EP4561574A1 - Dosing regimen for a nlrp3 inhibitor - Google Patents

Dosing regimen for a nlrp3 inhibitor

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Publication number
EP4561574A1
EP4561574A1 EP23754407.7A EP23754407A EP4561574A1 EP 4561574 A1 EP4561574 A1 EP 4561574A1 EP 23754407 A EP23754407 A EP 23754407A EP 4561574 A1 EP4561574 A1 EP 4561574A1
Authority
EP
European Patent Office
Prior art keywords
compound
nlrp3
auto
syndrome
nlrp3 inhibitor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23754407.7A
Other languages
German (de)
French (fr)
Inventor
Christopher John FARADY
Ewa GATLIK
Frank Derrick WALDRON-LYNCH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis AG filed Critical Novartis AG
Publication of EP4561574A1 publication Critical patent/EP4561574A1/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present disclosure relates to the field of pharmacy, particularly to a NLRP3 inhibitor for use in the treatment of an auto-inflammatory syndrome.
  • the disclosure also relates to a NLRP3 inhibitor or a pharmaceutical combination comprising a NLRP3 inhibitor, or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent, for use in the treatment of an auto-inflammatory syndrome; to a method for the treatment of an auto-inflammatory syndrome that 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 the treatment of an auto-inflammatory syndrome.
  • BACKGROUND Cryopyrin-associated periodic syndromes is a group of rare diseases characterized by skin, musculoskeletal, ocular, and neurological symptoms and chronic systemic inflammation that may lead to organ damage and/or amyloidosis and are caused by heterozygous gain-of-function mutations in the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) gene.
  • CAPS is classified into three clinical phenotypes based on a spectrum of disease severity: familial cold auto-inflammatory syndrome (FCAS), Muckle Wells syndrome (MWS) and neonatal onset multisystem inflammatory disease (NOMID) also called chronic, infantile, neurological, cutaneous and articular syndrome (CINCA) (Hoffman et al, (2019) Cryopyrin-Associated Periodic Syndromes (CAPS).
  • FCAS familial cold auto-inflammatory syndrome
  • MMS Muckle Wells syndrome
  • NOMID neonatal onset multisystem inflammatory disease
  • CINCA Cryopyrin-Associated Periodic Syndromes
  • Hashkes P Laxer R, Simon A (eds). Textbook of Autoinflammation. Springer, Cham. p. 347-365).
  • FCAS represents the mildest CAPS clinical phenotype and symptoms are typically limited to low grade fever, general rash, conjunctivitis and polyarthralgia, triggered 1-2 hours following cold exposure and resolve within 24 hours with warmth. These manifestations, episodes, or attacks usually begin in infancy and occur throughout life. Many patients with FCAS also show evidence of chronic inflammation between attacks, particularly a daily pattern of rash developing in the afternoon that can be associated with headache, myalgia, and fatigue by the evening though chronic inflammation rarely leads to amyloidosis ( ⁇ 2%) in this patient population. Familial Mediterranean Fever (FMF), caused by mutations of the MEFV gene, is the most common of all the known auto-inflammatory diseases.
  • FMF Familial Mediterranean Fever
  • MEFV Mutations in the MEFV gene reduce the activity of the pyrin protein, similar to the NLRP3 gene in MWS, FCAS and NOMID/CINCA, which disrupts control of the inflammation process.
  • FMF is characterized by recurrent episodes of painful inflammation in the abdomen, chest, or joints. These episodes are often accompanied by fever and sometimes a rash or headache. Occasionally inflammation may occur in other parts of the body, such as the heart; the membrane surrounding the brain and spinal cord; and in males, the testicles. Typically, episodes last 12 to 72 hours and can vary in severity. The length of time between attacks is also variable and can range from days to years. During these periods, affected individuals usually have no signs or symptoms related to the condition.
  • a buildup of protein deposits (amyloidosis) in the body's organs and tissues may occur, especially in the kidneys, which can lead to kidney failure.
  • Chronic inflammation and abnormal immune activity underlie and drive many serious human diseases ranging from rare and acute inflammatory diseases, rheumatologic indications, cardiovascular and metabolic diseases, neurodegenerative diseases, and cancer.
  • molecular danger signals produced by dying cells, metabolic dysregulation, environmental toxins, or the diet may function as stimuli to activate NLRP3 inflammasome (Mangan MSJ et al., Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov; 2018; 17(8):588-606).
  • NLRP3 nucleates assembly of an inflammasome complex that orchestrates innate and adaptive immune responses to drive a strong inflammatory response (Evavold et al., How Inflammasomes Inform Adaptive Immunity. J. Mol. Biol; 2018; 430(2):217-237).
  • Inflammasomes are large cytoplasmic, multimeric protein complexes assembled in response to danger signals, and inflammasome activation results in caspase-1 mediated production of interleukin-1 ⁇ (IL-1 ⁇ ) and interleukin-18 (IL-18) as well as pyroptosis (inflammatory mediated cell death) (Dinarello, A clinical perspective of IL-1 ⁇ as the gatekeeper of inflammation.
  • NLRP3 inhibition with NLRP3 inhibitors, blocking IL-1 ⁇ , IL-18, and pyroptosis, in these and other settings may provide a treatment for conditions where persistent inflammasome activation results in pathology (Ridker PM et al., Modulation of the interleukin-6 signaling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Eur. Heart J; 2018; 39(38):3499-3507.).
  • CANTOS Canakinumab Anti-Inflammatory Thrombosis Outcomes Study
  • MCC950 a selective, small-molecule inhibitor of NLRP3
  • PBMCs peripheral blood mononuclear cells
  • NLRP3 inhibitor MCC950/CRID3 failed to rescue mouse models of CAPS carrying a L351P mutation in NLRP3, which corresponds to the L353P mutation in human NLRP3 (Vande et al., MCC950/CRID3 potently targets the NACHT domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition.
  • supportive therapy may be widely available for milder symptoms such as fever, rash, and pain
  • individuals with an auto-inflammatory syndrome may require corticosteroids, and in some cases, biologic IL-1 blocking agents to treat or prevent more severe inflammatory activity.
  • NLRP3 inhibitors could provide additional benefit for patients as compared to biologics, and for those whose disease is insufficiently treated by the currently available therapies.
  • NLRP3 inhibitors which may be used to prevent or reduce the NLRP3 inflammasome response, and thus address the unmet medical need, including treating an auto- inflammatory syndrome that include CAPS, MWS, FCAS, NOMID/CINCA, and FMF.
  • Described herein are methods of treating a subject using an NLRP3 inhibitor, in particular Compound I, for use in treating an auto-inflammatory syndrome.
  • Described herein are also methods of treating an auto-inflammatory syndrome by administering to a subject in need thereof a therapeutically effective amount of an NLRP3 inhibitor, in particular Compound I.
  • an NLRP3 inhibitor in particular Compound I.
  • pharmaceutical combinations comprising a) Compound I and b) at least one further therapeutic agent, optionally in the presence of a pharmaceutically acceptable carrier, for use in the treatment of an auto-inflammatory syndrome and pharmaceutical compositions comprising them.
  • Compound I is Compound IA.
  • FIG. 1 A schematic overview of the treatment protocol detailed in Example 1.
  • Figure 2 A schematic overview of the study design of the first-in-human (FIH) study as detailed in Example 2.
  • DETAILED DESCRIPTION Herein are described methods of treating an auto-inflammatory syndrome by administering to a subject in need thereof an effective amount of Compound I or pharmaceutically acceptable salts thereof. Accordingly, in one aspect provided is a method of treating an auto-inflammatory syndrome comprising administering to a subject in need thereof an effective amount of Compound I or pharmaceutically acceptable salts thereof. Also provided is Compound I for use in treating an auto-inflammatory syndrome. In one embodiment of any method or use described herein, said Compound I is Compound IA. Definitions In order that the present document may be more readily understood, certain terms are first defined.
  • the term “comprising” encompasses “including” as well as “consisting of” e.g., a composition “comprising” X may consist exclusively of X or may include something additional, e.g., X + Y.
  • the articles “a” and “an” refer to one or to more than one (e.g., to at least one) of the grammatical object of the article.
  • 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” 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 10% from that numerical value.
  • the amount “about 10” includes 10 and any amounts from 9 to 11.
  • the term “about” in relation to a reference numerical value can also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value.
  • the numerical value described throughout can be “about” that numerical value even without specifically mentioning the term “about.”
  • the term “baseline” refers to a subject’s state or the degree of a condition, e.g., a disease, or one or more parameters associated with the state of a patient, observed before treatment, e.g., before administration of a compound, e.g., before administration of an Compound I optionally in combination with at least one further therapeutic agent, according to the described methods and uses.
  • the term “administering” in relation to a compound, e.g., the Compound I 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.
  • 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.
  • the term “pharmaceutically acceptable” means a nontoxic material that does not substantially interfere with the effectiveness of the biological activity of the active ingredient(s).
  • the term “patient” is used interchangeably with the term “subject” and includes any human or nonhuman animal.
  • nonhuman animal includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.
  • the compositions, methods, and uses described herein are in reference to a human patient or human subject.
  • a subject is “in need of” a treatment if such subject who is afflicted with the condition (i.e., disease, disorder, or syndrome) of interest and who would benefit biologically, medically, or in quality of life from such treatment.
  • auto-inflammatory syndrome is a form of inflammatory response syndrome that can be triggered or manifested by a variety of factors such as fatigue, stress or physical effort (e.g., FMF) and cold exposure (e.g., CAPS, MWS, FCAS, NOMID/CINCA).
  • 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.
  • treating includes the administration of a compound, e.g., the Compound I 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., cryopyrin- associated periodic syndromes (CAPS), familial cold auto-inflammatory syndrome (FCAS), Muckle Wells syndrome (MWS), neonatal onset multisystem inflammatory disease / chronic, infantile, neurological, cutaneous and articular syndrome (NOMID/CINCA), or Familial Mediterranean Fever (FMF)), preventing flare ups, alleviating the symptoms or arresting or inhibiting further development or manifestation of the disease, condition, disorder, or syndrome.
  • CPS cryopyrin- associated periodic syndromes
  • FCAS familial cold auto-inflammatory syndrome
  • MFS Muckle Wells syndrome
  • NOMID/CINCA neuronethelial Mediterranean Fever
  • FMF Familial Mediterranean Fever
  • the term “prevent”, “preventing”, or “prevention” in connection to a disease, condition, disorder, or syndrome refers to the prophylactic treatment of a subject who is at risk of developing a condition resulting in a decrease in the probability that the subject will develop the condition (e.g., specific disease or disorder or clinical symptom thereof associated with CAPS, FCAS, MWS, NOMID/CINCA, or FMF such as skin disease, arthralgia, myalgia, headache/migraine, conjunctivitis, fatigue/malaise, and organ or tissue damage).
  • CAPS cryopyrin-associated periodic syndromes
  • FCAS familial cold auto- inflammatory syndrome
  • MWS Muckle Wells syndrome
  • FMF Familial Mediterranean Fever
  • “treating familial cold auto-inflammatory syndrome (FCAS)” may refer to ameliorating, alleviating or modulating at least one of the symptoms or pathological features associated with familial cold auto-inflammatory syndrome (FCAS); e.g., low grade fever, general rash, conjunctivitis, polyarthralgia, headache, myalgia, and fatigue; e.g., may refer to slowing progression, reducing or stopping at least one of the symptoms or pathological features associated with familial cold auto- inflammatory syndrome (FCAS); e.g., low grade fever, general rash, conjunctivitis, polyarthralgia, headache, myalgia, and fatigue.
  • FCAS familial cold auto-inflammatory syndrome
  • excipient or “pharmaceutically acceptable excipient” means a pharmaceutically- acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material.
  • each component is “ pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • NLRP3 inhibitor is a compound that inhibits the ability of NLRP3 to induce the production of IL-1 ⁇ and/or IL-18 by directly binding to NLRP3, or by inactivating, destabilizing, altering distribution, of NLRP3 or otherwise.
  • an NLRP3 inhibitor has an hTHP-1 IC50 of ⁇ 1 ⁇ M in the hTHP-1 assay containing 2% fetal bovine serum defined herein.
  • the NLRP3 inhibitor is a compound of Compound I, Compound IA, or Compound IB.
  • the NLRP3 inhibitor is Compound IA
  • “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.
  • Compound I, Compound IA or Compound IB may be used in crystalline or amorphous form, as a solvate, e.g., a hydrate, or an unsolvated form.
  • 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 is also intended to include the tautomeric form containing the moiety .
  • 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; mixture of diastereomers).
  • 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 and Compound IB, a racemic mixture of Compound IA and Compound IB; Compound IA in enantiomerically pure form; or Compound IB in enantiomerically pure form.
  • Compound I is also intended to include enantiomeric excesses of either Compound IA or Compound IB
  • Compound IA may be present in an enantiomeric excess of about 90% about 91% about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5%.
  • Compound IB may be present in an enantiomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5%.
  • Any chemical formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Isotopes that can be incorporated into compounds of the disclosure include, for example, isotopes of hydrogen, carbon, nitrogen, and oxygen, such as 3 H, 11 C, 13 C, 14 C, and 15 N. Accordingly, it should be understood that methods of the present invention can or may involve compounds that incorporate one or more of any of the aforementioned isotopes, including for example, radioactive isotopes, such as 3 H and 14 C, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • Such isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, e.g., using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • the present invention encompasses embodiments that include all pharmaceutically acceptable salts of the compounds useful according to the invention provided herein.
  • pharmaceutically acceptable salt refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17 th 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.
  • preferred pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines.
  • the salt can be a hydrochloride salt.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the “dose” or amount of NLRP3 inhibitor e.g., Compound I, refers to the amount of the free base or free acid form of the compound.
  • 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.
  • therapeutically effective amount refers to an amount of the compound that will elicit the biological or medical response of a subject, for example, ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, condition, disorder, manifestation or syndrome, etc.
  • a therapeutically effective amount refers to the amount of the compound described herein that, when administered to a subject, is effective to at least partially alleviating, inhibiting, preventing and/or ameliorating an auto-inflammatory syndrome (e.g., cryopyrin-associated periodic syndromes (CAPS), familial cold auto-inflammatory syndrome (FCAS), Muckle Wells syndrome (MWS), neonatal onset multisystem inflammatory disease / chronic, infantile, neurological, cutaneous and articular syndrome (NOMID/CINCA), or Familial Mediterranean Fever (FMF).
