Peptide inhibitors of interleukin-23 receptor and uses thereof

Abstract

Uses of a peptide inhibitor of the interleukin-23 receptor (IL-23R) or a pharmaceutically acceptable salt or solvate form thereof for the treatment of generalized pustular psoriasis or erythrodermic psoriasis are described.

Description

Peptide Inhibitors of Interleukin-23 receptor and uses thereofCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 618,791, filed January 8, 2024, and U.S. Provisional Application No. 63 / 561,640, filed March 5, 2024, which are incorporated herein in all their entirety.FIELD

[0002] The present invention relates to methods for treatment of generalized pustular psoriasis or erythrodermic psoriasis using a peptide inhibitor of the interleukin-23 receptor (IL-23R), or a pharmaceutically acceptable salt or solvate form thereof.BACKGROUND

[0003] Generalized Pustular Psoriasis (GPP) is rare and represents active, unstable disease. The patient is pyrexial with red, painful, inflamed skin studded with monomorphic, sterile pustules which may coalesce to form sheets. Patients with GPP frequently need to be admitted to the hospital for management. Total or subtotal involvement of the skin by active psoriasis is known as Erythrodermic Psoriasis (EP). Chronic plaque psoriasis may gradually progress as plaques become confluent and extensive. EP may impair the thermoregulatory capacity of the skin, leading to hypothermia, high output cardiac failure, and metabolic changes including hypoalbuminemia and anemia due to loss of iron, vitamin B 12, and folate (Langley 2005, Ann Rheum Dis., 64 Suppl 2(Suppl 2):ii 18-ii25). Multiple therapies have been approved in Japan, however, there are still substantial unmet need for GPP and EP.

[0004] IL-23 is a heterodimer composed of a unique pl9 subunit and the p40 subunit shared with IL- 12, which is a cytokine involved in the development of interferon-y (IFN-y)-producing T helper 1 (TH1) cells. Although IL-23 and IL- 12 both contain the p40 subunit, they have different phenotypic properties. For example, animals that are deficient in IL- 12 are susceptible to inflammatory autoimmune diseases, whereas IL-23 deficient animals are resistant to such diseases, presumably due to a reduced number of CD4+ T cells producing IL-6, IL-17, and TNF in the CNS of IL-23 -deficient animals. IL-23 binds to IL-23R. Binding of IL-23 to IL-23R activates the Jak-Stat signaling molecules, Jak2, Tyk2, and Statl , Stat 3, Stat 4, and Stat 5, although Stat 4 activation is substantially weaker. In addition, different DNA-binding Stat complexes form in response to IL-23 as compared with IL- 12. IL-23R associates constitutively with Jak2 and in a liganddependent manner with Stat 3. In contrast to IL- 12, which acts mainly on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells.

[0005] Currently, there are no GPP-specific therapies approved in the USA or Europe. Monoclonal antibodies targeting the pl9 subunit of IL-23, such as guselkumab (Blauvelt 2017, J Am Acad Dermatol. 2017;76(3):405-417; Reich 2017, J Am Acad Dermatol. 2017;76(3):418-431) and Risankizumab (Gordon 2018, Lancet., 392( 10148) :650-661 ), have been approved for the treatment of GPP and EP in Japan (Sano 2018, J Dermatol., 45(5):529-539; Yamanaka 2023, J Dermatol., 50(2):195-202).

[0006] However, there is an unmet need for oral therapies for treating GPP and / or EP with high efficacy, long-term clinical remission, and good safety profile.SUMMARY OF THE INVENTION

[0007] The present invention addresses these needs by providing a peptide inhibitor or pharmaceutically acceptable salt or solvate forms thereof for use in oral administration to a subject in need of a treatment of Generalized Pustular Psoriasis (GPP) or Erythrodermic Psoriasis (EP).

[0008] Accordingly, in one general aspect, the invention provides a method for treating generalized pustular psoriasis or erythrodermic psoriasis in a subject in need thereof, comprising orally administering to the subject an effective amount of 100-300 mg per day of a compound of Formula (I):an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.

[0009] Some embodiments provide a method for treating generalized pustular psoriasis or erythrodermic psoriasis in a subject in need thereof, comprising orally administering to the subject an effective amount of 200 mg per day of a compound of Formula (I):an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.

[0010] In some embodiments, the effective amount is 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg per day of the compound of Formula (I), or an equivalent amount of the pharmaceutically acceptable salt or solvate thereof.

[0011] In some embodiments, the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof is administered at least once daily.

[0012] In some embodiments, the subject is fasting for at least 2 hours before the administering.

[0013] In some embodiments, wherein the subject takes Formula (I) or the pharmaceutically acceptable salt or solvate thereof on an empty stomach first thing in the morning.

[0014] In some embodiments, the subject is fasting for at least 30 minutes after the administering.

[0015] In some embodiments, the subject has received treatment methotrexate (MTX) or cyclosporine prior to receiving the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

[0016] In certain embodiments, the subject has a stable dose of <20mg / week methotrexate (MTX) or a stable dose of <5 mg / kg / day cyclosporine at least two weeks before the first administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof, provided that the subject is not on both MTX and cyclosporine at the same time from 2 weeks before the first administration of study intervention.

[0017] In some embodiments, the subject has received treatment with a stable dose of retinoid at least 2 weeks before the first administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

[0018] In some embodiments, the subject is a candidate for phototherapy or has a history of phototherapy prior to the treatment.

[0019] In some embodiments, the subject is a candidate for systemic treatment for psoriasis prior to the treatment or has a history of phototherapy or systemic treatment for psoriasis.

[0020] In some embodiments, the subject is an adult. In other embodiments, the subject is an adolescent.

[0021] In some embodiments, the subject has generalized pustular psoriasis prior to the treatment.

[0022] In certain embodiments, the subject has erythrodermic psoriasis (EP), a history of plaquetype psoriasis, and body surface area (BSA) of involvement of lesion for EP >80% prior to the treatment.

[0023] In some embodiments, the subject has GPP and a treatment using the compound of formula (I) as described herein achieves at least "minimally improved" rating, preferably “much improved” rating, more preferably “very much improved”, in Clinical Global Impression (CGI) scale according to Japanese Dermatological Association (JDA) total score), preferably at Week 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

[0024] In some embodiments, the subject has EP and a treatment using the compound of formula (I) as described herein achieves at least "minimally improved" rating, preferably “much improved” rating, more preferably “very much improved”, in Clinical Global Impression (CGI) scale, preferably at Week 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

[0025] In certain embodiments, the GPP or EP is successfully treated by a compound of formula (I),, as measured by at least one, two, three, four, five, six, seven, eight or nine of the following over time: (1) changes from baseline in the total score of the JDA severity index for GPP over time; (2) change in baseline in severity classification (mild, moderate, severe) of the JDA severity index for GPP over time; (3) change from baseline in body surface area (BSA) of involvement of lesion for EP over time; (4) achievement of an Investigator’s Global Assessment (IGA) score of cleared (0) or minimal (1) over time; (5) achievement of an IGA score of cleared (0) over time; (6) Percent improvement from baseline in Psoriasis Area and Severity Index (PASI) over time; (7) change from baseline in Dermatology Life Quality Index (DLQI) score over time; (8) achievement of a DLQI score of 0 or 1 over time; and (9) change from baseline in EQ-5D-5L (domain scores and visual analog scale [VAS]) over time.

