Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • 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
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods

Definitions

• the present disclosure relates to the field of pharmacy, particularly to an NLRP3 inhibitor for use in the treatment of osteoarthritis.
• the disclosure also relates to an NLRP3 inhibitor or a pharmaceutical combination comprising an NLRP3 inhibitor, and at least one further therapeutic agent, for use in the treatment of osteoarthritis; to a method for the treatment of osteoarthritis that involves administering an NLRP3 inhibitor or the combination; and to the use of an NLRP3 inhibitor or the combination for the manufacture of a medicament for the treatment of osteoarthritis.
• Osteoarthritis the most common joint disorder in the world, is a serious, chronic progressive joint disease with no known cure that has been associated with an increased risk of premature mortality (Osteoarthritis Research Society International 2016, Paper submitted to U.S. Food and Drug Administration; 01 December; Kluzek et al 2015, Ann Rheum Dis. 75(10): 1749-56).
• OA osteoarthritis Research Society International 2016.
• nonsurgical treatment of OA comprises both pharmacologic and nonpharmacologic modalities (such as patient education, referral to a physiotherapist, exercise, weight reduction, walking aids, knee braces, and footwear). All presently available pharmacologic therapies for OA provide symptomatic relief by transiently reducing pain but have not been shown to delay the structural damage associated with the progression of OA.
• TRR Total knee replacement surgery
• Pro-inflammatory cytokines such as interleukin-1 b (I L-1 b) are critical mediators of the disturbed metabolism and enhanced catabolism of joint tissue involved in OA (Fraenkel et al 1998, J Rheumatol., 1820-6), making anti-inflammatory therapy an attractive strategy to counteract OA.
• These inflammatory mediators induce downregulation of anabolic events, i.e. cartilage matrix production by chondrocytes and production of degrading enzymes (MMPs, ADAMTS) by chondrocytes and synovial cells, which cause the breakdown and loss of the cartilage matrix (van den Bosch 2019, Clin Exp Immunol. 153-166).
• NLRP3 inflammasome has been implicated as a major driver of inflammation associated with many chronic inflammatory diseases.
• NLRP3 senses a diverse range of danger signals, and responds by forming an inflammasome protein complex that drives an inflammatory response.
• NLRP3 inhibitors have been shown to block IL-1 b secretion, I L-18 secretion and pyroptotic cell death in response to a wide variety of NLRP3-dependent danger signals in vitro and in mechanistic mouse models in vivo.
• DMOAD disease-modifying osteoarthritis drug
• NLRP3 inhibitors which may be used to prevent or reduce the NLRP3 inflammasome response and thus address the unmet medical need in OA.
• an NLRP3 inhibitor disclosed herein can be developed as an OA drug to reduce pain, slow joint damage and improve function in adults with symptomatic OA by addressing the inflammatory aspect of the disease and delaying/preventing progression to end-stage OA.
• the present invention relates to methods for treating OA, e.g. knee OA, hand OA, hip OA, spinal OA, foot and ankle OA, by administering therapeutically effective amounts of an NLRP3 inhibitor, in particular Compound I or a pharmaceutically acceptable salt thereof, to a subject.
• an NLRP3 inhibitor in particular Compound I or a pharmaceutically acceptable salt thereof
• Described herein are also NLRP3 inhibitors, in particular Compound I or a pharmaceutically acceptable salt thereof, for use in treating OA, e.g. knee OA, hand OA, hip OA, spinal OA, foot and ankle OA.
• compositions or kits comprising them.
• Compound I is Compound IA.
• Figure 1 A schematic overview of the treatment protocol as detailed in Example 1.
• FIG. 2 A schematic overview of the study design of the first-in-human (FIH) study as detailed in Example 2.
• the term “about” or “approximate” in relation to a reference numerical value and its grammatical equivalents as used herein can include the numerical value itself and a range of values plus or minus 20% (preferably ⁇ 15%, more preferably ⁇ 10%, even more preferably ⁇ 5%) from that numerical value.
• the amount “about 10” includes 10 and any amounts from 8 to 12 or from 9 to 11.
• the term “about” in relation to a reference numerical value can also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value.
• the numerical value described throughout can be “about” that numerical value even without specifically mentioning the term “about.”
• baseline refers to a subject’s state or the degree of a condition, e.g., a disease, or one or more parameters associated with the state of a patient, observed before treatment, e.g., before administration of a compound, e.g., before administration of Compound I, or a pharmaceutically acceptable salt thereof, optionally in combination with at least one further therapeutic agent, according to the described methods and uses.
• administering in relation to a compound, e.g., 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.
• 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.
• 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.
• the compositions, methods, and uses described herein are in reference to a human patient or subject.
• a subject is “in need of” a treatment if such subject who is afflicted with the condition (i.e. , disease, disorder, or syndrome) of interest and who would benefit biologically, medically, or in quality of life from such treatment.
• condition i.e. , disease, disorder, or syndrome
• treatment is herein defined as therapeutic measures for the reduction or amelioration of the progression, severity and/or duration of an undesired physiological change or disorder (e.g. OA such knee OA), or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of the disorder resulting from the administration of one or more therapeutic agents.
