Treatment for recurrent pericarditis

Abstract

The present invention relates to the development of therapeutic compound of Formula (I) for the treatment of Recurrent Pericarditis. Specifically, the present invention provides a compound of Formula (I) or its pharmaceutically acceptable salt or suitable composition useful in the treatment of Recurrent Pericarditi s and other related disorders.

Description

[0001] TREATMENT FOR RECURRENT PERICARDITIS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the development of therapeutic compound of Formula (I) for the treatment of Recurrent Pericarditis. Specifically, the present invention provides a compound of Formula (I) or its pharmaceutically acceptable salt or suitable composition useful in the treatment of Recurrent Pericarditis and other related disorders.

[0004] BACKGROUND OF THE INVENTION

[0005] The nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing 3 (NLRP3 or NALP3) inflammasome are a major source of mucosal interleukin (IL)-1 p and the inflammasomes are mostly subject to activation by multiple aspects of inflammation-associated stress. NLRP3 is a cytosolic pattern recognition receptor (PRR) that senses exogenous and endogenous danger signals. The NLRP3 protein is made up of three domains: a leucine-rich repeat domain (LRR), a NOD containing a caspase activation and recruitment domain (CARD) (NACHT), and a pyrin domain (PYD). Upon activation, NLRP3 oligomerizes and triggers assembly of the adapter apoptosis-associated speck-like protein containing a CARD (ASC) via PYD- PYD interactions. ASC fibrils assemble into large structures, called ASC specks, and recruit pro-caspase- 1, leading to its autoproteolytic activation. The activated caspase- 1 is able to cleave pro-IL-1β and pro-IL-18 to generate the inflammatory cytokines IL-1β and IL-18 (Error! Reference source not found, et al., 2015; Error! Reference source not found, et al., 2012).

[0006] Involvement of the NLRP3 inflammasome in different kinds of diseases provides new avenues to design drugs targeting NLRP3 inflammasome. To date, clinical treatment of NLRP3 -related diseases targets IL-ip, with IL-1β antibodies or recombinant IL-1β receptor antagonist, such as canakinumab and anakinra, respectively. In addition, a few small-molecule compounds have shown anti-inflammatory effects on NLRP3 inflammasome activation in vitro, including MCC950, β-hydroxybutyrate (BHB), Bay 11-7082, dimethyl sulfoxide (DMSO) and type I interferon. However, most of these inhibitors are relatively nonspecific and have low efficacy. For inhibitors targeting IL-1β, it should be noted that IL-1β secretion is not the only product of NLRP3 inflammasome activation; instead, other proinflammatory cytokines, including high-mobility group box 1 (HMGB1) and IL- 18 may participate in the pathogenesis of these diseases. Moreover, IL-ip can be produced by inflammasome-independent pathways or other inflammasomes. Therefore, inhibitors targeting IL-1β may lead to unintended immunosuppressive effects besides preventing NLRP3 inflammasome activation itself. Pharmacological inhibitors specific to NLRP3 inflammasome may be the best choice for treatment of NLRP3-related diseases. (Error! Reference source not found, et al., 2019).

[0007] The pericardium is a double-walled sac containing the heart and the roots of the great vessels. It encloses the pericardial cavity, which contains pericardial fluid. Pericarditis is an inflammatory condition of the pericardium, the fibrous sac surrounding the heart. It can present acutely or chronically and is characterized by symptoms such as chest pain, pericardial friction rub, and electrocardiographic changes (Yehuda A. et. al.). While often benign, pericarditis can lead to severe complications, including cardiac tamponade and chronic constrictive pericarditis. Recurrent pericarditis, defined by repeated episodes of inflammation, poses significant therapeutic challenges.

[0008] Recent research has elucidated the pivotal role of the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome in the pathogenesis of pericarditis. In pericarditis, the activation of the NLRP3 inflammasome is a critical event that drives the inflammatory cascade. This activation results in the production of IL-ip, which amplifies the inflammatory response and contributes to the persistence and recurrence of the disease (Vecchie, A. et. al, 2021). Experimental models and clinical studies have demonstrated that inhibition of the NLRP3 inflammasome or blockade of IL-1 P can significantly mitigate inflammation and reduce recurrence rates (Mauro A. G. et. al, 2021). Therapeutic agents such as colchicine, which inhibits microtubule polymerization and the assembly of the NLRP3 inflammasome, and IL-1 blockers like anakinra and rilonacept, have shown efficacy in managing recurrent pericarditis. All current therapies are limited to injectable biologies therefore, there remains an unmet clinical need for more targeted and preferably small molecule or compounds as an alternative to IL-1 targeted biologies. The present invention discloses use of compound of formula (I) which may have beneficial effects in treating patients suffering from Recurrent Pericarditis.

[0009] Various sulfonylurea based compounds as NLRP3 modulators and their process for the preparation have been disclosed in the Bioorg Med Chem Lett; 2020 Nov l;30(21): 127571, which are useful in the treatment of the diseases or conditions mediated by NLRP3 or conditions in which interleukin 1β activity is implicates.

[0010] WO2023281455 discloses the use of NLRP3 modulators and its pharmaceutically acceptable salts for the treatment of Cryopyrin Associated Periodic Syndromes (CAPS).

[0011] W 02023026222 discloses the use of NLRP3 modulators and its pharmaceutically acceptable salts for the treatment of Parkinson Disease (PD).

[0012] WO2024180521 discloses the use of NLRP3 modulators and its pharmaceutically acceptable salts for the treatment of Inflammatory Bowl Diseases (IBD)

[0013] SUMMARY OF THE. INVENTION

[0014] The present invention provides a therapeutic compound of formula (I) or its pharmaceutically acceptable salts for the prevention and treatment of Recurrent Pericarditis and other related disorders selected from acute pericarditis (idiopathic, viral, post pericardiotomy syndromes, and connective tissue diseases), incessant pericarditis, pericardial effusion, cardiac tamponade, chronic constrictive pericarditis or effasive- constrictive pericarditis, myocarditis, endocarditis.

[0015] EMBODIMENTS OF THE INVENTION

[0016] In an embodiment the present invention provides a therapeutic compound of formula (I)

[0017]

[0018] Formula (I)

[0019] or its pharmaceutically acceptable salts suitable for the treatment and prevention of Recurrent Pericarditis and other related disorders.

[0020] In another embodiment, the present invention provides the administration of therapeutic compound of formula (I) or i ts pharmaceutically acceptable salts alone or in combination with other suitable agents, as therapeutic agent for the treatment and prevention of Recurrent Pericarditis and other related disorders.

[0021] In a further embodiment, the present invention provides compound of formula (I) or its pharmaceutically acceptable salts is administered with a standard-of-care drug for use in the treatment of recurrent pericarditis.

[0022] In a further embodiment, the present invention provides use of compound of formula (I) or its pharmaceutically acceptable salts for the treatment and prevention of Recurrent Pericarditis and other related disorders.

[0023] In yet another embodiment, the present invention provides a method of treating Recurrent Pericarditis and other related disorders using pharmaceutical composition of compound of formula (I) or its pharmaceutically acceptable salts.

[0024] In yet another embodiment, the present invention provides a suitable composition comprising the compound of formula (I) or its suitable pharmaceutical compositions for the treatment and prevention of Recurrent Pericarditis and other related disorders.

