CN116847842A

CN116847842A - IRAK4 degrading agent and use thereof

Info

Publication number: CN116847842A
Application number: CN202280014820.9A
Authority: CN
Inventors: J·戈洛布; J·戴维斯; A·麦克唐纳; 戎皓菁
Original assignee: Kemela Medical Co
Current assignee: Kemela Medical Co
Priority date: 2021-02-15
Filing date: 2022-02-15
Publication date: 2023-10-03

Abstract

IRAK4 degradation agents, formulations and unit dosage forms thereof, and methods of use thereof are provided.

Description

IRAK4 degrading agent and use thereof

Cross reference to related applications

The present application claims the benefit of U.S. provisional application Ser. No. 63/149,621, filed on day 2 and 15 of 2021, U.S. provisional application Ser. No. 63/263,055, filed on day 10 and 26 of 2021, and U.S. provisional application Ser. No. 63/265,466, filed on day 12 and 15 of 2021, each of which is incorporated herein by reference in its entirety.

Technical Field

The present application relates to formulations and dosage forms of IRAK4 degrading agent 5- ((1 r,4 r) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -N- (3- (difluoromethyl) -1- ((1 r,4 r) -4- ((3- (1- (2, 6-dioxopiperidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-4-yl) prop-2-yn-1-yl) oxy) piperidin-1-yl) methyl) cyclohexyl) -1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide (compound a) and methods of use thereof.

Background

Ubiquitin-proteasome pathway (UPP) is a critical pathway for the regulation of key regulatory proteins and for the degradation of misfolded or abnormal proteins. UPP is central to multiple cellular processes and, if absent or unbalanced, causes the pathogenesis of a variety of diseases. Covalent attachment of ubiquitin to specific protein substrates is accomplished via the action of E3 ubiquitin ligase.

UPP plays a key role in the degradation of important short-lived regulatory proteins in a variety of basal cellular processes, including cell cycle regulation, regulation of cell surface receptors and ion channels, and antigen presentation. Interleukin-1 receptor related kinase-4 (IRAK 4) is a key component of the bone marrow differentiation complex (myddosome), a polyprotein complex that is involved in innate immunity via toll-like receptors (TLRs) and Interleukin (IL) -1 receptor mediated signaling (Patra and Choi, molecular 2016,21 (11): 1529). IRAK4 proteins are ubiquitously expressed in a number of different tissue types, including skin, lymphoid tissue, bone marrow, gastrointestinal (GI) tract, and lung. IRAK4 functions depending on its kinase activity and its backbone properties, as required by the activation of bone marrow differentiation factor 88 (MyD 88) by the bone marrow differentiation corpuscle complex after TLR or IL-1R engagement (De Nardo) et al, J.Biol.chem.) 2018,293 (39): 15195; cushing et al, J.Biol.2014, 289 (15): 10865). NF-kB activation is dependent, inter alia, on the skeletal function of IRAK4 and is a key driver of cell proliferation and pro-inflammatory cytokine and chemokine production mediated by bone marrow differentiation activation.

There are many skin, rheumatic and GI autoimmune/autoimmune disease indications whose pathogenesis involves IL-1 family cytokines and TLR stimulation and where the pleiotropic effects of IRAK4 degradants on these pathways can provide significant advantages over current treatment options. There are further a variety of skin indications in which there is clinical proof of concept targeting the IL-1R/TLR pathway, but there is still a continuing highly unmet need for more effective therapeutic agents.

Disclosure of Invention

IRAK4 degrading agents 5- ((1 r,4 r) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -N- (3- (difluoromethyl) -1- ((1 r,4 r) -4- ((3- (1- (2, 6-dioxopiperidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-4-yl) prop-2-yn-1-yl) oxy) piperidin-1-yl) methyl) cyclohexyl) -1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide (compound a) formulations and unit dosage forms of the invention have been found to have certain advantages in the treatment of autoimmune/autoimmune diseases.

In one embodiment of the present disclosure, a spray-dried formulation is provided comprising compound a or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable polymer. In some aspects, the spray-dried formulation comprises compound a free base. In other aspects, the spray-dried formulation comprises compound a HCl. In some cases, the pharmaceutically acceptable polymer is selected from PVP-VA, HPMC, HPMCP-55, HPMCAS-M, TPGS, HPMCAS-L and MCC, preferably HPMCAS-M. The spray-dried formulation may comprise about 20% -40% wt/wt of compound a or a pharmaceutically acceptable salt thereof and about 60% -80% wt/wt of a pharmaceutically acceptable polymer. In certain aspects, the spray-dried formulation comprises 25:75 (% wt/wt) compound A free base HPMCAS-M.

In one embodiment of the present disclosure, a unit dosage form comprising a spray-dried formulation as disclosed herein is provided. In some aspects, the spray-dried formulation is about 45% -55% wt/wt unit dosage form. In other aspects, the unit dosage form further comprises a filler, wherein the filler is selected from mannitol, microcrystalline cellulose, or a mixture thereof. In certain aspects, the unit dosage form further comprises a slip agent, wherein the slip agent is colloidal silica. In certain aspects, the unit dosage form further comprises a disintegrant, wherein the disintegrant is croscarmellose sodium. In certain aspects, the unit dosage form further comprises a solubility enhancing agent, wherein the solubility enhancing agent is hydroxypropyl-beta-cyclodextrin (HP beta CD). In certain aspects, the unit dosage form further comprises a lubricant, wherein the lubricant is sodium stearyl fumarate.

In another embodiment of the compositions and methods of the invention, the unit dosage form comprises 10-500mg of compound a or a pharmaceutically acceptable salt thereof, e.g., the unit dosage form comprises 25mg or 100mg of compound a or a pharmaceutically acceptable salt thereof.

In other embodiments of the present disclosure, a method for treating an autoimmune/autoimmune disease or hematological malignancy in a patient is provided, comprising administering (e.g., orally) to the patient a therapeutically effective amount of a spray-dried formulation or unit dosage form described herein. In some aspects, the autoimmune/autoimmune disease is selected from skin, rheumatic, and gastrointestinal autoimmune/autoimmune diseases. In some aspects, the autoimmune/autoimmune disease is a skin autoimmune/autoimmune disease selected from the group consisting of atopic dermatitis (atopic dermatitis; AD) and suppurative sweat gland inflammation (hidradenitis suppurativa; HS).

In some embodiments, the method comprises administering (e.g., orally) up to about 1600mg of compound a, or a pharmaceutically acceptable salt thereof, to the patient, such as up to about 1400mg (e.g., daily). In some aspects, the methods comprise administering about 25 to 1400mg (e.g., about 25mg, about 50mg, about 75mg, about 100mg, about 150mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 800mg, about 1000mg, about 1200mg, or about 1400 mg) of compound a, or a pharmaceutically acceptable salt thereof, to a patient (e.g., daily).

These and other aspects of the disclosure will be apparent upon reference to the following embodiments. For this purpose, various references describing certain background information and procedures in more detail are set forth herein, and each of the references is hereby incorporated by reference in its entirety.

Drawings

FIG. 1 depicts a manufacturing process flow diagram depicting operations involving the manufacture of 25% compound A75% HPMCAS-M SDD and compound A25 mg and 100mg coated tablets.

Figure 2 depicts a phase 1 compound a trial design including double blind, placebo controlled, single incremental dose (single ascending dose; SAD) and multiple incremental dose (multiple ascending dose; MAD) trials.

Figure 3 depicts compound a Pharmacodynamics (PK) leading to SAD studies.

Figure 4 shows that compound a achieves deep and dose-dependent IRAK4 degradation after a single oral dose lasts at least 6 days.

Figure 5 shows that compound a achieved >95% IRAK4 degradation after a single dose.

Figure 6 shows robust IRAK4 degradation in lymphocytes and monocytes: flow cytometry results at SAD 7.

Figure 7 depicts the ex vivo cytokine stimulation method used in phase 1 compound a assays.

Figure 8 shows up to 97% of the maximum in vitro cytokine inhibitory effect 24-48h after cytokine induced dosing for LPS (TLR 4) stimulation or R848 (TLR 7) stimulation in whole blood.

Figure 9 shows compound a plasma concentrations in MAD studies.

Figure 10 shows robust IRAK4 degradation in lymphocytes and monocytes in MAD studies. * Data for 200mg QD were only up to day 14.

Figure 11 shows that lower doses of compound a achieved >98% IRAK4 degradation in PBMCs in MAD studies.

Figure 12 shows that lower doses of compound a achieved >90% irak4 degradation in lymphocytes and monocytes in MAD studies.

Figure 13 shows that once daily administration of compound a resulted in high skin exposure.

Figure 14 shows once daily administration of compound a results in a decrease in IRAK4 content in skin.

Figure 15 shows an image of substantial IRAK4 degradation in the dermis and epidermis of the skin.

Figure 16 shows ex vivo cytokine inhibition in whole nine disease-associated cytokines and chemokines.

Detailed Description

1. General description of certain embodiments of the invention

Compound a is a potent, highly selective, heterobifunctional small molecule therapeutic for the target IRAK4 and E3 ligase CRBN administered orally to mediate selective degradation of IRAK4 via the ubiquitin-proteinase system.

Compound a consisted of CRBN-target ligand and IRAK 4-target ligand joined by a chemical linker. Compound a forms a ternary complex via non-covalent binding to CRBN and IRAK4, bringing the E3 ligase (CRBN) into close proximity to IRAK4, which now acts as its new substrate. This proximity, which then freely mediates more rounds of ternary complex formation and IRAK4 degradation, leads to IRAK4 ubiquitination and proteasome degradation and final release of compound a.

In vitro and in vivo studies demonstrate the ability of compound a to selectively degrade its desired target IRAK4 and to inhibit downstream production of disease-associated pro-inflammatory cytokines and chemokines. In vitro, the ability of compound a to degrade IRAK4 in species was demonstrated in studies of mouse and rat spleen cells and canine, monkey and human PBMCs, wherein all species @ <10 nM) similar DCs were observed ₅₀ Values. In a series of in vitro studies in human Peripheral Blood Mononuclear Cells (PBMC), whole blood, and OCI-LY10 cells, compound A steadily decreased IRAK4 content, wherein DC ₅₀ Values were always in the low nM range. Various in vitro cytokine release assays demonstrate the ability of compound a to inhibit TLR agonists (lipopolysaccharides and R848) and IL-1β -induced pro-inflammatory cytokine production (including IL-6, TNF- α, granulocyte-macrophage colony stimulating factor and IL-8) in PBMCs, with IC50 values also in the low nM range. Finally, mass Spectrometry (MS) proteomic analysis of PBMCs treated with compound a exhibited selectivity of the compound for its target, with IRAK4 being the only degraded protein of over 9,000 proteins sampled.

In vivo, murine inflammation models demonstrate that compound a-induced IRAK4 degradation affects the ability of TLR-mediated and IL-1β -mediated Th1 and Th17 inflammation and neutrophil migration. In the MSU-crystal-induced (TLR 2/4 dependent) inflamed mouse air pocket model, compound a was administered twice daily at a dose ranging from 30mg/kg to 100mg/kg for 3 days not only significantly reduced IRAK4 content in the spleen, but also significantly reduced inflammatory secretions, including neutrophil and IL-1 β. Similar findings were observed in the imiquimod psoriasis model (TLR 7/8 dependent), where administration of compound a caused dose dependent degradation of IRAK4 in the spleen and skin associated with reduced skin thickness and significant reduction of IL-1 beta (p < 0.0001) and IL-6 (p <0.05; only 300 mg/kg) in the skin. Overall, efficacy was associated with achieving at least 80% or more IRAK4 gene knockouts in relevant tissues in the model system.

In vivo Pharmacokinetic (PK)/Pharmacodynamic (PD) studies in mice and dogs exhibited potent IRAK4 degradation by compound a. In wild-type mice, a single oral dose of 300mg/kg of compound a caused almost 100% degradation of IRAK4 in the skin and approximately 66% degradation in the spleen, which degradation lasted at least 48 hours after administration. In the skin and spleen, the maximum PD effect is obtained after tmax at each dose level. Oral administration at doses up to 10 mg/kg/day for 7 days also resulted in significant reduction of IRAK4 in skin and PBMCs in dogs, with compound a minimum plasma concentration levels as low as 3nM inducing >85% IRAK4 degradation in PBMCs and degradation below the quantitative limit in skin. Recovery of IRAK4 levels was noted 96 to 168 hours after the last dose in dogs, exhibiting the reversible nature of compound a-induced degradation. Taken together, these studies indicate potent, on-target and reversible effects of compound a against IRAK 4.

In vivo Pharmacokinetic (PK) studies in rats, dogs and monkeys, compound APK is characterized by moderate to high clearance, high distribution volume in steady state, moderate terminal half-life and low to moderate bioavailability. Compound a exhibited low solubility, moderate permeability, and was identified as a substrate for P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) in vitro. Compound a was highly bound to plasma proteins and was not significantly divided into erythrocytes throughout non-clinical species and humans. In the distribution study in rats, compound a was widely distributed in tissues, but there was limited penetration into the Central Nervous System (CNS).

In vitro and in vivo metabolic studies show that compound a undergoes oxidative metabolism via cytochrome P450 (CYP). Secretion studies in bile duct intubated (BDC) rats showed negligible renal clearance of compound a and micro-to-moderate biliary and intestinal secretion as parent drug. Metabolites produced in human-derived liver microsomes were also detected in rat, canine, and monkey-derived liver microsomes. In vitro drug-drug interaction studies, compound a exhibited possible time-dependent inhibition (TDI) of CYP2C19 and CYP3A4 and inhibited BCRP efflux, and thus could be the originator of sensitive CYP2C19, CYP3A4 and BCRP substrates. In contrast, compound a is metabolized primarily by CYP3A4 and is a substrate for P-gp and BCRP and has the potential to become a victim when co-administered with strong or moderate enzyme inhibitors or inducers.

Thus, in some embodiments, the present disclosure provides a method for treating an autoimmune/auto-inflammatory disease of the skin, such as Atopic Dermatitis (AD) and Hidradenitis Suppurativa (HS), in a patient, comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a method for treating AD in a patient, the method comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a method for treating HS in a patient, the method comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides formulations and unit dosage forms as described herein comprising compound a or a pharmaceutically acceptable salt thereof.

In the following disclosure, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, it will be understood by those skilled in the art that the methods and uses described herein may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the embodiments. Throughout the specification and the claims which follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" or "comprising" will be interpreted in an open, inclusive sense, i.e. "including but not limited to". Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Furthermore, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.

