaccharide (LPS) was evaluated compared to control conditions, followed by analysis of blood cell release of the inflammatory marker IL-1β. Statistical analysis All data were summarized using descriptive statistics and were listed and summarized in tabular and/or graphical form. Descriptive statistics for all relevant PK parameters included: n, arithmetic mean, standard deviation (SD), coefficient of variation (CV%), minimum, median, maximum, geometric mean, and geometric CV%. For t_max only median, minimum, and maximum are presented. 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. In 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. In 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. For the following treatments, the least-squares geometric mean ratios were presented together with 90% CIs: 100 mg Compound IA tablet fasted over 100 mg Compound IA suspension fasted, and 100 mg Compound IA tablet fed over 100 mg Compound IA tablet fasted. Combined individual and mean plots of the individual IL-1β concentrations versus time are presented by treatment. Modeling of Compound IA effects on a corrected, stimulated ex vivo Lipopolysaccharide (LPS) challenge in whole blood included evaluation of the relationship between LPS challenge results by conditionally weighted residual modeling. Results Subject disposition and demographics A total of 122 subjects were enrolled in the study. All 122 subjects were included in the safety and PD analysis sets, and all 94 subjects who received active treatment (Compound IA) were included in the PK analysis set. Overall, 58 (48%) male and 64 (52%) female subjects between 18 and 64 years of age and with a BMI between 18.9 and 29.4 kg/m² participated in the study. The majority of subjects 105 (86%) (Part A, n=57; Part C, n=42 and Part D, n=6) were white. Of the enrolled subjects, 107 (88%) subjects completed the study as per protocol and 15 (12%) subjects discontinued the study early. These early discontinuations included 1 out of 64 (2%) subjects in Part A, 13 out of 52 (25%) subjects in Part C, and 1 out of 6 (17%) subjects in Part D of the study. Reasons for study discontinuation included withdrawal due to adverse effects (AEs) in 12 (10%) subjects, and 1 (1%) subject each discontinued the study due to either withdrawal of consent, lost to follow-up, or study on temporary hold due to the COVID-19 pandemic (preventing visits; unrelated to the safety of Compound IA). All 4 discontinued subjects were replaced in Part C. Safety Single and multiple doses of Compound IA were generally well tolerated. No deaths or serious adverse events (SAEs) were reported during the study. Overall, 87/122 subjects (71%) reported treatment emergent adverse events (TEAEs); 66/94 subjects (70%) in Compound IA arm, and 21/28 (75%) subjects in placebo arm. 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. All 12 subjects received Compound IA; either as single dose (100 mg [n=1] or 600 mg [n=1]), or multiple dose (30 mg QD [n=2], 100 mg QD [n=3], 200 mg QD [n=2], or 50 mg BID [n=3]). These TEAEs were of mild to moderate intensity, generally started within 1 to 17 days after initiation of treatment with Compound IA and resolved within 1 to 18 days after onset; in all cases without concomitant treatment. For 10 subjects, these TEAEs led to treatment discontinuation. Two other subjects were early discontinued due to TEAEs that were unrelated to the study drug. Mild decreases in neutrophil and leukocyte counts were considered non-clinically significant and occasionally noted, which could be consistent with a PD effect of COMPOUND IA resulting from inhibition of IL-1β signaling downstream of NLRP3. One subject had a second-degree atrioventricular block that was not considered to be related to the study drug. No other clinically relevant findings were reported for vital signs, 12-lead ECG, 24-hour Holter monitoring, or physical examination. Pharmacokinetics The exposure to single doses of Compound IA increased in a less than dose-proportional manner when Compound IA was administered as crystalline suspension (3–300 mg), but increased dose-proportionally when administered as SDD suspension (100–600 mg). After QD administration of Compound IA dose range 30–200 mg for 2 weeks, only limited drug accumulation of about 1.1 to 1.3-fold was observed in reaching steady state. This is consistent with a mean t_1/2 ranging from 9.83 to 16.2 hours across QD and BID dose levels. At steady state, Compound IA demonstrated a very low CLss/F (~0.83 to 1.11 L/h) and Vss/F (~12.6 to 23.3 L), with low-to-moderate inter-subject variability across QD and BID dose levels of Compound IA. Renal clearance at steady state was relatively low (~0.008 L/h) compared to total oral clearance, hence unlikely to be a relevant clearance pathway in humans. Administration of a single dose of 100 mg Compound IA as crystalline suspension under fed conditions led to 2.05-fold increase of C_max and 1.49-fold for AUC_0-last of Compound IA compared to fasted conditions. For the crystalline tablet (100 mg Compound IA under fasted conditions), the median t_max of Compound IA was delayed from 2 to 5 hours, the C_max was 78% lower, and the t_1/2 was comparable between the crystalline tablet and suspension. The encapsulated crystalline tablets (25 mg and 50 mg bid under fed conditions) were characterized by a median lag time of 0.75 and 0.25 hours, respectively, and a median t_max of 4 hours on Day 1. 