[0025] The above and other embodiments of the present invention are disclosed further hereinafter. DETAIL DESCRIPTION OF THE INVENTION Definition:

[0026] As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0027] The terms ‘treatment’ or ‘treat' refer to slowing, stopping, or delaying the progression of the disease or clinical symptoms in a patient, as evidenced by a decrease or elimination of a clinical or diagnostic symptom of the disease, disorder or condition.

[0028] ’’Patient" includes both human and animals. " Mammal" means humans and other mammalian animals.

[0029] The term "preventing" refers to barring a subject from acquiring a disorder or disease in the first place.

[0030] A "subject" is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).

[0031] As used herein "treating" includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome. Delaying, inhibiting or preventing the progression of the disease, disorder or syndrome includes for example, delaying, inhibiting or preventing the progression of Recurrent Pericarditis and other related disorders.

[0032] The present invention describes a method of treating a subject suffering from Recurrent Pericarditis and other related disorders.

[0033] In an embodiment the present invention provides a compound of formula (I)

[0034]

[0035] Formula (I)

[0036] or its pharmaceutically acceptable salts suitable for the treatment or prevention of Recurrent Pericarditis and other related disorders selected from acute pericarditis (idiopathic, viral, post pericardiotomy syndromes, and connective tissue diseases), incessant pericarditis, pericardial effusion, cardiac tamponade, chronic constrictive pericarditis, and effusive-constrictive pericarditis, myocarditis, endocarditis.

[0037] In a further embodiment the present invention provides use of the compound of formula (I) or its suitable pharmaceutical compositions for the treatment or prevention Recurrent Pericarditis and other related disorders selected from acute pericarditis (idiopathic, viral, post pericardiotomy syndromes, and connective tissue diseases), incessant pericarditis, pericardial effusion, cardiac tamponade, chronic constrictive pericarditis, and effusive- constrictive pericarditis, myocarditis, endocarditis.

[0038] Therapeutic Applications

[0039] The invention provides for use of compound of formula (I) and pharmaceutical compositions described herein in treating Recurrent Pericarditis. The invention also provides methods of treating Recurrent Pericarditis by administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof. One aspect of the present invention provides a pharmaceutical composition comprising a com pound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in treating Recurrent Pericarditis wherein Formula (I) is represented by:

[0040]

[0041] Formula (I)

[0042] The pharmaceutical composition for use may be further characterized according to, for example, the identity of the components in the pharmaceutical composition, the route by which the pharmaceutical composition is administered to a subject, use of the pharmaceutical composition in combination with additional therapeutic agents, dosing amount of a compound of Formula (I) or pharmaceutically acceptable salt thereof, dosing frequency of the pharmaceutical composition, patients to be treated, and other features as described in more detail below.

[0043] Therapeutic Effects

[0044] The pharmaceutical composition for use can be further characterized according to therapeutic effects. For example, in certain embodiments, the use is characterized by inhibiting progression of Recurrent Pericarditis.

[0045] The term “pharmaceutical composition” refers to a mixture of an NLRP3 antagonist or other compound described herein with other chemical components (referred to collectively herein as “excipients”) such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the NLRP3 antagonist or other compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to rectal, oral, and intravenous, aerosol, and parenteral, ophthalmic, pulmonary, and topical administration.

[0046] Route of Administration

[0047] The pharmaceutical composition for use can be further characterized according to the route of administration for the pharmaceutical composition.

[0048] The compositions of the present invention can be delivered directly or in pharmaceutical compositions containing excipients, as is well known in the art. The present methods of treatment involve administration of an effective amount of compound of the present invention to a subject having or at risk for having Recurrent Pericarditis.

[0049] An effective amount, e.g., dose, of compound or drug can readily be determined by routine experimentation, as can an effective and convenient route of administration and an appropriate formulation. Various formulations and drug delivery systems are available in the art. (See, e.g., Gennaro, ed. (2000) Remington’s Pharmaceutical Sciences, and Hardman, Limbird, and Gilman, eds. (2001) The Pharmacological Basis of Therapeutics, supra.Suitable routes of administration may, for example, include oral, rectal, topical, nasal, pulmonary, ocular, intestinal, and parenteral administration. Primary routes for parenteral administration include intravenous, intramuscular, and subcutaneous administration. Secondary routes of administration include intraperitoneal, intra-arterial, intra-articular, intracardiac, intracistemal, intradermal, intralesional, intraocular, intrapleural, intrathecal, intrauterine, and intraventricular administration. The indication to be treated, along with the physical, chemical, and biological properties of the drug, dictate the type of formulation and the route of administration to be used, as well as whether local or systemic delivery would be preferred.

[0050] In a preferred embodiment, the present invention provides effective amount of formula (I) or its pharmaceutically acceptable salts are administered by oral route of administration.

[0051] In certain other embodiments, the pharmaceutical composition further comprises one or more pharmaceutical excipients. In certain embodiments, the pharmaceutical formulation is in the form of a tablet or capsule.

[0052] Dosing Amount

[0053] In certain embodiments, composition for use can be further characterized according to the dose of compound administered to a subject. For example, in certain embodiments, the pharmaceutical composition for use is further characterized according to the feature that the pharmaceutical composition provides the compound of Formula (I) or a pharmaceutically acceptable salt thereof at a dose in the range of 0.1 mg to 250 mg with respect to compound of formula (I) for the treatment and prevention of Recurrent Pericarditis, preferably 0.5 mg to 150 mg and more preferably 1 mg to 100 mg with respect to compound of formula (I) for the treatment and prevention of Recurrent Pericarditis.

[0054] In certain embodiments, the compound is administered in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 100 mg on each day the compound is administered to the subject. In a preferred embodiment, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about O.lmg to about 1 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 5 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 5 mg to about 10 mg the compound is administered to the subject each day. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 10 mg to about 15 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 15 mg to about 20 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 20 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 25 mg to about 30 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 30 mg to about 35 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 35 mg to about 40 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 40 mg to about 45 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 45 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 50 mg to about 55 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 55 mg to about 60 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 60 mg to about 65 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 65 mg to about 70 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 70 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 75 mg to about 80 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 80 mg to about 85 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 85 mg to about 90 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 90 mg to about 95 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 95 mg to about 100 mg on each day the compound is administered to the subject. In certain other embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 1 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 5 mg on each day the compound is administered to the subject In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 10 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 15 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 20 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 30 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 35 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 40 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 45 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 55 mg on each day the compound is administered to the subject In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 60 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 65 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 70 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 80 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 85 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 90 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 95 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 0.1 mg to about 100 mg on each day the compound is administered to the subject.

[0055] The amount of dose in the range of about 0.1 mg to about 100 mg according to present disclosure includes each integer and non-integer number between a particular range. The recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 0.1 to 5 includes 0.1, 0.5, 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0056] Dosing Schedule

[0057] The method may be further characterized according to a dosing schedule by which the pharmaceutical composition is to be administered to the subject. For example, in certain embodiments, the pharmaceutical composition is administered to the subject in the morning prior to the subject consuming food.

[0058] The compound of formula (I) or its pharmaceutically acceptable salts may be provided to the subject daily, weekly, either in a single dose or multiple doses as prescribed by physician to the person in need thereof.