• the terms “treatment,” “treating,” or “treat” refer to the reduction or stabilization of the progression of a disorder, such as OA, either physically by, e.g., reduction or stabilization of a discernible symptom, physiologically by, e.g., reduction or stabilization of a physical parameter, or both.
• beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and reversal (whether partial or total), whether detectable or undetectable.
• “treating OA such as knee OA, hand OA, hip OA, spinal OA, foot and ankle OA” may refer to ameliorating, alleviating or modulating at least one of the symptoms or pathological features associated with OA; e.g. reduce pain, slow joint damage and improve function; e.g., may refer to slowing progression, reducing or stopping at least one of the symptoms or pathological features associated with OA. 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.
• 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:
• 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 I L-1 b and/or IL-18 by directly binding to NLRP3, or by inactivating, destabilizing, altering distribution, of NLRP3 or otherwise.
• an NLRP3 inhibitor has an IC50 of ⁇ 1 mM of I L-1 b secretion in the hTHP-1 assay containing 2% fetal bovine serum defined herein.
• the NLRP3 inhibitor is a compound of Compound I, Compound I A, or Compound IB, or a pharmaceutically acceptable salt thereof. More preferably, the NLRP3 inhibitor is Compound IA, or a pharmaceutically acceptable salt thereof.
• 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 (i.e., (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide) or Compound IB (i.e., (S)-N'- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide) may be used in crystalline or amorphous form, as a solvate, e.g., a hydrate, or an unsolvated form.
• a solvate e.g., a hydrate, or an unsolvated form.
• Non-limiting exemplified compounds of the formulae described herein include a stereogenic sulfur atom.
• This disclosure provides examples of stereoisomer mixtures (e.g. racemic mixture of enantiomers).
• This disclosure also describes and exemplifies methods for separating individual components of said stereoisomer mixtures (e.g. resolving the enantiomers of a racemic mixture).
• Compound I for example, represents each of a non- racemic mixture of Compound IA 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 I A 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• phrases “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.
• the “dose” or amount of NLRP3 inhibitor refers to the amount of the free base or free acid form of the compound.
• 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.
• 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.
• 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.
• 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.
• 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 ameliorating, alleviating or modulating at least one of the symptoms or pathological features associated with OA; e.g. reduce pain, slow joint damage and improve function; e.g., may refer to slowing progression, reducing or stopping at least one of the symptoms or pathological features associated with OA. 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.
• “combination” refers to either a fixed combination in one unit dosage form (e.g., capsule, tablet, sachet or vial), free (i.e., non-fixed) combination, or a kit of parts for the combined administration where Compound I, or a pharmaceutically acceptable salt thereof, and the one or more additional therapeutic agents may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g., synergistic effect.
• co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of an additional therapeutic agent to a single subject in need thereof (e.g., a subject), and the additional therapeutic agent are intended to include treatment regimens in which Compound I and additional therapeutic agent are not necessarily administered by the same route of administration and/or at the same time.
• Each of the components of the presently described combination may be administered simultaneously or sequentially and in any order.
• Co-administration comprises simultaneous, sequential, overlapping, interval, and/or continuous administrations and any combination thereof.
• pharmaceutical combination 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.
• 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.
• combination comprising a) Compound I and b) at least one additional therapeutic agent as used herein (e.g., in any of the embodiments or in any of the claims herein), refers to a “non-fixed combination” and may be administered independently at the same time or separately within time intervals.
• 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).
• 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.
• 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.
• 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.
• 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.
• phrases “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.
• the present invention provides a method of treating osteoarthritis comprising administering an NLRP3 inhibitor to a subject.
• the osteoarthritis is knee, hand, hip, or spine osteoarthritis.
• Treatment with an NLRP3 inhibitor compound according to one of the dosing regimens described herein is expected to slow or halt the progress of osteoarthritis and reduce or eliminate symptoms associated with osteoarthritis as compared to treatment with placebo.
• treatment may decrease pain as measured by the Knee Injury and Osteoarthritis Outcome Score (KOOS) or the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score based on change from baseline.
• treatment may reduce stiffness associated with osteoarthritis.
• treatment may result in the reduction of the inflammation level of the osteoarthritis affected joint as determined by change from baseline in synovitis activity level measured from K trans by dynamic contrast-enhanced (DCE)-MRI.
• DCE dynamic contrast-enhanced
• treatment according to one of the presently described dosing regimens may improve or maintain (e.g., prevent further decrease) the function in the affected joint.
• treatment according to one of the presently described dosing regimens may prolong the survival of the joint affected with osteoarthritis and/or increase the subject’s quality of life.
• treatment according to a dosage regimen of the present invention may prevent or delay the need for joint replacement surgery. Treatment according to the dosing regimens described below may continue until such time as the subject no longer receives a therapeutic benefit.
• the NLRP3 inhibitor may be administered according to any known administration method.
• the NLRP3 inhibitor is administered via oral administration, e.g., as a tablet.
• Other possible routes of administration include, e.g., intradermal, intramuscular, intravenous, and intra-articular.