2. Definition of the definition

As used in this specification and the appended claims, the following terms and abbreviations have the indicated meanings unless specified to the contrary:

"Compound A" refers to IRAK4 degrading agent 5- ((1R, 4R) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -N- (3- (difluoromethyl) -1- ((1 r, 4R) -4- ((3- (1- (2, 6-dioxopiperidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-4-yl) prop-2-yn-1-yl) oxy) piperidin-1-yl) methyl) cyclohexyl) -1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide of the formula:

"Compound B" refers to IRAK4 degrading agent 5- ((1R, 4R) -2-oxa-5-azabicyclo [ 2.2.1) of the formula]Hept-5-yl) -N- (3- (difluoromethyl) -1- ((1 r, 4R) -4- ((4- ((3- (1- ((S) -2, 6-dioxopiperidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d)]Imidazol-4-yl) prop-2-yn-1-yl) oxy) piperidin-1-yl) methyl) cyclohexyl) -1H-pyrazol-4-yl) pyrazolo [1,5-a]Pyrimidine-3-carboxamide:

and "Compound C" refers to IRAK4 degrading agent 5- ((1R, 4R) -2-oxa-5-azabicyclo [ 2.2.1) of the formula]Hept-5-yl) -N- (3- (difluoromethyl) -1- ((1R, 4R) -4- ((4- ((3- (1- ((R) -2, 6-dioxopiperidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d)]Imidazol-4-yl) prop-2-yn-1-yl) oxy) piperidin-1-yl) methyl) cyclohexyl) -1H-pyrazol-4-yl) pyrazolo [1,5-a]Pyrimidine-3-carboxamide:

the molecular structure of compound a contains three chiral centers, including two fixed/stable centers around the mirin ring (R, R) and one epimerizable chiral center (R/S), yielding two diastereomers of (S, R) -compound a and (R, R) -compound a, respectively, referred to as compound B and compound C. In some embodiments, compound a is compound B. In some embodiments, compound a is compound C. In some embodiments, compound a is a mixture of compound B and compound C. In some embodiments, compound a is a substantially 1:1 mixture of compound B and compound C. Both diastereomers were rapidly interchanged both in vitro and in vivo. In some embodiments, compound a, compound B, compound C, or a pharmaceutically acceptable salt thereof, is amorphous. In some embodiments, compound a, compound B, compound C, or a pharmaceutically acceptable salt thereof is in crystalline form.

As used herein, the term "pharmaceutically acceptable salts" refers to those salts that are suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and within the scope of sound medical diagnosis. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail in journal of pharmaceutical Sciences (J.pharmaceutical Sciences) by S.M. Berge et al, 1977,66,1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups with inorganic acids (such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric) or organic acids (such as acetic, oxalic, maleic, tartaric, citric, succinic or malonic) or by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartate, benzenesulfonates, benzoates, bisulphates, borates, butyrates, camphorinates, camphorsulphonates, citrates, cyclopentanepropionates, digluconates, dodecylsulphates, ethanesulphonates, formates, fumarate, glucoheptonates, glycerophosphate, gluconate, hemisulphates, heptanonates, caprates, hydroiodinates, 2-hydroxy-ethanesulphonates, lactonates, lactates, laurates, lauryl sulphates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulphonates, nicotinates, nitrates, oleates, oxalates, palmates, pamonates, pectinates, persulphates, 3-phenylpropionates, phosphates, pivalates, propionates, stearates, succinates, sulphates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates and the like.

Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N ⁺ (C _1-4 Alkyl group ₄ And (3) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and uses such asAmine cations formed by counter ions of halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

As used herein, the term "about" or "approximately" has the meaning of being within 20% of a given value or range. In some embodiments, the term "about" refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.

3. Description of exemplary methods and uses

In some embodiments, the invention provides a method for treating an autoimmune/autoimmune disease or hematological malignancy in a patient, the method comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof. In some embodiments, the autoimmune/autoimmune disease is a skin autoimmune/autoimmune disease.

In some embodiments, the present disclosure provides a method for treating an autoimmune/auto-inflammatory disease of the skin, such as Atopic Dermatitis (AD) and Hidradenitis Suppurativa (HS), in a patient, comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof.

As used herein, the term "treating" refers to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder or one or more symptoms thereof as described herein. In some embodiments, the treatment may be administered after one or more symptoms have occurred. In other embodiments, the treatment may be administered in the absence of symptoms. For example, the treatment may be administered to a sensitive individual prior to onset of symptoms (e.g., based on a history of symptoms and/or based on genetic or other susceptibility factors). Treatment may also be continued after the symptoms have resolved, for example, to prevent or delay recurrence thereof.

As used herein, a patient or subject in need of prevention, in need of treatment, or in need of treatment refers to a patient or subject that would reasonably benefit from a given treatment or therapy according to diagnosis by an appropriate medical practitioner (e.g., a physician, nurse, or nurse practitioner in the case of a human, or a veterinarian in the case of a non-human mammal).

A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent (e.g., compound a) is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a patient or subject from the onset of a disease (e.g., AD) or promotes regression of the disease, as evidenced by: reduced severity of disease symptoms, increased frequency and duration of disease asymptomatic periods, or prevention of injury or disability due to affliction. The ability of a therapeutic agent to promote regression of a disease can be assessed using a variety of methods known to those of skill in the art, such as in a human subject during a clinical trial, in an animal model system that predicts efficacy in humans, or by analysis of agent activity in an in vitro assay.

In a preferred embodiment, a therapeutically effective amount of the drug (e.g., compound a) promotes regression to the point of elimination of the disease. In addition, the terms "effective" and "utility" with respect to treatment include pharmacological utility and physiological safety. Pharmacological utility refers to the ability of compound a to treat a disease in a patient. Physiological safety refers to toxic levels caused by administration of a drug, or other adverse physiological effects (side effects) at the cellular, organ and/or organism level.

As used herein, the term "therapeutic benefit" or "benefit from treatment" refers to an improvement in one or more of overall survival, progression free survival, partial response, complete response, and overall response rate, and may also include a decrease in severity of disease symptoms, an increase in frequency and duration of disease asymptomatic periods, or prevention of injury or disability due to illness.

As used herein, the term "patient" means an animal, preferably a mammal and most preferably a human.

As used herein, the term "subject" has the same meaning as the term "patient".

In some embodiments, the patient is 18 years old or older, such as 18 to 55 years old (inclusive), at the time of screening, and is generally good health except for AD or HS. In some embodiments, "good health" is defined as non-clinically relevant abnormalities identified by detailed medical history, physical examination (including BP and PR measurements), 12-lead ECG, and clinical laboratory tests.

In some embodiments, the patient is diagnosed with AD or HS for at least 6 months prior to day 1. In some embodiments, patients with AS have at least 25% treatable body surface area (excluding scalp and designated venous access area) at screening or at admission. In some embodiments, the patient has a panelist static overall assessment score of moderate (3) or severe (4) at screening or on day-1. In some embodiments, the patient has a BMI of 17.5 to 35.0kg/m ² The method comprises the steps of carrying out a first treatment on the surface of the And overall weight>50kg(110lb)。

In some embodiments, under the investigator's perspective, the patient does not have any clinically significant medical disorder, condition, disease (including active or potentially recurrent skin conditions other than AD or HS), significant physical examination or laboratory findings that may interfere with the study objective (e.g., conditions or findings that may expose the patient to unacceptable risk, confound treatment response or adverse event assessment or otherwise interfere with the patient's ability to complete the study by study participation).

In some embodiments, the patient does not have unstable AD or HS or a consistent requirement for a potent to the most potent topical corticosteroid to treat signs and symptoms of AD or HS. In some embodiments, the patient does not have an active systemic or local infection, including AD or HS, which are known to be active infections. In some embodiments, the patient does not have a history or sign of clinically significant or severe allergy (e.g., seasonal, pet dander, environmental, food) in need of acute or chronic treatment (patients with allergic rhinitis who do not require treatment or who are undergoing allergy treatment in compliance with one or more definitions of concomitant under-treatment stabilization regimens may be eligible to participate in the study). In some embodiments, the patient does not have recent (within 4 weeks of day 1) sunbath, tanning bed usage, or a history of Ultraviolet (UV) light B therapy or psoralen plus UV a (sunbath, tanning bed usage, and UV light therapy are prohibited during the study). In some embodiments, the patient does not have any planned surgery or medical procedure overlapping study participation from screening to study end. In some embodiments, the patient does not have any cancer or has a history of cancer in the last 5 years (except for curative treatment with squamous cell carcinoma, basal cell carcinoma, or carcinoma in situ of the surgically excised skin or cervix). In some embodiments, the patient does not have known sensitivity to any component of the study product. In some embodiments, the patient does not have a positive urine drug test. In some embodiments, the patient does not have a conventional drinking history of more than 7 drinks per week for female patients or 14 drinks per week for male patients (1 drink = 5 oz [150mL ] red wine or 12 oz [360mL ] beer or 1.5 oz [45mL ] white wine) within 6 months prior to screening. In some embodiments, the patient has not received treatment with the study product within 30 days or 5 half-lives (whichever is longer) prior to the first dose of the study product. In some embodiments, the patient has not received treatment with the CYP3A4 and P-gp inhibitor for 30 days or 5 half-lives (whichever is longer) prior to the first dose of study product. In some embodiments, after at least 5 minutes of supine placement, the patient does not have a screen supine BP ≡140mm Hg (systolic) or ≡90mm Hg (diastolic). If BP is 140mm Hg (systolic) or 90mm Hg (diastolic), BP should be repeated 2 more times and an average of 3 BP values should be used to determine eligibility for the patient. In some embodiments, the patient does not have a screened supine 12-lead ECG, indicating a QTc interval of >450 milliseconds or a QRS interval of >120 milliseconds. If QTc exceeds 450 milliseconds or QRS exceeds 120 milliseconds, the ECG should be repeated 2 more times and the average of 3 QTc or QRS values should be used to determine eligibility of the patient. In some embodiments, the patient does not have any of the following abnormalities in the clinical laboratory test at the time of screening, as assessed by the particular research laboratory and determined by a single repeat test (if deemed necessary): a) The content of aspartate aminotransferase or ALT is more than or equal to 1.5 xULN; b) The total bilirubin content is more than or equal to 1.5 XULN; patients with a history of Gilbert's syndrome may measure direct bilirubin and qualify for the study if the direct bilirubin level is less than or equal to ULN. In some embodiments, the patient does not use prescription or over-the-counter medications, including topical corticosteroids, vitamins, and dietary supplements, for 14 days or 5 half-lives (whichever is longer) prior to the first dose of study product. As an exception, acetaminophen/paracetamol (only if necessary) can be used in a dosage of 1 g/day or less. It is believed that limited use of non-prescription drugs that do not affect patient safety or overall study results may be optionally permitted after approval by the sponsor. Herbal nutritional supplements, including san john's (st. John's word), must be discontinued for at least 28 days prior to the first dose of the study product. In some embodiments, the patient does not supply approximately ≡400mL of blood (excluding plasma donors and platelet donors) or does not supply ≡200mL of blood for one month, 3 months prior to administration. In some embodiments, the patient does not have a history of susceptibility to heparin or heparin-induced thrombocytopenia. In some embodiments, the patient does not have a history of HIV, hepatitis b, hepatitis c, or syphilis; positive test for HIV, hepatitis b virus surface antigen, hepatitis b virus core antibody, hepatitis c virus antibody, syphilis or SARS-CoV-2 infection.

In some embodiments, the methods of the invention comprise orally administering a formulation as described herein. In some embodiments, the methods of the invention comprise administering a unit dosage form as described herein. In some embodiments, the methods of the invention comprise daily administration of a formulation or unit dosage form as described herein to a patient.

In some embodiments, the methods of the invention comprise daily administration to a patient of up to about 1600mg of compound a or a pharmaceutically acceptable salt thereof, e.g., up to about 25mg, up to about 50mg, up to about 75mg, up to about 100mg, up to about 150mg, up to about 200mg, up to about 300mg, up to about 400mg, up to about 500mg, up to about 600mg, up to about 800mg, up to about 1000mg, up to about 1200mg, or up to about 1400mg of compound a or a pharmaceutically acceptable salt thereof. In some embodiments, the methods of the invention comprise daily administration to a patient of about 25-1400mg (e.g., about 50-1400mg, about 75-1400mg, about 100-1400mg, about 150-1400mg, about 300-1400mg, about 600-1400mg, about 25-1000mg, about 50-1000mg, about 75-1000mg, about 100-1000mg, about 150-1000mg, or about 300-1000 mg) of compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the methods of the invention comprise daily administration to a patient of about 25-500mg (e.g., about 50-500mg, about 75-500mg, about 100-500mg, about 150-500mg, about 300-500mg, about 25-250mg, about 50-250mg, about 75-250mg, about 100-250mg, or about 150-250 mg) of compound a, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods of the invention comprise administering to a patient about 25mg of compound a, or a pharmaceutically acceptable salt thereof, daily, e.g., in a single 25mg unit dosage form. In some embodiments, the methods of the invention comprise administering to a patient about 50mg of compound a, or a pharmaceutically acceptable salt thereof, daily, e.g., in two 25mg unit dosage forms. In some embodiments, the methods of the invention comprise administering to a patient about 75mg of compound a, or a pharmaceutically acceptable salt thereof, daily, e.g., in three 25mg unit dosage forms. In some embodiments, the methods of the invention comprise administering to a patient about 100mg of compound a, or a pharmaceutically acceptable salt thereof, daily, e.g., in a single 100mg unit dosage form. In some embodiments, the methods of the invention comprise administering to a patient about 150mg of compound a, or a pharmaceutically acceptable salt thereof, daily, e.g., in a single 100mg and two 25mg unit dosage forms. In some embodiments, the methods of the invention comprise administering to a patient about 200mg of compound a, or a pharmaceutically acceptable salt thereof, daily, e.g., in two 100mg unit dosage forms. In some embodiments, the methods of the invention comprise administering to a patient about 300mg of compound a, or a pharmaceutically acceptable salt thereof, daily, e.g., in three 100mg unit dosage forms. In some embodiments, the methods of the invention comprise administering to a patient about 600mg of compound a, or a pharmaceutically acceptable salt thereof, daily, e.g., in six 100mg unit dosage forms. In some embodiments, the methods of the invention comprise administering to a patient about 1000mg of compound a, or a pharmaceutically acceptable salt thereof, daily, e.g., in ten 100mg unit dosage forms. In some embodiments, the methods of the invention comprise administering to a patient about 1400mg of compound a, or a pharmaceutically acceptable salt thereof, daily, e.g., in fourteen 100mg unit dosage forms. In some embodiments, the methods of the invention comprise administering a formulation or unit dosage form as described herein once daily. In some embodiments, the methods of the invention comprise administering a formulation or unit dosage form as described herein twice daily. In some embodiments, the methods of the invention comprise administering a formulation or unit dosage form as described herein three times daily. In some embodiments, the methods of the invention comprise administering a formulation or unit dosage form as described herein four to fourteen times a day.