[0059] In certain other embodiments, the pharmaceutical composition is administered to the subject once daily. In yet other embodiments, the pharmaceutical composition is administered to the subject once daily for at least 1 week. In yet other embodiments, the pharmaceutical composition is administered to the subject once daily for at least 2 weeks. In yet other embodiments, the pharmaceutical composition is administered to the subject once daily for at least 3 weeks. In yet other embodiments, the pharmaceutical composition is administered to the subject once daily for at least 4 weeks. In yet other embodiments, the pharmaceutical composition is administered to the subject once daily for at least 6 weeks. In yet other embodiments, the pharmaceutical composition is administered to the subject once daily for at least 8 weeks. In yet other embodiments, the pharmaceutical composition is administered to the subject once daily for at least 10 weeks. In yet other embodiments, the pharmaceutical composition is administered to the subject once daily for at least 12 weeks. In yet other embodiments, the pharmaceutical composition is administered to the subject once daily for at least 14 weeks. In yet other embodiments, the pharmaceutical composition is administered to the subject once daily for at least 16 weeks.

[0060] In another embodiment, the present invention provides a method of treating a subject suffering from Recurrent Pericarditis, which comprises treatment of a patient in need of such therapy, with compound of formula (I) or its pharmaceutically acceptable salts or suitable pharmaceutical compositions containing them.

[0061] In a further embodiment, the present invention provides the combination of compound of formula (I) or its pharmaceutically acceptable salts with other suitable agents as a therapeutic agents for the treatment of Recurrent Pericarditis and other related forms of disorders.

[0062] In an embodiment, the additional therapeutic agent used is selected from Colchicine, Inhibitors of interleukin- ip (e.g. Rilonacept, Canakinumab, and Anakinra); immune- suppressants (e.g., Methotrexate, Mercaptopurine, Cyclophosphamide), metabolic disorders drugs, corticosteroids, glucocorticoids, non-steroidal anti-inflammatory drugs, Gasdermin D inhibitors (e.g., Necrosulfonamide); Cox-2 specific inhibitors, TNF-a binding proteins (e.g., Infliximab, Etanercept), Interferon-13, Interferon, Interleukin-2, antihistamines, beta-agonist, BTK inhibitors, anticolinergics, anti-cancer agents; antiviral drugs, for example: Remdesivir, Lopinavir / Ritonavir, Favipiravir, Molnupiravir, Tamiflu; anti-malarial agents, for example: Choloroquinone, Hydroxyl Chloroquinone; or their suitable pharmaceutically acceptable salts. Further examples for use in combination with Non-Alcoholic Steato- Hepatitis (NASH) and fibrosis drugs; anticancer; antibiotics, for example Azithromycin; hormones, Aromatase inhibitors, Anticoagulants, antibodies, cytokines, anti-IL6 drugs; Antiparasitics; vaccines; Interferons; drug conjugates; Drags originally developed for SARS (ACE2 protein decoy); Intravenous vitamin C; inhibitors of mitogen-activated protein kinase signaling (ex: BAY 43-9006); Syk inhibitors; mTOR inhibitors; antibodies (Rituxan); and BCR / ABL antagonist. In an embodiment, the present invention provides compound of formula (I) or its pharmaceutically acceptable salts is administered with a standard-of-care drug for use in the treatment of recurrent pericarditis.

[0063] In an embodiment, the standard-of-care drug is colchicine.

[0064] In yet another embodiment, compound of formula (I) or its pharmaceutically acceptable salts is provided in the form of pharmaceutical composition.

[0065] In an embodiment, present invention provides a pharmaceutical composition comprising compound of formula (I) or its pharmaceutically acceptable salts for treatment of Recurrent Pericarditi, wherein compound of formula (I) is

[0066]

[0067] Formula (I)

[0068] In an embodiment, the present invention provides pharmaceutical composition comprising compound of formula (I) or its pharmaceutically acceptable salts and suitable pharmaceutically acceptable excipients for the treatment of Recurrent Pericarditis. In an embodiment, the pharmaceutically acceptable excipients described in the present invention are selected at least one from diluents, carriers, binders, disintegrating agents, lubricating agents, surface active agents and the like.

[0069] Diluents include, but are not limited to lactose monohydrate, polymethacrylates selected from Eudragit, potassium chloride, sulfobutylether b-cyclodextrin, sodium chloride and spray dried lactose, combinations thereof and other such materials known to those of ordinary skill in the art.

[0070] Carriers include, but are not limited to lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate and kaolin, crystalline cellulose and silicic acid, combinations thereof and other such materials known to those of ordinary skill in the art. Binders include, but are not limited to carbomers selected from carbopol, gellan, gum Arabic, hydrogenated vegetable oil, polymethacrylates selected from Eudragit, xanthan, lactose and Zein, combinations thereof and other such materials known to those of ordinary skill in the art.

[0071] Disintegrating agents Include, but are not limited to, bicarbonate salt, chitin, gellan gum, polacrillin potassium and docusate sodium, combinations thereof and other such materials known to those of ordinary skill in the art.

[0072] Lubricating agents used include, but are not limited to, glycerin behenate, hydrogenated vegetable oil. sodium stearyl fumarate and myristic acid, combinations thereof and other such materials known to those of ordinary skill in the art.

[0073] Surface active agents include but are not limited to, nonionic surfactants selected from alkyl poly glucosides, cocamide DEA, cocamide MBA, cocamide TEA, decyl maltoside and octyl glucoside; anionic surfactant selected from arachnidan acid and arachidonic acid; cationic surfactant selected from cetyl trimethylammonium bromide and cetylpyridinium chloride, combinations thereof and other such materials known to those of ordinary skill in the art.

[0074] The stable pharmaceutical composition may be made by dry mixing, wet granulation or dry granulation methods by techniques known to persons skilled in the art. Thus, for example,

[0075] In wet granulation process, the drug is mixed with one or more pharmaceutical excipients and granulated with suitable binding solution as described earlier, to form wet granules, the wet granules are dried and optionally sieved. The dried granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules. In dry mixing process, the drug is mixed with all the pharmaceutical excipients required. The blend is mixed with one or more suitable excipients from those described elsewhere and then final blend is either compressed into tablets or filled in capsules.

[0076] In dry granulation process, the drug is mixed with one or more pharmaceutical excipients and compressed into slugs and these slugs are passed through required sieve. The sieved granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules.

[0077] One or more solvents or vehicle used in the formulation are selected from water, acetone, chloroform, dichloromethane, ethyl alcohol, ethyl acetate, methyl alcohol, isopropyl alcohol and combinations thereof and other such materials known to those of ordinary skill in the art.