[0026] Further aspects, features and advantages of the present invention will be described in the detailed description of the invention and claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The foregoing and other objects, aspects, features, and advantages of exemplary embodiments will become more apparent and may be better understood by referring to the following description taken in conjunction with the accompanying drawings.

[0028] FIG. 1 illustrates a schematic overview of the study protocol of Example 1 . DBL = database lock, EP = Erythrodcrmic Psoriasis, GPP = Generalized Pustular Psoriasis, PE = primary endpoint, SE = secondary endpoint. Additional DBLs may occur after week 24 to support regulatory submissions and scientific disclosures.

[0029] FIG. 2 shows an XRPD pattern of a crystalline form of a hydrochloride salt of a compound of Formula (I).DETAILED DESCRIPTION OF THE INVENTION

[0030] The disclosed methods may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures, which form a part of this disclosure. It is to be understood that the disclosed methods are not limited to the specific methods described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods. All patents, published patent applications, and publications cited herein are incorporated by reference as if set forth fully herein.

[0031] Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

[0032] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a cell” includes a combination of two or more cells, and the like.

[0033] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list, and every combination of that list, is a separate embodiment. Forexample, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0034] Unless otherwise stated, any numerical values, such as a concentration or a concentration range described herein, are to be understood as being modified in all instances by the term “about.” Thus, a numerical value typically includes ± 10% of the recited value. For example, a concentration of 1 mg / mL includes 0.9 mg / mL to 1.1 mg / mL. Likewise, a concentration range of 1% to 10% (w / v) includes 0.9% (w / v) to 11% (w / v). As used herein, the use of a numerical range expressly includes all possible subranges, all individual numerical values within that range, including integers within such ranges and fractions of the values unless the context clearly indicates otherwise.

[0035] Unless otherwise indicated, the term “at least” preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the invention.

[0036] The transitional terms “comprising.” “consisting essentially of,” and “consisting of’ are intended to connote their generally accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) “consisting of” excludes any element, step, or ingredient not specified in the claim; and (iii) “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. Embodiments described in terms of the phrase “comprising” (or its equivalents) also provide as embodiments those independently described in terms of “consisting of’ and “consisting essentially of.”

[0037] It should also be understood that the terms “about,” “approximately,” “generally,” “substantially” and like terms, used herein when referring to a dimension or characteristic of a component of the preferred invention, indicate that the described dimension / characteristic is not a strict boundary or parameter and does not exclude minor variations therefrom that are functionally the same or similar, as would be understood by one having ordinary skill in the art. At a minimum, such references that include a numerical parameter would include variations that,using mathematical and industrial principles accepted in the art (e.g., rounding, measurement or other systematic errors, manufacturing tolerances, etc.), would not vary the least significant digit.

[0038] “Administering” refers to administration of the composition of the present invention to a subject.

[0039] A “fasted” state refers to abstaining from food intake for at least 2 hours before administration of the composition of the present invention and abstaining from food and liquid intake for at least 30 minutes after administration of the composition of the present invention.The “BSA”, or Body Surface Area, is a commonly used measure of involvement of skin disease. It is defined as the percentage of surface area of the body involved with the condition being assessed, (ie, GPP or EP). The handprint method for assessing BSA will be used in this study, where the surface area of the participant's hand including the palm and all 5 digits is used as a guide to estimate 1% BSA (Long CC, Finlay AY, Averill RW. The rule of hand: 4 hand areas = 2 FTU = 1 g. Arch Dermatol 1992; 128:1129-1130; Rossiter ND, Chapman P, Haywood IA. How big is a hand? Bums 1996; 22:230-231; Thomas CL, Finlay AY. The 'handprint' approximates to 1% of the total body surface area whereas the 'palm minus the fingers' does not. Br I Dermatol. 2007;157(5):1080-1081).

[0040] “Composition” as used herein is intended to encompass a product that includes the specified active product ingredient (API) (i.e., as defined in the instant specification as a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof) and pharmaceutically acceptable excipients, carriers or diluents as described herein, which results from combination of specific components.

[0041] The “Clinical Global Impressions Scale” or “CGI scale” is a tool to quantify and track patient progress and treatment response over time. It was developed for use in clinical trials to provide a brief, stand-alone assessment of the clinician's view of the patient's global functioning prior to and after initiating a study medication. The CGI scale provides an overall clinician- determined summary measure that takes into account all available information, including a knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function. The CGI has two components — the CGLSeverity, which rates illness severity, and the CGLImprovement (CGLI), which rates change from the initiation (baseline) of treatment. In particular, the CGI-S score obtained at the baseline (initiation) visit serves as a basis for making the assessment of CGI-I, which ismeasured by comparing the patient's overall clinical condition after the treatment to the CGI-S at the baseline. Evaluation for CGI will include comparison to the previous assessment at screening, comparison to screening assessment at Week 0, and comparison to Week 0 assessment for all other visits from Week 2. See, e.g., Busner J., The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont) 2007; 4 (7): 28-37. In some embodiment, the CGI scale has a seven-point scale as compared to the patient's condition prior to medication initiation: I -very much improved since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no change from baseline (the initiation of treatment); 5=minimally worse; 6= much worse; 7=very much worse since the initiation of treatment. In some embodiment, the CGI scale has a five-point scale as compared to the patient's condition prior to medication initiation: 1= very much improved, 2 = much improved, 3 = minimally improved, 4=no change from baseline, 5 = worsened [5],

[0042] In some embodiments, for GPP, the rating of the CGI scale is based on JDA severity index. In certain embodiment, for EP, the rating will be as provided in the study manual.

[0043] The “IGA scale” refers to the Investigator’s Global Assessment documents the investigator’s assessment of the participant’s psoriasis at a given time point. Overall lesions are graded for induration, erythema, and scaling. The participant’s psoriasis is assessed as cleared (0), minimal (1), mild (2), moderate (3), or severe (4) (provided in the study manual).

[0044] The “IDA severity index”, or Japanese Dermatological Association severity index, for GPP consists of area of erythema with pustules, area of erythema (total), area of edema, fever, WBC, CRP, and serum albumin (provided in the study manual). The total score of JDA severity index for GPP ranges between 0 and 17 (O=best, 17=worst). Area of erythema with pustules, area of erythema (total), and area of edema are rated as 0 to 3. Fever, WBC, CRP, and serum albumin are rated as 0 to 2.

[0045] The CGI rating based on JDA severity index for GPP can be assessed using the following criteria:Table AReference; Fujita H, Terui T, Hayama K et al. Japanese guidelines for the management and treatment of generalized pustular psoriasis: The new pathogenesis and treatment of GPP. 2018; 45(11): 1235-1270.

[0046] The CGI rating for EP, e.g., 1. Very much improved, 2. Much improved, 3. Minimally improved, 4. No change and 5. Worsened (including minimally worse, much worse, very much worse) can be assessed using the following criteria:Table BReference: Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37.

[0047] A “PASI score” refers to a numerical value resulting from evaluation using the Psoriasis Area and Severity Index (PASI). PASI is a system used for assessing and grading the severity of psoriatic lesions and their response to therapy. In the PASI system, the body is divided into four regions: the head, trunk, upper extremities, and lower extremities. Each of these areas is assessed and scored separately for erythema, induration, and scaling, which are each rated on a scale of 0 to 4 and extent of involvement on a scale of 0 to 6. The PASI produces a numeric score (a “PASI score”) that can range from 0 to 72. A higher score indicates more severe disease.