In some embodiments, where the patient administers about 600mg of compound a or a pharmaceutically acceptable salt thereof daily, the administration is twice daily or BID, i.e., about 300mg doses are administered independently. In some embodiments, in the case of a patient administered about 600mg of compound a or a pharmaceutically acceptable salt thereof, three times daily or TID is administered, i.e., three times independently, at a dose of about 200 mg. In some embodiments, in the case of a patient administered about 600mg of compound a or a pharmaceutically acceptable salt thereof, four times daily or QID is administered, i.e., four times independently, a dose of about 150 mg.

In some embodiments, where the patient administers about 800mg of compound a or a pharmaceutically acceptable salt thereof daily, the administration is twice daily or BID, i.e., about 400mg doses are administered independently. In some embodiments, in the case of a patient administered about 800mg of compound a, or a pharmaceutically acceptable salt thereof, three times daily or TID, i.e., three times independently, a dose of about 267 mg. In some embodiments, in the case of a patient administered about 800mg of compound a, or a pharmaceutically acceptable salt thereof, daily, four times daily or QID, i.e., four times independently, about 200mg doses.

In some embodiments, where the patient administers about 1000mg of compound a or a pharmaceutically acceptable salt thereof daily, the administration is twice daily or BID, i.e., two separate administrations of a dose of about 500mg are performed. In some embodiments, in the case of a patient administered about 1000mg of compound a or a pharmaceutically acceptable salt thereof, three times daily or TID is administered, i.e., three times independently administered a dose of about 333 mg. In some embodiments, in the case of a patient administered about 1000mg of compound a or a pharmaceutically acceptable salt thereof, four times daily or QID is administered, i.e., four times independently, a dose of about 250 mg.

In some embodiments, where the patient administers about 1200mg of compound a or a pharmaceutically acceptable salt thereof daily, the administration is twice daily or BID, i.e., about 600mg doses are administered independently. In some embodiments, in the case of a patient administered about 1200mg of compound a, or a pharmaceutically acceptable salt thereof, three times daily or TID, i.e., three times independently, about 400mg dose. In some embodiments, in the case of a patient administered about 1200mg of compound a or a pharmaceutically acceptable salt thereof, four times daily or QID is administered, i.e., four times independently, a dose of about 300 mg.

In some embodiments, where the patient administers about 1400mg of compound a or a pharmaceutically acceptable salt thereof daily, the administration is twice daily or BID, i.e., twice independently, at a dose of about 700 mg. In some embodiments, where the patient administers about 1400mg of compound a or a pharmaceutically acceptable salt thereof daily, the administration is three times daily or TID, i.e., three times independently, a dose of about 467 mg. In some embodiments, where the patient administers about 1400mg of compound a or a pharmaceutically acceptable salt thereof daily, the administration is four times daily or QID, i.e., four times independently, at a dose of about 350 mg.

In some embodiments, where the patient administers about 1600mg of compound a or a pharmaceutically acceptable salt thereof daily, the administration is twice daily or BID, i.e., two separate administrations of a dose of about 800 mg. In some embodiments, in the case of a patient administered about 1600mg of compound a or a pharmaceutically acceptable salt thereof, three times daily or TID is administered, i.e., three times independently administered a dose of about 533 mg. In some embodiments, where the patient administers about 1600mg of compound a or a pharmaceutically acceptable salt thereof daily, the administration is four times daily or QID, i.e., four times independently, at a dose of about 400 mg.

In some embodiments, the methods of the invention comprise orally administering about 25mg, about 50mg, about 75mg, about 100mg, about 150mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 800mg, about 1000mg, about 1200mg, or about 1400mg of compound a, or a pharmaceutically acceptable salt thereof, once a single dose.

In certain embodiments, the methods of the invention comprise administering up to about 200mg of compound a, or a pharmaceutically acceptable salt thereof, daily. In certain embodiments, the methods of the invention comprise administering up to about 200mg of compound a, or a pharmaceutically acceptable salt thereof, daily. In certain embodiments, the methods of the invention comprise administering up to about 200mg of compound a, or a pharmaceutically acceptable salt thereof, daily.

In some embodiments, the methods of the invention comprise administering a formulation or unit dosage form as described herein, wherein there is about 4-24 hours between two consecutive administrations. In some embodiments, there is about 4, about 6, about 8, about 12, about 18, or about 24 hours between two consecutive administrations.

In some embodiments, the methods of the invention comprise administering a formulation or unit dosage form as described herein, wherein there is about 1-7 days between two consecutive administrations. In some embodiments, there is about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days between two consecutive administrations.

In some embodiments, the methods of the invention comprise administering a formulation or unit dosage form as described herein, wherein there is about 1-4 weeks between two consecutive administrations. In some embodiments, there is about 1, about 2, about 3, or about 4 weeks between two consecutive administrations.

In some embodiments, the present disclosure provides a method of administering compound a to a patient in need thereof, comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof (e.g., in a formulation or unit dosage form as described herein), wherein a Cmax of compound a in the plasma of at most about 50ng/mL is achieved. In some embodiments, administration of compound a or a pharmaceutically acceptable salt thereof (e.g., in a formulation or unit dosage form as described herein) achieves a Cmax of compound a in the plasma of at most about 30ng/mL.

In some embodiments, the Cmax of compound A in the plasma comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 42, 43, 44, 45, 46, and any of the preceding 50, by any of the preceding 50, the range of concentrations being used. In some embodiments, the methods comprise administering compound a or a pharmaceutically acceptable salt thereof (e.g., in a formulation or unit dosage form as described herein), wherein a Cmax of compound a in the plasma of about 10ng/mL to about 20ng/mL, about 15ng/mL to about 25ng/mL, about 20ng/mL to about 30ng/mL, or about 25ng/mL to about 35ng/mL is achieved. In some embodiments, cmax of compound a in plasma as set forth in table 6 below is achieved. In some embodiments, the methods comprise daily administration of compound a or a pharmaceutically acceptable salt thereof (e.g., in a formulation or unit dosage form as described herein), wherein a Cmax of compound a in the plasma of about 10ng/mL to about 20ng/mL, about 15ng/mL to about 25ng/mL, about 20ng/mL to about 30ng/mL, or about 25ng/mL to about 35ng/mL is achieved on day 14. In some embodiments, the Cmax of compound a in the plasma listed in table 9 below is achieved on day 14.

In some embodiments, the present disclosure provides a method of administering compound a to a patient in need thereof, comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof (e.g., in a formulation or unit dosage form as described herein), wherein tmax of compound a in the plasma is achieved in up to about 30 hours.

In some embodiments, the achieved tmax of compound a in the plasma comprises about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, and 30 hours, or any range of tmax produced by using two of the foregoing times as endpoints. In some embodiments, the methods comprise administering compound a or a pharmaceutically acceptable salt thereof (e.g., in a formulation or unit dosage form as described herein), wherein the tmax of compound a in the plasma is achieved within about 5 hours to about 15 hours, about 10 hours to about 20 hours, or about 15 hours to about 25 hours. In some embodiments, tmax of compound a in plasma as set forth below in tables 6 and 9 is achieved.

In some embodiments, the present disclosure provides a method of administering compound a to a patient in need thereof, comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof (e.g., in a formulation or unit dosage form as described herein), wherein an AUC of compound a in the plasma of up to about 3000ng h/mL is achieved.

In some embodiments, AUC of compound a in plasma includes about 100ng h/mL, 200ng h/mL, 300ng h/mL, 4000 ng h/mL, 500ng h/mL, 600ng h/mL, 700ng h/mL, 800ng h/mL, 900ng h/mL, 1000ng h/mL, 1100ng h/mL, 1200ng h/mL, 630 ng h/mL, 1500ng h/mL, 460 ng h/mL, 1500ng h/mL, or any range of AUC produced by using two of the foregoing concentrations as endpoints. In some embodiments, the method comprises administering compound a or a pharmaceutically acceptable salt thereof (e.g., in a formulation or unit dosage form as described herein), wherein an AUC of compound a in the plasma of about 500ng h/mL to about 1000ng h/mL, about 1000ng h/mL to about 1500ng h/mL, about 1500ng h/mL to about 2000ng h/mL, or about 2000ng h/mL to about 2500ng h/mL is achieved. In some embodiments, the method comprises daily administration of compound a or a pharmaceutically acceptable salt thereof (e.g., in a formulation or unit dosage form as described herein), wherein an AUC of compound a in the plasma of about 100ng h/mL to about 1000ng h/mL, about 150ng h/mL to about 800ng h/mL, about 200ng h/mL to about 600ng h/mL, or about 300ng h/mL to about 500ng/mL is achieved. In some embodiments, AUC of compound a in plasma as set forth below in tables 6 and 9 is achieved.

In some embodiments, the present disclosure provides a method of administering compound a to a patient in need thereof, comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof (e.g., in a formulation or unit dosage form as described herein), wherein t1/2 of compound a in the plasma is from about 20 hours to about 40 hours. In some embodiments, t1/2 of compound a in the plasma is from about 20 hours to about 30 hours, from about 25 hours to about 35 hours, or from about 30 hours to about 40 hours. In some embodiments, t1/2 of compound a in plasma as set forth in table 6 below is achieved.

In some embodiments, the present disclosure provides a method of administering compound a to a patient in need thereof, comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof (e.g., in a formulation or unit dosage form as described herein), wherein greater than 80% IRAK4 degradation in PBMCs is achieved (e.g., IRAK4 content in lymphocytes and monocytes is measured by measuring PBMCs using mass spectrometry or using flow cytometry 48 hours after administration). In some embodiments, administration of about 150mg to about 1600mg of compound a, or a pharmaceutically acceptable salt thereof (e.g., in a formulation or unit dosage form as described herein) produces greater than 80% IRAK4 degradation in PBMCs 48 hours after administration. In some embodiments, administration of about 600mg to about 1600mg of compound a, or a pharmaceutically acceptable salt thereof (e.g., in a formulation or unit dosage form as described herein), produces greater than 90% IRAK4 degradation in PBMCs 48 hours after administration. In some embodiments, IRAK4 degradation in PBMCs as set forth below in table 4 or table 7 is achieved.

In some embodiments, the present disclosure provides a method of administering compound a to a patient in need thereof, comprising daily administration to the patient of a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof (e.g., in the form of a formulation or unit dosage form as described herein), wherein greater than 81% IRAK4 degradation in PBMCs is achieved (e.g., IRAK4 content in lymphocytes and monocytes is measured by measuring PBMCs using mass spectrometry or by measuring using flow cytometry on day 7 or day 14). In some embodiments, daily administration of about 25mg to about 200mg of compound a, or a pharmaceutically acceptable salt thereof (e.g., in the form of a formulation or unit dosage form as described herein) can result in IRAK4 degradation of greater than 87% in PBMCs on day 7 or day 14. In some embodiments, daily administration of about 50mg to about 200mg of compound a, or a pharmaceutically acceptable salt thereof (e.g., in the form of a formulation or unit dosage form as described herein) can result in greater than 93% IRAK4 degradation in PBMCs on day 7 or day 14. In some embodiments, IRAK4 degradation in PBMCs as listed in fig. 11 or fig. 12 is achieved.

In some embodiments, the present disclosure provides a method of administering compound a to a patient in need thereof, comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof (e.g., in the form of a formulation or unit dosage form as described herein), wherein inhibition of cytokines is achieved (e.g., percent change from baseline measured in isolated pro-inflammatory cytokines induced by R848 and LPS in whole blood about 24-48 hours after administration). In some embodiments, about 50% to about 99%, about 65% to about 98%, or about 79% to about 97% inhibition of cytokines in whole blood is achieved about 24-48 hours after administration. In some embodiments, cytokines include IFN-gamma, IL-12, IL-1β, IL-10, IL-6, TNF- α, IL-8, IL-17 and IL-23. In some embodiments, administration of up to about 1000mg of compound a, or a pharmaceutically acceptable salt thereof (e.g., in the form of a formulation or unit dosage form as described herein) can result in inhibition of up to about 97% IFN- γ, up to about 93% IL-12, up to about 92% IL-1β, up to about 89% IL-10, up to about 88% IL-6, up to about 88% TNF- α, up to about 81% IL-8, or up to about 79% IL-17 in whole blood about 24-48 hours after administration. In some embodiments, cytokine inhibition is achieved as set forth in table 5 below.

In some embodiments, the present disclosure provides a method of administering compound a to a patient in need thereof, comprising daily administration to the patient of a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof (e.g., in the form of a formulation or unit dosage form as described herein), wherein inhibition of cytokines is achieved (e.g., by measuring the percentage of change from baseline in R848 and LPS induced ex vivo in whole blood on days 7-14). In some embodiments, inhibition of cytokine in whole blood by about 28% to about 85%, about 40% to about 85%, or about 50% to about 85% is achieved on days 7-14. In some embodiments, cytokines include IFN-gamma, IL-12, IL-1β, IL-10, IL-6, TNF- α, IL-8, IL-17 and IL-23. In some embodiments, daily administration of up to about 200mg of compound A or a pharmaceutically acceptable salt thereof (e.g., in the form of a formulation or unit dosage form as described herein) can result in inhibition of up to about 85% IFN-gamma, up to about 72% IL-12, up to about 68% IL-1β, up to about 50% IL-10, up to about 54% IL-6, up to about 59% TNF- α, up to about 46% IL-8, or up to about 46% IL-17 in whole blood on days 7-14. In some embodiments, cytokine inhibition as listed in fig. 16 is achieved.

4. Description of exemplary formulations and dosage forms

Compound a exhibited a low water solubility of 3mg/mL or less over a physiological pH range with moderate permeability. Only a slight increase in solubility was observed in the biologically relevant fluids at pH 6.5 (FaSSIF <12 mg/mL) due to the presence of bile salts. Compound a can be experimentally classified as a BCS II compound. In early non-GLP studies, challenges were encountered in oral administration of standard formulations with crystalline compound a HCl in preclinical species. Thus, energized formulation methods were explored that could increase apparent solubility and potentially enhance the oral bioavailability of compound a in GLP toxicology regimens in rats and dogs.

A series of energized formulations, i.e., lipids, co-solvents with lipid combinations, amorphous solid dispersions with different polymers (amorphous solid dispersion; ASD) and cyclodextrin solutions were evaluated to optimize the pharmacokinetic profile of Compound A. A 30mg/mL 25% solution of hydroxypropyl-beta-cyclodextrin (HP beta CD) compound a was developed that provided a 2-4 fold increase in exposure in rats and dogs relative to all other formulations studied.

To increase apparent solubility in aqueous vehicles, ASD containing compound a and HP βcd were prepared via a spray drying process, resulting in a spray dried dispersion (spray dried dispersion; SDD). In both rats and dogs, 20% compound a and 80% HP beta CD SDD were used in GLP toxicology procedures. GLP test preparations were formulated as solutions from SDD dissolved in 0.1M acetate at pH3.5 to a final concentration of 25% HP beta CD (w/v).