[0078] In an embodiment, the present invention provides pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salts with other suitable agents as a therapeutic agent for use in the treatment of recurrent pericarditis. In an embodiment, the additional therapeutic agent used is selected from Inhibitors of interleukin- ip (e.g. Rilonacept, Canakinumab, and Anakinra); immune-suppressants (e.g., Methotrexate, Mercaptopurine, Cyclophosphamide), metabolic disorders drugs, corticosteroids, glucocorticoids, non-steroidal anti-inflammatory drugs, Gasdermin D inhibitors (e.g., Necrosulfonamide); Cox-2 specific inhibitors, TNF-u binding proteins (e.g., Infliximab, Etanercept), Interferon-13, Interferon, Interleukin-2, antihistamines, beta-agonist, BTK inhibitors, anticolinergics, anti-cancer agents; anti-viral drugs, for example: Remdesivir, Lopinavir / Ritonavir, Favipiravir, Molnupiravir, Tamiflu; anti- malarial agents, for example: Choloroquinone, Hydroxyl Chloroquinone; or their suitable pharmaceutically acceptable salts. Further examples for use in combination with Non- Alcoholic Steato- Hepatitis (NASH) and fibrosis drugs; anticancer; antibiotics, for example Azithromycin; hormones, Aromatase inhibitors, Anticoagulants, antibodies, cytokines, anti-IL6 drugs; Antiparasitics; vaccines; Interferons; drug conjugates; Drugs originally developed for SARS (ACE2 protein decoy); Intravenous vitamin C; inhibitors of mitogen-activated protein kinase signaling (ex: BAY 43-9006); Syk inhibitors; mTOR inhibitors; antibodies (Rituxan); and BCR / ABL antagonist.

[0079] In an embodiment, the present invention provides pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salts is administered with a standard-of-care drug for use in the treatment of recurrent pericarditis.

[0080] In an embodiment the standard-of-care drug is colchicine.

[0081] The present invention further discloses use of said compound of formula (I) or their suitable pharmaceutical compositions for the treatment of Recurrent Pericarditis.

[0082] In another embodiment, the present invention provides a method of treating Recurrent Pericarditis using pharmaceutical composition of compound of formula (I) or its pharmaceutically acceptable salts.

[0083] In a preferred embodiment, a method of treating Recurrent Pericarditis using compound of formula (I) or its pharmaceutical composition.

[0084] In another embodiment of the present invention provides a process for the preparation of a stable pharmaceutical composition of compounds of formula (1) or its pharmaceutically acceptable salts.

[0085] The compound of formula (I) was prepared as per the processes disclosed in the prior art such as those mentioned elsewhere in the specification.

[0086] The compound of Formula (I) is known as ZYIL1 or Usnoflast.

[0087] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

[0088] Examples:

[0089] Example - 1 Method:

[0090] To induce the pericarditis, Zymosan (5mg / rat) was injected into the pericardium of the male Wistar rats of 6-7 weeks age.

[0091] Firstly, rats were anaesthetized using isoflurane-oxygen and were maintained throughout the surgery. Later, the anterior chest of the rat was shaved and disinfected. A junction between the xiphoid and the sternum was located near to the intercostal space wherein half-inch incision was made using surgical blade. Further, an insulin syringe needle was placed against the right edge of the sternum and the chest wall was punctured to a depth of 2-3 mm. At this point, the tip of the needle was located within the pericardial cavity and generally did not hurt the cardiac and thoracic vasculature. Rats in the experimental group were injected with a 5 mg of Zymosan suspension. Rats in the sham control group were injected with 150 pL of sterile saline solution. After the injection, incision was closed by suturing muscle and skin layer using sterile thread followed by application of povidone-iodine solution over the sutured area.

[0092] Treatment of ZYIL1 (30mg / kg / p.o. / BID) and Colchicine (0.1mg / kg / p.o. / OD), was given from Day 1 -6. On day-6, rats were anesthetized to collect the blood and heart samples followed by sacrifice of the animals. Tissues were collected for histological analysis and gene expression studies.

[0093] Results:

[0094] Gross pathology indicated white damaged spots on the cardiac tissues following the zymogen injection. This was absent in the usnoflast treated group and was similar to a colchicine treated standard of care (SOC) group. Histopathological changes were graded, and scores were assigned on a scale of 1-4 based on severity of lesions. Based on histopathological changes in pericardium, it is concluded that intrapericardial administration of Zymosan-A at 5 mg / rat could induce the mild to moderate inflammatory lesion in pericardium consistent with the acute pericarditis. The animals treated with ZYIL1 at 30mg / kg showed minimal to mild pericarditis in few animals, whereas colchicine treated animals showed mild pericarditis. Hence, considering the severity and incidences of these lesions, it is concluded that ZYIL1 at 30mg / kg could show the potential to reduce the inflammatory condition in pericarditis model in rat at larger extent when compared to colchicine treated group under present study conditions.

[0095] Histology Score

[0096] 3

[0097] Vehicle Control

[0098] ZYIL1 (30 mg / kg, BID)

[0099] Colchicine (0.1 mg / kg, OD)

[0100] 1

[0101]

[0102] Groups

[0103] ♦ represents p<005 as compared io the vehicle control group

[0104] Figure 1: histological analysis and gene expression studies.

[0105] Example - 2

[0106] Method:

[0107] The effect of ZYIL1 was evaluated in a zymosan- A-induced acute pericarditis model in rats. Male Wistar rats, were randomly divided into different groups (n=8 per group):

[0108] 1. Sham control

[0109] 2. Vehicle control

[0110] 3. ZYIL1 (20 mg / kg, p.o., BID)

[0111] 4. ZYIL1 (30 mg / kg, p.o., BID)

[0112] 5. Colchicine (0.25 mg / kg, p.o., OD)

[0113] Different, groups of animals received their respective treatments immediately prior to surgery. To induce pericarditis, rats were anesthetized with isoflurane (induction: 4—5%, maintenance: 2-3%). The anterior chest was shaved and disinfected using isopropyl alcohol. The third intercostal space was identified by counting upward from the xiphoid space toward the neck. A 1 cm incision was made, and an insulin syringe was positioned adjacent to the sternum over the third intercostal space. The needle was inserted 3-4 mm deep toward the heart until resistance was felt, then retracted by approximately 1 mm. Subsequently, 300 μL of zymosan-A suspension (7.5 mg per rat) was slowly injected. The suspension was prepared in saline containing 0.1% talc. Following injection, the muscle layer was sutured using absorbable sutures, and the skin was closed with non¬ absorbable sutures. Sham control animals receive only saline.

[0114] Body weight was recorded daily, and treatments were administered from Day 0 to Day 6. On Day 7, blood samples were collected, and animals were sacrificed to access the pericardial inflammation and images of heart captured. Pericarditis severity was scored on a scale of 1 to 3 (mild to severe) based on morphological observations such as pericardial effusion, thickening, and opaqueness around the heart, immediately after opening the thoracic cavity. Then the heart tissues with intact pericardium were fixed in 10% formalin for histological analysis.

[0115] Results:

[0116] Zymosan-A injection resulted in the onset of pericarditis, as evidenced by pericardial effusion, thickening, and opaqueness observed in the vehicle group and was evident in increase in clinical sore (Fig. 2). Treatment with ZYIL1 showed 41% and 60% suppression in clinical score at 20 and 30 mg / kg doses respectively in a dose-related manner (Fig. 2). Colchicine treatment exhibited a 47% improvement in clinical score as compared to the vehicle control group. Moreover, histopathology study demonstrated an increased infiltration of leukocyte (referred as acute pericarditis) into the pericardium and associated pericardial thickening due to zymosan-A challenge (Fig. 3 and 4).