[0048] As used herein, a “PASI xx response” indicates a greater than or equal to xx% reduction in Psoriasis Area and Severity Index (PASI) score after treatment as compared to before treatment. In an illustrative example, a PASI 50 response in a subject treated with the composition of the present invention is a subject that has a greater than or equal to 50% reduction in PASI score after treatment. Hence, a subject having a PASI 72 score before treatment and having a PASI 36 score or lower after treatment is said to achieve a PASI 50 response.

[0049] “Patient” or “subject” refers to a living organism, which includes, but is not limited to a human subject suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Further non-limiting examples may include, but are not limited to, humans or other mammals. In some embodiments, the subject is a human.

[0050] “Pharmaceutically acceptable” excipient includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals or as conventionally understood in or by skilled artisans who work in the formulary arts. Pharmaceutically acceptable salts of thecompounds of the present invention are salts formed with acids, such as of mineral acids, organic carboxylic and organic sulfonic acids, hydrochloric acid, mcthancsulfonic acid, maleic acid, arc also possible provided a basic group, such as an amine, constitutes pail of the structure.

[0051] “Salt” as used herein refers to acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic.

[0052] The compounds of the invention may form solvates, for example with water (i.e. hydrates) or common organic solvents. As used herein, the term “solvate” means a physical association of the compounds of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The term “solvate” is intended to encompass both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid or ethanolamine and the like. The compounds of the invention may exert their biological effects when they are in solution. Solvates are well known in the pharmaceutical industry. They can be important to the process for the preparation of a substance (e.g. in relation to their purification, the storage of the substance (e.g. its stability) and the ease of handling the substance and are often formed as part of the isolation or purification stages of a chemical synthesis. A person skilled in the art can determine whether a hydrate or other solvate has formed by the isolation conditions or purification conditions used to prepare a given compound using techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and X-ray crystallography (e.g., single X-ray crystallography or X-ray powder diffraction).

[0053] As used herein, a “stable dose” refers to an average daily dose of a therapy that varied by less than 30% between two consecutive treatment periods. Due to the severity of the GPP and / or EP diseases, a subject can have concomitant therapy such as methotrexate (MTX), retinoid, or cyclosporine with a treatment of a compound of Formula (I) or a pharmaceuticallyacceptable salt or solvate thereof. In certain embodiments, the dose of the concomitant therapy remains the same, e.g., is not increased or reduced at least two weeks before the subject receiving the treatment with a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the dose of the concomitant therapy is not increased after the subject receiving the treatment with a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the dose of the concomitant therapy remains substantially the same, e.g., is not increased or decreased, after the subject receiving the treatment with a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0054] “Therapeutically effective amount” or “effective amount” used interchangeably herein, refers to an amount of a compound or of a pharmaceutical composition useful for treating or ameliorating an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. "Therapeutically effective amount" further includes within its meaning a nontoxic but sufficient amount of the particular drug to which it is referring to provide the desired therapeutic effect. The exact amount required will vary from subject to subject depending on factors such as the patient's general health, the patient's age, etc. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0055] “Safe and effective amount" as used herein in the context of a dose, dosage regimen, treatment or method refer to the effectiveness of a particular dose, dosage, or treatment regimen. Efficacy can be measured based on change in the course of the disease in response to an agent of the present invention. For example, the IL-23 receptor antagonist of the present invention (e.g., the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof) is administered to a subject in an amount and for a time sufficient to induce an improvement, preferably a sustained improvement, in at least one indicator that reflects the severity of the disorder that is being treated. Various indicators that reflect the extent of the subject's illness, disease or condition can be assessed for determining whether the amount and time of the treatment is sufficient. Such indicators include, for example, clinically recognized indicators ofdisease severity, symptoms, or manifestations of the disorder in question. The degree of improvement generally is determined by a physician, who can make this determination based on signs, symptoms, biopsies, or other test results, and who can also employ questionnaires that are administered to the subject, such as quality-of-life questionnaires developed for a given disease. For example, an IL-23 receptor antagonist of the present invention can be administered to achieve an improvement in a subject’s condition related to psoriasis.

[0056] “Subject” includes any human or nonhuman animal. “Nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. The terms “subject” and “patient” can be used interchangeably herein.

[0057] “Treat”, “treating” and “treatment” refer to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation.

[0058] The term, “pharmaceutical product” is product that contains an active pharmaceutical ingredient that has shown to be a safe and effective treatment of one or more indications as supported by findings from clinical trials regulated by a governmental authority, e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the Japan Pharmaceuticals and Medical Devices Agency, or the similar authority in other countries.

[0059] In one general aspect, the application relates to a method for treating generalized pustular psoriasis (GPP) or erythrodermic psoriasis (EP) in a subject in need thereof, comprising orally administering to the subject an effective amount of 100-300 mg per day of a compound of Formula (I):an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.

[0060] Compound of Formula (I) is a 13-amino acid peptide that binds directly to the IL-23R subunit and prevents IL-23, inhibiting proximal IL-23R signaling and downstream effector functions (e.g., cytokine secretion). The compound of Formula (I) has an amino acid string of Ac-[Pen]*-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]*-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3- Pal]-Sarc-NH2 (* [Pen] -[Pen]* form disulfide bond), wherein all amino acid residues are all in L forms. The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof can be present in any form, such as a pharmaceutically acceptable salt, hydrate, or other solvate. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof can be provided in crystalline form, in an amorphous form, or a semi-crystalline form.

[0061] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is a salt. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is an acetate salt. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is a bis-acctatc salt. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is an acetate. In some embodiments, the acetate of the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is an amorphous form. In some embodiments, the acetate of the compound of Formula (I) or a pharmaceutically acceptable saltor solvate thereof is the acetate salt. In some embodiments, the acetate of the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is the bis-acctatc salt. In some embodiments, the acetate salt of the composition of the present invention is an amorphous form. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is a solvate. In some embodiments, the acetate form of the compound of Formula (I) is the acetate solvate.

[0062] In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (I) useful for the invention includes hydrochloride salts, bis-hydrochloride salts, acetate salts, fumarate salts, glutarate salts, glycolate salts, mesylate salts, sulfate salts, and citrate salts.

[0063] In some embodiments, a crystalline form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing. In certain embodiment, a crystalline form of a partial hydrochloride salt of the compound of Formula (I) is used in a method of the application, and the crystalline form has an X-ray powder diffraction (XRPD) pattern with the following two theta peaks: 4.2920, 6.9201, 7.6600, 8.5693, 9.2667, 9.9817, 10.7256, 11.5429, 11.9937, 13.0633, 13.3317, 13.9650, 14.7879, 15.8430, 17.1481, 17.6468, 18.1402, 18.6158, 19.3291, 20.4899, 20.7090, or 21.7813 + / - 0.2 degrees two theta. In certain embodiment, a crystalline form of a hydrochloride salt of the compound of Formula (I) is used in a method of the application, and the crystalline form has an XRPD pattern with the following two theta peaks 0.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.6, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 degrees two theta + / - 0.2 degrees two theta. In certain embodiment, the crystalline form has an XRPD pattern depicted in FIG. 2.

[0064] In some embodiments, the effective amount is 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg per day of the compound of Formula (I), or an equivalent amount of the pharmaceutically acceptable salt or solvate thereof. In preferred embodiments, the effective amount is 200 mg per day of the compound of Formula (I), or an equivalent amount of the pharmaceutically acceptable salt or solvate thereof.

[0065] The effective amount of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof can be administered orally once or multiple times a day. In some embodiments, the effective amount of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof is administered once daily. In certain embodiments, thecompound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof is administered twice daily.