The first human (FIH) dosage form was constructed from knowledge obtained during GLP toxicology compounding. SDD using HP beta CD is an initial basis for efforts to improve drug delivery. Crystalline compound a was also investigated to investigate whether less complex dosage forms could be developed than HP beta CD based SDD tablets.

Initial FIH formulation screening PK studies were performed in dogs. The results indicate that standard Immediate Release (IR) crystalline tablets produced significantly lower exposure than HPMCAS-M based SDD tablets. The results also indicate that adding HPMCAS to HPMCAS-M based SDD tablets further provides enhanced exposure as compared to SDD tablets without HPMCAS. Based on these results, IR tablet dosage forms containing Compound A, HPMCAS-M (25:75) SDD with HP beta CD, compound A (3:1) were selected for further development. In an effort to reduce tablet weight, additional formulations with reduced amounts of HP beta CD were also developed, consisting of compound A: HPMCAS-M (25:75) SDD with HP beta CD: compound A (1.6:1).

A second preclinical PK canine study was conducted to compare GLP tox solution to two tablet formulations of hpβcd: compound a with 3.0:1 and 1.6:1 ratios. The results of this study demonstrate that GLP tox solutions potentially cause higher exposure than tablet formulations due to differences in dosage form (solution versus solid tablet). The results also demonstrate that exposure of compound a from both tablet formulations was comparable and that tablet hardness did not have a negative impact on exposure of either formulation. However, 1.6:1 HP beta CD: compound A tablet has lower exposure variability than 3.0:1 HP beta CD: compound A tablet. Furthermore, 1.6:1 of HP beta CD compound A formulation has a core tablet weight of less than 3.0:1 of HP beta CD compound A (800 mg versus 1000 mg). Thus, 1.6:1 HP beta CD: SDDIR tablet formulation based on Compound A HPMCAS-M was selected to support FIH testing.

In some embodiments, the present invention provides a formulation and/or unit dosage form comprising compound a or a pharmaceutically acceptable salt thereof. In some embodiments, the compound a formulation of the present invention is a spray-dried formulation comprising compound a or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dosage form of compound a of the present invention is a tablet comprising compound a or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets of the invention are Immediate Release (IR) tablets.

In some embodiments, the tablets of the invention comprise compound a free base. In some embodiments, the spray-dried formulations of the present invention comprise compound a free base. In some embodiments, compound a free base is amorphous. In some embodiments, compound a free base is in crystalline form.

In some embodiments, the tablets of the invention comprise a pharmaceutically acceptable salt of compound a. In some embodiments, the spray-dried formulations of the present invention comprise a pharmaceutically acceptable salt of compound a. In some embodiments, the pharmaceutically acceptable salt of compound a is amorphous. In some embodiments, the pharmaceutically acceptable salt of compound a is in crystalline form.

In some embodiments, the tablets of the invention comprise a compound a hydrochloric acid (HCl) salt. In some embodiments, the spray-dried formulation of the present invention comprises a compound a HCl salt. In some embodiments, the compound a HCl salt is amorphous. In some embodiments, the compound a HCl salt is in crystalline form.

In some embodiments, the tablets of the invention comprise an amorphous solid dispersion of compound a or a pharmaceutically acceptable salt thereof, manufactured by spray drying. In some embodiments, the dispersion-containing tablets of the invention provide enhanced oral bioavailability of compound a.

In some embodiments, the tablets of the invention comprise one or more pharmaceutically acceptable excipients or carriers, including (but not limited to): binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye transfer inhibitors, sweeteners, flavoring agents, emulsifiers, suspending and dispersing agents, preservatives, solvents, nonaqueous liquids, organic acids and carbon dioxide sources. In some embodiments, the IR tablets of the invention comprise one or more pharmaceutically acceptable excipients or carriers, including (but not limited to): starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants. Those skilled in the art will appreciate that some substances provide more than one purpose in a pharmaceutical composition. For example, some substances are binders that help hold the tablets together after compression, but are also disintegrants that help break apart the tablets once they reach the target delivery site. The choice of excipients and the amounts used can be readily determined by the formulation scientist based on the experience and consideration of standard procedures and with reference to works available in the art.

Suitable binders include (but are not limited to): starches (including potato starch, corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycols, propylene glycol, waxes and natural and synthetic gums (e.g., sodium alginate acacia), polyvinylpyrrolidone (PVP), cellulosic polymers (including hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose, ethylcellulose, hydroxyethyl cellulose (HEC), carboxymethyl cellulose and the like), veegum, carbomers (e.g., carbomers), sodium, dextrin, guar gum (guar gum), hydrogenated vegetable oils, magnesium aluminum silicate, maltodextrin, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), microcrystalline cellulose and the like. Binders also include, for example, acacia, agar, alginic acid, carbomer, carrageenan, cellulose acetate phthalate, carob bean gum, polydextrose, powdered sugar, copovidone, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl starch, hydroxypropyl methylcellulose, inulin, lactose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, povidone, sodium alginate, sodium carboxymethyl cellulose, starch, pregelatinized starch, stearic acid, sucrose, and zein.

Suitable fillers include (but are not limited to): talc, calcium carbonate (e.g., particulate or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

In some embodiments, the tablets of the invention comprise a pharmaceutically acceptable polymer. In some embodiments, the spray-dried formulations of the present invention comprise a pharmaceutically acceptable polymer. In some embodiments, the pharmaceutically acceptable polymer is polyvinylpyrrolidone/vinyl acetate copolymer (PVP-VA). In some embodiments, the pharmaceutically acceptable polymer is Hypromellose (HPMC). In some embodiments, the pharmaceutically acceptable polymer is hypromellose phthalate (HPMCP-55). In some embodiments, the pharmaceutically acceptable polymer is hypromellose acetate succinate MG grade (HPMCAS-M). In some embodiments, the pharmaceutically acceptable polymer is hypromellose acetate succinate LG grade (HPMCAS-L). In some embodiments, the pharmaceutically acceptable polymer is vitamin E TPGS (TPGS). In some embodiments, the pharmaceutically acceptable polymer is microcrystalline cellulose (MCC).

In some embodiments, the spray-dried formulation comprises about 5, 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, or about 95% wt/wt of compound a, or a pharmaceutically acceptable salt thereof. In some embodiments, the spray-dried formulation comprises about 10-75% wt/wt of compound a or a pharmaceutically acceptable salt thereof. In some embodiments, the spray-dried formulation comprises about 10-70, about 15-65, about 15-60, about 20-55, about 20-50, about 25-45, or about 25-40% wt of compound a or a pharmaceutically acceptable salt thereof. In some embodiments, the spray-dried formulation comprises about 25% wt/wt of compound a.

In some embodiments, the spray-dried formulation comprises about 5, 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, or about 95% wt/wt of the pharmaceutically acceptable polymer. In some embodiments, the spray dried formulation comprises about 5-95, about 10-95, about 15-90, about 20-90, about 25-90, about 30-85, about 35-85, about 40-85, about 45-80, about 50-80, about 55-80, or about 60-80% wt/wt of the pharmaceutically acceptable polymer. In some embodiments, the pharmaceutically acceptable polymer in the spray-dried formulation is selected from PVP-VA, HPMC, HPMCP-55, HPMCAS-M, TPGS and HPMCAS-L. In some embodiments, the spray-dried formulation comprises about 60-80% wt/wt of a pharmaceutically acceptable polymer selected from PVP-VA, HPMC, HPMCP-55, HPMCAS-M and HPMCAS-L. In some embodiments, the spray-dried formulation comprises about 75% wt/wt HPMCAS-M.

In some embodiments, the invention provides a spray-dried formulation comprising about 20-30:70-80 (% wt/wt) of compound A or a pharmaceutically acceptable salt thereof, HPMCAS-M. In some embodiments, the invention provides a spray-dried formulation comprising about 25:75 (% wt/wt) of compound A or a pharmaceutically acceptable salt thereof, HPMCAS-M. In some embodiments, the invention provides a spray-dried formulation comprising about 25:75 (% wt/wt) compound A free base HPMCAS-M.

In some embodiments, the spray-dried formulation of the present invention is selected from those spray-dried formulations described in example 1 below. In some embodiments, the present invention provides 25:75%wt/wt of compound A: HMPCAS-M Amorphous Solid Dispersion (ASD). In some embodiments, the present invention provides 25:75%wt/wt of compound A: HMPCAS-M Spray Dried Dispersion (SDD).

In some embodiments, the tablets of the invention comprise a spray-dried formulation of the invention and a pharmaceutically acceptable excipient or carrier. In some embodiments, the tablets of the invention comprise about 25-85% wt/wt of the spray-dried formulation of the invention. In some embodiments, the tablets of the invention comprise about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, or about 85% wt/wt of the spray-dried formulation of the invention. In some embodiments, the tablets of the present invention comprise about 20-80, about 25-75, about 30-70, about 35-70, about 40-65, or about 45-55% wt/wt of the spray-dried formulation of the present invention.

In some embodiments, the tablets of the invention comprise about 5-20% wt/wt of compound a. In some embodiments, the tablets of the invention comprise about 5, about 7.5, about 10, about 12.5, about 15, about 17.5, or about 20% wt/wt of compound a. In some embodiments, the tablets of the invention comprise about 12.5% wt/wt compound a.

In some embodiments, the tablets of the invention comprise about 30-50% wt/wt HMPCAS-M. In some embodiments, the tablets of the invention comprise about 30, about 32.5, about 35, about 37.5, or about 40% wt/wt HMPCAS-M. In some embodiments, the tablets of the invention comprise about 37.5% wt/wt HMPCAS-M.

In some embodiments, the tablets of the invention comprise a filler. In some embodiments, the filler is selected from mannitol, microcrystalline cellulose, or mixtures thereof. In some embodiments, the tablet comprises about 10-25% wt/wt filler (e.g., mannitol, microcrystalline cellulose). In some embodiments, the tablet comprises about 10, about 15, about 20, or about 25% wt/wt filler. In some embodiments, the tablet comprises 7.5% mannitol and 7.5% microcrystalline cellulose.

Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL-PH-101, AVICEL-PH-103AVICEL RC-581, AVICEL-PH-105 (FMC Inc., ma Kusi Hooke, pa., binder) and mixtures thereof. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103. TM. And starch 1500LM.

In some embodiments, the tablets of the invention comprise a disintegrant. Suitable disintegrants include (but are not limited to): agar; bentonite; cellulose, such as methyl cellulose and carboxymethyl cellulose; wood products; natural sponge; a cation exchange resin; alginic acid; gums, such as guar gum and veegum HV; citrus pulp; crosslinked celluloses, such as crosslinked carboxymethylcellulose; crosslinked polymers such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium (polacrilin potassium); starches, such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; an alignment agent; and mixtures thereof.

In some embodiments, the disintegrant is croscarmellose sodium (Ac-Di-Sol). In some embodiments, the tablet comprises about 5-15% wt/wt disintegrant. In some embodiments, the tablet comprises about 10, about 11, about 12, about 13, about 14, or about 15% wt/wt disintegrant. In some embodiments, the tablet comprises about 11-13% wt/wt disintegrant. In some embodiments, the tablet comprises about 12% wt/wt disintegrant. In some embodiments, the disintegrant comprises an intragranular and extragranular filler (e.g., ac-Di-Sol). In some embodiments, the disintegrant (e.g., ac-Di-Sol) is about 9.67% intragranular and about 2.33% extragranular.

In some embodiments, the tablets of the present invention comprise one or more glidants. Suitable slip agents include, but are not limited to, colloidal silica (CAB-O-SIL) and asbestos-free talc. In some embodiments, the slip agent is colloidal silica. In some embodiments, the tablet comprises about 0.5-5% wt/wt of the glidant. In some embodiments, the tablet comprises about 0.5, about 1, about 1.5, about 2, about 3, about 4, or about 5% wt/wt of the glidant. In some embodiments, the tablet comprises about 1-3% wt/wt of the glidant. In some embodiments, the tablet comprises about 1.5% wt/wt of the glidant. In some embodiments, the slip agent comprises an intra-and extra-granular particulate slip agent (e.g., colloidal silica). In some embodiments, the slip agent (e.g., colloidal silica) is about 1.00% intra-particle and about 0.50% extra-particle.

In some embodiments, the tablets of the present invention comprise one or more lubricants. Suitable lubricants include (but are not limited to): sodium stearyl fumarate, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Other lubricants include, for example, syloid silica gel (AEROSIL 200, manufactured by graves corporation (w.r.Grace Co.) of Baltimore, md.) of Baltire, maryland, condensed aerosols of synthetic silica (sold by Degussa Co.) of Prinox (Plano, tex.), CAB-O-SIL (a fumed silica product sold by Cabot Co.) of Boston, mass.) of Massachusetts, and mixtures thereof.

In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the tablet comprises about 0.5-5% wt/wt of the glidant. In some embodiments, the tablet comprises about 0.5, about 1, about 1.5, about 2, about 3, about 4, or about 5% wt/wt of the glidant. In some embodiments, the tablet comprises about 0.5-1.5% wt/wt glidant. In some embodiments, the tablet comprises about 1% wt/wt of the glidant. In some embodiments, the slip agent comprises an intra-and extra-granular slip agent (e.g., sodium stearyl fumarate). In some embodiments, the lubricant (e.g., sodium stearyl fumarate) is about 1.00% intra-granular and about 0.50% extra-granular.

In some embodiments, the tablets of the invention comprise a solubility enhancing agent. In some embodiments, the solubility enhancer is hydroxypropyl-beta-cyclodextrin (HP beta CD). In some embodiments, the tablet comprises about 10-30% wt/wt solubility enhancing agent. In some embodiments, the tablet comprises about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20% wt/wt solubility enhancing agent. In some embodiments, the tablet comprises about 15-25% wt/wt solubility enhancing agent. In some embodiments, the tablet comprises about 20% wt/wt solubility enhancing agent (e.g., HP beta CD).

In some embodiments, the present invention provides an IR tablet that has complete release in about 10 minutes during the tank dissolution test. In some embodiments, the IR tablets of the present invention have complete release in the tank dissolution test within about 9, about 8, about 7, about 6, or about 5 minutes. In some embodiments, the IR tablets of the present invention have complete release in about 4 minutes in the tank dissolution test. In some embodiments, the IR tablets of the present invention have complete release in about 3 minutes in the tank dissolution test. In some embodiments, the IR tablets of the present invention have complete release in about 2 minutes in the tank dissolution test. In some embodiments, the IR tablets of the present invention have complete release in about 1 minute in the tank dissolution test.

In certain embodiments, tablets of the present invention are manufactured using standard, art-recognized tablet handling procedures and equipment. In certain embodiments, the method for forming a tablet is direct compression comprising the powder, crystalline, and/or particulate compositions provided herein in solid form, alone or in combination with one or more excipients or carriers (e.g., carriers, additives, polymers, or the like). In certain embodiments, as an alternative to direct compression, tablets may be prepared using wet granulation or dry granulation processes. In certain embodiments, the tablet is molded with a moist or otherwise manageable material as a starting material rather than compressed. In certain embodiments, compression and granulation techniques are used. In some embodiments, the tablets of the invention are manufactured using the methods described in example 2 below (fig. 1).