[0117] ZYIL1 treatment demonstrated dose-related suppression of acute pericarditis and pericardial thickening score (Fig. 3 and 4). The effect of 30 mg / kg dose of ZYIL1 was statistically significant compared to the vehicle control groups in all the parameters assessed.

[0118] Figures: Clinical score for pericardial inflammation

[0119]

[0120] Figure 2: Effect of ZYIL1 clinical score for pericarditis

[0121] Acute Pericarditis score

[0122] (H&l Staining)

[0123]

[0124] Figure 3: Effect of ZYIL1 on acute pericarditis score (H& E staining) Pericardial Thickening Score

[0125] (H& E Staining)

[0126] Vehicle control

[0127] ZYIL1 (20 mg / kg)

[0128] ZYIL1 (30 mg / kg)

[0129] Colchicine (0.25 mg / kg)

[0130]

[0131] * Rep^senis P<005 as <%?• • •pared tc vehicle control gioap

[0132] Figure 4: Effect of ZYIL1 on pericardial thickening score (H& E staining)

[0133] Example - 3

[0134] Method:

[0135] The effect of ZYIL1 was investigated in zymosan-A-induced acute pericarditis model using rats. Thirty-two male Wistar rats of 8-10 weeks age were divided into 4 groups i.e.

[0136] 1) Sham control, 2) Vehicle control, 3) Colchicine (0.25mg / kg), 4) ZY1L1 (20mg / kg) + Colchicine (0.25mg / kg), and 5) ZYIL1 (30mg / kg) + Colchicine (0.25mg / kg), as 8 animals per group. Animals were treated just before the surgery. To induce pericarditis, rats were anesthetized with isoflurane (induction: 4—5%, maintenance: 2-3%). The anterior chest was shaved and disinfected using isopropyl alcohol. The third intercostal space was identified by counting upward from the xiphoid space toward the neck. A 1 cm incision was made, and an insulin syringe was positioned adjacent to the sternum over the third intercostal space. The needle was inserted 3-4 mm deep towards the heart until resistance was felt, then retracted by approximately 1 mm. Subsequently, 300 μL of zymosan-A suspension (7.5 mg per rat) was slowly injected. The suspension was prepared in saline containing 0.1% talc. Following injection, the muscle layer was sutured using absorbable sutures, and the skin was closed with non-absorbable sutures. Sham control animals received only saline.

[0137] Body weight was recorded daily, and treatments were administered from Day 0 to Day 6. On Day 7, blood samples were collected, and animals were sacrificed to assess the pericardial inflammation and capture the images of heart. Pericarditis severity was scored on a scale of 1 to 3 (mild to severe) based on morphological observations such as pericardial effusion, thickening, and opaqueness around the heart, Immediately after opening the thoracic cavity. Then the heart tissues with intact pericardium were fixed in 10% formalin for histological analysis (detailed histology report is available as addendum).

[0138] Results:

[0139] Zymosan-A injection resulted in the onset of pericarditis, as evidenced by pericardial effusion, thickening, and opaqueness observed in the vehicle group and was evident in increase in clinical sore (Fig. 1). Treatment with colchicine in combination with 20 and 30 mg / kg of ZY1L1 showed 42% and 50% suppression in clinical score respectively (Fig.

[0140] 5). Moreover, histopathology study demonstrated an increased infiltration of leukocyte (referred as acute pericarditis) into the pericardium and associated pericardial thickening due to zymosan-A challenge (Fig. 6 and 7). Treatment with colchicine in combination with ZY1L1 demonstrated dose-related suppression in acute pericarditis and pericardial thickening score (Fig. 6 and 7). The effect of combination of 30 mg / kg dose of ZYIL1 and colchicine showed a statistically significant improvement in the acute pericarditis and pericardial thickening score observed in the histopathology study.

[0141] Figures: Clinical Score pericardila inflammation

[0142] 3*1

[0143]

[0144] Groups

[0145] Figure 5: Effect of ZYIL1 clinical score for pericarditis

[0146] Acute Pericarditis Score

[0147] (H& E Staining)

[0148]

[0149] Figure 6: Effect of ZYIL1 acute pericarditis score (H& E staining) Pericardial Thickening Score

[0150] (H& E Staining?

[0151]

[0152] Figure 7: Effect of ZYIL1 pericardial thickening score (H& E staining)

[0153] Protocol Summary

[0154] Title: A Phase 3, Double-Blind, Parallel-Arm, Interventional Study to Evaluate the Efficacy and Safety of Usnoflast Treatment in Participants with Recurrent Pericarditis Short Title: PURSUIT Trial: Pericarditis snoflast Response Study with Unified Interventional Trial

[0155] Sponsor: Zydus Therapeutics Inc. 73C Route 31 N, Pennington, NJ 08534, USA Indication: Recurrent Pericarditis

[0156] Recurrent pericarditis is increasingly recognized as an autoinflammatory condition, with interleukin-1 (IL-1) playing a central role in its pathogenesis. Elevated C-reactive protein (CRP) levels and late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (MRI) suggest ongoing active inflammation rather than fibrosis. IL-1 inhibitors directly target this inflammatory pathway, offering a more precise therapeutic approach compared to broad-spectrum immunosuppressants, such as corticosteroids.

[0157] Recent research continues to affirm the central role of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in cardiovascular inflammation, including pericarditis. While IL-1β remains the canonical marker of NLRP3 activity, emerging evidence suggests that NLRP3 inhibition may also suppress IL- la. Preclinical studies have demonstrated that inhibition of the NLRP3 inflammasome effectively reduces IL-1α-mediated inflammation. For instance, MCC950, a well-characterized NLRP3 inhibitor was shown to reduce IL-1α secretion by 50-80% in a spontaneous colitis model, likely through downstream modulation of inflammatory signaling. In a dextran sulfate sodium (DSS)-induced colitis model in mice, treatment with usnoflast resulted in marked suppression of IL-1 a levels (5.44- and 4.96-fold reduction at 10 and 30 mg / kg, respectively), whereas DSS challenge resulted in 4.29-fold increase in IL-1α level. Clinical trials, such as anakinra (AIRTRIP) and rilonacept (RHAPSODY), have further shown rapid CRP normalization, faster symptom resolution, reduced recurrence risk, and successful steroid tapering or discontinuation. MRI findings using LGE helped identify that IL-1 inhibitors reduce inflammation more effectively than steroids in patients with pericarditis.

[0158] Zydus Therapeutics Inc. has developed usnoflast, a novel NLRP3 inflammasome inhibitor that suppresses the secretion of key inflammatory markers, such as IL-1α and IL-1β. Since activation of the NLRP3 inflammasome contributes to the inflammatory cascade in recurrent pericarditis, usnoflast represents a promising targeted approach for patients with multiple recurrences and an inflammatory phenotype.

[0159] The sponsor is conducting the current study (PURSUIT Trial) to evaluate the efficacy and safety of usnoflast in participants with recurrent pericarditis.