  • an auto-inflammatory syndrome e.g., cryopyrin-associated periodic syndromes (CAPS), familial cold auto-inflammatory syndrome (FCAS), Muckle Wells syndrome (MWS), neonatal onset multisystem inflammatory disease / chronic, infantile, neurological, cutaneous and articular syndrome (NOMID/CINCA), or Familial Mediterranean Fever (FMF).
  • “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 an Compound I and the one or more additional therapeutic agents may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g., synergistic effect.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of an additional therapeutic agent to a single subject in need thereof (e.g., a subject), and the additional therapeutic agent are intended to include treatment regimens in which the Compound I and additional therapeutic agent are not necessarily administered by the same route of administration and/or at the same time.
  • Each of the components of the presently described combination may be administered simultaneously or sequentially and in any order.
  • Co-administration comprises simultaneous, sequential, overlapping, interval, and/or continuous administrations and any combination thereof.
  • pharmaceutical combination as used herein means a pharmaceutical composition that results from the combining (e.g., mixing) of more than one active ingredient and includes both fixed and free combinations of the active ingredients.
  • fixed combination means that the active ingredients are administered to a subject simultaneously in the form of a single entity or dosage.
  • free combination means that the active ingredients as defined herein are administered to a subject as separate entities either simultaneously, concurrently or sequentially with no specific time limits, and in any order, wherein such administration provides therapeutically effective levels of the compounds in the subject’s body.
  • reference to the combination comprising a) a Compound I and b) at least one additional therapeutic agent as used herein refers to a “non-fixed combination” and may be administered independently at the same time or separately within time intervals.
  • spontaneous administration it is meant that the active ingredients as defined herein, are administered on the same day.
  • the active ingredients can be administered at the same time (for fixed or free combinations), or one at a time (for free combinations).
  • simultaneous administration may mean that during a period of two or more days of continuous co-administration only one of active ingredients as herein defined, is administered on any given day.
  • overlapping administration it is meant that during a period of two or more days of continuous co- administration, there is at least one day of simultaneous administration and at least one day when only one of active ingredients as herein defined, is administered.
  • continuous administration it is meant a period of co-administration without any void day.
  • the continuous administration may be simultaneous, sequential, or overlapping, as described above.
  • NLRP3 is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous NLRP3 molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.
  • Embodiments 1.1 to 1.32 An NLRP3 inhibitor for use in the treatment of an auto-inflammatory syndrome in a subject in need thereof.
  • 1.2 The NLRP3 inhibitor for use according to embodiment 1.1, wherein the NLRP3 inhibitor is administered to the subject at a total daily dose of about 50 mg to about 500 mg in single or divided doses, preferably about 50 mg to about 200 mg.
  • 1.3 The NLRP3 inhibitor for use according to embodiment 1.2, wherein the NLRP3 inhibitor is administered to the subject at a total daily dose of about 100 mg or about 200mg in single or divided doses.
  • NLRP3 inhibitor for use according to embodiment 1.3, wherein the NLRP3 inhibitor is administered to the subject at a dose of about 100 mg twice daily for three consecutive days and about 100 mg once in the morning on day four.
  • the auto-inflammatory syndrome is CAPS, FCAS, MWS, NOMID/CINCA, or FMF.
  • NLRP3 inhibitor for use according to embodiment 1.6 wherein said patient does not have an increase in White Cell Count (WCC) of more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% following the administration of the NLRP3 inhibitor.
  • WCC White Cell Count
  • NLRP3 inhibitor for use according to embodiment 1.6 wherein after cold exposure the patient exhibits a lower score on the Physician’s Global Assessment scale of at least 1, at least 2, at least 3, on a scale of 1-10 following administration of the NLRP3 inhibitor
  • NLRP3 inhibitor for use according to any one of embodiments 1.1 to 1.9, wherein the patient does not have an increase in C-Reactive Protein of more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% following the administration of the NLRP3 inhibitor.
  • the NLRP3 inhibitor for use according to any one of embodiments 1.1 to 1.10, wherein the patient does not exhibit an increase in IL-1 ⁇ or IL-18 of more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% following the administration of the NLRP3 inhibitor.
  • 1.12 The NLRP3 inhibitor for use according to any of the preceding enumerated embodiments, wherein the NLRP3 inhibitor is administered to the subject orally.
  • Compound I of the below embodiments is Compound IA (i.e. the R enantiomer) in an enantiomeric excess of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5%.
  • Compound IA is in enantiomeric excess of at least 90%. More preferably, Compound IA is in enantiomeric excess of at least 95%.
  • Embodiment 1 in one embodiment, provided herein is a method of treatment or reducing the symptoms of an auto- inflammatory syndrome in a subject in need thereof, comprising administering an effective amount of Compound I, or a pharmaceutically acceptable salt thereof. In one embodiment, provided herein is Compound I or a pharmaceutically acceptable salt thereof for use in treating an auto-inflammatory syndrome in a subject in need thereof. In some embodiments, provided herein is the use of Compound I, for the manufacture of a medicament for the treatment of an auto-inflammatory syndrome.
  • Embodiment 2 in one embodiment, provided herein is a method of treatment or reducing the symptoms of a Cryopyrin- associated periodic syndrome (CAPS) in a subject in need thereof, comprising administering an effective amount of Compound I, or a pharmaceutically acceptable salt thereof.
  • Compound I or a pharmaceutically acceptable salt thereof for use in treating a Cryopyrin-associated periodic syndrome (CAPS) in a subject in need thereof.
  • CAS Cryopyrin-associated periodic syndrome
  • the use of Compound I for the manufacture of a medicament for the treatment of a Cryopyrin-associated periodic syndrome (CAPS).
  • Embodiment 3 in one embodiment, provided herein is a method of treatment or reducing the symptoms of familial cold auto-inflammatory syndrome (FCAS) in a subject in need thereof, comprising administering an effective amount of Compound I, or a pharmaceutically acceptable salt thereof.
  • Compound I or a pharmaceutically acceptable salt thereof for use in treating familial cold auto-inflammatory syndrome (FCAS) in a subject in need thereof.
  • provided herein is the use of Compound I, for the manufacture of a medicament for the treatment of familial cold auto-inflammatory syndrome (FCAS).
  • Embodiment 4 in one embodiment, provided herein is a method of treatment or reducing the symptoms of Muckle Wells syndrome (MWS) in a subject in need thereof, comprising administering an effective amount of Compound I, or a pharmaceutically acceptable salt thereof. In one embodiment, provided herein is Compound I or a pharmaceutically acceptable salt thereof for use in treating Muckle Wells syndrome (MWS) in a subject in need thereof. In some embodiments, provided herein is the use of Compound I, for the manufacture of a medicament for the treatment of Muckle Wells syndrome (MWS).
  • MWS Muckle Wells syndrome
  • Embodiment 5 in one embodiment, provided herein is a method of treatment or reducing the symptoms of neonatal onset multisystem inflammatory disease / chronic, infantile, neurological, cutaneous and articular syndrome (NOMID/CINCA) in a subject in need thereof, comprising administering an effective amount of Compound I, or a pharmaceutically acceptable salt thereof.
  • Compound I or a pharmaceutically acceptable salt thereof for use in treating neonatal onset multisystem inflammatory disease / chronic, infantile, neurological, cutaneous and articular syndrome (NOMID/CINCA) in a subject in need thereof.
  • provided herein is the use of Compound I, for the manufacture of a medicament for the treatment of neonatal onset multisystem inflammatory disease / chronic, infantile, neurological, cutaneous and articular syndrome (NOMID/CINCA).
  • Embodiment 6 in one embodiment, provided herein is a method of treatment or reducing the symptoms of Familial Mediterranean Fever (FMF) in a subject in need thereof, comprising administering an effective amount of Compound I, or a pharmaceutically acceptable salt thereof.
  • Compound I or a pharmaceutically acceptable salt thereof for use in treating Familial Mediterranean Fever (FMF) in a subject in need thereof.
  • WCC White Cell Count
  • the patient does not have an increase in C-Reactive Protein of more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% following the administration of the NLRP3 inhibitor.
  • the patient does not exhibit an increase in IL-1 ⁇ or IL-18 of more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% following the administration of the NLRP3 inhibitor.
  • the patient after cold exposure the patient exhibits a lower score on the Physician’s Global Assessment scale of at least 1, at least 2, at least 3, on a scale of 1-10 following administration of the NLRP3 inhibitor.
  • Compound I or a pharmaceutically acceptable salt thereof may be administered to the subject at a total daily dose of about 50 mg to about 200 mg, as measured in the non-salt equivalents, in single or divided doses. In particular embodiments, Compound I is administered to the subject at a total daily dose of about 200 mg in single or divided doses.
  • Compound I is administered to the subject at a dose of about 100 mg twice daily for three consecutive days and about 100 mg once in the morning on day four.
  • a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is a tablet.
  • the pharmaceutical composition is administered as a whole or crushed tablet.
  • the pharmaceutical composition includes about 5 mg, 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.
  • a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof, for use in any of the embodiments described herein.
  • Compound I or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof orally.
  • Compound I is in the form of a table that is administered either whole or subdivided, i.e., crushed prior to administration.
  • Compound I may be administered via a nasogastric tube.
  • the preferred NLRP3 inhibitor is Compound IA.
  • Compound IA is 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%.
  • Subjects As discussed herein, subjects receiving the NLRP3 inhibitor as presently described can present symptoms of or be at risk of familial cold auto-inflammatory syndrome (FCAS), e.g., as hereinabove defined.
  • FCAS familial cold auto-inflammatory syndrome
  • a therapeutically effective amount of Compound I is administered to a patient, e.g., a mammal (e.g., a human).
  • compositions Compound I may be used as a pharmaceutical composition when combined with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier may contain, in addition to Compound I, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other known materials. The characteristics of the carrier will depend on the route of administration.
  • compositions for use in the compositions, uses, and methods described herein may also contain at least one or more additional therapeutic agents for treatment of the particular targeted disorder, disease, condition, or syndrome.
  • additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with Compound I.
  • the Compound I can be administered in combination with one or more conventional pharmaceutical excipients.
  • compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- ⁇ -tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-
  • Cyclodextrins such as ⁇ -, ⁇ , and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- ⁇ -cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein.
  • Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared.
  • the contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%.
  • Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, sub
  • compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes.
  • parenteral administration e.g., intratumoral
  • Such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified.
  • injectables either as liquid solutions or suspensions
  • solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified.
  • the preparation of such formulations will be known to those of skill in the art in light of the present disclosure.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • the carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia.2006, 10, 788–795.
  • the chemical entities described herein or a pharmaceutical composition thereof are suitable for local, topical administration to the digestive or GI tract, e.g., rectal administration.
  • Rectal compositions include, without limitation, enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, and enemas (e.g., retention enemas).
  • Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phen
  • suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound.
  • compositions for rectal administration are in the form of an enema.
  • the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or the like
  • a lubricant such as magnesium stearate or the like
  • a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG’s, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule).
  • Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.
  • physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms.
  • Various preservatives are well known and include, for example, phenol and ascorbic acid.
  • the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient.
  • solid oral dosage forms can further include one or more components that chemically and/or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and/or transverse colon and/or distal colon and/or small bowel.
  • Exemplary formulation techniques are described in, e.g., Filipski, K.J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety. Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls. Other examples include lower-GI targeting techniques.
  • enteric/pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid–methyl methacrylate copolymers), and Marcoat).
  • hydroxypropyl methylcellulose phthalate series Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid–methyl methacrylate copolymers), and Marcoat).
  • Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).
  • viscogens e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol
  • Stabilizers e.g., Pluronic (triblock copolymers), Cyclodextrins
  • Preservatives e.g., Benzalkonium chloride, ETDA, SofZ
  • Topical compositions can include ointments and creams.
  • Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives.
  • Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil.
  • Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.
  • Dosing regimen and modes of administration are adjusted to provide the optimum desired response (e.g., a therapeutic response).
  • the dosing regimen i.e., administered doses and/or frequency of the pharmaceutical composition comprising Compound I
  • the dosing regimen i.e., administered doses and/or frequency of the pharmaceutical combination comprising a) Compound I and b) at least one further therapeutic agent, may vary.
  • the dosage ranges from about 0.0001 to about 100 mg/kg, and more usually about 0.01 to about 30 mg/kg, of the subject’s body weight.
  • Compound I is administered at a daily dose of about 50 mg to about 500 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, about 50 mg to about 100 mg, about 50mg.
  • Compound I is administered at a daily dose of about 50 mg, about 100 mg, about 150 mg, or about 200 mg.
  • Compound I is administered once a day. In other embodiments, Compound I is administered two, three, or four times a day.
  • Compound I is administered at a daily total dose of about 200 mg, administered once or in two divided doses.
  • Compound I is Compound IA.
  • Compound IA is administered at a daily total dose of about 50 to 500 mg. More preferably, Compound 1A is administered at a daily dose of 200mg. In some embodiments, Compound IA is administered at a daily dose of 200 mg. In some embodiments, Compound IA is administered 100 mg twice a day.
  • the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.
  • a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. Dosages are repeated as necessary and may be in the range from about once per week up to about once every 10 weeks, e.g., once every 4 weeks or once every 8 weeks.
  • kits for use in the methods for treating or preventing cytokine release syndrome or cytokine storm syndrome may comprise Compound I in liquid or lyophilized form or a pharmaceutical composition comprising Compound I.
  • kits may comprise a means for administering Compound I (e.g., a syringe and vial, a prefilled syringe, a prefilled pen) and instructions for use.
  • kits may contain additional therapeutic agents (described elsewhere herein), e.g., for delivery in combination with Compound I.
  • the phrase “means for administering” is used to indicate any available implement for systemically administering a drug to a patient, including, but not limited to, a dropper, a pre-filled syringe, a vial and syringe, an injection pen, an autoinjector, an i.v. drip and bag, a pump, etc.
  • a patient may self-administer the drug (i.e., administer the drug on their own behalf), a caregiver may administer the drug to the patient, or a physician or other medical professional may administer the drug.
  • Each component of the kit is usually enclosed within an individual container, and all of the various containers are within a single package along with instructions for use.