In certain embodiments, the tablets of the invention comprise one or more diluents. Suitable diluents include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, anhydrous starch, microcrystalline cellulose (e.g., AVICEL), fine cellulose, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT), potassium chloride, sodium chloride, sorbitol, talc, and the like. Diluents also include, for example, ammonium alginate, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, compressible sugar, powdered sugar, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, isomalt, kaolin, lactitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-long chain triglycerides, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, polydextrose, polymethacrylates, dimethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, sulfobutyl ether-beta-cyclodextrin, talc, astragalus, trehalose and xylitol.

In some embodiments, the tablets of the present invention comprise one or more colorants. Suitable colorants include, but are not limited to, any approved, identified, water-soluble FD&C dye, and water insoluble FD suspended on alumina hydrate&C dyes, and lakes and mixtures thereof, e.gA colorant. Lakes are combinations formed by adsorption of a water-soluble dye onto an aqueous oxide of a heavy metal, resulting in an insoluble form of the dye.

In some embodiments, the tablets of the present invention comprise one or more flavoring agents. Suitable flavoring agents include, but are not limited to, natural flavoring agents extracted from plants (if solid), and synthetic blends of compounds that produce a desirable mouthfeel, such as peppermint and methyl salicylate.

In certain embodiments, the tablets of the invention comprise one or more sweeteners. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin and artificial sweeteners such as saccharin and aspartame.

In certain embodiments, the tablets of the invention comprise one or more emulsifying agents. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, astragalus, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate 20 Polyethylene oxide sorbitanMonooleate 80->80 Triethanolamine oleate).

In certain embodiments, the tablets of the present invention comprise one or more suspending and dispersing agents. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethyl cellulose (sodium carboxymethylcellulose), pectin, astragalus, veegum, acacia, sodium carboxymethyl cellulose (sodium carbomethylcellulose), hydroxypropyl methylcellulose, and polyvinylpyrrolidone.

In certain embodiments, the tablets of the invention comprise one or more preservatives. Suitable preservatives include, but are not limited to, glycerin, methyl and propyl parahydroxybenzoates, benzoic acid additives, sodium benzoate, and alcohols.

In certain embodiments, the tablets of the present invention comprise one or more wetting agents. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.

In certain embodiments, the tablets of the present invention comprise one or more solvents. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethanol, and syrup.

In certain embodiments, the tablets of the present invention comprise one or more nonaqueous liquids. Suitable non-aqueous liquids for use in the emulsion include, but are not limited to, mineral oil and cottonseed oil.

In certain embodiments, the tablets of the invention comprise one or more organic acids. Suitable organic acids include, but are not limited to, citric acid and tartaric acid.

In certain embodiments, the tablets of the invention comprise one or more carbon dioxide sources. Suitable carbon dioxide sources include, but are not limited to, sodium bicarbonate and sodium carbonate.

In certain embodiments, the tablets of the invention may be multiple compressed tablets, coated enteric coated tablets, or coated sugar coated or film coated tablets. Coated enteric coated tablets are compressed tablets which are coated with a protective coating against gastric acid butA substance that dissolves or disintegrates in the intestine, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar coated tablets are compressed tablets coated with a sugar coating, which can advantageously mask unpleasant taste or odor and protect the tablet from oxidation. Coated film coated tablets are compressed tablets covered by a thin layer or film of water soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. The film coating provides the same general features as the sugar coating. Multiple compressed tablets are compressed tablets prepared by more than one compression cycle, including layered tablets and compression coated or dry coated tablets. In some embodiments, the tablets of the invention comprise II brown film coating. In some embodiments, the +.A on the tablet of the invention>The II brown film coating comprises the components in the weight percentages as described in table 3. In some embodiments, the tablet of the present invention comprises +.>II yellow film coating. In some embodiments, the +.A on the tablet of the invention>II yellow film coating comprises the components in the weight percentages as described in Table 3.

The tablets of the invention may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more of the carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants.

The components of the tablets of the invention may be intragranular or extragranular. In some embodiments, the tablet comprises the intragranular compounds A, HPMCAS-M, mannitol, microcrystalline cellulose, hydroxypropyl-beta-cyclodextrin (HP beta CD), colloidal silicon dioxide, croscarmellose sodium, and sodium stearyl fumarate. In some embodiments, the tablet comprises extra-granular colloidal silica, croscarmellose sodium, and sodium stearyl fumarate. In some embodiments, the present invention provides a tablet of table 2.

In some embodiments, the tablets of the invention comprise about 10-250mg of compound a. In some embodiments, the tablets of the invention comprise about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, or about 250mg of compound a. In some embodiments, the tablets of the invention comprise about 25-100mg of compound a. In some embodiments, the tablets of the invention comprise about 25mg or 100mg of compound a.

In some embodiments, the invention provides a tablet of about 208mg comprising:

i) About 200mg of tablet core comprising

In the granule: about 25mg of compound a free base, about 75mg of HPMCAS-M, about 15mg of mannitol, about 15mg of microcrystalline cellulose, about 40mg of hydroxypropyl- β -cyclodextrin, about 19.34mg of croscarmellose sodium, about 2mg of sodium stearyl fumarate, and about 2mg of colloidal silicon dioxide; and

Outside the particles: about 4.66mg of croscarmellose sodium, about 1mg of sodium stearyl fumarate, and about 1mg of colloidal silicon dioxide; and

ii) about 8mgII yellow film coating comprising about 3.2mg polyvinyl alcohol, 1.616mg Macrogol/PEG, 1.872mg titanium dioxide, 0.128mg iron oxide and 1.184mg talc.

In some embodiments, the invention provides a tablet of about 824mg comprising:

i) About 800mg of tablet core comprising

In the granule: about 100mg of compound a free base, about 300mg of HPMCAS-M, about 45mg of mannitol, about 45mg of microcrystalline cellulose, about 160mg of hydroxypropyl-beta-cyclodextrin, about 77.36mg of croscarmellose sodium, about 8mg of sodium stearyl fumarate, and about 8mg of colloidal silicon dioxide; and

Outside the particles: about 18.64mg of croscarmellose sodium, about 4mg of sodium stearyl fumarate, and about 4mg of colloidal silicon dioxide; and

ii) about 24mgII yellow film coating comprising about 9.6mg polyvinyl alcohol, 4.848mg Macrogol/PEG, 5.616mg titanium dioxide, 0.384mg iron oxide and 3.552mg talc.

5. Methods and uses for treating diseases

In some embodiments, autoimmune/autoimmune diseases include inflammatory or allergic conditions of the skin, such as psoriasis, systemic pustular psoriasis (generalized pustular psoriasis; GPP), psoriasis vulgaris, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, leukoplakia, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus leaf (pemphigus foliaceus), tumor-like pemphigoid, epidermolysis bullosa, acne vulgaris, hidradenitis suppurativa, sheet Syndrome, pyogenic pyoderma, and other inflammatory or allergic conditions of the skin. In some embodiments, the inflammatory disease of the skin is selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, leukoplakia, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigoid vulgaris, deciduous pemphigoid, paraneoplastic pemphigoid, epidermolysis bullosa acquisita, or hidradenitis suppurativa.

In some embodiments, compound a may also be used to treat other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, to treat ocular diseases and conditions, such as ocular allergies, conjunctivitis, dry eye, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases involving autoimmune reactions or having autoimmune components or etiology, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure erythrocyte anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, wegener's disease, dermatomyositis, chronic active hepatitis, myasthenia gravis, steven-Johnson syndrome, idiopathic aphtha, autoimmune inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, dental root periostitis, vitronematosis, nephrosis, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine eye lesions, grave's disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), sjogren's syndrome, inflammatory bowel syndrome, inflammatory conditions of the human eye, inflammatory bowel syndrome, crohn's disease, inflammatory conditions of the kidney, ocular fluid, fulminal joint, fulminant joint inflammation, inflammatory conditions of the kidney, inflammatory joint diseases, for example including idiopathic nephrotic syndrome or slightly altered nephropathies), chronic granulomatosis, endometriosis, leptospirosis nephropathy, glaucoma, retinal diseases, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic conditions, obesity, retarded embryo growth, hypercholesteremia, heart disease, chronic heart failure, mesothelioma, anhidrosis ectodermal dysplasia, behcet's disease, pigment imbalance (incontinentia pigmenti), paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe bronchial and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, allergy, systemic allergic reactions, sinusitis, ocular allergies, silica-induced diseases, COPD (reduced lesions, airway inflammation, bronchial hyperreactivity, remodelling or disease exacerbations), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension multiple neuropathy, cataracts, muscle inflammation, systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, crohn's disease, bladder light, dacryocystitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrous tissue inflammation, gastritis, gastroenteritis, huntington's-wire Lai Zidian (Henosweat-Schonlein purpura), hepatitis, suppurative adenosis, immunoglobulin A nephropathy, crohn's disease, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, testosterone, osteomyelitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, local pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, arthromeningitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis.

In some embodiments, the inflammatory disease treatable according to the methods of the invention is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic Juvenile Idiopathic Arthritis (SJIA), cryptomelane-related periodic syndrome (CAPS), adult onset stele disease (Adult Onset Still's disease), macrophage Activation Syndrome (MAS), primary and secondary hemophagocytic lymphoproliferative disorders (HLH), familial mediterranean fever, NLRP12 self-inflammatory syndrome, and osteoarthritis.

In some embodiments, the treatable inflammatory disease is a TH 17-mediated disease. In some embodiments, the TH 17-mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, psoriasis vulgaris, hidradenitis suppurativa, and inflammatory bowel disease (including crohn's disease or ulcerative colitis).

In some embodiments, the inflammatory disease treatable according to the methods of the invention is selected from sjogren's syndrome; allergic conditions; osteoarthritis; ocular conditions such as ocular allergies, conjunctivitis, dry eye, and vernal conjunctivitis; and diseases affecting the nose, such as allergic rhinitis or chronic sinusitis with nasal polyps (CRSwNP).

In some embodiments, the present disclosure provides a method of treating Rheumatoid Arthritis (RA) in a patient, the method comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a method for treating hematological malignancies in a patient, the method comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutical thereofAcceptable salts. In some embodiments, the hematological malignancy is leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic Lymphocytic Leukemia (CLL), chronic lymphocytic lymphoma, primary exudative lymphoma, burkitt's lymphoma (Burkitt lymphoma)/leukemia, acute lymphoblastic leukemia, B-cell pre-lymphocytic leukemia, lymphoplasmacytic lymphoma, waldenstrom's macroglobulinemia macrogolibulinema; WM), spleen border region lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, AML, or MDS.

The following examples are provided for illustrative purposes only and should not be construed as limiting the invention in any way.

Illustrative examples

Compound a may be prepared by methods known to those of ordinary skill in the art, for example as described in WO 2019/133531 and WO 2020/010227, the contents of which are incorporated herein by reference in their entirety.

List of abbreviations

AD atopic dermatitis

AE adverse events

ALT alanine aminotransferase

BCRP (BCRP) breast cancer drug resistance protein

BMI body mass index

BP blood pressure

CRBN celecoxib (Cereblon)

DDI drug-drug interactions

ECG electrocardiogram

eCRF electronic case report form

FIH for the first time

FE food Effect

FFPE formalin fixed paraffin embedding

FSH follicle stimulating hormone

GEP Gene expression profiling

GI gastrointestinal tract

GLP good laboratory Specification

HDPE high density polyethylene

HED human equivalent dose

HIV human immunodeficiency virus

HR heart rate

HRT hormone replacement therapy

HS suppurative sweat gland inflammation

HV healthy volunteers

IC50 half maximal inhibitory concentration

ICF informed consent

International Commission on the coordination guidelines for ICH GCP good clinical specifications

IEC independent ethics committee

IF immunofluorescence

IL interleukins

IRAK4 Interleukin-1 receptor related kinase 4

IRB mechanism examination board

MAD multiple increasing doses

Metabolites in MIST safety test

MS mass spectrum

MyD88 bone marrow differentiation factor 88

Content of NOAEL at which no adverse reaction was observed

PBMC peripheral blood mononuclear cells

PD pharmacodynamics

P-gp P-glycoprotein

PK pharmacokinetics

RA rheumatoid arthritis

SAD single increment dose

SARS-CoV-2 severe acute respiratory syndrome coronavirus 2

SDD spray-dried dispersion

SAE serious adverse events

SAP statistical analysis plan

SD standard deviation

SoA assessment schedule

SOP standard operation program

SRC Security review Committee

TEAE treatment causes adverse events

TLR bell-like receptor

TNF tumor necrosis factor

ULN upper limit of normal value

UV ultraviolet light

WOCBP women of child bearing age

Definition:

ae (t 1-t 2) is secreted in urine at intervals during each collection interval.

Cumulative amount of Ae (0-t) secreted in urine during pooled collection intervals

AUC (0- ≡) is the area under the plasma concentration-time curve from time zero to infinite time.

AUC (0-last) is the area under the plasma concentration-time curve from time zero to the last measurable concentration.

Area under the plasma concentration-time curve during the AUC (0-tau) dosing interval.

Average concentration over Cavg dosing interval.

Apparent CL/F clearance.

The maximum value of the concentration observed for Cmax.

Concentration of ctrogh at the end of dosing interval.

F relative bioavailability of feeding/fasting.

fe (t 1-t 2) is the fraction of the dose secreted in urine during each collection interval at intervals.

Cumulative fraction of secreted doses of fe (0-t) in urine during pooled collection intervals

MRT average residence time.

t1/2 terminal half-life.

tmax reaches Cmax.

Cumulative ratio of RAUC AUC.

Cumulative ratio of RCmax Cmax.

Vz/F apparent distribution volume.

EXAMPLE 1 pharmaceutical products

Description of: compound a tablets, also known as "pharmaceuticals", are supplied in the form of 25mg standard round tablets with a dose intensity adjusted oblong tablets of 100 mg. Both dosage strengths were co-granulated and compressed into tablets of different sizes and film coated. Film coatings are added for taste masking and ease of swallowing.

The active compound a is contained in the tablet formulation in the form of an Amorphous Solid Dispersion (ASD). ASD is manufactured by spray drying and will be referred to as Spray Dried Dispersion (SDD). The SDD, also referred to as "drug intermediate", is 25 wt.% active compound A with HPMCAS-M (25% compound A:75% HPMCAS-M).

The composition of the drug intermediate, including the amounts and functions of the components and the quality criteria are provided in table 1. The composition of the compound a drug, including the amounts per unit, the function of the components and the quality criteria are provided in table 2. The composition of the film coating used for the test points and cGMP-manufactured tablets is provided in table 3. The composition of the test point tablet film coating contained all combinations of colorants that were acceptable throughout. In addition to titanium dioxide, cGMP manufacture tablets use a subset of these pigments in equivalent, lower or zero levels.