[0160] Objectives and Endpoints:

[0161] Objectives Endpoints

[0162] Primary Efficacy

[0163] To assess the efficacy of usnoflast vs * The first recurrence of pericarditis, defined placebo in the double-blind, placebo- as the time from randomization to the onset controlled, randomized withdrawal period3of symptoms resulting in an adjudicated recurrence

[0164] Key Secondary Efficacy

[0165]

[0166] To assess the efficacy of usnoflast vs » Maintenance of clinical response, defined placebo in the double-blind, placebo- as a weekly average of daily chest pain NRS controlled, randomized withdrawal periods <2 and CRP level <0.5 mg / dL, at Week 24

[0167] * Percentage of days with no or minimal chest pain, defined as non-missing weekly average of daily chest pain NRS <2, in the first 24 weeks

[0168] • Achieving or maintaining absent or minimal pericarditis symptoms (based on the 7~point PGIPS) at Week 24

[0169] Objectives Endpoints

[0170] Secondary Efficacy

[0171] To assess the efficacy of usnoflast vseTime to chest pain NRS >4 from placebo in the double-blind, placebo- randomization

[0172] controlled, randomized withdrawal period8• Time to CRP >1 mg / dL from randomization

[0173] » Time to new or worsening pericardial effusion from randomization

[0174] • Percentage of days with no or minimal pain per participant during the double-blind, placebo-controlled, randomized withdrawal period

[0175] • Change over time in the SF-36 Physical Component Score at scheduled study visits up to Week 52

[0176] • Change over time in the SF-36 Mental Component Score at scheduled study visits up to Week 52

[0177] • Achieving or maintaining absence or minimal pericarditis symptoms, as measured

[0178]

[0179] by the PGIPS at scheduled study visits up to Week 52

[0180] • Resolution in pericardial inflammation as assessed by cardiac MRI, among participants with pericardial inflammation at baselineb

[0181] Other Secondary Efficacy

[0182] To assess the efficacy of usnoflast in the * Achievement of clinical response, defined open-label, run-in period

[0183] as chest pain NRS <2, CRP <0.5 mg / dL, absent or mild pericardial effusion on ECHO (<10 mm), at the end of the open-label, run - in period

[0184] * Percentage of days with no or minimal pain * Achievement of a complete discontinuation of corticosteroids within 12 weeks during the open-label, run-in period * Time to normalization of CRP level (< 0.5 mg / dL)

[0185] » Change from baseline in the amount of pericardial effusion at each of the scheduled study visits

[0186] * Resolution of ECG changes related to pericarditis

[0187] » Change from baseline in QoL, as measured by the QoL questionnaire (SF-36) at scheduled study visits

[0188]

[0189] Abbreviations: CRP, C-reactive protein; ECHO, echocardiogram; MRI, magnetic resonance imaging; NRS, Numerical Rating Scale; PGIPS, Patient Global Impression of Pericarditis Severity; QoL, quality of life; SF-36, 36-Item Short Form Health Survey.aAll participants will be withdrawn from the study when the requisite number of events has been accrued.

[0190] bUnless otherwise specified, the baseline will be the last available measurement recorded prior to the first dose of the study treatment during the open-label, run-in period. Where necessary for scheduling purposes, a baseline cardiac MRI may be obtained up to 10 days after enrollment in the study if approved by the medical monitor.

[0191] Primary and Key Secondary Efficacy Estimands Estimands with Rationales for Strategies to Address ICEs

[0192] Estimand Label Estimand Description

[0193] Primary Efficacy Objective

[0194] Estimand 1 Log-rank test to compare survival rates of time to the first recurrence pericarditis event between participants with recurrent pericarditis in the usnoflast 75 mg arm and participants in the placebo arm with observed data, regardless of treatment discontinuation or the use of protocol-prohibited medication. The use of a bailout medication or death during the randomized withdrawal period will be counted as an event of interest. HR and its 95% CI for the endpoint will be estimated via a stratified Cox proportional model as a sensitivity analysis.

[0195] Key Secondary Efficacy Objectives

[0196] Estimand 2 Difference in proportions of participants who maintain their clinical response at Week 24 between participants with recurrent pericarditis in the usnoflast 75 mg arm and the placebo arm, regardless of treatment discontinuation or the use of protocol”

[0197]

[0198] prohibited medication. The use of a bailout medication or death during the randomized withdrawal period will be counted as loss of the response.

[0199] Estimand 3 Mean difference in percentage of days with no or minimal chest pain in the first 24 weeks between participants with recurrent pericarditis in the usnoflast 75 mg arm and the placebo arm, regardless of treatment discontinuation or the use of protocol- prohibited medication. Those days after use of a bailout medication or death will be considered with chest pain.

[0200] Estimand 4 Difference in proportions of participants who achieving or maintaining absent or minimal pericarditis symptoms (based on the 7-point PGIPS) at Week 24 between participants with recurrent pericarditis in the usnoflast 75 mg arm and the placebo arm, regardless of treatment discontinuation or the use of protocol-prohibited medication. The use of a bailout medication or death during the randomized withdrawal period will be counted as loss of the response.

[0201] Rationale for Strategies

[0202] To address ICEs, such as treatment compliance, treatment policy is most regulatory relevant in a confirmatory trial. For an ICE of use of a bailout medication or death, a composite strategy to treat the ICE as the study endpoint event is a reasonable conservative strategy.

[0203]

[0204] Abbreviations: HR, hazard ratio; ICE, intercurrent event; PGIPS, Patient Global Impression of Pericarditis Severity. Key Criteria for Inclusion and Exclusion:

[0205] The key inclusion criteria are as follows: The participant is an adult male or female, must be at least 18 years of age; has a confirmed diagnosis of recurrent pericarditis; presents with signs of disease recurrence, including chest pain score of >4 on at least 1 day within 5 days.

[0206] of enrollment and CRP ≥1 mg / dL (or equivalent if using an assay other than high- sensitivity); has a chest pain (pericarditis) score >4 based on the 11 -point Numerical Rating Scale (NRS) on Day 0 (Visit 2) of the open-label, run-in period.

[0207] The key exclusion criteria are as follows: The participant has secondary pericarditis caused by tuberculosis (TB), cancer, purulent infection, or systemic autoimmune / autoinflammatory diseases; has planned sternotomy or pericardiotomy during the study period; had received protocol-defined prior therapy; has any of the protocol-defined laboratory abnormalities at screening; has taken protocol-defined concomitant medications that are substrates of drug metabolizing enzymes (CYP1A2 and / or CYP2B6).

[0208] Study Design;

[0209] * This is a Phase 3, double-blind, parallel-arm, interventional study to evaluate the efficacy and safety of usnoflast treatment in participants with recurrent pericarditis.

[0210] ® Participants with recurrent pericarditis, including those who are also receiving any combination of nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and corticosteroids as a standard of care treatment, will be included in the study. « Eligible participants will be enrolled in the study as described below:

[0211] Open-Label, Run-In Period (Single-Blind)

[0212] ® Approximately 87 eligible participants will be enrolled, and all participants will receive usnoflast 75 mg twice daily (BID) for 12 weeks and concomitant medications will be tapered and stopped beginning Week 2 so that all concomitant medications are to be withdrawn by the Week 10 visit.

[0213] > Double-Blind, Placebo-Controlled, Randomized Withdrawal Period ® Participants who achieve clinical response (chest pain NRS <2, CRP <0.5 mg / dL, absent or mild pericardial effusion on echocardiogram [ECHO <10mm]) and receiving no concomitant medications for pericarditis since Week 10 of the open-label, run-in period) will be randomized in a 1: 1 ratio to one of the 2 treatment arms: the usnoflast (75 mg BID) arm or the placebo arm (BID) and will receive study treatment for up to 52 weeks.