• the NLRP3 inhibitor may also be administered according to any known means for administering a therapeutic to a patient, including, but not limited to, a pre-filled syringe, a vial and syringe, an injection pen, an autoinjector, an i.v. drip and bag, a pump, a patch pump, etc.
• a patient may self-administer the drug (i.e. , administer the drug on their own behalf) or a physician may administer the drug.
• the methods of treatment of the present invention comprise administering an NLRP3 inhibitor according to a dosing regimen.
• the dosing regimen comprises administering an NLRP3 inhibitor at a total daily dose of about 10 mg to about 100 mg in a single dose or divided doses to a subject.
• the dosing regimen comprises administering an NLRP3 inhibitor at a total daily dose of about 20 mg to about 50 mg in a single dose or divided doses to a subject.
• the dosing regimen comprises administering an NLRP3 inhibitor at a total daily dose of about 20 mg in a single dose or divided doses to a subject.
• the dosing regimen comprises administering an NLRP3 inhibitor at a total daily dose of about 50 mg in a single dose or divided doses to a subject.
• the dosing regimen comprises administering an NLRP3 inhibitor at about 10 mg twice daily to a subject.
• the dosing regimen comprises administering an NLRP3 inhibitor at about 25 mg twice daily to a subject.
• the dosing regimen comprises administering an NLRP3 inhibitor at about 10 mg twice daily to a subject for about 14 consecutive days.
• the dosing regimen comprises administering an NLRP3 inhibitor at about 25 mg twice daily to a subject for about 70 consecutive days.
• the doses are administered to a subject during or after consuming food.
• the time interval between the administration of two subsequent doses is about 10-14 hours.
• the methods of treatment relate to the treatment of knee osteoarthritis.
• the subject in the methods of treatment is a human subject.
• the administration of the NLRP3 inhibitor decreases pain in the osteoarthritis affected joint as determined by KOOS score based on change from baseline.
• the administration of the NLRP3 inhibitor reduces the inflammation level of the osteoarthritis affected joint as determined by change from baseline in synovitis activity level measured from K trans by dynamic contrast-enhanced (DCE)-MRI.
• DCE dynamic contrast-enhanced
• the level of serum high sensitivity C-Reactive Protein decreases in a subject by 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% as determined by change from baseline.
• the level of IL-1 b or IL-18 decreases in a subject by 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% as determined by change from baseline.
• the subject does not exhibit any skin rash.
• the NLRP3 inhibitor is administered to the subject orally.
• the NLRP3 inhibitor is comprised in a tablet formulation.
• at least one further therapeutic agent is administered.
• the NLRP3 inhibitor is Compound I, or a pharmaceutically acceptable salt thereof:
• the NLRP3 inhibitor is Compound IA, or a pharmaceutically acceptable salt thereof.
• Compound IA has an enantiomeric excess of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5%.
• the NLRP3 inhibitor is Compound IB, or a pharmaceutically acceptable salt thereof.
• Compound IB has an enantiomeric excess of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5%.
• An NLRP3 inhibitor for use in the treatment of osteoarthritis or the use of an NLRP3 inhibitor in the manufacture of a medicine for the treatment of osteoarthritis wherein the NLRP3 inhibitor is administered to a subject at a total daily dose of about 10 mg to about 100 mg in a single dose or divided doses.
• NLRP3 inhibitor for use according to embodiment 26.1, wherein the NLRP3 inhibitor is administered to a subject at a total daily dose of about 20 mg to about 50 mg in a single dose or divided doses.
• 2 The NLRP3 inhibitor for use according to any one of embodiments 26.1-26.11, wherein administration of the NLRP3 inhibitor decreases pain in the osteoarthritis affected joint as determined by KOOS score based on change from baseline.
• NLRP3 inhibitor for use according to any one of embodiments 26.1-26.12, wherein administration of the NLRP3 inhibitor reduces the inflammation level of the osteoarthritis affected joint as determined by change from baseline in synovitis activity level measured from K trans by dynamic contrast-enhanced (DCE)-MRI.
• DCE dynamic contrast-enhanced
• NLRP3 inhibitor for use according to any one of embodiments 26.1-26.18, comprising administering at least one further therapeutic agent.
• 26.26 A pharmaceutical composition comprising an NLRP3 inhibitor of embodiments 26.20 to 26.24, for use according to any one of embodiments 26.1 to 26.25.
• Compound I of the below embodiments is Compound IA (i.e. the R enantiomer) in an enantiomeric excess of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5%.
• Compound IA is in enantiomeric excess of at least 90%. More preferably, Compound IA is in enantiomeric excess of at least 95%.
• a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
• the pharmaceutical composition is a tablet.
• the pharmaceutical composition is administered as a whole or crushed tablet.
• the pharmaceutical composition includes about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg in each unit dose.
• composition comprising Compound I, or a pharmaceutically acceptable salt thereof, for use in any of the embodiments described herein.
• Compound I is administered to a subject in need thereof orally.
• Compound I, or a pharmaceutically acceptable salt thereof is in the form of a tablet that is administered either whole or subdivided, i.e., crushed prior to administration.
• Compound I may be administered via a nasogastric tube.