Table 1. Composition of drug intermediate (SDD): 25% Compound A75% HPMCAS-M

Component (A)	Function of	Composition (%)
			Compound A ^a	Active ingredient	25.0
Hydroxypropyl methylcellulose acetyl succinate (HPMCAS-M), NF	Stabilizing agent	75.0
			Methanol ^b ，USP/NF	Spray drying solvent	NA
Dichloromethane (dichloromethane) ^b ，USP/NF	Spray drying solvent	NA
			Water for injection ^b ，USP	Spray drying solvent	NA

^a The crude drug is supplied in the form of compound a HCl. The Active Pharmaceutical Ingredient (API) (compound a free base) was combined with HPMCAS-M in a ratio of 25%:75% to give a spray-dried dispersion, also referred to as a "pharmaceutical intermediate".

^b These ingredients are manufacturing aids and are not found in the pharmaceutical product in significant amounts.

TABLE 2 pharmaceutical Unit composition of Compound A25 mg and 100mg tablets

Usp=united states pharmacopeia (United States Pharmacopeia), nf=national formulary (National Formulary), ep=european pharmacopeia (European Pharmacopoeia)

^a The amount of mannitol used was adjusted to compensate for the measured efficacy of the spray-dried dispersion.

^b Water is removed during manufacture. Which is a processing aid and is not present in significant amounts in the finished pharmaceutical product.

^c The target weight of the tablet core increases during film coating.

TABLE 3 preparation of test points of Compound A25 mg and 100mg and cGMP tabletsII film coating composition->

USP = united states pharmacopeia; NF = national formulary; EP = european pharmacopoeia; JECFA = joint review board of food additives;

JP = japanese pharmacopoeia; JPE = Japanese medical excipient

EXAMPLE 2 pharmaceutical manufacturing Process

Description of: pharmaceutical products are manufactured using methods and apparatus commonly used to produce SDDs and immediate release tablets commonly available in the pharmaceutical industry. A description of the manufacturing method and steps is provided in table 4. A manufacturing process flow diagram describing the operations involved in manufacturing a 25% compound a:75% hpmcas-M SDD and compound a 25mg and 100mg coated tablets is shown in fig. 1 below.

The method can be reasonably tuned while maintaining the same basic production steps to compensate for different lot sizes or equipment characteristics, or based on experience gained from previous production lots.

TABLE 4 pharmaceutical manufacturing method

Example 3 evaluation of safety, tolerability, pharmacokinetics and pharmacodynamics of oral administration of Compound A in healthy adult volunteers and patients with Atopic Dermatitis (AD) or suppurative sweat dermatitis (HS) phase 1 random, placebo control, single and multiple increasing dose trials

The object is: to assess the safety, tolerability, pharmacokinetics (PK) and Pharmacodynamics (PD) of compound a after single and multiple oral doses administered at ascending dose levels in Healthy Volunteers (HV) and after multiple doses in patients with AD or HS.

Overview of study design: this is the first human (FIH), phase 1 compound a study that will characterize the safety, PK and PD of compound a after a single dose and after repeated dosing in adult HV and in patients with HS or AD. First, the dose range of compound a in a single escalation dose (SAD) escalation group was investigated in adult HV (part a). To understand the Food Effect (FE) on PK and PD of compound a in HV, a maximum of 2 SAD groups are specified in part a, where HV will return to the second treatment period and will receive the same treatment as originally dispensed but in the feeding state. Safety and PK data from at least 3 completed SAD groups will determine the start of the 14 day Multiple Ascending Dose (MAD) portion of the study and the appropriate dose (portion B). A single cohort of up to 20 patients with AD or HS (at least 10 patients with AD) will then be recruited (part C), and after dose escalation in part B, compound a is administered to these patients for 14 days in accordance with the dose and time course selected after safety, PK and PD data review by the Safety Review Committee (SRC).

Part a: part a is a double blind, randomized, placebo controlled, SAD, sequential group study of 56 adult HVs, which are divided into 7 groups of eight HVs each. Seven incremental single doses (1 dose level per group) will be studied. One or more other groups may be added as desired. Within each group, 6 HVs will be randomized to receive compound a and 2 HVs will be randomized to receive placebo.

In the SAD section, the planned compound A doses were 25, 75, 150, 300, 600, 1000 and 1400mg. The pharmacokinetic parameters of the content of unoael at which no adverse reaction was observed (NOAEL) from the 28-day compound a toxicokinetic study in rats and dogs were used to calculate the predicted exposure ratio for human AUC and Cmax relative to compound a. These data are based on AUC of NOAEL in rats and dogs, respectively, indicating that the initial dose of 25mg is 79-to 159-fold exposure safety margin. The safety margin decreases with increasing dose. After HV safety and PK data review in the 25mg dose group, the dose levels of the subsequent SAD group may be adjusted from those proposed, but not more than the specified fold increase in exposure indicated for each dose level.

At each dose level, 2 sentinel HVs (1 receiving compound a and 1 receiving placebo) were first dosed with the study product. Safety data up to 24 hours post administration of these sentinel HVs were reviewed by the investigator to ensure acceptable tolerability before starting administration of the study product to the rest of the HVs in the group. Within the group the HV will be staggered in order of administration such that the administration of individual HV will be at least 10 minutes apart. After completion of each dose level, the mid-blinding PK data up to day 5 and the safety data up to day 14 will be reviewed by the SRC before proceeding to the next dose level. If the results of the safety analysis of the previous dose administered are satisfactory at the discretion of the investigator and safety physician, each subsequent dose is administered.

In addition, the effect of food intake on PK of compound a was also investigated by selecting a maximum of 2 SAD groups that would return to the second treatment period and would receive the same treatment allocation in the feeding regime (within 30 minutes of FDA standard high fat breakfast completion). The clearance period between the first treatment and the second treatment will be 14 days or 5 times the half-life of compound a (whichever is longer). The selection of a group will be based on security and PK data from previous group occurrences in part a. The expected exposure in the FE study will not exceed the highest expected exposure in the next planned SAD study group, where the safety and tolerability of compound a is established (e.g., SAD 5 exposures in the fed state will not exceed SAD 6 prominent exposures in the fasted state).

HV will be screened for eligibility to participate in the study for up to 26 days (day-28) before day-2 entering the study center. A satisfactory HV will enter the study center on day-2 and will discharge on day 5 after all scheduled assessments are completed. After discharge, the HV will return to the study center for follow-up interrogation on days 7, 10 and 14.

Part B: part B is a double-blind, randomized, placebo-controlled, MAD, sequential group study of 48 adult HVs, divided into 4 groups of 12 adult HVs each. One or more additional groups may be added as desired.

The MAD portion of the study will evaluate compound a at 4 dose levels administered 14 days a day in succession. The selection of compound a dose will be guided by safety, tolerability and PK data in humans from the SAD part of the study. The initial dose level of the first MAD group will be identified based on the PK observed in at least the first 3 SAD groups and will be the dose where the predicted ssaucτ and ssCmax are lower than the exposure observed in the highest dose SAD group where compound a was confirmed to be safe and tolerable. Increased dose levels in subsequent MAD groups will be identified based on the safety and PK observed in the aforementioned SAD and MAD groups. The dose escalation between each MAD group will not exceed 100%. The maximum daily exposure proposed in the highest dose MAD group will not exceed the highest exposure establishing safety and tolerability of compound a in the SAD study.

Within each group, 9 HVs will be randomized to receive compound a and 3 HVs will be randomized to receive placebo.

Compound a or placebo will be scheduled to be administered orally once a day after an overnight fast of 10 hours, from day 1 to day 14 (inclusive). However, the dosing interval and duration of dosing may vary after review of safety, PK and PD data from part a.

As a precaution, part a of the study will utilize a sentinel dosing strategy. This policy will not be used in part B unless the security and PK data from part a otherwise indicate (e.g., security issues). After completion of each MAD dose level, the PK/PD data up to day 15 and the safety data up to day 28 will be reviewed by the SRC before proceeding to the next dose level. After reviewing the newly emerging security, PK and PD data from the first 2 MAD groups, this review period may be altered in either way, subject to regimen correction.

HV will be screened for eligibility to participate in the study for up to 26 days (day-28) before day-2 entering the study center. A satisfactory HV will enter the study center on day-2 and will discharge on day 21 after all scheduled assessments are completed. After discharge on day 21, the HV will return to the study center for follow-up interrogation on day 28. After review of the newly emerging security, PK and PD data, additional interviews can be planned.

Part C: part C is an open-label multi-dose study of a single group of up to 20 patients with AD or HS (at least 10 patients with AD) and will begin after part B is completed. Part C will be based on both inpatients and outpatients, and the patient will continue safety tracking on day 28. Dose regimens for limiting patients to clinical units and requirements will be selected by SRC from safety, PK and PD data after completion of part B.

Patients currently planned will be screened for eligibility from day-42, and those who are eligible for participation will enter the clinical unit on day-2. Patients will be limited to clinical units as in part B, from day-2 to day 2 and day 13 to day 15, and all other interviews will be performed as outpatients; however, this is subject to a satisfactory review of the security, PK and PD data emerging from parts a and B, and follows protocols with investigators and sponsors. Patients may be required to have the limitations listed in section B.

The termination rules based primarily on safety were defined for individual study participants, individual dose groups, and the entire study, considering emerging PK and PD findings.

Number of investigators and study centers: approximately 2 investigators and study centers are expected to participate in this study. The second research center will participate as needed to support enrollment.

Study population and number of study participants: the total number of study participants is determined visually by the number of groups required for minimum and maximum effective doses.

● Part a: approximately 110 HVs will be screened to achieve 56 HVs assigned to the study product.

● Part B: approximately 100 HVs will be screened to achieve 48 HVs assigned to the study product.

● Part C: approximately 40 patients with AD or HS will be screened to achieve a maximum of 20 patients assigned to the study product.

Inclusion criteria

For healthy volunteers (part A and B)

1. At screening, males HV or females HV of 18 to 55 years of age (inclusive) have a body weight of at least 50kg and a Body Mass Index (BMI) of 18.0 and 30.0kg/m at consent ² (including the endpoints).

2. Healthy volunteers must be confirmed as negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection test at screening and day-2.

3. Evidence of an informed consent record of the individual signed and selected date indicates that all relevant aspects of this study have been informed of HV.

4. Male HV and its companion with fertility potential must agree to use a highly effective contraceptive method or 2 acceptable contraceptive methods up to 90 days after study product administration. A male or female has fertility potential if it is considered biologically viable by the investigator and has active sexual life. HV and its partners that have been surgically sterilized less than 6 months prior to the day of informed consent must agree to use any medically acceptable contraceptive method.

5. Female HV without fertility potential must meet at least 1 of the following criteria: a) The post-stop state is achieved as defined below: stopping regular menstruation for at least 12 consecutive months without alternative pathogenetic or physiological etiology; and has a serum Follicle Stimulating Hormone (FSH) level that confirms post-menopausal status; b) Undergo recorded hysterectomy and/or bilateral ovariectomy; and c) completing the medical diagnosis of ovarian failure.

6. Women with fertility potential HV must agree on the following combinations of TWO until 90 days after study product administration: a) Method of preventing contraception: condoms (male or female) with or without spermicide, caps or caps with spermicide; b) IUD; and c) a contraceptive based on a hormone.

7. Female subjects may not be pregnant, lactating or breast feeding or are scheduled to become pregnant (including egg feeding) within 90 days of the last study drug administration.

8. Female subjects must have a negative result of the serum pregnancy test at screening and follow-up.

Hv must be willing and able to follow scheduled consultations, treatment plans, laboratory tests and other research procedures.

For patients (section C)

The patient must meet all of the following inclusion criteria in order to be eligible for participation in the study:

1. male or female patients aged 18 to 55 years (inclusive) at screening and generally have good health status except for AD or HS. Good health is defined as non-clinically relevant abnormalities identified by detailed medical history, physical examination (including BP and PR measurements), 12-lead ECG, and clinical laboratory tests.

2. At the time of screening and on day-2, patients must be confirmed as negative in the SARS-CoV-2 infection test.

2. Male patients and their partners with fertility potential must agree to use a highly effective contraceptive method or 2 acceptable contraceptive methods up to 90 days after study product administration. A male or female has fertility potential if it is considered biologically viable by the investigator and has active sexual life. Patients and their partners who have been surgically sterilized less than 6 months prior to the day of informed consent must agree to use any medically acceptable method of contraception.

3. Female patients without fertility potential must meet at least 1 of the following criteria: a) The post-stop state is achieved as defined below: stopping regular menstruation for at least 12 consecutive months without alternative pathogenetic or physiological etiology; and has a serum FSH level confirming post-menopausal status; b) Undergo recorded hysterectomy and/or bilateral ovariectomy; and c) completing the medical diagnosis of ovarian failure.

4. Female patients with fertility potential must agree on the following combinations of TWO until 90 days after study product administration: a) Method of preventing contraception: condoms (male or female) with or without spermicide, caps or caps with spermicide; b) IUD; and c) a contraceptive based on a hormone.

5. Female patients may not be pregnant, nursing or breastfed or are scheduled to become pregnant (including egg feeding) within 90 days of the last study drug administration.

6. Female patients must have a negative result of the serum pregnancy test at screening and follow-up.

7. Before day 1, it was diagnosed with AD or HS for at least 6 months.

8. Patients with AD: at least 25% treatable body surface area (excluding scalp and designated venous access area) was present at screening or at admission.

9. At screening or on day-1, investigators with moderate (3) or severe (4) static overall assessment scores.

10. Having a weight of 17.5 to 35.0kg/m ² BMI of (b); overall weight>50kg(110lb)。

11. Evidence of an informed consent record of the individual sign up and selected date indicates that the patient has been informed of all relevant aspects of the study.

12. Patients willing and able to follow scheduled questionnaires, treatment plans, laboratory tests, and other research procedures.

13. Venous access was performed with a venous access site with AD unaffected, uninfected skin to allow repeated PK sampling.

Exclusion criteria

For healthy volunteers (part A and B)

Healthy volunteers meeting any of the following criteria will be excluded from the study:

1. Healthy volunteers that did not meet the inclusion criteria above.

2. Healthy volunteers tended to scar around the keloid scar (excluded only in part B).

3. Pregnant, women attempting to become pregnant or lactating HV.

4. Healthy volunteers with a clinically relevant medical history or presence of respiratory, GI, kidney, liver, blood, lymph, nerve, cardiovascular, mental, musculoskeletal, genitourinary, immune, skin or connective tissue diseases or disorders;

5. healthy volunteers with clinically relevant surgical history.

6. Healthy volunteers with clinically relevant family history.

7. Healthy volunteers with a history of related specific reactions, including any confirmed significant allergic reaction (rubella or systemic allergic reaction) or multiple drug allergies (inactive hay fever is acceptable) to any drug.