[0214] ® A safety follow-up visit will occur 1 week after the last dose of the study treatment.

[0215] Duration of Treatment:

[0216] The total duration of the study for each participant will be up to approximately 69 weeks, including the screening period, and 1-week safety follow-up visit after the double-blind, placebo-controlled, randomized withdrawal treatment period. However, the overall study duration may be determined by the time required to accumulate approximately 29 events of recurren t pericarditis after randomization, as the study is event-driven.

[0217] All participants will have the option to receive treatment with usnoflast by rolling over into a 52-week, open-label extension study once they have experienced a recurrence or they are withdrawn when the requisite number of events has been accrued.

[0218] Efficacy Assessments:

[0219] The efficacy assessment includes the following: clinical response to usnoflast treatment, recurrence of pericarditis, cardiac MRI, CRP level, and quality of life (QoL), as measured by the QoL questionnaire (36-Item Short Form Health Survey [SF-36]).

[0220] Safety Assessments:

[0221] Safety assessments will include the following: adverse events (AEs), including serious AEs, and AEs of special interest, physical examination, vital signs, 12-lead electrocardiograms, and clinical safety laboratory tests (glucose profile, hematology, biochemistry, urinalysis, viral serology, and others). Details of Applicable Monitoring Committee:

[0222] Clinical Events Adjudication Commitee’. An independent adjudication committee will review and adjudicate all reported events of recurrent pericarditis that occur during the double-blind, placebo-controlled, randomized withdrawal period of the study. The procedures for adjudicating events will be described in a separate charter. This will be done independent of the investigators, and in a manner blinded to treatment assignment.

[0223] Data and Safety Monitoring Committee (DSMC): All data, including events of recurrent pericarditis, will be reviewed by the DSMC. This committee will consist of an independent and external group separate from the personnel conducting the study and will determine whether the study should be stopped or continued without modification based on the benefit-risk assessment. Further details will be provided in a separate charter.

[0224] Description of Study Treatments:

[0225] During the open-label, run-in period, all eligible participants will be instructed to self¬ administer usnoflast (75 mg BID)* orally each day.

[0226] During the double-blinded, placebo-controlled, randomized withdrawal period, all eligible participants will be instructed to self-administer the study treatment (usnoflast

[0227] [75 mg BID] or matching placebo [BID])* orally each day.

[0228] *Usnoflast or matching placebo will be supplied as 25 mg and 50 mg capsules.

[0229] Participants will need to take 2 capsules (25 mg and 50 mg each) in the morning and 2 capsules (25 mg and 50 mg each) in the evening each day.

[0230] The details of the study treatments are provided in the table below.

[0231] Study Treatments Open-Label, Double-Blind, Placebo-Controlled, Randomized Administered Study Run-In Period Withdrawal Period

[0232] Period

[0233] Study Treatment Usnoflast Usnoflast Placebo

[0234] Name

[0235]

[0236] Study Treatment White to off White to off white colored White to off white Description white colored powder filled in Size “0” hard colored powder powder filled gelatin capsules having white containing all inactive in Size “0” colored opaque cap and white ingredients filled in Size hard gelatin colored opaque body. “0” hard gelatin capsules capsules having white colored having white opaque cap and white colored opaque colored opaque body. cap and white

[0237] colored opaque

[0238] body.

[0239] Type Drug Drug Placebo for Drug

[0240] Dose Formulation Capsule Capsule Capsule

[0241] Unit Dose Strength 25 mg and 50 25 mg and 50 mg N / A

[0242] mg

[0243] Dosage Level 75 mg BID (2 75 mg BID (2 capsules [25 mg BID

[0244] capsules [25 and 50 mg each] in the

[0245] mg and 50 mg morning and 2 capsules [25

[0246] each] in the mg and 50 mg each] in the

[0247] morning and 2 evening)

[0248] capsules [25

[0249] mg and 50 mg

[0250] each] in the

[0251] evening)

[0252] Route of Oral Oral Oral Administration

[0253] Use Experimental Experimental Placebo

[0254]

[0255] Sourcing Provided centrally by the sponsor or locally by the study site, subsidiary, or designee.

[0256] Study Period Open-Label, Run-In Double-Blind, Placebo- Period Controlled, Randomized Withdrawal Period

[0257] Packaging and Labeling Study treatments (usnoflast or matching placebo) will be packaged by the sponsor according to all local legal requirements. The capsules will be packed in 60 CC HDPE bottle with child-resistant cap. Each bottle and carton will be labeled and packed according to the randomization list as provided by an independent statistician and in accordance with applicable regulatory requirements (ie, the labels will include the study code and additional information, such as batch / lot number and storage conditions).

[0258]

[0259] Abbreviations: BID: twice daily; N / A, not applicable.

[0260] Statistical Considerations:

[0261] Sample size:

[0262] The sample size for this study was determined to achieve 90% power to detect a statistically significant difference in disease recurrence between the 2 study arms (ie, in the double-blind, placebo-controlled, randomized withdrawal period). The primary analysis will be a log-rank test with a 1 -sided significance level of α=0.025 a participant allocation ratio of 1:1, a hypothesized hazard ratio (HR) of 0.3, an event rate of 85% in the placebo arm in 52 weeks, and a 15% drop-out rate in the double-blinded, placebo- controlled, randomized withdrawal period. This leads to a sample size calculation of 26 participants per study arm, or a total of approximately 52 participants randomized into the double-blinded, placebo-controlled, randomized withdrawal period. The total number of events required to meet the desired power is 29 events (19 from the placebo arm and 10 from the usnoflast arm).

[0263] To ensure sufficient participants are available at the end of the open-label, run-in period to randomize into the double-blinded, placebo-controlled, randomized withdrawal period, approximately 87 participants will be enrolled into the open-label, run-in period assuming 60% of participants will respond to usnoflast and be eligible for randomization. All participants who achieve clinical response eligible responders at the end of die open-label, run-in period will be randomized into the double-blind, placebo-controlled, randomized withdrawal period

[0264] Analysis Sets: 'The following participant analysis sets will be used in the statistical analyses.

[0265] Enrolled Set: The enrolled set will consist of all participants who sign the informed consent form.

[0266] Run-in Set: The run-set will consist of all participants who are in the enrolled set and receive at least one dose of usnoflast during the open-label, run-in period.

[0267] Full Analysis Set (FAS): The FAS will consist of all participants who were randomized into the double-blinded, placebo-controlled, randomized withdrawal period and randomly assigned to receive the study treatment. All analyses using the FAS will group participants according to randomized treatment.

[0268] Per Protocol Set (PPS): The PPS will consist of all FAS participants who fulfill all inclusion / exclusion criteria, and have no significant protocol deviations. All analyses using the PPS will group participants according to treatment actually received.

[0269] Safety Set: The safety set will consist of all participants who received any study treatment (ie, usnoflast or placebo). All analyses using die safety set will group participants according to treatment actually received.