• Method A Shim-pack XR-ODS, C18, 3x50 mm, 2.5 urn 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 urn); mobile phase, Water (10mmol/L NH4HC03) and ACN, UV detection 254/210 nm.
• NMR was recorded on BRUKER NMR 300.03 MHz, DUL-C-H, ULTRASHIELDTM300, AVANCE II 300 B-ACSTM120 or BRUKER NMR 400.13 MHz, BBFO, ULTRASHIELDTM400, AVANCE III 400, B-ACSTM120 or BRUKER AC 250 NMR instrument with TMS as reference measured in ppm (part per million).
• Step 1 N-(tert-butyldimethylsilyl)-N'-(1 ,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide:
• Step 2 N'-(1 ,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimidamide:
• the Compound I product obtained as described in the previous step was resolved by Chiral-Prep-HPLC using the following conditions: Column, CHIRAL Cellulose-SB, 2*25 cm, 5 urn; 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.
• 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 l-d.
• Step 5 N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide: Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide (5 g, 22.5 mmol) in THF (100 ml_). Then to the above was added NaH (60% wt, 1.8 g, 45.0 mmol) in portions in an ice/water bath.
• Step 6 N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2- sulfonimidamide:
• Boc t-butyloxy carbonyl
• DIEA N,N-diisopropylethylamine
• DPPA diphenylphosphoryl azide
• dppf 1,T-Bis(diphenylphosphino)ferrocene
• HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
• ⁇ HMDS lithium bis(trimethylsilyl)amide
• NBS N-bromosuccinimide
• NCS N-chlorosuccinimide
• Pd(dppf)Cl2 dichloro[1,T-bis(diphenylphosphino)ferrocene]palladium
• Ph phenyl
• TBAF tetrabutylammonium fluoride
• TBS tert-butyldimethylsilyl
• TBSCI tert-butyldimethylsilyl chloride
• TBDPSCI tert-butyldiphenylsilyl chloride
• TsOH 4-methylbenzenesulfonic acid
• the starting dose for Compound IA for participants enrolled in this trial is set at 10 mg twice daily (b.i.d.) for two weeks to assess tolerability, followed by a single-step dose escalation to 25 mg b.i.d. for 10 weeks, for a total treatment period of 12 weeks.
• the initial dose level was selected primarily on data from the first-in-human (FIH) study (Example 2), in which skin rashes have been observed in some participants dosed once daily with 30, 100, and 200 mg Compound IA.
• the mechanism of the skin rash is yet unknown and b.i.d. dosing could potentially mitigate risk and is therefore being explored.
• the two-week run-in period at a lower dose of 10 g b.i.d. will also inform about the extent of peripheral PD marker inhibition.
• FIG. 1 is a schematic overview of the treatment protocol with Compound IA (i.e. the R enantiomer of Compound I).
• Compound IA i.e. the R enantiomer of Compound I.
• 10 mg of Compound IA will be dosed orally twice daily for 13 consecutive days and 10 mg in the morning of Day 14, i.e. total dose of the first arm is 270 mg.
• the second arm of the study will begin directly after the first arm: 25 mg will be dosed in the evening of Day 14, and then 25 mg will be dosed twice daily for 69 days and in the morning of Day 84, i.e. the total dose of the second arm is 3500 mg.
• the endpoint (EP) for the primary objective is the change from baseline in Knee injury and Osteoarthritis Outcome Score (KOOS) pain sub-scale at week 12.
• the endpoints (EP) for the secondary objectives are as follows:
• Safety endpoints including vital signs, ECG parameters, safety laboratory assessment and adverse events
• Exploratory objectives may include but are not changes in exploratory biomarkers in limited to NLRP3 pathway markers, e.g., participants treated with COMPOUND IA inflammatory chemokines/cytokines (e.g., vs. placebo CXCL10, IL1b, IL6, TNF-a and IL18) in serum and synovial fluid and Caspase 1 in serum.
• COMPOUND IA inflammatory chemokines/cytokines e.g., vs. placebo CXCL10, IL1b, IL6, TNF-a and IL18
• COMPOUND IA Plasma concentrations of COMPOUND IA in plasma in participants COMPOUND I A and exploratory biomarkers with OA (e.g. I L1 b, IL6, IL18, orCXCLIO) or inflammatory markers such as hsCRP in circulation
• OA e.g. I L1 b, IL6, IL18, orCXCLIO
• inflammatory markers such as hsCRP in circulation
• COMPOUND IA such as AUCIast and Cmax the drug target pathway, or other relevant (if feasible) genetic pathways confer differential Due to the exploratory nature of this exposure or response to the COMPOUND objective, other specific endpoints are not IA predefined.
• biomarkers for Normalization may include normalization of synovial fluid to systemic but are not limited to total protein (synovial levels fluid collection at week 12) and urea.
• biomarkers e.g., biomarker sampling methods (e.g., hsCRP) in transdermal blood samples. transdermal blood samples.
• Placebell ⁇ TM composite covariate personality on response to treatment (placebo score) calculated for each participant by integrating participant personality characteristics (captured with MPsQ questionnaires) and other pertinent baseline features.