  • 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 NH 4 HCO 3 ) and ACN, UV detection 254/210 nm. NMR was recorded on BRUKER NMR 300.03 MHz, DUL-C-H, ULTRASHIELD TM 300, AVANCE II 300 B-ACS TM 120 or BRUKER NMR 400.13 MHz, BBFO, ULTRASHIELD TM 400, AVANCE III 400, B-ACS TM 120 or BRUKER AC 250 NMR instrument with TMS as reference measured in ppm (part per million).
  • Step 2 N'-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide
  • N-(tert-butyldimethylsilyl)-N'-(1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide 535 mg, crude, 1.0 mmol) in THF (10 mL).
  • Compound IA and Compound IB 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.
  • Step 2 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole-5-sulfonamide
  • n-BuLi 2.5 M in THF, 35.2 mL, 88.0 mmol
  • the resulting solution was stirred for 0.5 h at -78 o C and then SO2 was introduced into the above reaction mixture.
  • Step 3 2-Acetylthiazole-5-sulfonamide Into a 250-mL round-bottom flask was placed a solution of 2-(2-methyl-1,3-dioxolan-2-yl)thiazole-5- sulfonamide (12.5 g, 50.0 mmol) in THF (125 mL). To the above was added aq. HCl (4 N, 50.0 mL). The resulting solution was stirred for 6 h at 70 o C. 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.
  • 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 80 o C and then was cooled to 0 o C 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.
  • 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 0 o C. The resulting solution was stirred for 2 h at RT and then was diluted with 500 mL of water.
  • Step 3 Methyl 2-sulfamoylthiazole-5-carboxylate Into a 2-L round-bottom flask was placed methyl 2-(chlorosulfonyl)thiazole-5-carboxylate as a crude solution in DCM (900 mL). To the solution was introduced NH 3 (g) below 0 o C for 20 minutes. The resulting solution was stirred for 1 h at RT and then concentrated under vacuum.
  • 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).
  • Step 5 N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide
  • a solution of 5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide 5 g, 22.5 mmol
  • THF 100 mL
  • NaH 60% wt, 1.8 g, 45.0 mmol
  • ACN acetonitrile
  • Davephos 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl
  • 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
  • Example 1 Clinical study with Compound IA An open-label, single arm phase II study of Compound IA to assess the safety, tolerability and efficacy in participants with familial cold auto-inflammatory syndrome (FCAS) who show evidence of inflammatory activity after the cold challenge performed during screening.
  • Figure 1 is a schematic overview of the treatment protocol with Compound IA (i.e. the R enantiomer of Compound I).
  • Compound IA 100 mg will be dosed twice daily for 3 days and 100 mg in the morning of Day 4.
  • the primary objective of this study is to assess the efficacy of Compound IA to reduce cold-induced inflammation in participants with FCAS.
  • the endpoint (EP) for the primary objective is the change from pre-challenge to the highest post- challenge value of white cell count (WCC).
  • the secondary objectives of the study are as follows: 1. To assess safety and tolerability of Compound IA 2. To assess the efficacy of Compound IA to improve the signs and symptoms of FCAS 3. To assess the effect of Compound IA on patient reported outcomes The endpoint (EP) for the secondary objectives are as follows: 1. Safety endpoints (including vital signs, ECG parameters, safety laboratory assessment and adverse events) 2.
  • the cold challenge protocol was developed to study the acute inflammatory mechanisms after general cold exposure in FCAS patients and to investigate the effect of pretreatment with IL-1 blocking therapeutics.
  • Participants with a history of transient self-limiting rash, fever and/or arthralgia that are pathognomonic of FCAS following cold exposure that resolve with warmth will undergo a maximum of two controlled cold challenges while domiciled at the clinical site under medical supervision to trigger a transient inflammatory response.
  • participants will be returned to an ambient temperature of approximately 25°C for at least 24 hours at the clinical site, to ensure resolution of the inflammatory response.
  • Typical symptoms and signs triggered by cold challenge in participants with FCAS include increase in markers of systemic inflammation (e.g.
  • Treatment period • Treatment initiation visit: Participants who meet all inclusion and no exclusion criteria, including showing evidence of inflammatory activity after the cold challenge performed during screening, will be enrolled on Day 1 and treatment will be initiated.
  • the first dose of Compound IA will be administered in the clinic and study treatment will be dispensed to the participant for continued treatment at home. Participants may be domiciled during the treatment period for convenience of the participants and/or logistical aspects, at the discretion of the participant and investigator.
  • Cold Challenge Participants will be admitted to the clinic in the morning of Day 3, the day prior to cold challenge, and will be domiciled for a total of three days or longer if mandated by the investigator or by local regulations. On Day 3, participants will undergo safety assessments and then stay in a room with ambient temperature, preferably above 25°C, to ensure stable conditions prior to the cold challenge. On the morning of Day 4, pre-challenge assessments will be performed and breakfast will be served.
  • a pre-dose PK sample will be collected and the last dose of study treatment will be administered.
  • One hour after study treatment administration another PK sample will be collected and the cold challenge will be initiated.
  • the cold challenge lasts for 45 minutes.
  • participants will be monitored until the next morning (Day 5).
  • the participants will be discharged after the last assessment on Day 5 or later, at the discretion of the investigator.
  • Follow up period to ensure participants' safety after treatment discontinuation and recovery from the cold challenge. • Participants will be followed-up for an end of study evaluation at the Study completion visit, approximately 10 days after last dose.
  • Key inclusion criteria 1. Written informed consent must be obtained before any study-specific assessment is performed 2. Male and female participants aged between 18-80 years inclusive 3. Body mass index within the range of 18-35 kg/m 2 4.
  • Participants with a genetic diagnosis of FCAS Participants with a clinical history and investigations consistent with FCAS, in the absence of a history or diagnosis of amyloidosis and/or organ damage (e.g. deafness, periorbital edema, lymphadenopathy, and serositis) 6. Participants who have evidence of inflammatory activity after the screening cold challenge 7. Clinical history of active disease in the screening period in response to cold exposure in the environment on at least one occasion, as assessed by the Physician global assessment of auto- inflammatory disease activity > minimal Key exclusion criteria 1. Participants carrying NLRP3 mutations not responsive to NLRP3 inhibition including, but not limited to, L353P carriers (based on Principal Investigator/registry data, published evidence and/or Novartis internal studies) 2.
  • the exceptions are: anakinra, canakinumab and/or other investigational IL-1/NLRP3 binding or blocking therapy, which must be discontinued at screening.
  • Participants with innate e.g.
  • TLR immunodeficiencies defects in IFN- ⁇ signaling
  • acquired immune deficiencies e.g. AIDS
  • Live vaccines within 4 weeks of Day 1 i.e. first dose of Compound IA
  • Absolute peripheral blood neutrophil count of ⁇ 1000/mm 3 8.
  • Estimated GFR (eGFR) ⁇ 90 mL/min/1.73m2 (based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula) 9. History or current diagnosis of ECG abnormalities indicating significant safety risk for participant enrolled 10.
  • CKD-EPI Chronic Kidney Disease Epidemiology Collaboration
  • Pregnant or nursing (lactating) women where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human serum chorionic gonadotropin (hCG) laboratory test 11.
  • Women of child-bearing potential defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 10 days after stopping of study treatment 12.
  • WCC White Cell Count
  • Physician global assessment of auto-inflammatory disease activity • Physician's Severity Assessment of Auto-inflammatory Disease Signs and Symptoms • Patients Global Assessment of Disease Activity Key safety assessments • Physical examination • Vital signs • ECG parameters • Pregnancy and assessment of fertility • Monitoring of laboratory markers in blood and urine • Adverse event and serious adverse event monitoring Other assessments • Inflammatory markers (including but not limited to absolute neutrophil count (ANC), high sensitivity C-reactive protein (hsCRP) and serum amyloid A (SAA)) • Plasma concentrations of Compound IA and pharmacokinetic parameters • Pharmacodynamic, inflammasome pathway and inflammation related biomarkers in serum e.g.
  • ANC absolute neutrophil count
  • hsCRP high sensitivity C-reactive protein
  • SAA serum amyloid A
  • the primary objective will be achieved and Compound IA will be considered efficacious in treating cold-induced inflammation in participants with FCAS if the estimated difference in change from pre- challenge of total WCC between treatment and screening period is: 1. statistically significant (p ⁇ 0.10) and 2. lower than -4x109cells/L
  • the change from pre-challenge to the highest post-challenge WCC will be analyzed by a linear model, including pre-challenge values as covariates and modeling period effect, taking into account the intra- participant correlation.
  • a dose of 200 mg Compound 1A administered once daily for up to 14 days provided mean AUC0-24h and Cmax at steady-state of 182 ⁇ g*h/mL and 26.4 ⁇ g/mL.
  • b NOAEL Cmax ( ⁇ g/mL) and AUC0-24h ( ⁇ g*h/mL) from 13-week toxicology studies for rat (30 mg/kg): 52.9 and 400 and for monkey (150 mg/kg): 258 and 3540, respectively.
  • administration of Compound IA in this study is considered safe.
  • Drug-drug interaction issues Evaluation and recommendations for drug-drug interaction clinical studies of cytochrome P450 (CYP) substrates/modulators and Compound IA are based on in vitro / preclinical data and physiology-based PK simulations.
  • Compound IA is expected to be eliminated mainly via hepatic CYP-mediated metabolism with CYP2C9 (68%) and CYP3A4 (29%) as the main contributing enzymes. Participants who are poor CYP2C9 metabolizers will be excluded from this study. Considering treatment duration and sufficient safety margins, administration of Compound IA is considered safe even under conditions of elevated exposures to Compound IA.
  • Anti-rejection/immune modulatory therapies e.g., anakinra, canakinumab or other investigational IL-1/NLRP3 binding or blocking therapy
  • Live vaccine • Strong or moderate inducers of CYP2C9 or strong inducers of CYP3A including carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, rifabutin, mitotane and St.
  • Drugs that are strong or moderate inhibitors of CYP3A Compound IA was identified in vitro as a substrate of CYP3A, so an increase in systemic exposure of Compound IA when co-administered with strong CYP3A inhibitors such as antiviral drugs (e.g., ritonavir), antifungal (e.g., itraconazole, ketoconazole) and antibiotics (e.g., erythromycin, clarithromycin) cannot be ruled out.
  • antiviral drugs e.g., ritonavir
  • antifungal e.g., itraconazole, ketoconazole
  • antibiotics e.g., erythromycin, clarithromycin
  • Example 2 Clinical first-in-human (FIH) study with COMPOUND IA: Study design The study design was comprised of 4 parts: a single ascending dose (SAD; Part A), relative bioavailability of tablet formulations (Part B), multiple ascending doses (MAD; Part C), and relative bioavailability and food effect (Part D) ( Figure 2). 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, 8 groups of 8 eligible subjects were enrolled.
  • SAD single ascending dose
  • Part B relative bioavailability of tablet formulations
  • MAD multiple ascending doses
  • Part D relative bioavailability and food effect
  • COMPOUND IA 3, 10, 30, 100, 300 mg of crystalline suspension and 100, 300, 600 mg of SDD under fasted conditions.
  • Group 1 of Part A 2 sentinel subjects were dosed at least 24 hours before the rest of the group was dosed, to ensure maximum safety.
  • Part B was skipped because the data collected in Part A provided an adequate comparison of crystalline and SDD formulations.
  • Part C eligible subjects were enrolled in 6 different groups.
  • COMPOUND IA 10, 30 mg of crystalline suspension and 100, 200 mg of SDD suspension for 14 days
  • QD once daily
  • BID twice daily
  • Subjects were dosed in Part C following a review of the 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 profile of the crystalline tablet formulation of COMPOUND IA nonclinical safety pharmacology and toxicology program supported evaluation was compared between fed and fasted conditions, and with the PK profile of the crystalline suspension of COMPOUND IA under fasted conditions.
  • Subjects received 3 doses of COMPOUND IA with a 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 fed condition). Based on these doses, subjects were randomly assigned to 1 of 6 treatment sequences (1 subject per sequence) prepared using a Williams design (Wang B-S, Wang X-J, Gong L-K.
  • PK assessment 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.
  • blood samples were collected at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose; on Days 2, 4, 7, 9, and 11: at pre-dose; after the last dose on Day 14: at 24 and 36 hours (Day 15), and 48 hours (Day 16) post-dose; and at the follow-up visit.
  • PK parameters were estimated using noncompartmental analysis maximum concentration in plasma (Cmax); time to maximum concentration (tmax); concentration at 24 h post-dose (C24h) (Part A); Lag time: time of observation prior to the first quantifiable concentration (tlag); 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
  • PD Pharmacodynamic
  • PK parameters were calculated using non-compartmental methods using software Phoenix Version 8.1. Concentrations below the lower limit of quantification were treated as zero in summary statistics for concentration data alone. The linear trapezoidal rule was used for AUC calculation. Regression analysis of the terminal plasma elimination phase for the determination of t1/2 included at least 3 data points after Cmax. Parameters with an adjusted r2 below 0.80 were flagged but included in the descriptive statistics.
  • the parameters AUC0–inf, %AUCextra, CL/F, and VZ/F with an %AUCextra above 20% were excluded from the descriptive statistics.
  • dose proportionality was explored using a regression power model relating logarithmically (log)-transformed Cmax, AUC0–last, and AUC0–inf to the log-transformed dose level. Point estimates for the intercept and the slope and corresponding to 90% confidence intervals (CIs) for the slope were calculated.
  • CIs 90% confidence intervals
  • Part C dose proportionality was not explored.
  • Part D the relative bioavailability of the crystalline tablet versus the crystalline suspension, as well as the effect of food, was explored using an analysis of variance (ANOVA) model on the PK data.
  • ANOVA analysis of variance
  • the ANOVA model included fixed effects for treatment, period, and sequence, and a random effect for subject within sequence.
  • 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 IL-1 ⁇ concentrations versus time are presented by treatment.
  • a Bayesian Emax PK/PD model was applied to characterize the inhibitory potency of COMPOUND IA on the release of IL-1 ⁇ .
  • the model was developed using the rstan library in the free software environment R (version 4.0.5).
  • TEAEs The majority of TEAEs reported by 84 (69%) subjects were of mild intensity, while 15 subjects (12%) reported moderate TEAEs.
  • SOC system organ class
  • SOC system organ class
  • 20 TEAEs of maculopapular skin rash and/or pruritus were considered AEs of special interest as they were considered to be related to the study drug.