8. Healthy volunteers with a history of related drug allergy.

9. Healthy volunteers with history of alcoholism.

10. Healthy volunteers with history of drug abuse.

11. Healthy volunteers with any known factor, condition or disease, study implementation or interpretation of the outcome (e.g. drug or alcohol dependence or mental illness) that may interfere with therapeutic compliance.

12. Healthy volunteers positive for alcohol and drugs of abuse were tested at screening and at each occasion. Note that at least 48 hours prior to screening, alcohol intake is not allowed prior to each return visit;

13. Healthy volunteers consuming more than 14 units of alcohol a week. (unit = 1 glass red wine (125 mL) = 1 spirit measurement = 1/2 pint beer).

14. Healthy volunteers smoked or smoked (or equivalent) and/or used or already used nicotine-based products within 6 months prior to admission.

15. Healthy volunteers exhibiting excessive xanthine consumption (more than 8 cups of coffee or equivalent per day).

16. Healthy volunteers with significant infection or known inflammatory processes at screening.

17. Healthy volunteers with acute GI symptoms (e.g., nausea, vomiting, diarrhea, heartburn) at the time of screening or admission.

18. Healthy volunteers with acute infection, such as influenza, at screening or admission.

19. Healthy volunteers who did not agree to use a highly effective, medically acceptable contraceptive method.

20. Results from clinical laboratory safety tests on healthy volunteers out of local reference range at screening and admission

21. Healthy volunteers with positive hepatitis b surface antigen, hepatitis c antibody, hepatitis b core antibody, hepatitis c antibody or Human Immunodeficiency Virus (HIV) antibody, SARS-CoV-2 infection at any time within 3 months prior to study, or other known infections requiring antibiotic therapy.

22. Healthy volunteers with positive QuantiFERON gold test and/or history of pulmonary tuberculosis.

23. After at least 5 minutes of supine placement, healthy volunteers with screening supine BP ∈140mm Hg (contractility) or ≡90mm Hg (diastole) were not present. If BP is 140mm Hg (systolic) or 90mm Hg (diastolic), BP should be repeated 2 more times and an average of 3 BP values should be used to determine HV eligibility.

24. Healthy volunteers screening for supine 12-lead ECG demonstrated QTc interval >450 milliseconds or QRS interval >120 milliseconds. If QTc exceeds 450 milliseconds or QRS exceeds 120 milliseconds, the ECG should be repeated 2 more times and the average of 3 QTc or QRS values should be used to determine the eligibility of HV.

25. Healthy volunteers using any prescribed drug within 30 days of study product administration or less than 5 half-lives (whichever is longer).

26. Healthy volunteers taking non-steroidal anti-inflammatory drugs within 30 days of study product administration or less than 5 half-lives (longer).

27. Healthy volunteers on over-the-counter medication that did not include conventional vitamins and acetaminophen, but included a large dose (20 to 600 times the recommended daily dose) of vitamin therapy had been used within 7 days of the first dose.

28. Healthy volunteers enrolled in any study drug or device clinical study 3 months prior to the first dose of this study.

29. Healthy volunteers have previously participated in research products or devices involving biological administration of a target of any immune pathway within 1 year prior to screening.

30. Healthy volunteers who had received the last dose of study product but subsequently prolonged follow-up before more than 3 months.

31. Healthy volunteers who received KT-474 in another study or group previously in this study.

32. Healthy volunteers who had lost or had been supplied with more than 500mL of blood within 3 months prior to screening or who were intended to be supplied with blood or blood products during the study.

33. Healthy volunteers of grapefruit, grapefruit juice, seville oranges, seville orange pectin, and Seville orange juice or other products containing grapefruit or Seville orange have been consumed 7 days before entering the research center and for the duration of the residential period.

34. A healthy volunteer for a investigator site staff and its family members who are directly involved in a study, a site staff who is otherwise supervised by an investigator, or an employee who is directly involved in the study, including its family members.

35. Healthy volunteers either pure vegetarian or with medical meal restrictions.

36. Healthy volunteers who cannot reliably communicate with the investigator.

37. Healthy volunteers who are unlikely to cooperate with the study requirements.

For patients (section C)

Patients meeting any of the following criteria will be excluded from the study:

1. under the investigator's view, there are any clinically significant medical disorders, conditions, diseases (including active or potentially recurrent skin conditions other than AD or HS), significant physical examination or laboratory findings that may interfere with the study objective (e.g., conditions or findings that may expose the patient to unacceptable risk, confound treatment response or adverse event assessment or otherwise interfere with the patient's ability to complete the study by study participation).

2. With unstable AD or HS or a consistent requirement for potent to most potent topical corticosteroids to manage signs and symptoms of AD or HS.

3. Active systemic or local infections, including AD or HS, known as active infections.

4. A patient with allergic rhinitis who has a history or sign of clinically significant or severe allergy (e.g. seasonal, pet dander, environment, food) in need of acute or chronic treatment (who does not need treatment or who is on-going allergy treatment meeting the definition of one or more concomitant under-treatment stabilization regimens may be eligible to participate in the study).

5. There was a recent history of sunbath, tanning bed usage, or Ultraviolet (UV) light B therapy or psoralen plus UV a (sunbath, tanning bed usage, and UV light therapy were inhibited during the study period (within 4 weeks of day 1).

6. From screening to the end of the study, there are any planned surgical or medical procedures that will overlap with study participation.

7. With any cancer or with a history of cancer over the past 5 years (except for treatment with surgically resected squamous cell carcinoma, basal cell carcinoma or in situ cancer of the skin or cervix).

8. With a known sensitivity to any of the components of the research product.

9. Testing positive urine medicine.

10. More than 7 drinks per week for female patients or a conventional drinking history of 14 drinks per week for male patients (1 drink = 5 oz [150mL ] red wine or 12 oz [360mL ] beer or 1.5 oz [45mL ] white wine) within 6 months prior to screening.

11. Treatment with the study product was performed within 30 days or 5 half-lives (whichever is longer) before the first dose of study product.

12. Treatment with CYP3A4 and P-gp inhibitors was performed within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study product.

13. After at least 5 minutes of supine placement, supine BP was screened for either 140mm Hg (systolic) or 90mm Hg (diastolic). If BP is 140mm Hg (systolic) or 90mm Hg (diastolic), BP should be repeated 2 more times and an average of 3 BP values should be used to determine eligibility for the patient.

14. Screening supine 12 lead ECG confirmed QTc interval >450 milliseconds or QRS interval >120 milliseconds. If QTc exceeds 450 milliseconds or QRS exceeds 120 milliseconds, the ECG should be repeated 2 more times and the average of 3 QTc or QRS values should be used to determine eligibility of the patient.

15. As assessed by a particular research laboratory and determined by a single repeat test (if deemed necessary), patients did not have any of the following abnormalities in the clinical laboratory test at the time of screening: a) The content of aspartate aminotransferase or ALT is more than or equal to 1.5 xULN; b) The total bilirubin content is more than or equal to 1.5 XULN; patients with a history of Gibber's syndrome may have direct measurement of bilirubin and will be eligible for this study, provided that the direct bilirubin content is less than or equal to ULN.

16. No prescription or over-the-counter drugs including topical corticosteroids, vitamins and dietary supplements were used for 14 days or 5 half-lives (longer) prior to the first dose of study product. As an exception, acetaminophen/paracetamol (only if necessary) can be used in a dosage of 1 g/day or less. It is believed that limited use of non-prescription drugs that do not affect patient safety or overall study results may be warranted on a case-by-case basis after approval by the sponsor. The herbal nutritional supplements (including san johnsons) must be discontinued for at least 28 days prior to the first dose of the study product.

17. Pregnant female patients; a lactating female patient; female patients with fertility potential who are unwilling or unable to use the highly effective contraceptive method as outlined in the present protocol for the duration of the study and at least 90 days after the last dose of study product.

18. Approximately ≡400mL of blood (excluding plasma donors and platelet donors) or ≡200mL of blood was supplied within 3 months prior to dosing.

19. Has a history of susceptibility to heparin or heparin-induced thrombocytopenia.

History of hiv, hepatitis b, hepatitis c or syphilis; positive test for HIV, hepatitis b virus surface antigen, hepatitis b virus core antibody, hepatitis c virus antibody, syphilis or SARS-CoV-2 infection.

21. Is unwilling or unable to meet the criteria in this scenario.

22. For a investigator site staff and its family members who are directly involved in a study, a site staff who is otherwise supervised by an investigator, or an employee who is directly involved in the study, including patients of its family members.

23. Other acute or chronic medical or psychiatric conditions, including recent (over the past year) or active suicidal ideation or behavioral or laboratory abnormalities that may increase the risk associated with study participation or study product administration or may interfere with interpretation of the study results, and the investigation of inNIV diagnosis by the investigator makes patients unsuitable for entering this study.

Treatment group and study duration: the 2 treatment groups were compound a and placebo.

● Part a: screening (26 days), pre-treatment constraints (2 days), treatment (1 day), post-treatment constraints (5 days) and tracking (13 days).

● Part B: screening (26 days), pre-treatment constraints (2 days), treatment (14 days), post-treatment constraints (7 days) and tracking (7 days).

● Part C: screening (40 days), constraints before treatment (2 days), treatment (14 days) and tracking (14 days).

Study targets:

the main object is:

● Determination of safety and tolerability of Compound A when administered in HV at increasing dose levels in single and multiple oral doses and following multiple doses in patients with AD or HS

Secondary objective:

● To characterize PK profile of compound a and its diastereoisomers, compound B and compound C, after single and multiple doses of compound a in HV and after multiple doses in patients with AD or HS.

Exploring the target:

● PD patterns of compound a were characterized after single and multiple doses in HV and after multiple doses in patients with AD or HS.

● The concentration of compound a in the skin after multiple doses in HV and patients with AD or HS was characterized.

● The effect of food on the PK profile of compound a and its diastereoisomers, compound B and compound C, after a single dose of compound a in HV was evaluated.

● Compound a metabolite profile after multiple doses of compound a in HV was assessed.

● Blood and skin were assessed for candidate biomarkers for messenger ribonucleic acid (mRNA) after HV and multiple doses of compound a in patients with AD or HS.

Study endpoint:

the main end point is:

● Treatment induces (severe) adverse events ([ S ] AE)

● Concomitant medication

● Clinical laboratory testing

O-hematology

Condensation circle

Chemical method

Urine analysis and urine microscopy

● Vital signs

Pulse rate (bpm)

Systolic Blood Pressure (BP) (mm Hg)

Diastolic BP (mm Hg)

Respiratory rate o

Temperature o

● Safety electrocardiogram and dynamic electrocardiogram

Heart rate (bpm), PR, QRS, QT, QTcF

Secondary endpoint:

● Pharmacokinetic assessment in HV and patients with AD or HS

The following (but not limited to) plasma PK parameters for compound a, compound B and compound C will be calculated as needed:

plasma concentration-time from time zero to infinite time area under curve [ AUC (0- ≡) ] (single dose only) area under plasma concentration-time curve from time zero to last measurable concentration [ AUC (0-last) ], area under concentration-time curve during dosing interval [ AUC (0- τ) ] maximum observed concentration (Cmax), time to Cmax (tmax), apparent clearance (CL/F), apparent distribution volume (Vz/F), terminal half-life (t 1/2), mean Residence Time (MRT), and dose normalized AUC and Cmax

After repeated administration only, the cumulative ratio (RAUC, RCmax), the average concentration (Cavg) within the administration interval, and the concentration at the end of the administration interval (Ctrough)

Diastereomer ratio: ratio of diastereomeric Compound B to Compound C (Cmax, AUC and concentration per sampling time)

The following (but not limited to) urine PK parameters for compound a, compound B and compound C in the SAD and MAD groups will be calculated as needed:

acquisition interval and accumulation amount: unchanged drug secreted in urine [ Ae (t 1-t 2), ae (0-t) ], unchanged drug fraction [ fe (t 1-t 2), fe (0-t) ]

Kidney Clearance (CLR)

Exploring the end point:

the main end point is:

● Pharmacodynamic endpoint

IRAK4 content in Whole blood by FLOW (part A, B, C)

IRAK4 content in peripheral blood mononuclear cells by Mass Spectrometry (MS) (parts A, B and C)

IRAK4 content in skin puncture biopsy by MS and immunofluorescence (parts B and C)

Proinflammatory cytokines and chemokines (parts B and C) in skin punch biopsies by MS and Gene Expression Profile (GEP)

Proinflammatory cytokine and chemokine production after ex vivo stimulation of whole blood by flow fluorometry (parts A and B)

Plasma hypersensitive C-reactive protein content by flow fluorometry (section B and C)

Plasma serum amyloid A and pro-inflammatory cytokines analyzed by flow fluorometry and ELISA, which may include, but are not limited to, tumor necrosis factor-alpha, interleukin (IL) -6, IL-1 beta, IL-4, and IL-5 (only part C)

mRNA content variation by RNAseq in PBMC (part B and C)

● Pharmacokinetic endpoint

AUC (0- +), AUC (0-last), cmax, tmax, CL/F, vz/F, t1/2, MRT, F (relative bioavailability fed/fasted) and dose normalized AUC and Cmax for compound a, compound B and compound C suitable for FE studies.

Metabolic profile (metabolite in safety test [ MIST analysis) will be performed on PK samples from the 2 high dose HV MAD groups after study completion and will not be part of the clinical study report.

Compound a concentration in skin perforation biopsy (parts B and C)

The statistical method comprises the following steps:

safety and tolerability

All data will be listed in full. The report of safety data for all study participants receiving at least 1 dose of compound a or placebo will include the incidence and type of AEs, as well as the absolute values and changes in BP, heart beat rate, oral temperature, clinical laboratory data, physical examination, neurological examination data, and 12-lead electrocardiogram data from pre-dose to post-dose time points.

Pharmacokinetics of drugs

Analysis of PK data will be performed for all study participants receiving a dose of compound a. Pharmacokinetic parameters for compound a, compound B and compound C will be summarized and descriptive statistics (including mean, median, standard deviation and coefficient of variation) will be generated for each dose group. Dose ratios will be assessed graphically for AUC and Cmax. The relative bioavailability of the food effect will be assessed based on AUC and Cmax.

Pharmacodynamics of medicine

Pharmacodynamic analysis will be performed on all study participants receiving at least one dose of compound a or placebo. Analysis of IRAK4 content and modulation of pro-inflammatory cytokine and chemokine assessments would be considered exploratory. The mixed effect analysis of the differential model will be used to compare the pre-treatment IRAK4 content of the activity relative to placebo. The baseline IRAK4 content will be used as a covariate for the model. Study participants treated with placebo will be pooled throughout the group and used as a single treatment group for comparison with each active treatment group.