• This study uses a randomized, 2 treatment arm, parallel-group, participant and investigator-blinded, placebo-controlled design to evaluate the safety and tolerability of oral Compound IA in approximately 108 participants with symptomatic, inflammatory knee OA, and determining efficacy of Compound IA as evidenced by reduction in knee pain by KOOS (knee injury and osteoarthritis outcome score) after 12 weeks of treatment.
• KOOS knee injury and osteoarthritis outcome score
• the study consists of a screening period of up to 45 days, used to assess eligibility and to taper participants off disallowed medications.
• eligible participants will be randomized to one of the treatment arms.
• Eligible participants will enter the treatment period, which will begin with a 2-week titration period where they will receive Compound IA 10 mg twice daily or placebo orally for 14 consecutive days, followed by a 10-week treatment period where they will receive Compound IA 25 mg twice daily or placebo orally.
• An end of study visit will occur 15 days after the last dose and a post study safety contact will occur 30 days after last dose.
• the total study duration from screening until end of study is expected to be a maximum of 19 weeks.
• the assessment to address the primary objective will be performed at the end of the treatment period (week 12).
• the screening period consists of 2 visits, a screening visit and a baseline visit.
• Treatment period The treatment period will consist of 5 visits.
• the treatment period will consist of 5 visits:
• Participants will be followed-up for an end of study evaluation at the End of study visit, approximately 15 days after last dose (Day 99).
• a safety follow-up call will be performed approximately 30 days after the last dosing (Day 114) to record any potential safety event.
• BMI Body weight (kg) / [Height (m)]2
• Symptomatic OA with pain (Numeric Rating Scale [NRS] 5-9, inclusive) in the target knee for the majority of days in the last 3 months prior to screening.
• NRS Numeric Rating Scale
• the patient will be given a diary to record pain and use of analgesic medications.
• the participant must be compliant with filling in the diary at least 5 out of 7 days prior to Baseline, and have PRO reported NRS Pain 35 to £9 at Screening and Baseline.
• KOOS pain sub-scale score ⁇ 60 in index knee at screening and baseline.
• Radiographic disease K&L grade 2 or 3 knee osteoarthritis in the target knee, as per the OARSI Atlas, confirmed by X-ray at screening.
• CE-MRI contrast enhanced MRI
• Patients taking paracetamol/acetaminophen, including combination drugs containing low dose opioids can continue using this as per the package insert/doctor's instruction • Patients taking any other analgesic medication, including NSAIDs and selective COX-2 inhibitors but excluding topical NSAIDs or steroids, for any pain indication including knee pain, must be willing to switch at Screening to paracetamol/acetaminophen, including combination drugs containing low dose opioids, as per the package insert/doctor's instruction. NSAIDs are allowed only as rescue medication, but must not be used within 48 hours or five half-lives, whichever is longer, prior to any PRO assessment.
• autoimmune disease with inflammatory arthritides including but not limited to rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus), crystal-induced arthritides (gout, pseudogout associated arthritis), active acute or chronic infection or past infection of the knee joint, Lyme disease involving the knee, reactive arthritis, systemic cartilage disorders, moderate to severe fibromyalgia (widespread pain index, WPI, >4 out of 19), or a known systemic connective tissue disease.
• Participant has an unstable target knee joint, knee hardware or insufficiently reconstructed ligaments based on medical history and physical examination by the Investigator at screening.
• Participant has symptomatic, isolated patello-femoral pain in the index knee as per the Investigator's examination at screening.
• COVID- 19 specific It is highly recommended that PCR or antigen testing for COVID-19 be completed within 1 week prior to first dosing. If testing is performed, negative test results are required prior to enrolment into the study. Additional testing may occur at the discretion of the investigating physician. COVID-19 testing should be completed via nasal or throat swabs. If testing is not performed, the investigator must document their discussion with the participant regarding testing, and the rationale for not testing, in the source documentation. This requirement may be ignored if the pandemic is declared ended by the country where the site is located, and resumed if the pandemic recurs.
• Any diagnosed psychiatric condition that includes, but is not limited to, a history of mania, bipolar disorder, psychotic disorder, schizophrenia, or schizoaffective disorder, depression or anxiety which may jeopardize participant safety or compliance with study procedures, as judged by the investigator.
• Unstable target knee joint including, but not limited to, posttraumatic or congenital laxity or insufficiently reconstructed ligaments based on medical history and/or physical examination by the Investigator.
• any local i.a. treatment into the knee including but not restricted to viscosupplementation and corticosteroids within 12 weeks prior to Day 1; long term treatment (>14 days) with oral corticosteroids >5 mg/day within 4 weeks prior to Day 1; oral glucosamine, chondroitin sulfate, or any nutraceutical with potential activity on cartilage repair within 2 weeks prior to Day 1; systemic Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) or selective COX-2 inhibitors within 48 hours or five half-lives, whichever is longer, from PRO assessments; any other immunomodulatory drugs or treatment which cannot be discontinued or switched to a different medication within 28 days or 5 half-lives of screening(whichever is longer if required by local regulations), or until the expected PD effect has returned to baseline.