[0066] The compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof can be administered in any suitable pharmaceutical compositions, including, but are not limited to a liquid composition, such as a solution composition, a solid composition, such as a tablet composition. When the composition is a tablet, the tablet can include two or more different phases, including an internal phase and an external phase that can contain a core. The tablet composition can also include one or more coatings.

[0067] Compositions intended for oral use can contain one or more excipients including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets are acceptable. These excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.

[0068] In some embodiments, a composition useful for the invention comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 5 mg to about 300 mg; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 10 mg to about 300 mg; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 10 mg to about 200 mg; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 10 mg to about 100 mg; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 50 mg to about 250 mg; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises thecompound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 100 mg to about 250 mg; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 50 mg to about 200 mg; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 100 mg to about 200 mg; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof in an amount of about 150 mg to about 250 mg; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition includes 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275 or 300 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition is a tablet. In some embodiments, the tablet is film coated. In some embodiments, the tablet is an immediate-release tablet. In some embodiments, the tablet is an immediate-release film-coated tablet. In some embodiments, the composition is a solution.

[0069] In some embodiments, the composition is an oral immediate-release film-coated tablet containing 25 mg of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients.

[0070] In some embodiments, the composition includes 50 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition is a tablet. In some embodiments, the tablet is film coated. In some embodiments, the tablet is an immediate-release tablet. In some embodiments, the tablet is an immediate-release film-coated tablet. In some embodiments, the composition is a solution.

[0071] In some embodiments, the composition is an oral immediate-release film-coated tablet containing 50 mg of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients.

[0072] In some embodiments, the composition includes 100 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition is a tablet. In some embodiments,the tablet is film coated. Tn some embodiments, the tablet is an immediate-release tablet. In some embodiments, the tablet is an immediate-release film-coated tablet. In some embodiments, the composition is a solution.

[0073] In some embodiments, the composition is an oral immediate-release film-coated tablet containing 100 mg of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients.

[0074] In some embodiments, the composition includes 200 mg of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients. In some embodiments, the composition is a tablet. In some embodiments, the tablet is film coated. In some embodiments, the tablet is an immediate-release tablet. In some embodiments, the tablet is an immediate-release film-coated tablet. In some embodiments, the composition is a solution.

[0075] In some embodiments, the composition is an oral immediate-release film-coated tablet containing 200 mg of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof; and one or more pharmaceutically acceptable excipients.

[0076] In some embodiments, the subject is fasting before the administration of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof. For example, the subject is fasting for at least 1 hour, preferably at least 2 hours before the administering, such as fasting for at least 1, 2, 3 or 4 hours before the administering.

[0077] In some embodiments, the subject is fasting after the administration of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof. For example, the subject is fasting for at least 10 minutes, preferably at least 30 minutes, after the administering, such as fasting for at least 10, 20, 30, 60, 90 or 120 minutes after the administering.

[0078] In some embodiments, the subject is fasting before and after the administration of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof. For example, the subject is fasting for at least 1 hour, preferably at least 2 hours before the administering, such as fasting for at least 1, 2, 3 or 4 hours before the administering, and the subject is also fasting for at least 10 minutes, preferably at least 30 minutes, after the administering, such as fasting for at least 10, 20, 30, 60, 90 or 120 minutes after the administering. In certain embodiments, the subject is fasting for at least 2 hours before theadministration of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof, and the subject is fasting for at least 30 minutes after the administration.

[0079] An effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate form thereof can be administered to a subject in need of a treatment of EP or GPP alone or together with another treatment for EP or GPP. In certain embodiments, the subject has received a treatment with methotrexate (MTX) and / or cyclosporine, preferably prior to receiving the initial administration of a compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

[0080] In certain embodiments, the subject has a stable dose of <20mg / week methotrexate (MTX) or a stable dose of <5 mg / kg / day cyclosporine at least two weeks before the first administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof, provided that the subject is not on both MTX and cyclosporine at the same time from 2 weeks before the first administration of study intervention. In certain embodiments, the administration of the stable dose of MTX or cyclosporine continues after the administration of the effective amount of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

[0081] In some embodiments, the subject has received treatment with a stable dose of retinoid at least 2 weeks before the first administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the administration of the stable dose of retinoid continues after the administration of the effective amount of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

[0082] In some embodiments, the subject is a candidate for phototherapy or has a history of phototherapy prior to the treatment. In some embodiments, the subject is a candidate for systemic treatment for psoriasis prior to the treatment or has a history of phototherapy or systemic treatment for psoriasis.

[0083] In some embodiments, the subject has rash on 10% or more of the body surface area (BSA). In some embodiments, the subject has rash on 10% or more of the body surface area (BSA), if effect is not noted by at least existing systemic therapies including phototherapy, and / or the subject has refractory rash, articular symptoms, or pustules. In some embodiments, the subject has rash on 10% or more of the body surface area (BSA), if effect is not noted by at leastexisting systemic therapies including phototherapy but excluding biologies, and / or the subject has refractory rash, articular symptoms, or pustules,

[0084] In some embodiments, the subject is not concomitantly receiving a treatment with another biologic, apremilast or deucravacitinib .

[0085] In certain embodiments, a method of the application results in successful treatment of GPP based on CGI scale according to JPA at week 16. In certain embodiments, a method of the application results in successful treatment of GPP based on CGI scale according to JPA over time.

[0086] In some embodiments, the subject has GPP prior to the treatment and the subject has at least "minimally improved" rating in CGI scale according to JDA total score at Week 16 after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has at least "minimally improved" rating in CGI scale according to JDA total score before Week 16, such as at or before Week 15, 14, 13, 12, 11 or 10, after the initial administration of the compound of compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has at least "minimally improved" rating in CGI scale according to JDA total score after Week 16, such as at or after Week 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

[0087] In some embodiments, the subject has GPP prior to the treatment and the subject has at least "much improved" rating in CGI scale according to JDA total score at Week 16 after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has at least "much improved" rating in CGI scale according to JDA total score before Week 16, such as at or before Week 15, 14, 13, 12, 11 or 10, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has at least "much improved" rating in CGI scale according to JDA total score after Week 16, such as at or after Week 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

[0088] In some embodiments, the subject has GPP prior to the treatment and the subject has "very much improved" rating in CGI scale according to JDA total score at Week 16 after theinitial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has “very much improved" rating in CGI scale according to IDA total score before Week 16, such as at or before Week 15, 14, 13, 12, 11 or 10, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has "very much improved" rating in CGI scale according to JDA total score after Week 16, such as at or after Week 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

[0089] In certain embodiments, a method of the application results in successful treatment of EP based on CGI scale at week 16. In certain embodiments, a method of the application results in successful treatment of EP based on CGI scale over time. In some embodiments, the CGI rating is based on IDA severity index for GPP assessed using the criteria described in Table A. In some embodiments, the CGI rating for EP can be assessed using the criteria described in Table Bin some embodiments, the subject has EP prior to the treatment and the subject has at least "minimally improved" rating in CGI scale at Week 16 after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has at least "minimally improved" rating in CGI scale before Week 16, such as at or before Week 15, 14, 13, 12, 11 or 10, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has at least "minimally improved" rating in CGI scale after Week 16, such as at or after Week 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

[0090] In some embodiments, the subject has EP prior to the treatment and the subject has at least "much improved" rating in CGI scale at Week 16 after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has at least "much improved" rating in CGI scale before Week 16, such as at or before Week 15, 14, 13, 12, 11 or 10, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has at least "much improved" rating in CGI scale after Week 16, such as at or after Week17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