  • These TEAEs were of mild-to-moderate intensity, generally started within 1–17 days of initiation of treatment with COMPOUND IA, and resolved within 1–18 days of onset; all cases resolved without concomitant treatment. For 10 subjects, TEAEs led to treatment discontinuation. Two other subjects discontinued early due to TEAEs that were unrelated to the study drug.
  • 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.
  • Total cumulative amount of COMPOUND IA excreted in urine increased in linear manner with increasing multiple dose levels.
  • COMPOUND IA was mostly excreted within 12 hours.
  • the mean fraction of dose excreted was in the range 0.3%-0.4% and 0.7%-1.1% and renal clearance was in the range 3.6-5.0 mL/h and 6.8-9.1 mL/h, respectively.
  • the mean t 1/2 of COMPOUND IA was comparable between the tablet (18.6 hours) and suspension (17.7 hours) formulations.
  • Pharmacodynamics Dose-dependent decreases in concentrations of ex vivo stimulated IL-1 ⁇ (with mean nadir concentrations of ⁇ 5%–20% of the baseline value) were observed with increasing single and multiple oral doses of COMPOUND IA. At most dose levels of COMPOUND IA, the inhibition of IL-1 ⁇ release 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.
  • COMPOUND IA an NLRP3 antagonist COMPOUND IA was administered orally for the first time to human subjects, exploring safety, tolerability, PK, and PD properties. Initial doses were selected based on predicted human PK and anticipated efficacious doses, as well nonclinical safety from animal and in vitro data. Safety Single and multiple doses of COMPOUND IA or placebo were generally well tolerated. No deaths or SAEs were reported during the study. Similar rates of TEAEs were observed between subjects who received COMPOUND IA (70%) and placebo (75%). The majority of TEAEs reported by subjects were mild (69%) or moderate (12%) in severity. Subcutaneous tissue and gastrointestinal disorder TEAEs were only reported by subjects who received COMPOUND IA, not placebo.
  • 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, independent of formulation used.
  • Safety and tolerability data of other NLRP3 inhibitors tested in clinical trials like ZYIL1 or dapasuntrile (Parmar DV, Kansagra KA, Momin T, Patel HB, Jansari GA, Bhavsar J, Shah C, Patel JM, Ghoghari A, Barot A, Sharma B, Viswanathan K, Patel HV, Jain MR.
  • COMPOUND IA has a very low apparent oral clearance (CLss/F ⁇ 1.0 L/h), which relates to ⁇ 2% of human liver blood flow and a low apparent volume of distribution (Vss/F) of ⁇ 12.6–23.3 L. Slight drug accumulation of ⁇ 1.2-fold after QD dosing and 2- fold after BID dosing was observed in reaching steady state, consistent with an effective t 1/2 of ⁇ 10 hours, as determined for crystalline tablets when given with food. Pharmacodynamics Nonclinical studies have suggested that COMPOUND IA blocks the release of IL-1 ⁇ using a range of NLRP3-dependent activators. This has been observed also with e.g.
  • MCC950 which selectively inhibits NLRP3 activation (Tapia-Abellan A, Angosto-Bazarra D, Martinez-Banaclocha H, de Torre-Minguela C, Ceron-Carrasco JP, Perez-Sanchez H, Arostegui JI, Pelegrin P. MCC950 closes the active conformation of NLRP3 to an inactive state. Nat Chem Biol 2019; 15: 560-64) or with ZYIL1 compound, which demonstrated >90% IL-1b inhibition in healthy subjects. In contrary dapansutrile (OLT1177), another NLRP3 inhibitor only partially reduced release of IL-1b in healthy subjects and patients with gout flare.
  • OHT1177 another NLRP3 inhibitor only partially reduced release of IL-1b in healthy subjects and patients with gout flare.
  • IL-1 ⁇ production can be mediated by other inflammasomes or by inflammasome-independent pathways (Gaidt MM, Hornung V. Alternative inflammasome activation enables IL-1beta release from living cells. Curr Opin Immunol 2017; 44: 7- 13); thus, inhibitors aimed at IL-1 ⁇ can result in unintentional immunosuppressive effects. Therefore, pharmacological inhibitors which specifically target the NLRP3 inflammasome alone could be a better option for treatment of NLRP3-associated diseases (Zahid A, Li B, Kombe AJK, Jin T, Tao J.
  • COMPOUND IA 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 a BID dosing regimen and PK/PD data supported dose and formulation selection for further development.
  • the safety and tolerability, PK, and PD results suggest that COMPOUND IA has the potential to be an effective oral first-in-class innate immune modulator warranting further clinical evaluation.
  • Example 3 The following procedures are suitable for testing the activity of NLRP3 inhibitors, as per those disclosed herein. Procedure 1: IL-1 ⁇ production in PMA-differentiated THP-1 cells stimulated with Gramicidin.
  • THP-1 cells were purchased from the American Type Culture Collection and sub-cultured according to instructions from the supplier. Prior to experiments, cells were cultured in complete RPMI 1640 (containing 10% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 ⁇ g/ml)), and maintained in log phase prior to experimental setup. 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 30mM stock. On the day of the experiment the media was removed and adherent cells were detached with trypsin for 5 minutes.
  • PMA Phorbol 12-myristate 13-acetate
  • Procedure 2 1. Experimental procedure 1.1 Cell Culture 1) Culture THP-1 cells in the complete RPMI-1640 medium with 10% FBS at 37 ° C, 5% CO 2 . 2) Passage the cells every 3 days by inoculating 3x10 5 cells per ml. 1.2 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.
  • FIG.3 depicts the layout of the microplate.
  • FIG.3 depicts the layout of the plates: HC: 100 ⁇ M CRID3 (MCC950) + 5 ⁇ M gramicidin LC:5 ⁇ M Gramicidin.
  • IL-1 ⁇ detection 1) Homogenize the 5x diluent #5 with a vortex and add 1 volume of stock solution in 4 volumes of distilled water. 2) Thaw 20x stock solution of anti-IL1 ⁇ -Cryptate-antibody and anti-IL1 ⁇ XL-antibody. Dilute these two antibodies to 1x with detection buffer #3. 3) Pre-mix the two ready-to-use antibody solutions just prior to use.

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Abstract

The present disclosure relates to the field of pharmacy, particularly to a NLRP3 inhibitor for use in the treatment of an auto-inflammatory syndrome. The disclosure also relates to a NLRP3 inhibitor or a pharmaceutical combination comprising a NLRP3 inhibitor, or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent, for use in the treatment of an auto-inflammatory syndrome; to a method for the treatment of an auto-inflammatory syndrome that 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 the treatment of an auto- inflammatory syndromes. In particular N'-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide and enantiomers thereof are used for treating auto-inflammatory syndrome, in particular cryopyrin-associated periodic syndromes (CAPS), familial cold auto-inflammatory syndrome (FCAS), Muckle Wells syndrome (MWS), neonatal onset multisystem inflammatory disease / chronic, infantile, neurological, cutaneous and articular syndrome (NOMID/CINCA), or Familial Mediterranean Fever (FMF).

Description

DOSING REGIMEN FOR A NLRP3 INHIBITOR TECHNICAL FIELD The present disclosure relates to the field of pharmacy, particularly to a NLRP3 inhibitor for use in the treatment of an auto-inflammatory syndrome. The disclosure also relates to a NLRP3 inhibitor or a pharmaceutical combination comprising a NLRP3 inhibitor, or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent, for use in the treatment of an auto-inflammatory syndrome; to a method for the treatment of an auto-inflammatory syndrome that 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 the treatment of an auto-inflammatory syndrome. BACKGROUND Cryopyrin-associated periodic syndromes (CAPS) is a group of rare diseases characterized by skin, musculoskeletal, ocular, and neurological symptoms and chronic systemic inflammation that may lead to organ damage and/or amyloidosis and are caused by heterozygous gain-of-function mutations in the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) gene. CAPS is classified into three clinical phenotypes based on a spectrum of disease severity: familial cold auto-inflammatory syndrome (FCAS), Muckle Wells syndrome (MWS) and neonatal onset multisystem inflammatory disease (NOMID) also called chronic, infantile, neurological, cutaneous and articular syndrome (CINCA) (Hoffman et al, (2019) Cryopyrin-Associated Periodic Syndromes (CAPS). In: Hashkes P, Laxer R, Simon A (eds). Textbook of Autoinflammation. Springer, Cham. p. 347-365). FCAS represents the mildest CAPS clinical phenotype and symptoms are typically limited to low grade fever, general rash, conjunctivitis and polyarthralgia, triggered 1-2 hours following cold exposure and resolve within 24 hours with warmth. These manifestations, episodes, or attacks usually begin in infancy and occur throughout life. Many patients with FCAS also show evidence of chronic inflammation between attacks, particularly a daily pattern of rash developing in the afternoon that can be associated with headache, myalgia, and fatigue by the evening though chronic inflammation rarely leads to amyloidosis (~2%) in this patient population. Familial Mediterranean Fever (FMF), caused by mutations of the MEFV gene, is the most common of all the known auto-inflammatory diseases. Mutations in the MEFV gene reduce the activity of the pyrin protein, similar to the NLRP3 gene in MWS, FCAS and NOMID/CINCA, which disrupts control of the inflammation process. FMF is characterized by recurrent episodes of painful inflammation in the abdomen, chest, or joints. These episodes are often accompanied by fever and sometimes a rash or headache. Occasionally inflammation may occur in other parts of the body, such as the heart; the membrane surrounding the brain and spinal cord; and in males, the testicles. Typically, episodes last 12 to 72 hours and can vary in severity. The length of time between attacks is also variable and can range from days to years. During these periods, affected individuals usually have no signs or symptoms related to the condition. However, without treatment to help prevent attacks and complications, a buildup of protein deposits (amyloidosis) in the body's organs and tissues may occur, especially in the kidneys, which can lead to kidney failure. Chronic inflammation and abnormal immune activity underlie and drive many serious human diseases ranging from rare and acute inflammatory diseases, rheumatologic indications, cardiovascular and metabolic diseases, neurodegenerative diseases, and cancer. In these settings, molecular danger signals produced by dying cells, metabolic dysregulation, environmental toxins, or the diet may function as stimuli to activate NLRP3 inflammasome (Mangan MSJ et al., Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov; 2018; 17(8):588-606). Once activated, NLRP3 nucleates assembly of an inflammasome complex that orchestrates innate and adaptive immune responses to drive a strong inflammatory response (Evavold et al., How Inflammasomes Inform Adaptive Immunity. J. Mol. Biol; 2018; 430(2):217-237). Inflammasomes are large cytoplasmic, multimeric protein complexes assembled in response to danger signals, and inflammasome activation results in caspase-1 mediated production of interleukin-1β (IL-1β) and interleukin-18 (IL-18) as well as pyroptosis (inflammatory mediated cell death) (Dinarello, A clinical perspective of IL-1β as the gatekeeper of inflammation. Eur J Immunol; 2011; 41(5):1203-17). Through the production of IL-1β and IL-18, the NLRP3 inflammasome has been implicated as a major driver of inflammation associated with auto- inflammatory, acute and chronic inflammatory diseases, such as CAPS. Potentially NLRP3 inhibition with NLRP3 inhibitors, blocking IL-1β, IL-18, and pyroptosis, in these and other settings may provide a treatment for conditions where persistent inflammasome activation results in pathology (Ridker PM et al., Modulation of the interleukin-6 signaling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Eur. Heart J; 2018; 39(38):3499-3507.). In auto-inflammatory syndromes, by directly inhibiting the NLRP3 inflammasome, NLRP3 inhibitors could address the underlying etiology of the disease. MCC950, a selective, small-molecule inhibitor of NLRP3, has demonstrated activity of inhibiting NLRP3 inflammasome activation in vivo in multiple NLRP3-dependent mouse models and inhibiting IL-1β release in ex vivo samples of peripheral blood mononuclear cells (PBMCs) from individuals with CAPS (Coll et al., A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med; 2015;21(3):248-55). However, administration of NLRP3 inhibitor MCC950/CRID3 failed to rescue mouse models of CAPS carrying a L351P mutation in NLRP3, which corresponds to the L353P mutation in human NLRP3 (Vande et al., MCC950/CRID3 potently targets the NACHT domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition. PLoS Biol; 2019;17(9):e3000354). While supportive therapy may be widely available for milder symptoms such as fever, rash, and pain, individuals with an auto-inflammatory syndrome may require corticosteroids, and in some cases, biologic IL-1 blocking agents to treat or prevent more severe inflammatory activity. NLRP3 inhibitors could provide additional benefit for patients as compared to biologics, and for those whose disease is insufficiently treated by the currently available therapies. Herein is provided NLRP3 inhibitors which may be used to prevent or reduce the NLRP3 inflammasome response, and thus address the unmet medical need, including treating an auto- inflammatory syndrome that include CAPS, MWS, FCAS, NOMID/CINCA, and FMF. SUMMARY OF THE DISCLOSURE Described herein are methods of treating a subject using an NLRP3 inhibitor, in particular Compound I, for use in treating an auto-inflammatory syndrome. Described herein are also methods of treating an auto-inflammatory syndrome by administering to a subject in need thereof a therapeutically effective amount of an NLRP3 inhibitor, in particular Compound I. Further provided herein are specific dose regimens for the methods or use of an NLRP3 inhibitor, in particular Compound I, described herein. Additionally described herein are pharmaceutical combinations comprising a) Compound I and b) at least one further therapeutic agent, optionally in the presence of a pharmaceutically acceptable carrier, for use in the treatment of an auto-inflammatory syndrome and pharmaceutical compositions comprising them. Preferably, wherein Compound I is Compound IA. Further features and advantages of the described methods and uses will become apparent from the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. A schematic overview of the treatment protocol detailed in Example 1. Figure 2: A schematic overview of the study design of the first-in-human (FIH) study as detailed in Example 2. DETAILED DESCRIPTION Herein are described methods of treating an auto-inflammatory syndrome by administering to a subject in need thereof an effective amount of Compound I or pharmaceutically acceptable salts thereof. Accordingly, in one aspect provided is a method of treating an auto-inflammatory syndrome comprising administering to a subject in need thereof an effective amount of Compound I or pharmaceutically acceptable salts thereof. Also provided is Compound I for use in treating an auto-inflammatory syndrome. In one embodiment of any method or use described herein, said Compound I is Compound IA. 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 term “comprising” encompasses “including” as well as “consisting of” e.g., a composition “comprising” X may consist exclusively of X or may include something additional, e.g., X + Y. As used herein, the articles “a” and “an” refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. 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” 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 10% from that numerical value. For example, the amount “about 10” includes 10 and any amounts 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 an Compound I 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., the Compound I 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, 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 human 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. As used herein, the term “auto-inflammatory syndrome” is a form of inflammatory response syndrome that can be triggered or manifested by a variety of factors such as fatigue, stress or physical effort (e.g., FMF) and cold exposure (e.g., CAPS, MWS, FCAS, NOMID/CINCA). 