• NSAIDs systemic Non-Steroidal Anti-Inflammatory Drugs
• 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 15 days after stopping of investigational drug.
• liver disease or liver injury as indicated by abnormal liver function tests (as defined below) including but not limited to SGOT (AST), SGPT (ALT), alkaline phosphatase, serum bilirubin, albumin and prothrombin time.
• SGOT AST
• SGPT ALT
• alkaline phosphatase serum bilirubin
• albumin prothrombin time
• Any single parameter may not exceed 2 x upper limit of normal (ULN).
• Pain primary endpoint
• PROs Patient Reported Outcomes
• Synovitis (secondary endpoint), articular cartilage volume/thickness and effusion volume (exploratory endpoints) will be evaluated from MRI.
• Pharmacodynamic (PD) samples will be obtained and evaluated in all participants at all dose levels, including the placebo group.
• PROs Patient Reported Outcomes
• the participant will be given the PRO measure(s) to be completed at the scheduled visit before other clinical assessments are conducted.
• the questionnaires should be completed in the language most familiar to the participant.
• the participant should be given sufficient space and time to complete the PRO measure(s).
• a participant's refusal to complete all or any part of a PRO measure should be documented in the Case Report/Record Form (CRF).
• Study staff should check the PRO measure(s) collected for completeness and ask the participant to complete any missing responses.
• Completed PROs, including any unsolicited comments written by the participant must be reviewed and assessed by the investigator for responses which may include potential AEs or SAEs before any clinical study examinations are conducted. If AEs or SAEs are confirmed, then study investigators should not encourage the participant to change responses reported in the completed questionnaires.
• Knee Injury and Osteoarthritis Outcomes Score KOOS
• Knee-related pain will be assessed as the primary endpoint by means of the Knee Injury and Osteoarthritis Outcomes Score (KOOS) measure collected at regular intervals (Roos EM, Davis AM (2012) Recommendations for publication of cross-cultural validation studies of patient-reported outcomes (PROs) in Osteoarthritis and Cartilage. Osteoarthritis Cartilage p. 4-5.).
• the KOOS includes 42 items grouped into five sub-scales: Pain, Other Symptoms, Activities of Daily Living (ADL), Function in Sport and Adventure (Sport/Rec), and Knee-related Quality of Life (QoL).
• Each sub-scale is scored separately on a scale from 0 to 100, with a higher number indicating better condition (Collins NJ, Misra D, Felson DT, et al (2011) Measures of knee function: International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form, Knee Injury and Osteoarthritis Outcome Score (KOOS), Knee Injury and Osteoarthritis Outcome Score Physical Function Short Form (KOOS-PS), Knee Outcome Survey Activities of Daily Living Scale (KOS-ADL), Lysholm Knee Scoring Scale, Oxford Knee Score (OKS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Activity Rating Scale (ARS), and Tegner Activity Score (TAS).
• IKDC International Knee Documentation Committee
• the PRO KOOS score is an expanded version of the WOMAC score, which traditionally has been used in OA clinical trials (KOOS User Guide 2003).
• KOOS includes WOMAC OA Index LK3.0 in its complete and original format and WOMAC scores are able to be calculated. Therefore, the KOOS score provides a more comprehensive assessment as it also includes functioning in sport and recreation, as well as knee-related quality of life. KOOS requires approximately 10 minutes for participants to complete.
• the Numerical Rating Scale (NRS) for Pain (Hawker GA, Mian S, Kendzerska T, et al (2011) Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP).
• WPI Widespread Pain Index
• WPI Widespread Pain Index
• a pain diary will also be completed by the participant daily during the 12-weeks study and transferred to the CRF at each visit, beginning with Screening.
• This diary will be used to record basic pain medication, rescue medication and pain levels, daily. The participant may choose when, but should assess their pain intensity at approximately the same time every day.
• the NRS pain assessment in the diary and the NRS pain assessment performed during study visits should be documented separately in the CRF.
• participants At each study visit from Screening to Day 84, participants must be provided with a new pain diary that covers at least the period until the next planned visit. Prescription or use of pain medications will still need to be documented as Concomitant Medications according to Section 6.2.1.
• MRI will be obtained from the target knee to select participants with active synovitis and visualize the cartilage and other structures through the knee.
• the imaging protocol will be developed to quantify changes in synovitis, effusion volume, and volume and thickness of cartilage in the index region (i.e. , the region where most cartilage damage occurs in OA participants with KL 2-3) during treatment.
• the index region is defined as the union of the femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage sub-regions in the knee.
• FMA femoral medial anterior
• FMC central
• FMP posterior
• the safety of the treatment period is supported by 13-week GLP toxicology studies in rat and cynomolgus monkey.
• the expected mean steady-state daily systemic drug exposure at 25 mg b.i.d. dosed with food in participants will remain about 7-fold lower than the mean NOAEL plasma AUC in rat with even larger safety margins on free AUC (14-fold) or Cmax (17-fold (total) and 34-fold (free)).
• the expected mean steady-state drug exposure (total and unbound) will remain at least 49-fold lower than the exposure noted at NOAEL dose of 150 mg/kg/day (highest tested dose) in monkeys.