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-1β (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-1β 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. Based on the fractional maximum stimulation effect (E_max) model tested with a Hill coefficient, the arithmetic mean (±SD) of the observed stimulation effect of IL-1β was 1820 (±102) ng/L, and the E_max of IL-1β was -0.985 (±0.00277). The median potency of Compound IA inhibiting 90% of the ex-vivo stimulated IL-1β release (IC₉₀) in the (LPS) challenge was a concentration of 3.18 μM (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-1β release were EC₅₀: 0.141 μM (90% CI: 0.114, 0.171), EC₉₀: 2.57 μM (90% CI: 2.24, 2.94), and IC₅₀: 0.146 μM (90% CI: 0.118, 0.179) Discussion Single and multiple doses of Compound IA or placebo were generally well tolerated. No deaths or serious adverse events (SAEs) were reported during the study. TEAEs like skin rash and/or pruritus were considered related to the study drug. The majority of TEAEs reported by subjects were mild (69%) and moderate (12%) in severity. The maculopapular and/or pruritic skin rashes were most frequently reported at the higher multiple dose levels of Compound IA, suggesting a relationship with exposure to Compound IA. Following single oral doses of Compound IA under fasted conditions, Compound IA was rapidly absorbed with a median t_max ranging from 0.76 to 3.00 hours across dose levels. However, with higher dose range 30–600 mg the median t_max was slightly delayed (1.5 to 3.0 hours) indicating a slower absorption compared to the lower doses (3 and 10 mg: 0.76 and 1.00 hours, respectively). The increase in drug exposure was less than dose-proportional with crystalline suspension (particularly 100 and 300 mg), whereas dose-proportional increase in exposure was observed with SDD suspension (100–600 mg), indicating solubility-limited absorption of crystalline material at doses ≥100 mg. Multiple doses and formulations of Compound IA showed no deviations from dose proportional drug exposure after 2 weeks signifying that multiple dose PK was linear and were not limited by solubility. Following oral doses of Compound IA on Day 1, a slight delay in absorption was observed with encapsulated crystalline tablets under fed condition. This slower absorption was in line with bioavailability results where no clear effect of food on t_max was observed. These findings suggest the lag absorption time was due to encapsulation. 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-1β using broad range of NLRP3-dependent activators. This has been observed with di-aryl sulfonylurea compounds which are structurally similar to Compound IA [15]. In this study, dose-dependent decreases in concentrations of IL-1β were observed with increasing single and multiple oral doses of Compound IA. IL-1 β production can be mediated by other inflammasomes or by inflammasome independent pathways; thus, inhibitors aimed at IL-1β 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. This may be consistent with a PD effect of Compound IA resulting from inhibition of signaling downstream of NLRP3, similar to known effects of anti- IL-1β monoclonal antibody canakinumab. The AUCs of subjects with heterogenous CYP2C9 genotypes were higher than those observed in subjects with normal CYP2C9 activity. These results suggest that the clearance of Compound IA is affected by reduced CYP2C9 activity caused by specific genetic variants. In summary, single and multiple oral doses of Compound IA were well tolerated for up to 14 days in healthy subjects, with no safety or tolerability concerns. The PK profile of Compound IA is compatible with a twice daily dosing regimen. The safety and tolerability, PK, and PD results suggests that Compound IA has the potential to be an effective oral first- in-class innate immune modulator warranting further clinical evaluation. 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-1β 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 μg/ml)), and maintained in log phase prior to experimental setup. Prior to the experiment, compounds were dissolved in dimethyl sulfoxide (DMSO) to generate a 30mM stock. The compound stock was first pre-diluted in DMSO to 3, 0.34, 0.042 and 0.0083 mM intermediate concentrations and subsequently spotted using Echo550 liquid handler into an empty 384-well assay plate to achieve desired final concentration (e.g.100, 33, 11, 3.7, 1.2, 0.41, 0.14, 0.046, 0.015, 0.0051, 0.0017 μM). DMSO was backfilled in the plate to achieve a final DMSO assay concentration of 0.37%. The plate was then sealed and stored at room temperature until required. 