[0091] In some embodiments, the subject has EP prior to the treatment and the subject has at least "very much improved" rating in CGI scale at Week 16 after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has at least "very much improved" rating in CGI scale before Week 16, such as at or before Week 15, 14, 13, 12, 11 or 10, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has at least "very much improved" rating in CGI scale after Week 16, such as at or after Week 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

[0092] In certain embodiments, a method of the application results in successful treatment of GPP or EP as measured by at least one, two, three, four, five, six, seven, eight or nine of the following over time: (1) changes from baseline in the total score of the JDA severity index for GPP over time; (2) change in baseline in severity classification (mild, moderate, severe) of the JDA severity index for GPP over time; (3) change from baseline in body surface area (BSA) of involvement of lesion for EP over time; (4) achievement of an Investigator’s Global Assessment (IGA) score of cleared (0) or minimal (1) over time; (5) achievement of an IGA score of cleared (0) over time; (6) Percent improvement from baseline in Psoriasis Area and Severity Index (PASI) over time; (7) change from baseline in Dermatology Fife Quality Index (DEQI) score over time; (8) achievement of a DEQI score of 0 or 1 over time; and (9) change from baseline in EQ-5D-5E (domain scores and visual analog scale [VAS]) over time.

[0093] In certain embodiments, the administration of an effective amount of a compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof according to an embodiment of the application achieves an IGA score of cleared (0) or minimal (1), IGA score of cleared (0), PASI 90 response, PASI 100 response, and / or DEQI score of 0 or 1 at a significantly higher rate than placebo. In certain embodiments, at Week 16 after the initial administration of an effective amount of a compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof, a significantly greater improvement (reduction) in GPP or EP as measured byPAST total score, BSA, PSSD symptoms score, and PSSD signs score from baseline is achieved than placebo.

[0094] In some embodiments, the subject has erythrodermic psoriasis (EP), a history of plaquetype psoriasis, and body surface area (BSA) of involvement of lesion for EP >80% prior to the treatment.

[0095] In one embodiment of the application, a method of treating GPP in a subject in need thereof, comprises orally administering to the subject once daily an effective amount of 200 mg / day of a compound of Formula (1):an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, wherein the subject is fasting for at least 2 hours before the administering and for at least 30 minutes after the administering. In certain embodiments, the subject has received treatment a stable dose of <20 mg / week methotrexate (MTX) or a stable dose of %5 mg / kg / day cyclosporine from 2 weeks before the first administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof, provided that the subject is not on both MTX and cyclosporine at the same time from 2 weeks before the first administration of study intervention. In other embodiments, the subject has received treatment with a stable dose of retinoid from 2 weeks before the first administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof. In other embodiments, the subject is a candidate for phototherapy or has a history of phototherapy prior to the treatment. In certain embodiments, thesubject has achieved at least “minimally improved” rating, preferably “much improved” rating, more preferably “very much improved”, in CGI scale according to JDA) total score, preferably at Week 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

[0096] In one embodiment, a method for treating EP in a subject in need thereof comprises orally administering to the subject once daily an effective amount of 200 mg / day of a compound of Formula (I):an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, wherein the subject is fasting for at least 2 hours before the administering and for at least 30 minutes after the administering. In certain embodiments, the subject has a history of plaque-type psoriasis, and body surface area (BSA) of involvement of lesion for EP >80% prior to the treatment. In certain embodiments, the subject has received treatment a stable dose of <20 mg / week methotrexate (MTX) or a stable dose of ^=5 mg / kg / day cyclosporine from 2 weeks before the first administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof, provided that the subject is not on both MTX and cyclosporine at the same time from 2 weeks before the first administration of study intervention. In other embodiments, the subject has received treatment with a stable dose of retinoid from 2 weeks before the first administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof. In further embodiments, the subject is a candidate for phototherapy or has a history of phototherapyprior to the treatment. In certain embodiments, the subject has achieved at least "minimally improved" rating, preferably “much improved” rating, more preferably “very much improved”, in CGI at Week 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.EXAMPLES

[0097] The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed embodiments.Example 1: A phase 3 study of a crystalline form of a hydrochloride salt of a peptide for treating generalized pustular psoriasis or erythrodermic psoriasis

[0098] IL-23 receptor antagonist peptide as used in this example refers to a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, specifically a hydrochloride salt of compound of Formula (I) in a crystalline form (“PEPTIDE A”).

[0099] In particular, this is a Phase 3, open-label, multicenter study to evaluate the efficacy and safety of PEPTIDE A for the treatment of participants with GPP or EP. A target of 16 (GPP, n=8; EP, n=8) participants will be enrolled in this study. All participants will take PEPTIDE A from Week 0. The total duration of this study for each participant is approximately 165 weeks, which includes: a ~5-week screening period, a 52-week treatment period, a 104-week long-term extension treatment period (LTE), and a 4-week safety follow-up period. All the participants will receive PEPTIDE A 200 mg once daily for 52 weeks. Participants completing Week 52 visit may be eligible to enroll in the LTE. The LTE will begin at the end of Week 52 and will continue until Week 156. All the participants will have a 4-week safety follow-up period at the end of the treatment period or after the last dose of study intervention. Efficacy, safety, PK, immunogenicity, and biomarkers will be assessed during the study.

[0100] Screening for eligible participants will be performed within 5 weeks before first dose administration of the study intervention.Eligibility Criteria:

[0101] Inclusion Criteria: each potential participant must satisfy all of the enrollment criteria for the study, which include:• >12 years of age at the Screening Visit.• Diagnosis of GPP or EP at screening.• for GPP, a diagnosis must be classified based on the criteria for diagnosis of GPP by the Japanese Dermatological Association.• for EP, has a history of plaque-type psoriasis. In addition, has an involved BSA of lesion >80% at baseline.• Candidate for phototherapy or systemic treatment for psoriasis (either naive or history of previous treatment).• In case of receiving methotrexate (MTX) or cyclosporine, the participant must be on stable dose from 2 weeks before the first administration of study intervention with doses of MTX <20 mg / week OR cyclosporine <5 mg / kg / day.• Note: Participants must not be on both MTX and cyclosporine at the same time from 2 weeks before the first administration of study intervention.• In case of receiving retinoid, the participant must be on stable dose from 2 weeks before the first administration of study intervention.• For participants >12 to <18 years of age body weight must be >40 kg at baseline.