• 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.
• Anti-rejection/immune modulatory therapies e.g., anakinra, canakinumab or other investigational IL-1/NLRP3 binding or blocking therapy
• CYP2C9 or strong inducers of CYP3A including carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, rifabutin, mitotane and St. John’s wort (Hypericum perforatum)
• CYP2C9 Strong inhibitors of CYP2C9 including miconazole, berberine (herbal product), sulfaphenazole, fluconazole, resveratrol (herbal product)
• 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.
• 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
• SAD single ascending dose
• Part B relative bioavailability of tablet formulations
• MAD multiple ascending dose
• Part D relative bioavailability and food effect
• T2 Test Formulation 2 (crystalline tablet)
• T3 Test Formulation 3 (spray-dried dispersion suspension)
• Part A eight cohorts of eight eligible subjects were enrolled. Each subject received a single oral dose of Compound IA (3, 10, 30, 100, 300 mg of crystalline suspension and 100, 300, 600 mg of spray-dried dispersion (SDD) under fasted conditions. As this was a FIH study, two sentinel subjects were dosed first, at least 24 hours before the rest of the cohort was dosed, to assure maximum safety. Part B was skipped because the data from Part A provided for an adequate comparison of crystalline and SDD formulations.
• Compound IA 3, 10, 30, 100, 300 mg of crystalline suspension and 100, 300, 600 mg of spray-dried dispersion (SDD) under fasted conditions.
• SDD spray-dried dispersion
• Part C eligible subjects were enrolled in six different cohorts. Each subject received once daily (QD) multiple doses of Compound IA (10, 30 mg of crystalline suspension and 100, 200 mg of SDD for 14 days) in fasted condition, and (25, 50 mg of encapsulated crystalline tablet for 13 days and single dose on Day 14 or placebo) under fed condition. Subjects were dosed in Part C following review available safety, tolerability and PK data from preceding groups in Part A.
• Part D had an open-label, randomized, 3-period crossover design consisting of 1 group of 6 subjects.
• the PK of the crystalline tablet formulation of Compound IA was compared between fed and fasted conditions, and with the PK of the crystalline suspension of Compound IA under fasted conditions.
• Subjects received 3 doses of Compound IA with washout period of 7-14 days between each dose (Dose 1: 100 mg oral suspension in fasted condition; Dose 2: 100 mg oral tablet in fasted condition; Dose 3: 100 mg oral tablet in fasted condition). Based on these doses, subjects were randomly assigned to 1 of 6 treatment sequences (1 subject per sequence) prepared using Williams design.
• Eligible subjects were healthy male, and female aged between 18 to 64 years with body mass index (BMI) 318.5 and £ 30.0 kg/m 2 . No subject participated in more than 1 part or group. A written informed consent was obtained prior to any study procedure. Subjects participating in Part D had to be willing and able to consume the entire high-fat breakfast meal in the designated timeframe. Subjects were excluded if they had history of major psychiatric disorders, diagnosis of intellectual disability, clinically significant vital signs abnormality, and using tobacco products within 90 days prior to (the first) drug administration through follow-up.
• 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
• AE adverse event 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).
• PK parameters were calculated using noncompartmental methods using software Phoenix Version 8.1. Concentrations below the lower limit of quantification (LLOQ) were treated as zero in summary statistics for concentration data only. The linear trapezoidal rule was used for AUC calculation. Regression analysis of the terminal plasma elimination phase for the determination of /2 included at least 3 data points after C max . Parameters with an adjusted r 2 below 0.80 were flagged but included in the descriptive statistics. The parameters AUCo-i nf , %AUC extra , CL/F, and VZ/F with an %AUC extra above 20% were excluded from the descriptive statistics.
• Part A dose proportionality was explored using a regression power model relating logarithmically (log)-transformed C max , AUCo-i ast , and AUCo-i nf to the log-transformed dose level. Point estimates for the intercept and the slope and corresponding 90% confidence intervals (Cls) for the slope were calculated. For Part C, dose proportionality was not explored.
• Part D the relative bioavailability of the Test Formulation (crystalline tablet, SDD and crystalline tablet) versus the Reference Formulation (crystalline suspension), as well as the effect of food, was explored using an analysis of variance (ANOVA) model on the PK data.
• ANOVA analysis of variance
• Modeling of Compound IA effects on a corrected, stimulated ex vivo Lipopolysaccharide (LPS) challenge in whole blood included evaluation of the relationship between LPS challenge results by conditionally weighted residual modeling.
• LPS Lipopolysaccharide
• TEAEs were of mild to moderate intensity, generally started within 1 to 17 days after initiation of treatment with Compound IA and resolved within 1 to 18 days after onset; in all cases without concomitant treatment. For 10 subjects, these TEAEs led to treatment discontinuation. Two other subjects were early discontinued due to TEAEs that were unrelated to the study drug.
• the exposure to single doses of Compound IA increased in a less than dose-proportional manner when Compound IA was administered as crystalline suspension (3-300 mg), but increased dose-proportionally when administered as SDD suspension (100-600 g).