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 μg/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 µl). Cells were incubated with compounds for 1 hour and then stimulated with gramicidin (5μM) (Enzo) for 2 hours. Plates were then centrifuged at 340g for 5 min. Cell free supernatant (40µL) was collected using a 96-channel PlateMaster (Gilson) and the production of IL-1β was evaluated by HTRF (cisbio). The plates were incubated for 18 h at 4ºC and read using the preset HTRF program (donor emission at 620 nm, acceptor emission at 668 nm) of the SpectraMax i3x spectrophotometer (Molecular Devices, software SoftMax 6). A vehicle only control and a dose titration of CRID3 (100 - 0.0017 μM) were run concurrently with each experiment. Data was normalized to vehicle-treated samples (equivalent to 0% inhibition) and CRID3 at 100 µM (equivalent to 100% inhibition). Compounds exhibited a concentration-dependent inhibition of IL-1β production in PMA- differentiated THP-1 cells. Procedure 2: IL-1β 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. Prior to experiments, cells were cultured in complete RPMI 1640 (containing 10% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml)), and maintained in log phase prior to experimental setup. Prior to the experiment THP-1 were treated with PMA (Phorbol 12-myristate 13-acetate) (20 ng/ml) for 16-18 hours. Compounds were dissolved in dimethyl sulfoxide (DMSO) to generate a PAT059585-WO-PCT 30mM stock. 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, resuspended in RPMI 1640 (containing 2% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml). The cells were plated in a 384-well plate at a density of 50,000 cells/well (final assay volume 50 µl). Compounds were first dissolved in assay medium to obtain a 5x top concentration of 500µM.10 step dilutions (1:3) were then undertaken in assay medium containing 1.67% DMSO.5x compound solutions were added to the culture medium to achieve desired final concentration (e.g.100, 33, 11, 3.7, 1.2, 0.41, 0.14, 0.046, 0.015, 0.0051, 0.0017 μM). Final DMSO concentration was at 0.37%. Cells were incubated with compounds for 1 hour and then stimulated with gramicidin (5μM) (Enzo) for 2 hours. Plates were then centrifuged at 340g for 5 min. Cell free supernatant (40µL) was collected using a 96-channel PlateMaster (Gilson) and the production of IL-1β was evaluated by HTRF (cisbio). A vehicle only control and a dose titration of CRID3 (100 - 0.0017 μM) were run concurrently with each experiment. Data was normalized to vehicle-treated samples (equivalent to 0% inhibition) and CRID3 at 100 µM (equivalent to 100% inhibition). Compounds exhibited a concentration-dependent inhibition of IL-1β production in PMA-differentiated THP-1 cells. Procedure 3: 1. Experimental procedure: Cell Culture Culture THP-1 cells in the complete RPMI-1640 medium with 10% FBS at 37°C, 5% CO₂. Passage the cells every 3 days by inoculating 3x10⁵ cells per ml. 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 2.5x10⁷ 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. Incubate for 1h at 37°C, 5% CO₂. Prepare 5x gramicidin, add 10 µl per well, the final concentration is 5 µM, incubate for 2hrs at 37°C, 5% CO₂. Centrifuge at 350 g for 1 min. Pipet 16µl supernatant by apricot, and transfer into white 384 proxiplate. HC: 100 ^M CRID3 (MCC950) + 5 µM gramicidin LC：5 µM Gramicidin. IL-1β detection Homogenize the 5x diluent #5 with a vortex and add 1 volume of stock solution in 4 volumes of distilled water. Thaw 20x stock solution of anti-IL1β-Cryptate-antibody and anti-IL1β XL-antibody. Dilute these two antibodies to 1x with detection buffer #3. Pre-mix the two ready-to-use antibody solutions just prior to use. Dispense 4ul of pre-mixed Anti-IL1β antibodies working solution into all wells. Seal the plate and incubate overnight at 4 ^oC. Read the cell plate using EnVison and plot Readout vs. the test compound concentration to calculate the IC₅₀. 2. Data Analysis: IC₅₀ of compounds can be calculated using the following formulas Formula for IC₅₀ % inhibition =100-100 x [HC_ave-Readout / (HC_ave – LC_ave)] Fit the normalized data in a dose-response manner using XLfit, and calculate the compound concentration. The following table 10 shows the biological activity of compounds in hTHP-1 assay containing 2% fetal bovine serum: <0.008 µM = “++++++”; ≥0.008 and <0.04 µM = “+++++”; ≥0.04 and <0.2 µM = “++++”; ≥0.2 and <1 µM = “+++”; ≥1 and <5 µM = “++”; ≥5 and <30 µM

Table 10: Compound hTHP-1 IC₅₀ I ++++ IA +++++ PAT059585-WO-PCT IB +++ All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. The present invention and its embodiments have been described in detail. However, the scope of the present invention is not intended to be limited to the particular embodiments of any process, manufacture, composition of matter, compounds, means, methods, and/or steps described in the specification. Various modifications, substitutions, and variations can be made to the disclosed material without departing from the spirit and/or essential characteristics of the present invention. Accordingly, one of ordinary skill in the art will readily appreciate from the invention that later modifications, substitutions, and/or variations performing substantially the same function or achieving substantially the same result as embodiments described herein may be utilized according to such related embodiments of the present invention. Thus, the following claims are intended to encompass within their scope modifications, substitutions, and variations to processes, manufactures, compositions of matter, compounds, means, methods, and/or steps disclosed herein. The claims should not be read as limited to the described order or elements unless stated to that effect. It should be understood that various changes in form and detail may be made without departing from the scope of the appended claims.