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” includes the administration of a compound, e.g., the Compound I 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., cryopyrin- associated periodic syndromes (CAPS), familial cold auto-inflammatory syndrome (FCAS), Muckle Wells syndrome (MWS), neonatal onset multisystem inflammatory disease / chronic, infantile, neurological, cutaneous and articular syndrome (NOMID/CINCA), or Familial Mediterranean Fever (FMF)), preventing flare ups, alleviating the symptoms or arresting or inhibiting further development or manifestation of the disease, condition, disorder, or syndrome. As used herein, the term “prevent”, “preventing”, or “prevention” in connection to a disease, condition, disorder, or syndrome (e.g., cryopyrin-associated periodic syndromes (CAPS), familial cold auto- inflammatory syndrome (FCAS), Muckle Wells syndrome (MWS), neonatal onset multisystem inflammatory disease / chronic, infantile, neurological, cutaneous and articular syndrome (NOMID/CINCA), or Familial Mediterranean Fever (FMF)) refers to the prophylactic treatment of a subject who is at risk of developing a condition resulting in a decrease in the probability that the subject will develop the condition (e.g., specific disease or disorder or clinical symptom thereof associated with CAPS, FCAS, MWS, NOMID/CINCA, or FMF such as skin disease, arthralgia, myalgia, headache/migraine, conjunctivitis, fatigue/malaise, and organ or tissue damage). For example, “treating familial cold auto-inflammatory syndrome (FCAS)” may refer to ameliorating, alleviating or modulating at least one of the symptoms or pathological features associated with familial cold auto-inflammatory syndrome (FCAS); e.g., low grade fever, general rash, conjunctivitis, polyarthralgia, headache, myalgia, and fatigue; e.g., may refer to slowing progression, reducing or stopping at least one of the symptoms or pathological features associated with familial cold auto- inflammatory syndrome (FCAS); e.g., low grade fever, general rash, conjunctivitis, polyarthralgia, headache, myalgia, and fatigue. It may also refer to preventing or delaying one or more of the described symptoms, e.g., slow the progress of, halt, or reverse disease, condition, disorder, manifestation or syndrome progression and improve clinical outcomes. Also “treating” may refer to slow the progress of, halt, or reverse disease, condition, disorder, manifestation or syndrome progression and improve clinical outcomes, e.g, moving from a higher number to a lower number on a 5-point scale of disease-associated clinical signs and symptoms as follows: 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 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 inactivating, destabilizing, altering distribution, of NLRP3 or otherwise. Typically, an NLRP3 inhibitor has an hTHP-1 IC50 of <1 µM 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. More preferably the NLRP3 inhibitor is Compound IA 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. Compound I, Compound IA or Compound IB may be used in crystalline or amorphous form, as a solvate, e.g., a hydrate, or an unsolvated form. 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 is also intended to include the tautomeric form containing the moiety . 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; mixture of diastereomers). 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 and Compound IB, a racemic mixture of Compound IA and 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. 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 preferred. 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, preferred 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, 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, 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 used herein, the term “therapeutically effective amount” of the compound described herein refers to an amount of the compound that will elicit the biological or medical response of a subject, for example, ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, condition, disorder, manifestation or syndrome, etc. In one non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound described herein that, when administered to a subject, is effective to at least partially alleviating, inhibiting, preventing and/or ameliorating an auto-inflammatory syndrome (e.g., cryopyrin-associated periodic syndromes (CAPS), familial cold auto-inflammatory syndrome (FCAS), Muckle Wells syndrome (MWS), neonatal onset multisystem inflammatory disease / chronic, infantile, neurological, cutaneous and articular syndrome (NOMID/CINCA), or Familial Mediterranean Fever (FMF). 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 an Compound I 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 the 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, 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) 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. Enumerated Embodiments (embodiments 1.1 to 1.32): 1.1 An NLRP3 inhibitor for use in the treatment of an auto-inflammatory syndrome in a subject in need thereof. 1.2 The NLRP3 inhibitor for use according to embodiment 1.1, wherein the NLRP3 inhibitor is administered to the subject at a total daily dose of about 50 mg to about 500 mg in single or divided doses, preferably about 50 mg to about 200 mg. 1.3 The NLRP3 inhibitor for use according to embodiment 1.2, wherein the NLRP3 inhibitor is administered to the subject at a total daily dose of about 100 mg or about 200mg in single or divided doses. 1.4 The NLRP3 inhibitor for use according to embodiment 1.3, wherein the NLRP3 inhibitor is administered to the subject at a dose of about 100 mg twice daily for three consecutive days and about 100 mg once in the morning on day four. 1.5 The NLRP3 inhibitor for use according to any one of embodiments 1.1 to 1.4, wherein the auto-inflammatory syndrome is CAPS, FCAS, MWS, NOMID/CINCA, or FMF. 1.6 The NLRP3 inhibitor for use according to any one of embodiments 1.1 to 1.5, wherein the auto-inflammatory syndrome is FCAS. 1.7 The NLRP3 inhibitor for use according to embodiment 1.6, wherein said patient does not have an increase in White Cell Count (WCC) of more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% following the administration of the NLRP3 inhibitor. 1.8 The NLRP3 inhibitor for use according to embodiment 1.6, wherein after cold exposure the patient exhibits a lower score on the Physician’s Global Assessment scale of at least 1, at least 2, at least 3, on a scale of 1-10 following administration of the NLRP3 inhibitor 1.9 The NLRP3 inhibitor for use according to embodiment 1.6, wherein after cold exposure the patient exhibits a lower score on the Physician’s Global Assessment scale of at least 10%, at least 20%, at least 30%, on a scale of 1-100 following administration of the NLRP3 inhibitor. 1.10 The NLRP3 inhibitor for use according to any one of embodiments 1.1 to 1.9, wherein the patient does not have an increase in C-Reactive Protein of more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% following the administration of the NLRP3 inhibitor. 1.11 The NLRP3 inhibitor for use according to any one of embodiments 1.1 to 1.10, wherein the patient does not exhibit an increase in IL-1β or IL-18 of more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% following the administration of the NLRP3 inhibitor. 1.12 The NLRP3 inhibitor for use according to any of the preceding enumerated embodiments, wherein the NLRP3 inhibitor is administered to the subject orally. 1.13 The NLRP3 inhibitor for use according to any of the preceding enumerated embodiments, wherein the NLRP3 inhibitor is present in a tablet formulation. 1.14 The NLRP3 inhibitor for use according to any one of enumerated embodiments 1.1 to 1.6, wherein the NLRP3 inhibitor is Compound I, or a pharmaceutically acceptable salt thereof: . 1.15 The NLRP3 inhibitor for use according to embodiment 1.14, wherein Compound I comprises Compound IA enantiomer, or a pharmaceutically acceptable salt thereof: . 1.16 The NLRP3 inhibitor for use according to embodiment 1.15, wherein Compound I comprises Compound IB enantiomer, or a pharmaceutically acceptable salt thereof: . 1.17 The NLRP3 inhibitor for use according to embodiment 1.15, wherein Compound IA has an enantiomeric excess of at least 90%. 1.18 The NLRP3 inhibitor for use according to embodiment 1.16, wherein Compound IB has an enantiomeric excess of at least 90%. 1.19 A pharmaceutical composition comprising an NLRP3 inhibitor of embodiments 1.12 to 1.18, for use according to any preceding enumerated embodiment. 1.20 A pharmaceutical combination comprising an NLRP3 inhibitor of embodiments 1.12 to 1.18, and at least one further therapeutic agent, for use according to any preceding enumerated embodiment, further comprising. Uses and methods 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%. Embodiment 1 In one embodiment, provided herein is a method of treatment or reducing the symptoms of an auto- inflammatory syndrome in a subject in need thereof, comprising administering an effective amount of Compound I, or a pharmaceutically acceptable salt thereof. In one embodiment, provided herein is Compound I or a pharmaceutically acceptable salt thereof for use in treating an auto-inflammatory syndrome in a subject in need thereof. In some embodiments, provided herein is the use of Compound I, for the manufacture of a medicament for the treatment of an auto-inflammatory syndrome. Embodiment 2 In one embodiment, provided herein is a method of treatment or reducing the symptoms of a Cryopyrin- associated periodic syndrome (CAPS) in a subject in need thereof, comprising administering an effective amount of Compound I, or a pharmaceutically acceptable salt thereof. In one embodiment, provided herein is Compound I or a pharmaceutically acceptable salt thereof for use in treating a Cryopyrin-associated periodic syndrome (CAPS) in a subject in need thereof. In some embodiments, provided herein is the use of Compound I, for the manufacture of a medicament for the treatment of a Cryopyrin-associated periodic syndrome (CAPS). Embodiment 3 In one embodiment, provided herein is a method of treatment or reducing the symptoms of familial cold auto-inflammatory syndrome (FCAS) in a subject in need thereof, comprising administering an effective amount of Compound I, or a pharmaceutically acceptable salt thereof. In one embodiment, provided herein is Compound I or a pharmaceutically acceptable salt thereof for use in treating familial cold auto-inflammatory syndrome (FCAS) in a subject in need thereof. In some embodiments, provided herein is the use of Compound I, for the manufacture of a medicament for the treatment of familial cold auto-inflammatory syndrome (FCAS). Embodiment 4 In one embodiment, provided herein is a method of treatment or reducing the symptoms of Muckle Wells syndrome (MWS) in a subject in need thereof, comprising administering an effective amount of Compound I, or a pharmaceutically acceptable salt thereof. In one embodiment, provided herein is Compound I or a pharmaceutically acceptable salt thereof for use in treating Muckle Wells syndrome (MWS) in a subject in need thereof. In some embodiments, provided herein is the use of Compound I, for the manufacture of a medicament for the treatment of Muckle Wells syndrome (MWS). Embodiment 5 In one embodiment, provided herein is a method of treatment or reducing the symptoms of neonatal onset multisystem inflammatory disease / chronic, infantile, neurological, cutaneous and articular syndrome (NOMID/CINCA) in a subject in need thereof, comprising administering an effective amount of Compound I, or a pharmaceutically acceptable salt thereof. In one embodiment, provided herein is Compound I or a pharmaceutically acceptable salt thereof for use in treating neonatal onset multisystem inflammatory disease / chronic, infantile, neurological, cutaneous and articular syndrome (NOMID/CINCA) in a subject in need thereof. In some embodiments, provided herein is the use of Compound I, for the manufacture of a medicament for the treatment of neonatal onset multisystem inflammatory disease / chronic, infantile, neurological, cutaneous and articular syndrome (NOMID/CINCA). Embodiment 6 In one embodiment, provided herein is a method of treatment or reducing the symptoms of Familial Mediterranean Fever (FMF) in a subject in need thereof, comprising administering an effective amount of Compound I, or a pharmaceutically acceptable salt thereof. In one embodiment, provided herein is Compound I or a pharmaceutically acceptable salt thereof for use in treating Familial Mediterranean Fever (FMF) in a subject in need thereof. In some embodiments, provided herein is the use of Compound I, for the manufacture of a medicament for the treatment of Familial Mediterranean Fever (FMF). In any of the embodiments described here, the patient does not have an increase in White Cell Count (WCC) of more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% following the administration of the NLRP3 inhibitor. In any of the embodiments described herein, the patient does not have an increase in C-Reactive Protein of more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% following the administration of the NLRP3 inhibitor. In any of the embodiments described herein, the patient does not exhibit an increase in IL-1β or IL-18 of more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% following the administration of the NLRP3 inhibitor. In any of the embodiments of treating or reducing symptoms of FCAS described herein, after cold exposure the patient exhibits a lower score on the Physician’s Global Assessment scale of at least 1, at least 2, at least 3, on a scale of 1-10 following administration of the NLRP3 inhibitor. In any of the embodiments of treating or reducing symptoms of FCAS described herein, after cold exposure the patient exhibits a lower score on the Physician’s Global Assessment scale of at least 10%, at least 20%, at least 30%, on a scale of 1-100 following administration of the NLRP3 inhibitor. In any of the embodiments described herein, Compound I or a pharmaceutically acceptable salt thereof may be administered to the subject at a total daily dose of about 50 mg to about 200 mg, as measured in the non-salt equivalents, in single or divided doses. In particular embodiments, Compound I is administered to the subject at a total daily dose of about 200 mg in single or divided doses. In yet particular embodiments, Compound I is administered to the subject at a dose of about 100 mg twice daily for three consecutive days and about 100 mg once in the morning on day four. 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 5 mg, 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. 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 is in the form of a table 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. For all of the embodiments defined herein, the preferred NLRP3 inhibitor is Compound IA. In particular embodiments, Compound IA is 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%. Subjects As discussed herein, subjects receiving the NLRP3 inhibitor as presently described can present symptoms of or be at risk of familial cold auto-inflammatory syndrome (FCAS), e.g., as hereinabove defined. Combination therapy In practicing some of the methods of treatment or uses described herein, a therapeutically effective amount of Compound I is administered to a patient, e.g., a mammal (e.g., a human). Additionally, for less severe cases of FCAS, patients may be treated in a supportive manner, managing the symptoms like fever, muscle pain, or fatigue. For more severe cases of FCAS, the use of immunosuppressive agents like corticosteroids may be necessary, but judgment must be used to avoid negating the effect of drugs intended to activate the immune system. Pharmaceutical compositions Compound I may be used as a pharmaceutical composition when combined with a pharmaceutically acceptable carrier. Such a composition may contain, in addition to Compound I, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other known materials. The characteristics of the carrier will depend on the route of administration. The pharmaceutical compositions for use in the compositions, uses, and methods described herein may also contain at least one or more additional therapeutic agents for treatment of the particular targeted disorder, disease, condition, or syndrome. Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with Compound I. In specific embodiments, the Compound I can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, ^, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK.2012). Routes of Administration and Composition Components In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral). Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof. Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia.2006, 10, 788–795. In certain embodiments, the chemical entities described herein or a pharmaceutical composition thereof are suitable for local, topical administration to the digestive or GI tract, e.g., rectal administration. Rectal compositions include, without limitation, enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, and enemas (e.g., retention enemas). Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy- metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM) , lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate. In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema. In other embodiments, the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.). Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG’s, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated. Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid. In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient. In certain embodiments, solid oral dosage forms can further include one or more components that chemically and/or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and/or transverse colon and/or distal colon and/or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K.J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety. Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls. Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric/pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid–methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap. Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)). Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing. In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers. Dosing regimen and modes of administration Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). Depending on the compound used, the targeted disease, condition, disorder, or syndrome and the relevant stages of the same, the dosing regimen, i.e., administered doses and/or frequency of the pharmaceutical composition comprising Compound I may vary. Depending on the compound used, the disease, condition, disorder, or syndrome and the relevant stages of the same, the dosing regimen, i.e., administered doses and/or frequency of the pharmaceutical combination comprising a) Compound I and b) at least one further therapeutic agent, may vary. For administration of Compound I in the methods for treating an auto-inflammatory syndrome, the dosage ranges from about 0.0001 to about 100 mg/kg, and more usually about 0.01 to about 30 mg/kg, of the subject’s body weight. In particular embodiments, Compound I is administered at a daily dose of about 50 mg to about 500 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, about 50 mg to about 100 mg, about 50mg. In particular embodiments, Compound I is administered at a daily dose of about 50 mg, about 100 mg, about 150 mg, or about 200 mg. In particular embodiments, Compound I is administered once a day. In other embodiments, Compound I is administered two, three, or four times a day. In preferred embodiments, Compound I is administered at a daily total dose of about 200 mg, administered once or in two divided doses. Preferably, Compound I is Compound IA. Preferably, Compound IA is administered at a daily total dose of about 50 to 500 mg. More preferably, Compound 1A is administered at a daily dose of 200mg. In some embodiments, Compound IA is administered at a daily dose of 200 mg. In some embodiments, Compound IA is administered 100 mg twice a day. In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. Dosages are repeated as necessary and may be in the range from about once per week up to about once every 10 weeks, e.g., once every 4 weeks or once every 8 weeks. Kits Herein are also encompassed kits for use in the methods for treating or preventing cytokine release syndrome or cytokine storm syndrome, which may comprise Compound I in liquid or lyophilized form or a pharmaceutical composition comprising Compound I. Additionally, such kits may comprise a means for administering Compound I (e.g., a syringe and vial, a prefilled syringe, a prefilled pen) and instructions for use. These kits may contain additional therapeutic agents (described elsewhere herein), e.g., for delivery in combination with Compound I. The phrase “means for administering” is used to indicate any available implement for systemically administering a drug to a patient, including, but not limited to, a dropper, a pre-filled syringe, a vial and syringe, an injection pen, an autoinjector, an i.v. drip and bag, a pump, etc. With such items, a patient may self-administer the drug (i.e., administer the drug on their own behalf), a caregiver may administer the drug to the patient, or a physician or other medical professional may administer the drug. Each component of the kit is usually enclosed within an individual container, and all of the various containers are within a single package along with instructions for use. It is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination is consistent with the description of the embodiments. It is further to be understood that the embodiments provided above are understood to include all embodiments, including such embodiments as result from combinations of embodiments. Other features, objects, and advantages of the described methods and uses will be apparent from the description and drawings, and from the claims. 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: Compound I: Compound I: N'-(1,2,3,5,6,7-hexahydro-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 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: 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). 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: Intermediate I OH N'-(tert-butyldimethylsilyl)-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 - 78oC. The resulting solution was stirred for 0.5 h at -78oC 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 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 70oC. 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:
N'-(tert-butyldimethylsilyl)-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 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 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 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 Example illustrates 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: Clinical study with Compound IA An open-label, single arm phase II study of Compound IA to assess the safety, tolerability and efficacy in participants with familial cold auto-inflammatory syndrome (FCAS) who show evidence of inflammatory activity after the cold challenge performed during screening. Figure 1 is a schematic overview of the treatment protocol with Compound IA (i.e. the R enantiomer of Compound I). Compound IA 100 mg will be dosed twice daily for 3 days and 100 mg in the morning of Day 4. The primary objective of this study is to assess the efficacy of Compound IA to reduce cold-induced inflammation in participants with FCAS. The endpoint (EP) for the primary objective is the change from pre-challenge to the highest post- challenge value of white cell count (WCC). The secondary objectives of the study are as follows: 1. To assess safety and tolerability of Compound IA 2. To assess the efficacy of Compound IA to improve the signs and symptoms of FCAS 3. To assess the effect of Compound IA on patient reported outcomes The endpoint (EP) for the secondary objectives are as follows: 1. Safety endpoints (including vital signs, ECG parameters, safety laboratory assessment and adverse events) 2. Change from pre-challenge to post-challenge in Physician’s global assessment of auto- inflammatory disease activity and Physician's severity assessment of auto-inflammatory disease signs and symptoms 3. Change from pre-challenge to post-challenge in patients global assessment of disease activity Exploratory objectives Endpoints for exploratory objectives • To assess the effect of Compound IA on • Change in absolute neutrophil count (ANC), markers of systemic inflammation high sensitivity C-reactive protein (hsCRP) and serum amyloid A (SAA) from pre- challenge to post-challenge • To evaluate the PK of Compound IA • PK parameters of Compound IA in plasma such as AUClast, AUCtau, Cmax, Ctrough, Tmax • To evaluate the effect of CYP2C9 • Differences between different CYP2C9 polymorphism on PK of Compound IA metabolizers in PK parameters of Compound IA such as AUClast and Cmax (if feasible) • To assess the pharmacokinetic / • Plasma concentrations and PK parameters of pharmacodynamic (PK/PD) relationship Compound IA and pathway-related markers of of Compound IA NLRP3 such as, but not limited to IL-1β, IL- 6, IL-18 • To assess the effect of Compound IA on • Soluble biomarkers such as, but not limited to pharmacodynamic, inflammasome pathwa IL-1β, IL-6, IL-18, IL-18BP, CXCL10, y and inflammation related biomarkers Caspase-1 and proteomics • To perform genetic research to investigate • Genetic variants of relevant genes drug-related response mechanism, to better understand the safety and efficacy of Compound IA Study design This is an open-label, single-arm, multiple dose, study with approximately 6 participants with FCAS and confirmed NLRP3 gain-of-function mutations who show evidence of inflammatory activity after the cold challenge performed during screening. The cold challenge protocol was developed to study the acute inflammatory mechanisms after general cold exposure in FCAS patients and to investigate the effect of pretreatment with IL-1 blocking therapeutics. Participants with a history of transient self-limiting rash, fever and/or arthralgia that are pathognomonic of FCAS following cold exposure that resolve with warmth will undergo a maximum of two controlled cold challenges while domiciled at the clinical site under medical supervision to trigger a transient inflammatory response. Following the 45 minute cold challenge, participants will be returned to an ambient temperature of approximately 25°C for at least 24 hours at the clinical site, to ensure resolution of the inflammatory response. Typical symptoms and signs triggered by cold challenge in participants with FCAS include increase in markers of systemic inflammation (e.g. WCC, neutrophils), low-grade fever, rash and arthralgia beginning 1 hour after challenge, peaking at 4-8 hours and abating by the next day with no reports of long-term sequalae (Hoffman et al., Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet; 2004;364(9447):1779-85.). The study involves three periods: • Screening period including a screening cold challenge (up to three months) • Treatment period including a second cold challenge (total of 5 days duration) • Follow up period concluded with a Study completion visit (10 days after dose administration) Screening period to confirm that the study inclusion and exclusion criteria are met and for performing clinical observations and biological sampling: • Screening visit: Informed consent will be collected and participants evaluated for eligibility. For those participants that qualify for the screening cold challenge, prohibited medication will be stopped. Results from laboratory samples collected at the Screening visit, as well as reports of active disease from the participant, must be available prior to scheduling the screening cold challenge. • Screening Cold Challenge: The participants are domiciled for three days in connection with the screening cold challenge. On the first day (Day -10), the participants will be admitted in the morning, go through safety assessments and then stay in a room with ambient temperature, preferably above 25°C, to ensure stable conditions prior to the cold challenge. On the second day (Day -9), after pre-challenge assessments and breakfast, participants will undergo a cold challenge for 45 minutes followed by monitoring over the next 23 hours. On the third day (Day -8), the participants will be discharged after the last assessment, or later at the discretion of the investigator. Participants should have a minimum of one week of recovery from cold challenge prior to enrollment and initiation of treatment. Treatment period • Treatment initiation visit: Participants who meet all inclusion and no exclusion criteria, including showing evidence of inflammatory activity after the cold challenge performed during screening, will be enrolled on Day 1 and treatment will be initiated. • The first dose of Compound IA will be administered in the clinic and study treatment will be dispensed to the participant for continued treatment at home. Participants may be domiciled during the treatment period for convenience of the participants and/or logistical aspects, at the discretion of the participant and investigator. • Cold Challenge: Participants will be admitted to the clinic in the morning of Day 3, the day prior to cold challenge, and will be domiciled for a total of three days or longer if mandated by the investigator or by local regulations. On Day 3, participants will undergo safety assessments and then stay in a room with ambient temperature, preferably above 25°C, to ensure stable conditions prior to the cold challenge. On the morning of Day 4, pre-challenge assessments will be performed and breakfast will be served. Directly after breakfast, a pre-dose PK sample will be collected and the last dose of study treatment will be administered. One hour after study treatment administration, another PK sample will be collected and the cold challenge will be initiated. The cold challenge lasts for 45 minutes. After the end of the cold challenge, participants will be monitored until the next morning (Day 5). The participants will be discharged after the last assessment on Day 5 or later, at the discretion of the investigator. Follow up period to ensure participants' safety after treatment discontinuation and recovery from the cold challenge. • Participants will be followed-up for an end of study evaluation at the Study completion visit, approximately 10 days after last dose. Key inclusion criteria 1. Written informed consent must be obtained before any study-specific assessment is performed 2. Male and female participants aged between 18-80 years inclusive 3. Body mass index within the range of 18-35 kg/m2 4. Participants with a genetic diagnosis of FCAS 5. Participants with a clinical history and investigations consistent with FCAS, in the absence of a history or diagnosis of amyloidosis and/or organ damage (e.g. deafness, periorbital edema, lymphadenopathy, and serositis) 6. Participants who have evidence of inflammatory activity after the screening cold challenge 7. Clinical history of active disease in the screening period in response to cold exposure in the environment on at least one occasion, as assessed by the Physician global assessment of auto- inflammatory disease activity > minimal Key exclusion criteria 1. Participants carrying NLRP3 mutations not responsive to NLRP3 inhibition including, but not limited to, L353P carriers (based on Principal Investigator/registry data, published evidence and/or Novartis internal studies) 2. Participants currently being treated with anti-rejection and/or immunomodulatory drugs and the treatment cannot be discontinued or switched to a different medication within 28 days or 5 half- lives (whichever is the longer if required by local regulations), or until the expected pharmacodynamic effect has returned to baseline for immunomodulatory therapeutic antibodies, prior to screening cold challenge and for the duration of the study The exceptions are: anakinra, canakinumab and/or other investigational IL-1/NLRP3 binding or blocking therapy, which must be discontinued at screening. As soon as the criteria for evidence of active disease are met, participants can proceed to the screening cold challenge 3. Clinically significant, suspected active or chronic bacterial (including Mycobacterium tuberculosis), viral or fungal infection within 30 days prior to dosing 4. Participants with innate (e.g. TLR immunodeficiencies, defects in IFN-γ signaling) or acquired immune deficiencies (e.g. AIDS) 5. Presence of human immunodeficiency virus (HIV) infection, hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc), or hepatitis C antibodies at screening 6. Live vaccines within 4 weeks of Day 1 (i.e. first dose of Compound IA) 7. Absolute peripheral blood neutrophil count of ≤1000/mm3 8. Estimated GFR (eGFR) ≤90 mL/min/1.73m2 (based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula) 9. History or current diagnosis of ECG abnormalities indicating significant safety risk for participant enrolled 10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human serum chorionic gonadotropin (hCG) laboratory test 11. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 10 days after stopping of study treatment 12. Any significant concurrent medical condition that, in the opinion of the investigator, could affect the participant’s ability to tolerate or complete the study Efficacy assessments: • White Cell Count (WCC) • Physician global assessment of auto-inflammatory disease activity • Physician's Severity Assessment of Auto-inflammatory Disease Signs and Symptoms • Patients Global Assessment of Disease Activity Key safety assessments • Physical examination • Vital signs • ECG parameters • Pregnancy and assessment of fertility • Monitoring of laboratory markers in blood and urine • Adverse event and serious adverse event monitoring Other assessments • Inflammatory markers (including but not limited to absolute neutrophil count (ANC), high sensitivity C-reactive protein (hsCRP) and serum amyloid A (SAA)) • Plasma concentrations of Compound IA and pharmacokinetic parameters • Pharmacodynamic, inflammasome pathway and inflammation related biomarkers in serum e.g. IL- 1β, IL-6, IL-18, IL-18 binding protein (IL-18BP), CXCL10, caspase-1 and proteomics Data analysis The primary objective will be achieved and Compound IA will be considered efficacious in treating cold-induced inflammation in participants with FCAS if the estimated difference in change from pre- challenge of total WCC between treatment and screening period is: 1. statistically significant (p<0.10) and 2. lower than -4x109cells/L The change from pre-challenge to the highest post-challenge WCC will be analyzed by a linear model, including pre-challenge values as covariates and modeling period effect, taking into account the intra- participant correlation. Rationale for dose/regimen, duration of treatment A dose of 100 mg administered twice daily as a tablet has been selected for this study based on the preliminary PK results and preliminary PK/PD relationship. Compound IA tablets will be administered shortly after completion of a meal and all doses will be taken approximately 12 h apart (+/- 1h). A positive food effect on PK (2.05-fold increase in peak plasma level (Cmax) and 1.49-fold increase in AUClast) was demonstrated with 100 mg tablets. The apparent terminal elimination half-life of Compound IA tablet under fed conditions is approximately 10 hours, thus after multiple dosing, the steady state is anticipated by Day 4. There is no established occupancy marker for NLRP3. Ex vivo whole blood, LPS-stimulated IL-1β secretion data from the FIH study has been used to estimate the efficacious dose. Based on the results of this assay, the mean total Compound IA plasma trough concentration required to inhibit 90% of stimulated IL-1β release (IC90) in healthy participants is on average 3.17 μM, equivalent to ~1.3 μg/mL. Higher concentrations are likely needed in participants with FCAS based on the 3-5-fold larger in vitro IC50 values for inhibition of IL-1β secretion measured in PBMCs from patients with certain FCAS- associated mutations as compared to healthy participants. This is presumably due to mutations in the NLRP3 protein that affect the binding KD of the compound. Assuming plasma levels 5 times above IC90 value derived from the preliminary PK/PD study for a 24-hour period are needed to maintain complete target occupancy in participants with FCAS, doses of 100 mg administered twice daily shortly after completion of a meal will be used to assure full NLRP3 inhibition on Day 4. In a human study in healthy volunteers, a = dose of 200 mg Compound 1A administered once daily for up to 14 days provided mean AUC0-24h and Cmax at steady-state of 182 µg*h/mL and 26.4 µg/mL. For the 100 mg tablet dosed twice daily the predicted steady-state mean AUC0-24h (225 µg*h/mL) is 1.2-fold higher and Cmax (12.1 µg/mL) is 2.2-fold lower than corresponding PK parameters in the healthy volunteers administered 200 mg of Compound 1A. The safety of the treatment period is supported by 13-week good laboratory practice (GLP) toxicology studies in rat and cynomolgus monkeys. Table 1 Predicted human PK, Based on Safety margin b Safety margin b steady-state total or free to 13-week GLP RAT to 13-week exposure NOAEL based on: GLP MONKEY NOAEL based on: Cmax,ss AUC0- Cmax AUC0-24h Cmax AUC0-24h (µg/mL) 24h,ss (µg*h/mL) Total a 4.4 1.8 21 16 12.1 225 Unbound 8.8 3.6 17 13 a Based on total exposure. For unbound exposure (corrected for plasma protein binding) safety margins are higher for rat (2x) and lower for monkey (0.8x). b NOAEL Cmax (µg/mL) and AUC0-24h (µg*h/mL) from 13-week toxicology studies for rat (30 mg/kg): 52.9 and 400 and for monkey (150 mg/kg): 258 and 3540, respectively. Considering the short treatment duration of 4 days and sufficient safety margins, administration of Compound IA in this study is considered safe. Drug-drug interaction issues Evaluation and recommendations for drug-drug interaction clinical studies of cytochrome P450 (CYP) substrates/modulators and Compound IA are based on in vitro / preclinical data and physiology-based PK simulations. Compound IA is expected to be eliminated mainly via hepatic CYP-mediated metabolism with CYP2C9 (68%) and CYP3A4 (29%) as the main contributing enzymes. Participants who are poor CYP2C9 metabolizers will be excluded from this study. Considering treatment duration and sufficient safety margins, administration of Compound IA is considered safe even under conditions of elevated exposures to Compound IA. Prohibited drugs and herbal medications • Anti-rejection/immune modulatory therapies (e.g., anakinra, canakinumab or other investigational IL-1/NLRP3 binding or blocking therapy) • Live vaccine • Strong or moderate inducers of CYP2C9 or strong inducers of CYP3A including carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, rifabutin, mitotane and St. John’s wort (Hypericum perforatum) • Strong inhibitors of CYP2C9 including miconazole, berberine (herbal product), sulfaphenazole, fluconazole, resveratrol (herbal product) • Other investigational products Drugs to be used with caution • Drugs that are metabolized by CYP3A In vitro metabolism studies showed that Compound IA might have the potential to induce the metabolism of drug substrates metabolized by isoenzyme CYP3A. Therefore, investigators, at their discretion, may administer concomitant medications known to be metabolized by CYP3A4/5. Patients receiving such medications may require dose titration or increase of the concomitant drug. Particularly, caution is advised when Compound IA is co-administered with drugs that are sensitive substrates of CYP3A and/or have a narrow therapeutic index. • Drugs that are strong or moderate inhibitors of CYP3A Compound IA was identified in vitro as a substrate of CYP3A, so an increase in systemic exposure of Compound IA when co-administered with strong CYP3A inhibitors such as antiviral drugs (e.g., ritonavir), antifungal (e.g., itraconazole, ketoconazole) and antibiotics (e.g., erythromycin, clarithromycin) cannot be ruled out. Investigators may, at their discretion, co-administer known inhibitors of CYP3A, but their duration should be kept as short as possible, and patients must be closely monitored. Example 2: Clinical first-in-human (FIH) study with COMPOUND IA: Study design The study design was comprised of 4 parts: a single ascending dose (SAD; Part A), relative bioavailability of tablet formulations (Part B), multiple ascending doses (MAD; Part C), and relative bioavailability and food effect (Part D) (Figure 2). 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, 8 groups of 8 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 SDD under fasted conditions). In Group 1 of Part A, 2 sentinel subjects were dosed at least 24 hours before the rest of the group was dosed, to ensure maximum safety. Part B was skipped because the data collected in Part A provided an adequate comparison of crystalline and SDD formulations. In Part C, eligible subjects were enrolled in 6 different groups. Each subject received multiple doses of COMPOUND IA (10, 30 mg of crystalline suspension and 100, 200 mg of SDD suspension for 14 days) once daily (QD) in a fasted state, or twice daily (BID) (25, 50 mg of encapsulated crystalline tablet for 13 days and single dose on Day 14 or placebo) under fed conditions. Subjects were dosed in Part C following a review of the 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 profile of the crystalline tablet formulation of COMPOUND IA nonclinical safety pharmacology and toxicology program supported evaluation was compared between fed and fasted conditions, and with the PK profile of the crystalline suspension of COMPOUND IA under fasted conditions. Subjects received 3 doses of COMPOUND IA with a 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 fed condition). Based on these doses, subjects were randomly assigned to 1 of 6 treatment sequences (1 subject per sequence) prepared using a Williams design (Wang B-S, Wang X-J, Gong L-K. The Construction of a Williams Design and Randomization in Cross-Over Clinical Trials Using SAS. Journal of Statistical Software 2009; 29). Subjects Eligible subjects were healthy volunteers, aged between 18 and 64 years, with a body mass index (BMI) ≥18.5 and ≤30.0 kg/m2. No subject participated in >1 part or group. 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 a history of major psychiatric disorders, diagnosis of intellectual disability, clinically significant vital sign abnormality, or use of tobacco products within 90 days prior to (the first) drug administration to 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 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 assessment 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). Pharmacokinetic (PK) assessment 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, blood 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. In multiple ascending dose (MAD) part, relative to dosing on Days 1 and 14, urine pools were collected over 24 hours for QD doses (0-12h and 12-24h) and over 12 hours for BID doses. Plasma samples were analyzed by a fully validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS). COMPOUND IA concentrations >1 ng/mL (the lower limit of quantification, LLOQ) were determined with a precision of ≤4.4% and an accuracy of −2.0% to 1.5% relative error. Urine samples were analysed by LC-MS/MS with LLOQ of 1 ng/mL. Concentrations below LLOQ were set to 0. The following PK parameters were estimated using noncompartmental analysis maximum concentration in plasma (Cmax); time to maximum concentration (tmax); concentration at 24 h post-dose (C24h) (Part A); Lag time: time of observation prior to the first quantifiable concentration (tlag); time of the last quantifiable concentration (tlast); area under the concentration-time curve from time 0 to the last quantifiable concentration (AUC0-last); area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf); area under the plasma concentration-time curve from time 0 to 24 hour post-dose (AUC0-24); terminal phase rate constant (Kel); terminal phase half-life (t1/2); apparent total body clearance (CL/F); and apparent volume of distribution at terminal phase (Vz/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 (AUC0-tau); apparent clearance at steady state (CLss/F); accumulation ratio based on AUC0-tau (Rac,AUC); and accumulation ratio based on Cmax (Rac,Cmax). Pharmacodynamic (PD) assessment To determine the PD response to NLRP3 inhibition pathway, whole blood samples were collected for exploratory PD analysis (Part A and Groups 1–3 of Part C). Analysis of the inflammatory marker IL- 1β was performed after ex vivo stimulation of whole blood samples with lipopolysaccharide (LPS). The whole blood stimulation by 1 μg/mL of LPS was successful and the analysis of IL-1β concentrations in plasma samples performed using a validated electrochemiluminescence assay was found to be valid and scientifically acceptable. LLOQ after dilution was 64.6 ng/L. Statistical analysis All data were summarized using descriptive statistics and are 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 tmax only median, minimum, and maximum are presented. PK parameters were calculated using non-compartmental methods using software Phoenix Version 8.1. Concentrations below the lower limit of quantification were treated as zero in summary statistics for concentration data alone. The linear trapezoidal rule was used for AUC calculation. Regression analysis of the terminal plasma elimination phase for the determination of t1/2 included at least 3 data points after Cmax. Parameters with an adjusted r² below 0.80 were flagged but included in the descriptive statistics. The parameters AUC0–inf, %AUCextra, CL/F, and VZ/F with an %AUCextra above 20% were excluded from the descriptive statistics. In Part A, dose proportionality was explored using a regression power model relating logarithmically (log)-transformed Cmax, AUC0–last, and AUC0–inf to the log-transformed dose level. Point estimates for the intercept and the slope and corresponding to 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 crystalline tablet versus the crystalline suspension, as well as the effect of food, was explored using an analysis of variance (ANOVA) model on the PK data. The ANOVA model included fixed effects for treatment, period, and sequence, and a random effect for subject within sequence. 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 IL-1β concentrations versus time are presented by treatment. To characterize the inhibitory potency of COMPOUND IA on the release of IL-1β, a Bayesian Emax PK/PD model was applied. The model was developed using the rstan library in the free software environment R (version 4.0.5). Convergence issues (possible related to fitting of the baseline value with inter-individual variability) were the final rationale for selecting the Bayesian method over the frequentist method, which was initially evaluated too – and the reason for including only one parameter with inter-individual variability. Two results are presented: one with estimation of the maximal inhibition and the other one assuming the ability of full inhibition (Emax = 1). Ex-vivo LPS stimulated results were corrected for unstimulated results for the same sample. Concentrations below LLOQ were set to half of the LLOQ (IL-1β) and to 0 (COMPOUND IA). Results Subject disposition and demographics A total of 122 subjects were enrolled in the study. All 122 were included in the safety and PD analysis sets, and the 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 (105 [86%]) of subjects (Part A, n=57; Part C, n=42, Part D, n=6) were Caucasian. Of the enrolled subjects, 107 (88%) completed the study per protocol and 15 (12%) discontinued the study early. The early discontinuations included 1 of 64 (2%) subjects in Part A, 13 of 52 (25%) subjects in Part C, and 1 of 6 (17%) subjects in Part D. Reasons for study discontinuation included withdrawal due to AEs in 12 (10%) subjects, with 1 (1%) subject each discontinuing the study either due to withdrawal of consent, loss to follow-up, or the study being on temporary hold due to the COVID-19 pandemic (preventing visits; unrelated to the safety of COMPOUND IA). A total of 4 discontinued subjects were replaced in Part C. Safety Single and multiple doses of COMPOUND IA were generally well tolerated. No deaths or serious AEs (SAEs) were reported during the study. Overall, 87/122 subjects (71%) reported treatment-emergent AEs (TEAEs): 66/94 subjects (70%) in the COMPOUND IA arm and 21/28 (75%) subjects in the placebo arm. The majority of TEAEs reported by 84 (69%) subjects were of mild intensity, while 15 subjects (12%) reported moderate TEAEs. The frequently-reported system organ class (SOC) events in >20% of 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 study drug- related, including 21/94 (22%) who received COMPOUND IA and 3/28 (11%) who received placebo. For 12/122 (10%) subjects, 20 TEAEs of maculopapular skin rash and/or pruritus were considered AEs of special interest as they were considered to be related to the study drug. All 12 subjects received COMPOUND IA, either as single (100 mg CS [n=1] or 600 mg SDD [n=1]) or multiple doses (30 mg QD CS [n=2], 100 mg QD SDD [n=3], 200 mg QD SDD[n=2], or 50 mg BID ECT [n=3]). These TEAEs were of mild-to-moderate intensity, generally started within 1–17 days of initiation of treatment with COMPOUND IA, and resolved within 1–18 days of onset; all cases resolved without concomitant treatment. For 10 subjects, TEAEs led to treatment discontinuation. Two other subjects discontinued early due to TEAEs that were unrelated to the study drug. Mild decreases in neutrophil and leukocyte counts were considered non-clinically significant and only noted occasionally, 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 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 