• QD administration of Compound IA dose range 30-200 mg for 2 weeks, only limited drug accumulation of about 1.1 to 1.3-fold was observed in reaching steady state. This is consistent with a mean ti /2 ranging from 9.83 to 16.2 hours across QD and BID dose levels.
• Compound IA demonstrated a very low CLss/F (-0.83 to 1.11 L/h) and Vss/F (-12.6 to 23.3 L), with low-to-moderate inter-subject variability across QD and BID dose levels of Compound IA. Renal clearance at steady state was relatively low (-0.008 L/h) compared to total oral clearance, hence unlikely to be a relevant clearance pathway in humans.
• the arithmetic mean ( ⁇ SD) of the observed stimulation effect of I L-1 b was 1820 ( ⁇ 102) ng/L, and the E max of I L-1 b was -0.985 ( ⁇ 0.00277).
• the median potency of Compound IA inhibiting 90% of the ex-vivo stimulated I L-1 b release (IC 90 ) in the (LPS) challenge was a concentration of 3.18 mM (90% Cl: 2.84; 3.54).
• the effective concentrations relative to the estimated maximum therapeutic effect and inhibitory concentrations relative to 100% inhibition of Compound IA resulting from ex-vivo stimulated IL-1 b release were EC 50 : 0.141 pM (90% Cl: 0.114, 0.171), EC 90 : 2.57 pM (90% Cl: 2.24, 2.94), and IC 50 : 0.146 pM (90% Cl: 0.118, 0.179)
• Compound IA was rapidly absorbed with a median W ranging from 0.76 to 3.00 hours across dose levels. However, with higher dose range 30-600 mg the median W was slightly delayed (1.5 to 3.0 hours) indicating a slower absorption compared to the lower doses (3 and 10 mg: 0.76 and 1.00 hours, respectively).
• the increase in drug exposure was less than dose-proportional with crystalline suspension (particularly 100 and 300 mg), whereas dose-proportional increase in exposure was observed with SDD suspension (100-600 mg), indicating solubility-limited absorption of crystalline material at doses 3100 mg.
• Compound IA as 100 mg crystalline tablet showed a positive food effect with increased C max and AUC by 2.05 and 1.49-fold in the fed (high-fat, high-calorie meal) vs fasted state, respectively.
• Median T max for 100 mg crystalline tablet was 5 hours, while shorter T max values (0.76-3.0 hours) were reported for suspensions.
• Compound IA has a very low oral clearance (CLss/F ⁇ 1.0 L/h), which relates to £ 2% of human liver blood flow and a low volume of distribution (Vss/F) of -12.6-23.3 L. Slight drug accumulation of about 1.2-fold was observed after once daily dosing and 2-fold after twice daily dosing was observed in reaching steady state consistent with an effective half-life of approximately 10 hours as determined for crystalline tablet when given with food.
• Nonclinical studies have suggested that Compound IA blocks the release of I L-1 b using broad range of NLRP3-dependent activators. This has been observed with di-aryl sulfonylurea compounds which are structurally similar to Compound IA [15]
• dose-dependent decreases in concentrations of IL-1 b were observed with increasing single and multiple oral doses of Compound IA.
• IL-1 b production can be mediated by other inflammasomes or by inflammasome independent pathways; thus, inhibitors aimed at I L-1 b can result in unintentional immunosuppressive effects. Therefore, pharmacological inhibitors which specifically target the NLRP3 inflammasome only could be a better option for treatment of NLRP3-associated disease.
• Compound IA has the potential to be an effective oral first- in-class innate immune modulator warranting further clinical evaluation.
• Procedure 1 IL-13 production in PMA-differentiated THP-1 cells stimulated with Gramicidin.
• THP-1 cells were purchased from the American Type Culture Collection and sub cultured according to instructions from the supplier. Cells were cultured in complete RPMI 1640 (containing 10% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 pg/ml)), and maintained in log phase prior to experimental setup. Prior to the experiment, compounds were dissolved in dimethyl sulfoxide (DMSO) to generate a 30mM stock. The compound stock was first pre-diluted in DMSO to 3, 0.34, 0.042 and 0.0083 mM intermediate concentrations and subsequently spotted using Echo550 liquid handler into an empty 384-well assay plate to achieve desired final concentration (e.g.
• DMSO dimethyl sulfoxide
• DMSO was backfilled in the plate to achieve a final DMSO assay concentration of 0.37%. The plate was then sealed and stored at room temperature until required.
• THP-1 cells were treated with PMA (Phorbol 12-myristate 13-acetate) (20 ng/ml) for 16-18 hours. On the day of the experiment the media was removed and adherent cells were detached with trypsin for 5 minutes. Cells were then harvested, washed with complete RPMI 1640, spun down, and resuspended in RPMI 1640 (containing 2% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 pg/ml). The cells were plated in the 384-well assay plate containing the spotted compounds at a density of 50,000 cells/well (final assay volume 50 mI).
• PMA Phorbol 12-myristate 13-acetate
• Procedure 2 IL-13 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 pg/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
• IC 50 of compounds can be calculated using the following formulas

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