[0102] Exclusion Criteria: a potential subject is excluded if the subject meets any of the following criteria:• The study participant has a total score of JDA severity index for GPP >14 at baseline if participants have a diagnosis of GPP.• The study participant has a differential diagnosis of the erythroderma (eg, erythroderma caused by lymphoma or drug eruption) other than EP.• The study participant has a history of or current diagnosis or signs or symptoms of severe, progressive, or uncontrolled liver, renal; cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances.• The study participant has a history of amyloidosis.• Known allergies, hypersensitivity, or intolerance to PEPTIDE A or its excipients.• The study participant had major surgery, (e.g., requiring general anesthesia) within 8 weeks before screening, or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study.• Note: Participants with planned surgical procedures to be conducted under local anesthesia may participate.• The study participant had transplanted organ (with exception of a comeal transplant >12 weeks before the first dose administration of study intervention).• All participants with suicidal ideation in the 26 weeks prior to screening that may be defined as a C-SSRS rating of: Wish to be Dead, Non-Specific Active Suicidal Thoughts, or Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act and is considered to be at risk by the investigator.• PHQ-9 score >15 at screening or baseline.• History of drug or alcohol abuse within 1 year before screening.• Certain restrictions on prior / concomitant therapy or clinical Study Experience. Interventions

[0103] The PEPTIDE A dose selection for the Phase 3 studies in psoriasis is based on the observed dose-response and modeled E-R analyses of efficacy data (i.e., PASI and IGA) from a Phase 2b Study. A population PK-based E-R analysis of that Phase 2b Study data shows that CavgPEPTIDE A concentrations describe the E-R relationship better than Ctrough. In that Phase 2b Study, both a dose-response and an E-R analysis show a dose / exposure-dependent increase in clinical efficacy with a PEPTIDE A dose of 100 mg twice daily providing biologic-like efficacy without evidence of dose-related safety or tolerability signals. Based on several modeling approaches, it is predicted that a PEPTIDE A 200 mg once daily dose will provide comparable inhibition of IL-23R and clinical efficacy (i.e., PASI and IGA) as the 100 mg twice daily dose. Therefore, considering the simpler once daily vs twice daily dose regimen from a patient acceptability and compliance perspective, a dose of PEPTIDE A 200 mg once daily has been selected for the Phase 3 efficacy and safety studies. The AUC exposure estimate at the regimen of 200 mg once daily is at least 15-fold lower than exposures at the NOAEL in the rat and monkey studies.For adult participants:

[0104] For adult participants, the study intervention must be swallowed whole. Participants will be instructed to take the study intervention at approximately the same time every day upon waking with 240 mL (8 oz) water on an empty stomach (no food intake for at least 2 hours before and for at least 30 minutes after taking the study intervention).For adolescent participants:

[0105] For adolescent participants, the participant’s legal guardian or caregiver may assist with administration of the study intervention.

[0106] For adolescent participants, the study intervention should be swallowed whole. Adolescent participants will be instructed to take the study intervention at approximately the same time every day upon waking with 240 mL (8 oz) water on an empty stomach (no food intake for at least 2 hours before and for at least 30 minutes after taking the study intervention).

[0107] If adolescent participants have difficulty swallowing tablets, the study intervention may be suspended in a glass of water and taken within 15 minutes. It may take a few minutes for the tablet to fully disperse. The tablet may not disperse completely (milky to cloudy appearance), and small pieces may be seen in the water and are safe to swallow. After drinking the study intervention, rinse and swirl the glass with more water and swallow to ensure all the study intervention is taken. The total amount of water to be used for the dispersion of the tablet and rinsing should be at least 240 mL (about 8 oz or 1 cup).Table 1. Outcome Measures

[0108] Efficacy evaluations chosen for this study are consistent with those utilized to evaluate other therapies for psoriasis. Investigator assessments (ClinROs), including CGI scale, JDA severity scale, BSA of involvement of lesion, IGA, and PASI, and PROs, including DLQI for adult participants, EQ-5D-5L, and CDLQI for adolescent participants, will be used to assess efficacy in this study.

[0109] Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs, and PQCs, from clinical studies arc crucial for the protection of participants, investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting of safety information; all clinical studies conducted by the sponsor, or its affiliates will be conducted in accordance with those procedures.

[0110] Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally acceptable representative) for the duration of the study.

[0111] Plasma samples will be used to evaluate the PK of PEPTIDE A. Plasma collected for PK may additionally be used to evaluate safety or efficacy aspects that address concerns arising during or after the study period. Participant confidentiality will be maintained.

[0112] Level of mediators relevant to the pathophysiology of psoriasis or inflammation including but not limited to IL-23, IL- 17 A, IL-17F, IL-22 and beta-def ensin-2 will be evaluated to assess the impact of PEPTIDE A on inflammatory proteins in the serum.

[0113] Serum samples will be screened for antibodies binding to PEPTIDE A and the titer of confirmed positive samples will be reported. Other analyses may be performed to further characterize the immunogenicity of PEPTIDE A.Example 2. Preparation of a Crystalline Form of a Hydrochloride Salt of a Compound of Formula (I)

[0114] The compound of Formula (I) has the sequence of Ac-[Pen]*-N-T-[W(7-Me)]- [Lys(Ac)]-[Pen]*-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3-Pal]-Sarc-NH2 (in which [Pen]*-[Pen]* form a disulfide bond):

[0115] 18.9 kg Rink amide AM resin (substitution: 0.95 mmol / g) were loaded into a 1000 LSPPS reactor and the SPPS was performed. Each SPPS cycle consists of Fmoc cleavage, coupling with the respective building block and obligatory capping. For Fmoc cleavage the resin was treated with 20% piperidine in DM (10 ml / g resin each) for 5 ± 2 min and 10 ± 2 min at 25 °C. Couplings were performed using the building blocks, coupling reagents and conditions depicted in Table 2. with DMF as solvent (10 ml / g resin). For capping, the resin was treated with acidic anhydride and pyridine in DMF (volumetric ratio DMF I Ac2O / pyridine 50:1:1; DMF: 10 ml / g resin) for 20 min. Diisopropyl carbonate (DIC) was added in two portions, with the second portion was added after about 20 to 30 minutes after the first portion.Table 2:

[0116] Final acetylation of the peptide resin was performed with acidic anhydride and pyridine in DMF (volumetric ratio DMF / Ac2O / pyridine 10:1:1; DMF: 10 ml / g resin) for 20 min. After drying at 25 - 35 °C 72.8 kg linear peptide-Rink amide AM resin were obtained.TFA cleavage

[0117] In a jacketed reactor 100 g of the above resin were added at 18°C to 700 mL of the cleavage cocktail, consisting of 630 mL TFA, 35 mL TIS, 17.5 mL EDT, and 17.5 mL water. The temperature increased to 30 °C upon addition of the resin, and the mixture was stirred for further 35 min at 30 °C. The mixture was cooled to 20 °C, and the resin was filtered off and washed two times with 100 mL TFA each. The filtrates were combined and cooled to -15 °C. For precipitation 4.0 L diisopropyl ether were added within 20 min maintaining the temperature of the solution / suspension at 7 °C. After complete addition of diisopropyl ether, the temperature was increased to 22 °C and the suspension stirred for 2.5 h.

[0118] The suspension was then transferred to a filter dryer, and the precipitated crude product was filtered off at ambient temperature. The filter cake was subsequently washed three times with 300 mL of diisopropyl ether each and dried in vacuo at 30 °C over night to yield 52.87 g of linear peptide as the TFA salt.Oxidation and purification by preparative HPLC

[0119] 28 g of linear peptide as the TFA salt was dissolved in 280 mL 30% AcOH in water at ambient temperature. 3.71 g iodine and 7.17 g potassium iodide were dissolved in 280 mL water. Both the peptide and the iodine / iodide-solution were added in parallel to a vigorously stirred mixture of 2.2 L 30% AcOH in water at ambient temperature within 60 min. After complete addition of both solutions, a brown oxidation mixture was obtained. After stirring for 30 min at ambient temperature, IPC indicated nearly full conversion of starting material. 3.5 g Vitamin C were added 1.5 h after complete addition of the peptide and iodine solutions. The then obtained yellow solution was stirred for 10 min. The oxidation mixture was filtrated over a fritted glass funnel before applying to the prep. RP-HPLC column. The chromatographic conditions were the same as used in Example 3. All fractions were adjusted with 18% HO inwater to pH 7. The fractions collected during prep. RP-HPLC were analyzed by UHPLC.Fractions containing > 98% product were pooled for subsequent isolation.Isolation

[0120] 420 mL of product pool had been obtained after oxidation and preparative HPLC purification. By a test lyophilization the product concentration of this solution was determined as approx. 29 g / L, which corresponds to a theoretical yield of approx. 12.2 g.