[0270] Pharmacokinetic Set (PKS): The PKS will consist of a subgroup of participants (n=24) during the open-label, run-in period for PK analysis. The FAS will be used for the analysis of efficacy endpoints and treatment exposure data. The PPS will be used for supportive analysis of the primary efficacy endpoint.

[0271] All PK analysis will be done in the PKS.

[0272] Statistical Methods:

[0273] Statistical analysis will be performed using SAS software (Version 9.4 or higher). Unless otherwise stated, all the continuous variables will be summarized using descriptive statistics, such as n, mean, SD, median, minimum, and maximum. Categorical variables will be summarized using frequency and percentage. Data will be listed in data listings. All statistical tests will be 1 -sided and performed using a 2.5% significance level, leading to 95% (2 sided) Cis.

[0274] The primary endpoint of the study is the time from randomization to the first event of recurrent pericarditis. The homogeneity of overall survival rates in participants treated with usnoflast 75 mg versus participants treated with placebo will be estimated using the log-rank test stratified for randomization stratification.

[0275] Details of the statistical analyses, methods, and data conventions will be described in the statistical analysis plan.

[0276] In the treatment of recurrent pericarditis, It is observed that Usnoflast will significantly reduce the frequency of recurrent pericarditis events (signs and symptoms) compared to placebo. The placebo arm is expected to experience a higher number of recurrent pericarditis events than the Usnoflast arm.

Claims

We claim:

1. A method for the treatment of Recurrent Pericarditis and other related forms of disorders which comprises administering a compound of formula (I) / ( p 9NXI"Formula (I)or its pharmaceutically acceptable salts.

2. The method as claimed in claim 1, wherein other related form of disorders is selected from acute pericarditis (idiopathic, viral, post pericardiotomy syndromes, and connective tissue diseases), incessant pericarditis, pericardial effusion, cardiac tamponade, chronic constrictive pericarditis or effusive-constrictive pericarditis, myocarditis and endocarditis.

3. The method as claimed in claim 1, wherein therapeutically effective amount of compound of formula (1) or its pharmaceutically acceptable salt is selected from 0.1 mg to 250 mg, preferably selected from 0.5 mg to 150 mg, more preferably selected from 1 mg to 100 mg.

4. The method as claimed in claim 1, wherein compound of formula (1) or its pharmaceutically acceptable salt is administered by oral, topical or parenteral route of administration, preferably adm inistered by an oral route of administration.

5. The method as claimed in claim 1, wherein compound of formula (1) or its pharmaceutically acceptable salt is administered in combination with other suitable agents as a therapeutic agent for the treatment and prevention of Recurrent Pericarditis and other related disorders.

6. The method as claimed in claim 1, wherein compound of formula (1) or its pharmaceutically acceptable salt is administered with a standard-of- care drugs for the treatment and prevention of Recurrent Pericarditi and other related disorders.

7. The method as claimed in claim 6, wherein the standard-of-care drug is colchicine.

8. The method as claimed in claim 1, wherein compound of formula (1) or its pharmaceutically acceptable salt is administered in the form of pharmaceutical composition.

9. Use of the compound of formula (1) as c laimed in any one of the preceding claims for the preparation of a medicament for the treatment of Recurrent Pericarditis and other related forms of disorders.

10. Use of the compound of formula (1) as claimed in any one of the preceding claims wherein the compound is administrated in a daily dosage range is selected from 0.1 mg to 250 mg. preferably selected from 0.5 mg to 150 mg, more preferably selected from 1 mg to 100 mg.

11. A pharmaceutical composition comprising compound of formula (1) or its pharmaceutically acceptable salts for the treatment of Recurrent Pericarditis and other related forms of disorders, wherein compound of formula (1) isFormula (1)12. The pharmaceutical composition as claimed in claim 9, wherein other related form of disorders is selected from acute pericarditis (idiopathic, viral, post pericardiotomy syndromes, and connective tissue diseases), incessant pericarditis, pericardial effusion, cardiac tamponade, chronic constrictive pericarditis or effusive-constrictive pericarditis, myocarditis and endocarditis.

13. The pharmaceutical composition as claimed in claim 9, wherein therapeutically effective amount of compound of formula (1) or its pharmaceutically acceptable salt is selected from 0.1 mg to 250 mg, preferably selected from 0.5 mg to 150 mg, more preferably selected from 1 mg to 100 mg.

14. The pharmaceutical composition as claimed in claim 9, wherein compound of formula (1) or its pharmaceutically acceptable salt is administered by oral, topical or parenteral route of administration, preferably administered by an oral route of administration.

15. The pharmaceutical composition as claimed in claim 9 comprising compound of formula (1) and other pharmaceutically acceptable excipients for the treatment of Recurrent Pericarditis and other related forms of disorders.

16. The pharmaceutical composition as claimed in claim 9, wherein compound of formula (1) or its pharmaceutically acceptable salt is administered with other suitable agents as a therapeutic agent for the treatment and prevention of Recurrent Pericarditis and other related disorders.

17. The pharmaceutical composition as claimed in claim 9, wherein compound of formula (I) or its pharmaceutically acceptable salt is administered with a standard-of-care drug for use in the treatment of recurrent pericarditis.

18. The pharmaceutical composition as claimed in claim 16, wherein the standard-of-care drug is colchicine.

19. Use of the pharmaceutical composition as claimed in claim 9 for the preparation of medicament for the treatment of Recurrent Pericarditis and other related forms of disorders.

20. The pharmaceutical composition as claimed in claim 13, wherein other pharmaceutically acceptable excipients are selected from diluents, carriers, binders, disintegrating agents, lubricating agents, encapsulating agent and the like.

21. The pharmaceutical composition as claimed in any one of the preceding claims, wherein Diluents include, but are not limited to microcrystalline cellulose, polymethacrylates selected from Eudragit, potassium chloride, sulfobutylether b-cyclodextrin, sodium chloride and spray dried lactose, combinations thereof and other such materials known to those of ordinary skill in the art.

22. The pharmaceutical composition as claimed in as claimed in any one of the preceding claims, wherein carriers are selected from lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate and kaolin, crystalline cellulose, silicic acid and suitable combination thereof.

23. The pharmaceutical composition as claimed in as claimed in any one of the preceding claims, wherein binders are carbopol, gellan, gum Arabic, hydrogenated vegetable oil, polymethacrylates selected from Eudragit, xanthan, lactose and Zein, pregelatinizedstarch, combinations thereof and other such materials known to those of ordinary skill in the art,24. The pharmaceutical composition as claimed in any one of the preceding claims, wherein disintegrating agents are selected from pregelatinized starch, bicarbonate salt, chitin, gellan gum, polacrillin potassium and docusate sodium, combinations thereof and other such materials known to those of ordinary skill in the art.

25. The pharmaceutical composition as claimed in any one of the preceding claims, wherein lubricating agents are selected from magnesium stearate, glycerin behenate, hydrogenated vegetable oil, sodium stearyl fumarate and myristic acid, combinations thereof and other such materials known to those of ordinary skill in the art.

26. The pharmaceutical composition as claimed in any one of the preceding claims wherein Encapsulating agent is selected from empty hard gelatin capsule shells.

27. Method of treating Recurrent Pericarditis and other related form of disorders using compound of formula (I) or its pharmaceutically acceptable salts wherein compound of formula (I) isFormula (I)

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