Claims

PAT059585-WO-PCT CLAIMS 1. A method of treatment for reducing the risk of or preventing cardiovascular events or cardiovascular diseases, comprising administering a NLRP3 inhibitor to a subject in need thereof. 2. The method of treatment according to claim 1, comprising 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 in need thereof. 3. The method according to claim 1 or 2, wherein the NLRP3 inhibitor is administered to a subject in need thereof at a total daily dose of about 10 mg to about 50 mg in a single dose or divided doses. 4. The method according to any one of claims 1 to 3, wherein the NLRP3 inhibitor is administered to a subject in need thereof at a total daily dose of about 25 mg in a single dose or divided doses. 5. The method according to any one of claims 1 to 4, wherein the NLRP3 inhibitor is administered to a subject in need thereof at a total daily dose of about 50 mg in a single dose or divided doses. 6. The method according to any one of claims 1 to 5, wherein the NLRP3 inhibitor is administered to a subject during or after consuming food. 7. The method according to any one of claims 1 to 6, wherein the time interval between the administration of two subsequent doses is about 22-26 hours. 8. The method according to any one of claims 1-7, wherein the method of treatment relates to reducing circulating levels of an inflammatory marker as determined by change from baseline. 9. The method according to claim 8, wherein the inflammatory marker is selected from IL-6 serum levels, IL-18 serum levels, hsCRP, soluble ASC, IL-1β, CXL9, CXCL10, hsIFNg, von- Willebrand-Factor (vWF), myeloid/lymphoid cell activation/enumeration by flow cytometry (whole blood/PBMC) and lipid parameters (e.g. LDL, Lp(a), apolipoproteins). PAT059585-WO-PCT 10. The method according to claim 8 or 9, wherein the inflammatory marker is selected from IL-6 serum levels, IL-18 serum levels and hsCRP. 11. The method according to any one of claims 1 to 10, wherein the subject has a high hsCRP level of ≥ 2 mg/L before first administration of the NLRP3 inhibitor. 12. The method according to any one of claims 1 to 11, wherein the subject to be treated has a known heart disease. 13. The method according to any one of claims 1 to 12, wherein the subject to be treated is known to be a carrier of a clonal expansion of hematopoietic cell lines with somatic mutations (i.e. 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%. 14. The method according to any one of claims 1 to 13, wherein the cardiovascular disease or cardiovascular event is selected from non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, and hospitalization for unstable angina requiring unplanned revascularization. 15. The method of claim 14, wherein the cardiovascular disease or cardiovascular event is non-fatal myocardial infarction. 16. The method of claim 14, wherein the cardiovascular disease or cardiovascular event is non-fatal stroke. 17. The method of claim 14, wherein the cardiovascular disease or cardiovascular event is cardiovascular death. 18. The method of claim 14, wherein the cardiovascular disease or cardiovascular event is hospitalization for unstable angina requiring unplanned revascularization. 19. The method of claim 14, wherein 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. PAT059585-WO-PCT 20. The method of any one of claims 1 to 19, wherein the subject 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 determined by change from baseline. 21. The method according to any one of claims 1 to 20, wherein 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. 22. The method according to any one of claims 1 to 21, wherein the subject does not exhibit any skin rash. 23. The method according to any one of claims 1 to 22, wherein the NLRP3 inhibitor is administered to the subject orally. 24. The method according to any one of embodiments 1 to 23, wherein the NLRP3 inhibitor is comprised in a tablet formulation. 25. The method according to any one of embodiments 1 to 24, wherein at least one further therapeutic agent is administered. 26. The method according to any one of embodiments 1 to 25, wherein the NLRP3 inhibitor is Compound I, or a pharmaceutically acceptable salt thereof: H₂ ^N _O O .

27. The method according to any one of embodiments 1 to 26, wherein the NLRP3 inhibitor is Compound IA, or a pharmaceutically acceptable salt thereof.