[0121] From the overall pool volume, 120 mL were transferred to a round-bottom flask, and the initial pH of 7.51 was adjusted with 4.5 mL of 1 M HC1 aq. to pH 3.00. Acetonitrile was evaporated from the product solution at 40 °C in vacuo, until water started to evaporate. After evaporation, 80 mL of aqueous product solution were remaining (pH 2.54), of which 40 mL were transferred to a reactor connected to a heating / cooling system and applied for the subsequent isolation.

[0122] The pH of the solution was then adjusted to pH 3.75 by addition of 1.0 mL of 0.5 M NH4HCO3 within 65 min. To the clear yellow solution 1% (w / w) the compound of Formula (I) was added as seeding material and the formed thin suspension was stirred for 60 min at 25 °C. The pH of the suspension was then adjusted to pH 4.50 by addition of 2.9 mL of 0.5 M NH4HCO3 within 125 min. After stirring the suspension for 30 min at 25 °C the pH had dropped to pH 4.12. The pH was then re-adjusted to 4.50 by addition of 0.2 mL of 0.5 M NH4HCO3. After stirring for 16 h at 25 °C a thick suspension was present, which was filtered (1 min filtration time) over a glass nutsche filter (G4) and washed without stirring with 1.59 mL of water (1 vol. eq.; 1 min filtration time). The washed filter cake was dried in vacuo at 25 °C for 16 h in a vacuum oven. The dried product was finally unloaded from the filter.

[0123] In total, 1.77 g of the compound of Formula (I) (partial HC1 salt) was isolated out of 60 mL of product pool, which calculates to 12.4 g of the compound of Formula (I) out of the entire 420 mL of product pool. For the isolated material a purity (HPLC) of 99.4%, a chloride content (titration) of 1.6%, a water content (KF) of 3.6%.

[0124] An X-ray powder diffraction (XRPD) pattern of the partial hydrochloride salt of the compound of Formula (I) confirmed its crystallinity. The following two theta peaks were observed: 4.2920, 6.9201, 7.6600, 8.5693, 9.2667, 9.9817, 10.7256, 11.5429, 11.9937, 13.0633, 13.3317, 13.9650, 14.7879, 15.8430, 17.1481, 17.6468, 18.1402, 18.6158, 19.3291, 20.4899, 20.7090, or 21.7813 + / - 0.2 degrees two theta.Example 3. Synthetic Procedure for a Crystalline Hydrochloride Salt of a compound of Formula (I)

[0125] Crystalline hydrochloride salt of the compound of Formula (I) (30 g) prepared according to Example 2 was dissolved in 120 mL of methanol and 51.4 mL of water. The dissolution was carried out in an EasyMax 402, under stirring at 40 °C. 57.1 mL of sodium chloride 1 M were dosed to the EasyMax reactor at over 1 h. The solution was then seeded with 300 mg of seeds of the hydrochloride salt of the compound of Formula (I) prepared according to Example 3. The slurry was then aged for 8 h under stirring at 40 °C. The slurry was cooled to 5 °C at a cooling rate of O.lK / min. An extra 114.31 mL of sodium chloride 1 M were dosed to the EasyMax reactor over 4 h and the slurry was aged for extra 5 h. The solid was isolated by vacuum filtration and washed twice with 30 mL of water and twice with 30 mL of isopropanol. The solid was dried atmospherically.

[0126] The isolated solid of the crystalline hydrochloride form of the compound of Formula (I) had a purity (UPLC) of 99.3 area% and a water content (KF) of 6.33 wAv%. The chloride content of the isolated crystalline hydrochloride form of the compound of Formula (I) was assayed by ion chromatography and found to be 0.64 molar equivalents to the compound of Formula (I). An XRPD pattern of the crystalline hydrochloride form of the compound of Formula (I) confirmed its crystallinity (FIG. 2). The following two theta peaks were observed: 3.8, 4.2, 6.9, 7.6, 8.5, 9.3,9.4, 10.0, 10.8, 11.6, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2,16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 degrees two theta + / - 0.2 degrees two theta.

Claims

CLAIMS1. A method for treating generalized pustular psoriasis or erythrodermic psoriasis in a subject in need thereof, comprising orally administering to the subject an effective amount of 100-300 mg per day of a compound of Formula (I):an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.

2. The method of claim 1, wherein the effective amount is about 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg per day of the compound of Formula (I), or an equivalent amount of the pharmaceutically acceptable salt or solvate thereof.

3. The method of claim 2, wherein the effective amount is about 200 mg per day.

4. The method of any one of claims 1-3, wherein the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof is administered once daily.

5. The method of any one of claims 1-3, wherein the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof is administered on an empty stomach first thing in the morning.

6. The method of any one of claims 1-5, wherein the subject is fasting for at least 2 hours before the administering.

7. The method of any one of claims 1- 6, wherein the subject is fasting for at least 30 minutes after the administering.

8. The method of any one of claims 1 -7, wherein the subject has received treatment methotrexate or cyclosporine prior to receiving the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

9. The method of any one of claims 1-8, wherein the subject has a stable dose of <20mg / week methotrexate or a stable dose of <5 mg / kg / day cyclosporine at least two weeks before the first administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof, provided that the subject is not on both MTX and cyclosporine at the same time from 2 weeks before the first administration of study intervention.

10. The method of any one of claims 1-9, wherein the subject has received treatment with a stable dose of retinoid at least 2 weeks before the first administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

11. The method of any one of claims 1-10, wherein the subject is a candidate for phototherapy or has a history of phototherapy prior to the treatment.

12. The method of any one of claims 1-10, wherein the subject is a candidate for systemic treatment for psoriasis prior to the treatment or has a history of phototherapy or systemic treatment for psoriasis.

13. The method of any one of claims 1-12, wherein the subject has generalized pustular psoriasis prior to the treatment.

14. The method of claim 13, wherein the subject has at least "minimally improved" rating, preferably “much improved” rating, more preferably “very much improved”, in Clinical Global Impression scale according to Japanese Dermatological Association total score), preferably at Week 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

15. The method of any one of claims 1-12, wherein the subject has erythrodermic psoriasis, a history of plaque-type psoriasis, and body surface area of involvement of lesion for EP > 80% prior to the treatment.

16. The method of claim 15, wherein the subject has at least "minimally improved" rating, preferably “much improved” rating, more preferably “very much improved”, in CGI at Week 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, after the initialadministration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

17. The method of any one of claims 1-16, where the GPP or EP is successfully treated as measured by at least one, two, three, four, five, six, seven, eight or nine of the following over time: (1) changes from baseline in the total score of the JDA severity index for GPP over time; (2) change in baseline in severity classification (mild, moderate, severe) of the JDA severity index for GPP over time; (3) change from baseline in body surface area of involvement of lesion for EP over time; (4) achievement of an Investigator’s Global Assessment score of cleared (0) or minimal (1) over time; (5) achievement of an Investigator’s Global Assessment score of cleared (0) over time; (6) Percent improvement from baseline in Psoriasis Area and Severity Index over time; (7) change from baseline in Dermatology Life Quality Index score over time; (8) achievement of a Dermatology Life Quality Index score of 0 or 1 over time; and (9) change from baseline in EQ-5D-5L (domain scores and visual analog scale) over time.