Phase 1 SAD results:

phase 1 SAD results included data from seven single dose groups of compound a, containing 57 healthy volunteer subjects grouped at 6:2 at random with a single oral dose of compound a or placebo. The data demonstrate a robust dose-dependent IRAK4 reduction in PBMCs maintained for up to 6 days as measured by mass spectrometry, resulting in 94-96% median IRAK4 reduction relative to baseline achieved at the first three dose levels at 48 hours post-dose, achieving strong mechanism demonstration (table 4). Flow cytometry revealed that the effect of compound a on IRAK4 content was similar to that in lymphocytes and monocytes.

TABLE 4 percent IRAK4 variation from baseline in PBMC at 48 hours post-dose using mass spectrometry

Biological demonstration was established by doses associated with a median IRAK4 reduction of ≡85% in PBMCs 24-48 hours post-dose and inhibition of ex vivo R848-mediated or LPS-mediated induction of multiple pro-inflammatory cytokines in whole blood at exposure, with an average maximum cytokine inhibition of up to 97% (table 5). Compound a exhibited oral bioavailability, half-life support for daily dosing, and dose-dependent plasma exposure at higher doses and plateau proportioned to less than the dose after 1000 mg. Compound a is safe and well tolerated; mild to moderate, self-limiting headache and GI symptoms are the most common reported treatment-related adverse events, and severe adverse events are not reported.

Table 5 average maximum percent change from baseline at 24-48 hours for ex vivo proinflammatory cytokines induced by R848 and LPS in whole blood at group 7.

Proinflammatory cytokines

IFNγ

IL1β

IL6

IL8

IL10

IL12

IL17

TNFα

R848

-97％ ²

-92％ ¹

-88％ ¹

-54％

-89％ ¹

-93％ ¹

-79％ ¹

-88％ ²

LPS

-42％

-68％ ¹

-62％ ¹

-81％ ¹

-83％ ¹

-35％ ²

-43％ ²

-42％ ²

¹ Value of =p<0.01； ² Value of =p<0.05 for comparison with placebo

In vivo ≡85% IRAK4 gene knockdown in circulating PBMCs caused robust TLR/IL-1R pathway inhibition as demonstrated by up to 97% inhibition of whole blood ex vivo response to TLR agonists. Daily dosing of compound a was assessed in the Multiple Ascending Dose (MAD) portion of the current trial; based on the PK profile of the drug and the observed PK-PD relationship, similar levels of IRAK4 degradation and cytokine inhibition with substantially lower daily doses are possible. The potent broad effects of IRAK4 gene knockout on a number of different pro-inflammatory cytokines involved in a number of autoimmune inflammatory diseases underscores the potential of compound a as a first class of oral anti-inflammatory drugs, especially for the constantly changing external environment of safe, widely active small molecule anti-inflammatory agents.

PK results are summarized in table 6 and figure 3.

TABLE 6 PK results

SAD number	Dosage of	Cmax(ng/mL)	tmax(h)	AUC(ng.h/mL)	t1/2(h)
						1	25mg	3.49(61.2)	8.0(6.0-8.0)	112(65.4)	25.2(27.0)
2	75mg	9.08(36.6)	7.0(6.0-8.0)	288(36.7)	28.7(10.1)
						3	150mg	12.7(25.7)	9.0(8.0-10.0)	483(21.9)	31.6(22.1)
4	300mg	17.4(29.6)	8.0(8.0-24.0)	848(30.4)	26.6(13.1)
						5	600mg	24.2(27.5)	12.0(6.00-24.0)	1520(17.4)	30.1(47.2)
6	1000mg	27.8(34.4)	20.0(6.0-24.0)	1950(63.5)	40.2(25.9)
						7	1600mg	27.3(36.2)	24.0(12.0-48.0)	1920(43.0)	36.4(46.9)

Consistent PK was observed after single dosing: cmax is achieved between 7-24 hours, half-life = 25-40 hours. An increased dose-dependent exposure was observed smoothly after the 1000mg dose, with a change in exposure between low to moderate subjects.

IRAK4 degradation results are shown in table 7 and fig. 4-6. Degradation was detected by mass spectrometry in circulating PBMCs. IRAK4 levels terminated at 48-72 hours (days 3-4) and IRAK4 reduction persisted for at least 6 days after dosing in all dose groups. SAD 5/6/7 achieves a lower limit of quantitation (LLOQ).

TABLE 7 percent IRAK4 reduction in PBMC at 48 hours post-dose using mass spectrometry

	N	Average IRAK4 variation	Median IRAK4 change	P value
					Placebo	13	-1％	-2％	--
25mg	6	-26％	-39％	0.1
					75mg	6	-73％	-75％	<0.0001
150mg	6	-81％	-82％	<0.0001
					300mg	6	-84％	-89％	<0.0001
600mg	7	-96％	-96％	<0.0001
					1000mg	5	-93％	-94％	<0.0001
1600mg	6	-95％	-95％	<0.0001

P-value relative to placebo

Blind SAD security: no SAE. All treatment-related AEs (table 8) recovered or resolved. No study treatment related AEs in any other group.

Clinically relevant laboratory abnormalities: SAD 5: n=1; ALT elevation (2.5×uln) -slow regression to baseline and AST elevation (3.8×uln), regression on day 21.

ECG results: there were no significant ECG changes and no clinically significant QTcF prolongation.

Table 8 study treatment related AE

* From investigator assessment

SAD overview:

single doses were well tolerated in SAD phase 1 studies, with mild self-limiting headache and GI symptoms being the most common treatment-related AEs seen at doses ≡600 mg. Compound a was stable, dose dependent and maintained (up to 6 days) IRAK4 reduction in PBMCs with median 94-96% KD (reaching the limit of quantitation) plateau 48 hours after 600 mg. Biological demonstration is established by demonstrating extensive and potent ex vivo cytokine inhibition in whole blood. Up to 79-97% inhibition induced by R848 or LPS of 8 different pro-inflammatory cytokines, comprising: IFN-g (97%), IL-12 (93%), IL-1b (92%), IL-10 (89%), IL-6 (88%), TNF-a (88%), IL-8 (81%) and IL-17 (79%) were observed. The maximum cytokine effect was seen with compound a exposure corresponding to >85% degradation in PBMCs. The compound ASAD phase 1 results confirm the mechanism demonstration and biological demonstration for target protein degradation in placebo-controlled studies.

Stage 1 MAD results:

phase 1 MAD results included data from four compound A multi-dose groups MAD 1-4 (25 mg, 50mg, 100mg, and 200mg QDs). The MAD portion of the study showed that once daily administration of compound a resulted in higher steady state exposure (fig. 9).

TABLE 9 steady state (day 14) PK parameters

Geometric mean (% CV) reported for all parameters except tmax, where median (range) is presented. The cumulative ratio represents the fold change in exposure from day 1 to day 14.

Compound a displayed 3 to 4 fold increase on day 14 exposure and day 14C _trough Appear in anticipation of>In the range of 90% irak4 degradation. Steady state was achieved at day 7 of dosing.

Figure 10 shows that compound a achieves complete and sustained IRAK4 degradation at multiple daily oral doses (14 days). IRAK4 degradation was detected by mass spectrometry in circulating PBMCs. Steady state IRAK4 reduction was achieved between day 7 and day 14 and returned to baseline on day 28 (2 weeks after the last dose). The 3 groups (MADs 2 through 4) in the MAD group were near or exceeded the lower limit of quantification (LLOQ).

Figure 11 shows that lower doses of compound a achieved a plateau of >98% IRAK4 degradation by mass spectrometry with IRAK4 reduction in PBMCs after 100mg administration.

FIG. 12 shows that compound A achieved >90% degradation in monocytes at > 100mg as detected by flow cytometry and that maximum degradation in monocytes was observed at day 14 in 200mg dosing

Figure 13 shows that once daily dosing resulted in high skin exposure beyond plasma. The results show an increased exposure up to day 14, wherein C in the skin _trough The content was about 10 times higher than the plasma on day 14.

Figure 14 shows that compound a administered at 200mg reduced IRAK4 near LLOQ in skin at day 14 as determined by mass spectrometry, gene knockdown at 200mg up to 90%. The baseline IRAK4 content of skin is substantially lower compared to PBMC. Similar degradation in PBMCs showed that the effect of compound a was independent of baseline expression levels.

Figure 15 shows substantial IRAK4 degradation in the dermis and epidermis of the skin.

Figure 16 shows ex vivo cytokine inhibition in whole nine disease-associated cytokines and chemokines on days 7-14.

MAD overview:

multiple daily doses of up to 200mg (MAD 4) over 14 days were safe and well tolerated. Steady state plasma levels were reached on day 7, with exposure on day 14 being increased approximately 3-fold over day 1. Complete IRAK4 gene knockout in PBMC is comparable to SAD, achieved at substantially lower doses: between day 7 and day 14 >95% decrease at 50-200mg at steady state. MAD results showed that the strongest inhibition induced by the ex vivo cytokines at 100mg, corresponding to >90% degradation in monocytes, was comparable to the administration of SAD at 1000-1600 mg. Drug accumulation was observed in the skin up to day 14, resulting in a pre-dose content that was about 10 times higher than plasma. Dose-dependent IRAK4 degradation achieved in skin on day 14 >65%, correlated with skin compound a content; higher exposure in skin seems to be required for IRAK4 KD compared to blood.

While a number of embodiments of the invention have been described, it will be apparent that the underlying examples can be varied to provide other embodiments that utilize the compounds and methods of the invention. It is, therefore, to be understood that the scope of the invention is to be defined by the application and the appended claims, and not by the specific embodiments presented herein by way of example.

Claims

1. A spray-dried formulation comprising compound a or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable polymer;

wherein compound a is 5- ((1 r,4 r) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -N- (3- (difluoromethyl) -1- ((1 r,4 r) -4- ((4- ((3- (1- (2, 6-dioxopiperidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-4-yl) prop-2-yn-1-yl) oxy) piperidin-1-yl) methyl) cyclohexyl) -1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide.

2. The spray-dried formulation of claim 1 comprising compound a free base.

3. The spray-dried formulation of claim 1 comprising compound a HCl.

4. The spray dried formulation of any one of claims 1-3, wherein the pharmaceutically acceptable polymer is selected from PVP-VA, HPMC, HPMCP-55, HPMCAS-M, TPGS, HPMCAS-L and MCC.

5. The spray-dried formulation of any one of claims 1-4, comprising about 20% -40% wt/wt compound a or a pharmaceutically acceptable salt thereof.

6. The spray-dried formulation of any one of claims 1-5, comprising about 60% -80% wt/wt of a pharmaceutically acceptable polymer.

7. The spray dried formulation of any one of claims 1 to 6, comprising 25:75 (% wt/wt) compound a free base HPMCAS-M.

8. A unit dosage form comprising the spray-dried formulation of any one of claims 1 to 7.

9. The unit dosage form of claim 8, wherein the spray-dried formulation comprises about 45% -55% wt/wt of the unit dosage form.

10. The unit dosage form according to claim 8 or 9, further comprising a filler, wherein the filler is selected from mannitol, microcrystalline cellulose, or mixtures thereof.

11. The unit dosage form of any one of claims 8-10, further comprising a slip agent, wherein the slip agent is colloidal silica.

12. The unit dosage form according to any one of claims 8-11, further comprising a disintegrant, wherein the disintegrant is croscarmellose sodium.

13. The unit dosage form of any one of claims 8-12, further comprising a solubility enhancing agent, wherein the solubility enhancing agent is hydroxypropyl-beta-cyclodextrin (HP beta CD).

14. The unit dosage form according to any one of claims 8-13, further comprising a lubricant, wherein the lubricant is sodium stearyl fumarate.

15. The unit dosage form of any one of claims 8-14, comprising about 10-500mg of compound a or a pharmaceutically acceptable salt thereof.

16. The unit dosage form of any one of claims 8-15, comprising about 25mg or about 100mg of compound a or a pharmaceutically acceptable salt thereof.

17. The unit dosage form of any one of claims 8-16, which is a tablet of about 208mg comprising:

i) About 200mg of tablet core comprising

18. The unit dosage form of any one of claims 8-16, which is a tablet of about 824mg comprising:

i) About 800mg of tablet core comprising

19. A method for treating an autoimmune/autoimmune disease or hematological malignancy in a patient, comprising administering to the patient a therapeutically effective amount of the spray-dried formulation of any one of claims 1-7 or the unit dosage form of any one of claims 8-18.

20. The method of claim 19, wherein the autoimmune/autoimmune disease is selected from skin, rheumatic and gastrointestinal autoimmune/autoimmune diseases.

21. The method of claim 20, wherein the autoimmune/autoimmune disease is a skin autoimmune/autoimmune disease selected from the group consisting of Atopic Dermatitis (AD) and Hidradenitis Suppurativa (HS).

22. The method of any one of claims 18-21, wherein the method comprises administering up to about 1600mg of compound a, or a pharmaceutically acceptable salt thereof, to the patient.

23. The method of any one of claims 19-22, wherein the method comprises administering up to about 1400mg of compound a, or a pharmaceutically acceptable salt thereof, to the patient.

24. The method of any one of claims 19-23, wherein the method comprises daily administration of about 25-1400mg (e.g., about 25mg, about 50mg, about 100mg, about 150mg, about 200mg, about 500mg, about 1000mg, or about 1400 mg) of compound a, or a pharmaceutically acceptable salt thereof, to the patient.

25. The method of any one of claims 19-23, wherein the method comprises administering at most 100mg, at most 150mg, or at most 200mg of compound a, or a pharmaceutically acceptable salt thereof, daily.

26. The spray-dried formulation according to any one of claims 1 to 7 or the unit dosage form according to any one of claims 8 to 18 for use in the manufacture of a medicament for the treatment of autoimmune/autoimmune inflammatory diseases or hematological malignancies in a patient.

27. The use according to claim 26, wherein the autoimmune/autoimmune disease is selected from skin, rheumatic and gastrointestinal autoimmune/autoimmune diseases.

28. The use according to claim 27, wherein the autoimmune/autoimmune disease is a skin autoimmune/autoimmune disease selected from Atopic Dermatitis (AD) and Hidradenitis Suppurativa (HS).

29. The use of any one of claims 26-28, wherein the method comprises administering up to about 1600mg of compound a, or a pharmaceutically acceptable salt thereof, to the patient.

30. The use of any one of claims 26-29, wherein the method comprises administering up to about 1400mg of compound a, or a pharmaceutically acceptable salt thereof, to the patient.

31. The use of any one of claims 26-30, wherein the method comprises daily administration of about 25-1400mg (e.g., about 25mg, about 50mg, about 100mg, about 150mg, about 200mg, about 500mg, about 1000mg, or about 1400 mg) of compound a, or a pharmaceutically acceptable salt thereof, to the patient.

32. The use of any one of claims 26 to 30, wherein the method comprises daily administration of up to 100mg, up to 150mg, or up to 200mg of compound a, or a pharmaceutically acceptable salt thereof.