As indicated by dose-normalized Cmax and AUC, plasma exposure to single doses of COMPOUND IA increased in a less than dose-proportional manner when COMPOUND IA was administered as a crystalline suspension (3–300 mg, slopes [90% CIs]: 0.518 [0.460; 0.577] for Cmax and 0.701 [0.614; 0.788] for AUC0 last). Although the mean AUC0-last appeared to increase dose proportionally at the lower dose levels (3 mg to 30 mg), the mean AUC0-last were similar at the 100 mg and 300 mg dose levels (79500 (CV 54.8%) versus 64400 ng∙h/mL (CV 23.5%), respectively). Exposure increased dose-proportionally when administered as an SDD suspension (100–600 mg, slopes [90% CIs]: 0.913 [0.802; 0.1.024] for Cmax and 1.121 [0.977; 0.1.265] for AUC0-last). After QD administration of COMPOUND IA dose range 30–200 mg for 2 weeks, only limited drug accumulation of ~1.1–1.3-fold was observed in reaching steady state. This is consistent with a mean t1/2 ranging from 9.83–16.2 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. Total cumulative amount of COMPOUND IA excreted in urine increased in linear manner with increasing multiple dose levels. COMPOUND IA was mostly excreted within 12 hours. On Days 1 and 14, the mean fraction of dose excreted was in the range 0.3%-0.4% and 0.7%-1.1% and renal clearance was in the range 3.6-5.0 mL/h and 6.8-9.1 mL/h, respectively. Administration of a single dose of 100 mg COMPOUND IA as a crystalline suspension under fed conditions led to a 2.05-fold increase of Cmax and 1.49-fold for AUC0–last of COMPOUND IA compared with fasted conditions. For the crystalline tablet (100 mg COMPOUND IA under fasted conditions), the median tmax of COMPOUND IA was delayed from 2 to 5 hours, the Cmax was 78% lower, the AUC was similar (104%) and the t1/2 was comparable between the crystalline tablet and suspension. The encapsulated crystalline tablets (25 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 tmax of 4 hours on Day 1. The mean t1/2 of COMPOUND IA was comparable between the tablet (18.6 hours) and suspension (17.7 hours) formulations. Pharmacodynamics Dose-dependent decreases in concentrations of ex vivo stimulated IL-1β (with mean nadir concentrations of ~5%–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 release 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 (Emax) model tested with a Hill coefficient, the typical baseline (E0) (±SD) of the observed stimulation effect of IL-1β was 1820 (±102) ng/L; the Emax of IL-1β was –0.985 (±0.00277) and the hill coefficient was 0.758 (±0.0351). The effective concentrations relative to the estimated maximum effect of COMPOUND IA resulting from ex vivo stimulated IL-1β release were EC50: 59 ng/mL (90% CI: 48, 72), EC90: 1080 ng/mL (90% CI: 942, 1240). When considering full inhibition (fixing Emax = 1) then the plasma concentrations of COMPOUND IA inhibiting 50% and 90% of the LPS ex vivo stimulated IL-1β release (IC50 and IC90) were respectively 61 ng/mL (90% CI: 50; 70) and 1340 ng/mL (90% CI: 1190; 1490) and the hill coefficient was 0.715 (±0.0333). The similarity between the models indicates limited influence of the imputation of values below LOQ to LOQ/2. Discussion There is an unmet medical need to widen therapeutic modalities for patients suffering from inflammasome NLRP3-mediated inflammatory, metabolic and neurodegenerative diseases that offer an effective and predictable treatment option without increased risk of AEs. In this study, an NLRP3 antagonist COMPOUND IA was administered orally for the first time to human subjects, exploring safety, tolerability, PK, and PD properties. Initial doses were selected based on predicted human PK and anticipated efficacious doses, as well nonclinical safety from animal and in vitro data. Safety Single and multiple doses of COMPOUND IA or placebo were generally well tolerated. No deaths or SAEs were reported during the study. Similar rates of TEAEs were observed between subjects who received COMPOUND IA (70%) and placebo (75%). The majority of TEAEs reported by subjects were mild (69%) or moderate (12%) in severity. Subcutaneous tissue and gastrointestinal disorder TEAEs were only reported by subjects who received COMPOUND IA, not placebo. 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, independent of formulation used. Safety and tolerability data of other NLRP3 inhibitors tested in clinical trials like ZYIL1 or dapasuntrile (Parmar DV, Kansagra KA, Momin T, Patel HB, Jansari GA, Bhavsar J, Shah C, Patel JM, Ghoghari A, Barot A, Sharma B, Viswanathan K, Patel HV, Jain MR. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Oral NLRP3 Inflammasome Inhibitor ZYIL1: First- in-Human Phase 1 Studies (Single Ascending Dose and Multiple Ascending Dose). Clin Pharmacol Drug Dev.2023; 12: 202-211; Marchetti C, Swartzwelter B, Gamboni F, Neff CP, Richter K, Azam T, Carta S, Tengesdal I, Nemkov T, D'Alessandro A, Henry C, Jones GS, Goodrich SA, Laurent JP, Jones TM, Scribner CL, Barrow RB, Altman RD, Skouras DB, Gattorno M, Grau V, Janciauskiene S, Rubartelli A, Joosten LAB, Dinarello CA. OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc Natl Acad Sci USA. 2018; 115: E1530-E1539; Klück V, Jansen TLTA, Janssen M, Comarniceanu A, Efdé M, Tengesdal IW, Schraa K, Cleophas MCP, Scribner CL, Skouras DB, Marchetti C, Dinarello CA, Joosten LAB. Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial. Lancet Rheumatol.2020; 2: e270- e280), did not include any drug-related skin reactions, pointing towards a specific COMPOUND IA- related effect, and not due to a mode of action. Pharmacokinetics Following single oral doses of COMPOUND IA under fasted conditions as suspensions (3-300 mg CS, 100-600 mg SDD), COMPOUND IA was in general rapidly absorbed with a median tmax ranging from 0.76–3.00 hours across dose levels. However, with the higher dose range 30–600 mg the median tmax was slightly delayed (1.5–3.0 hours) compared with lower doses (3 and 10 mg: 0.76 and 1.00 hours, respectively). The increase in drug exposure was less than dose-proportional with a crystalline suspension (particularly 100 and 300 mg), while a dose-proportional increase in exposure was observed with a SDD suspension (100–600 mg), indicating solubility-limited absorption of crystalline material in 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 parameters were linear and 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 agreement with bioavailability results where no clear effect of food on tmax was observed. These findings suggest the lag absorption time was due to encapsulation. Renal clearance was determined to be ~ 0.004 L/h (Day 1) or 0.008 L/h (Day 14), approximating to <0.8% of an oral dose. This shows that direct secretion of COMPOUND IA into urine is not expected to be a major elimination route for this drug in humans. COMPOUND IA as 100 mg crystalline tablets showed a positive food effect (greater exposure with food) with increased Cmax and AUC by 2.05- and 1.49-fold in the fed (high-fat, high-calorie meal) vs fasted state, respectively. Median Tmax for 100 mg crystalline tablets was 5 hours, while shorter Tmax values (0.76–3.0 hours) were reported for suspensions. COMPOUND IA has a very low apparent oral clearance (CLss/F ~1.0 L/h), which relates to ≤2% of human liver blood flow and a low apparent volume of distribution (Vss/F) of ~12.6–23.3 L. Slight drug accumulation of ~1.2-fold after QD dosing and 2- fold after BID dosing was observed in reaching steady state, consistent with an effective t1/2 of ~10 hours, as determined for crystalline tablets when given with food. Pharmacodynamics Nonclinical studies have suggested that COMPOUND IA blocks the release of IL-1β using a range of NLRP3-dependent activators. This has been observed also with e.g. MCC950, which selectively inhibits NLRP3 activation (Tapia-Abellan A, Angosto-Bazarra D, Martinez-Banaclocha H, de Torre-Minguela C, Ceron-Carrasco JP, Perez-Sanchez H, Arostegui JI, Pelegrin P. MCC950 closes the active conformation of NLRP3 to an inactive state. Nat Chem Biol 2019; 15: 560-64) or with ZYIL1 compound, which demonstrated >90% IL-1b inhibition in healthy subjects. In contrary dapansutrile (OLT1177), another NLRP3 inhibitor only partially reduced release of IL-1b in healthy subjects and patients with gout flare. 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 (Gaidt MM, Hornung V. Alternative inflammasome activation enables IL-1beta release from living cells. Curr Opin Immunol 2017; 44: 7- 13); thus, inhibitors aimed at IL-1β can result in unintentional immunosuppressive effects. Therefore, pharmacological inhibitors which specifically target the NLRP3 inflammasome alone could be a better option for treatment of NLRP3-associated diseases (Zahid A, Li B, Kombe AJK, Jin T, Tao J. Pharmacological Inhibitors of the NLRP3 Inflammasome. Front Immunol 2019; 10: 2538). Safety laboratory findings were a 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 the anti- IL-1β monoclonal antibody canakinumab (Dhimolea E. Canakinumab. MAbs 2010; 2: 3-13). COMPOUND IA exhibited rapid onset of action on IL-1b inhibition with clear dose response over the entire dose range investigated, both after single and multiple doses, and no obvious delay in onset, suggesting a direct PK/PD relationship. To maintain ~90% of IL-1b inhibition over 24h, a dose of 25 mg twice daily as a crystalline tablet was chosen for the phase 2a study in knee osteoarthritis. A recent report from a COMPOUND IA early phase 2a clinical trial involving patients with COVID- 19-associated pneumonia and impaired respiratory function, also showed that COMPOUND IA 50 mg BID tablet was well-tolerated in this group of patients and no new safety signals were identified. Results indicated a trend towards improved response in patients, who received COMPOUND IA on top of SoC vs SoC alone. Sub-analysis in patients with more severe inflammation (high CRP) but lower corticosteroid doses showed faster reduction and normalization of inflammatory markers in the COMPOUND IA+SoC group (Madurka I, Vishnevsky A, Soriano JB, Gans SJ, Ore DJS, Rendon A, Ulrik CS, Bhatnagar S, Krishnamurthy S, Mc Harry K, Welte T, Fernandez AA, Mehes B, Meiser K, Gatlik E, Sommer U, Junge G, Rezende E. COMPOUND IA: a new oral NLRP3 inhibitor-tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function. Infection 2022: 1-14). 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 a BID dosing regimen and PK/PD data supported dose and formulation selection for further development. The safety and tolerability, PK, and PD results suggest that COMPOUND IA has the potential to be an effective oral first-in-class innate immune modulator warranting further clinical evaluation. Example 3 The following procedures are suitable for testing the activity of NLRP3 inhibitors, as per those disclosed herein. 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. 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 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 2 1. Experimental procedure 1.1 Cell Culture 1) Culture THP-1 cells in the complete RPMI-1640 medium with 10% FBS at 37°C, 5% CO2. 2) Passage the cells every 3 days by inoculating 3x105 cells per ml. 1.2 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. FIG.3 depicts the layout of the microplate. 1.3 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. 1.4 THP-1 Stimulation 1) Wash adherent THP-1 cells with PBS, and detach cells with 4ml trypsin for T225 flask. 2) Centrifuge cells at 350g for 5 min, re-suspend cells with RPMI-1640 containing 2% FBS and count cells with trypan blue. 3) 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. 4) Seed 50k cells in 40ul RPMI-1640 with 2% FBS per well in 384-well plate. 5) Incubate for 1h at 37°C, 5% CO2. 6) Prepare 5x gramicidin, add 10 ^l per well, the final concentration is 5 ^M, incubate for 2hrs at 37°C, 5% CO2. 7) Centrifuge at 350 g for 1 min. 8) Pipet 16 ^l supernatant by apricot, and transfer into white 384 proxiplate. FIG.3 depicts the layout of the plates: HC: 100 ^M CRID3 (MCC950) + 5 ^M gramicidin LC：5 ^M Gramicidin. 1.5 IL-1β detection 1) Homogenize the 5x diluent #5 with a vortex and add 1 volume of stock solution in 4 volumes of distilled water. 2) Thaw 20x stock solution of anti-IL1β-Cryptate-antibody and anti-IL1β XL-antibody. Dilute these two antibodies to 1x with detection buffer #3. 3) Pre-mix the two ready-to-use antibody solutions just prior to use. 4) Dispense 4ul of pre-mixed Anti-IL1β antibodies working solution into all wells 5) Seal the plate and incubate overnight at 4 oC. 6) Read the cell plate using EnVison and plot Readout vs. the test compound concentration to calculate the IC50. 2. Data Analysis: 1. IC50 of compounds can be calculated using the following formulas Formula for IC50 % inhibition =100-100 x [HCave-Readout / (HCave – LCave)] 2. Fit the normalized data in a dose-response manner using XLfit, and calculate the compound concentration. Table 2 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 = “+”. 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

CLAIMS: 1. A method of treating an auto-inflammatory syndrome in a patient in need thereof, comprising administering a therapeutically effective amount of an NLRP3 inhibitor. 2. A method of reducing the symptoms of an auto-inflammatory syndrome in a patient in need thereof, comprising administering a therapeutically effective amount of an NLRP3 inhibitor. 3. The method according to claim 1 or 2, wherein the NLRP3 inhibitor is administered to the subject at a total daily dose of about 50 mg to about 500 mg in single or divided doses, optionally about 50 mg to about 200 mg. 4. The method according to claim 3, wherein the NLRP3 inhibitor is administered to the subject at a total daily dose of about 100 mg in single or divided doses. 5. The method according to claim 4, wherein the NLRP3 inhibitor is administered to the subject at a dose of about 100 mg twice daily for three consecutive days and about 100 mg once in the morning on day four. 6. The method according to any one of claims 1 to 5, wherein the auto-inflammatory syndrome is cryopyrin-associated periodic syndromes (CAPS), familial cold auto-inflammatory syndrome (FCAS), Muckle Wells syndrome (MWS), neonatal onset multisystem inflammatory disease / chronic, infantile, neurological, cutaneous and articular syndrome (NOMID/CINCA), or Familial Mediterranean Fever (FMF). 7. The method according to any one of claims 1 to 6, wherein the auto-inflammatory syndrome is familial cold auto-inflammatory syndrome (FCAS). 8. The method according to any one of claims 1 to 7, wherein said patient does not have an increase in White Cell Count (WCC) of more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% following the administration the NLRP3 inhibitor. 9. The method according to any one of claims 1 to 7, wherein after cold exposure the patient exhibits a lower score on the Physician’s Global Assessment scale of at least 1, at least 2, at least 3, on a scale of 1-10 following administration of the NLRP3 inhibitor 10. The method according to any one of claims 1 to 7, wherein after cold exposure the patient exhibits a lower score on the Physician’s Global Assessment scale of at least 10%, at least 20%, at least 30%, on a scale of 1-100 following administration of the NLRP3 inhibitor. 11. The method according to any one of claims 1 to 10, wherein the patient does not have an increase in C-Reactive Protein of more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% following the administration of the NLRP3 inhibitor. 12. The method according to any one of claims 1 to 11, wherein the patient does not exhibit an increase in IL-1β or IL-18 of more than about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% following the administration of the NLRP3 inhibitor. 13. The method according to any of the preceding claims, wherein the NLRP3 inhibitor is administered to the subject orally. 14. The method according to any of the preceding claims, wherein the NLRP3 inhibitor is present in a tablet formulation. 15. The method according to any of the preceding claims, comprising administering at least one further therapeutic agent. 16. The method according to any of the preceding claims, wherein the NLRP3 inhibitor is Compound I, or a pharmaceutically acceptable salt thereof: . 17. The method according to claim 16, wherein Compound I is Compound IA enantiomer, or a pharmaceutically acceptable salt thereof: . 18. The method according to claim 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%. 19. The method according to claim 16, wherein Compound I is Compound IB enantiomer, or a pharmaceutically acceptable salt thereof:
. 20. The method according to claim 19, 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%.
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