18. A method for treating generalized pustular psoriasis in a subject in need thereof, comprising orally administering to the subject once daily an effective amount of about 200 mg / day of a compound of Formula (I):an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, wherein the subject is fasting for at least 30 minutes after the administering.

19. The method of claim 18, comprising orally administering to the subject once daily an effective amount of about 200 mg / day of a hydrochloride salt of a compound of Formula20. The method of claim 19, comprising orally administering a crystalline form of the hydrochloride salt of a compound of Formula (I).

21. The method of claim 20, wherein the crystal form has an X-ray powder diffraction (XRPD) pattern with the following two theta peaks: 4.2920, 6.9201, 7.6600, 8.5693, 9.2667, 9.9817, 10.7256, 11.5429, 11.9937, 13.0633, 13.3317, 13.9650, 14.7879, 15.8430, 17.1481, 17.6468, 18.1402, 18.6158, 19.3291, 20.4899, 20.7090, or 21.7813 + / - 0.2 degrees two theta.

22. The method of claim 21, wherein the crystal form has an XRPD pattern with the following two theta peaks: 0.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.6, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 degrees two theta + / - 0.2 degrees two theta.

23. The method of claim 22, wherein the crystal form has an XRPD pattern of FIG. 2.

24. The method of any one of claims 18-23, wherein the subject has received treatment a stable dose of <20 mg / week methotrexate or a stable dose of <5 mg / kg / day cyclosporine from 2 weeks before the first administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof, provided that the subject is not onboth MTX and cyclosporine at the same time from 2 weeks before the first administration of study intervention; the subject has received treatment with a stable dose of retinoid from 2 weeks before the first administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof; and / or the subject is a candidate for phototherapy or has a history of phototherapy prior to the treatment.

25. The method of any one of claims 18-24, wherein the subject has at least “minimally improved” rating, preferably “much improved” rating, more preferably “very much improved”, in Clinical Global Impression scale according to Japanese Dermatological Association (JDA) total score), preferably at Week 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

26. The method of any one of claims 18-25, where the GPP or EP is successfully treated as measured by at least one, two, three, four, five, six, seven, eight or nine of the following over time: (1) changes from baseline in the total score of the JDA severity index for GPP over time; (2) change in baseline in severity classification (mild, moderate, severe) of the JDA severity index for GPP over time; (3) change from baseline in body surface area of involvement of lesion for EP over time; (4) achievement of an Investigator’s Global Assessment score of cleared (0) or minimal (1) over time; (5) achievement of an Investigator’s Global Assessment score of cleared (0) over time; (6) Percent improvement from baseline in Psoriasis Area and Severity Index over time; (7) change from baseline in Dermatology Life Quality Index score over time; (8) achievement of a Dermatology Life Quality Index score of 0 or 1 over time; and (9) change from baseline in EQ-5D-5L (domain scores and visual analog scale) over time.

27. A method for treating erythrodermic psoriasis in a subject in need thereof, comprising orally administering to the subject once daily an effective amount of about 200 mg / day of a compound of Formula (I):an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, wherein the subject is fasting for at least 30 minutes after the administering, preferably the subject has a history of plaque-type psoriasis, and body surface area of involvement of lesion for EP >80% prior to the treatment.

28. The method of claim 17, comprising orally administering to the subject once daily an effective amount of about 200 mg / day of a hydrochloride salt of a compound of Formula (I):

29. The method of claim 28, comprising orally administering a crystalline form of the hydrochloride salt of a compound of Formula (I).

30. The method of claim 29, wherein the crystal form has an X-ray powder diffraction (XRPD) pattern with the following two theta peaks: 4.2920, 6.9201, 7.6600, 8.5693, 9.2667, 9.9817, 10.7256, 11.5429, 11.9937, 13.0633, 13.3317, 13.9650, 14.7879, 15.8430, 17.1481, 17.6468, 18.1402, 18.6158, 19.3291, 20.4899, 20.7090, or 21.7813 + / - 0.2 degrees two theta.

31. The method of claim 30, wherein the crystal form has an XRPD pattern with the following two theta peaks: 0.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.6, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 degrees two theta + / - 0.2 degrees two theta.

32. The method of claim 31, wherein the crystal form has an XRPD pattern of FIG.

233. The method of any one of claims 27-32, wherein the subject has received treatment a stable dose of <20 mg / week methotrexate or a stable dose of <5 mg / kg / day cyclosporine from 2 weeks before the first administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof, provided that the subject is not on both MTX and cyclosporine at the same time from 2 weeks before the first administration of study intervention; the subject has received treatment with a stable dose of retinoid from 2 weeks before the first administration of the compound of Formula (I) or thepharmaceutically acceptable salt or solvate thereof; and / or the subject is a candidate for phototherapy or has a history of phototherapy prior to the treatment.

34. The method of any one of claims 27 and 33, wherein the subject has at least ''minimally improved" rating, preferably “much improved” rating, more preferably “very much improved”, in CGI at Week 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, after the initial administration of the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof.

35. The method of any one of claims 27-34, where the GPP or EP is successfully treated as measured by at least one, two, three, four, five, six, seven, eight or nine of the following over time: (1) changes from baseline in the total score of the JDA severity index for GPP over time; (2) change in baseline in severity classification (mild, moderate, severe) of the JDA severity index for GPP over time; (3) change from baseline in body surface area of involvement of lesion for EP over time; (4) achievement of an Investigator’s Global Assessment score of cleared (0) or minimal (1) over time; (5) achievement of an Investigator’s Global Assessment score of cleared (0) over time; (6) Percent improvement from baseline in Psoriasis Area and Severity Index over time; (7) change from baseline in Dermatology Life Quality Index score over time; (8) achievement of a Dermatology Life Quality Index score of 0 or 1 over time; and (9) change from baseline in EQ-5D-5L (domain scores and visual analog scale) over time.

36. The method of any one of claims 1-17, wherein the equivalent amount of a hydrochloride salt of the compound of Formula (I) is administered to the subject.

37. The method of claim 36, wherein the hydrochloride salt of the compound of Formula (I) is in a crystal form.

38. The method of claim 37, wherein the crystal form has an X-ray powder diffraction (XRPD) pattern with the following two theta peaks: 4.2920, 6.9201, 7.6600, 8.5693, 9.2667, 9.9817, 10.7256, 11.5429, 11.9937, 13.0633, 13.3317, 13.9650, 14.7879, 15.8430, 17.1481, 17.6468, 18.1402, 18.6158, 19.3291, 20.4899, 20.7090, or 21.7813 + / - 0.2 degrees two theta.

39. The method of claim 38, wherein the crystal form has an XRPD pattern with the following two theta peaks: 0.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.6, 12.0, 12.2,12.8, 13.1 , 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 degrees two theta + / - 0.2 degrees two theta.

40. The method of claim 39, wherein the crystal form has an XRPD pattern of FIG. 2.

41. The method of any one of claims 18-40, wherein the the subject takes Formula (I) or the pharmaceutically acceptable salt or solvate thereof on an empty stomach first thing in the morning.

42. An effective amount of 100-300 mg per day of a compound of Formula (I):an equivalent amount of a pharmaceutically acceptable salt or solvate thereof for use in orally administering to a subject in need of a treatment of generalized pustular psoriasis or erythrodermic psoriasis.

43. The method of any one of claims 1-40 or the use of claim 41, wherein the subject is an adult.

44. The method of any one of claims 1-40 or the use of claim 41, wherein the subject is an adolescent.

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