Administration regimen

Abstract

Orismilast is provided herein for use in the treatment of diseases or disorders that are restored by inhibiting PDE4 in a subject, wherein orismilast is administered to the subject according to a specific dosing regimen. Orismilast is also provided for use in the treatment of pruritus associated with atopic dermatitis.

Description

[Technical Field]

[0001] The present invention relates to orismilast for use in the treatment of diseases or disorders that are cured by inhibiting PDE4 in a subject, wherein orismilast is administered to the subject according to a specific dosing regimen. [Background technology]

[0002] Phosphodiesterases (PDEs) constitute a superfamily of enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate, intracellular secondary messengers that play a crucial role in mediating biological responses generated by diverse extracellular signals. Eleven families of PDE enzymes have been identified, and the PDE4 family comprises four subtypes (A-D) and more than 20 isoforms (Houslay MD, et al., “Keynote review: phosphodiesterase-4 as a therapeutic target”, Drug Discov Today; 2005, 10(22):1503-1519 2005). PDEs are the sole cellular pathway for the degradation of cyclic nucleotides, highlighting their crucial role in regulating these secondary messengers at the intracellular level and, consequently, in various functional responses of the cell (Dastidar SG et al., “Therapeutic benefit of PDE4 inhibitors in inflammatory diseases”. Curr Opin Investig. Drugs. 2007;8(5):364-372). PDE4 is a cAMP-specific PDE expressed by immune and inflammatory cells, including T lymphocytes, neutrophils, eosinophils, monocytes, dendritic cells, and macrophages (Spina et al., “PDE4 inhibitors: current status”; Br.J.Pharmacol. 2008;155(3):308-315). In these cells, PDE4 is the major PDE form, and PDE4 inhibitors increase cAMP levels. High intracellular cAMP levels downregulate inflammatory activity and upregulate anti-inflammatory activity, leading to, for example, a decrease in proliferation and cytokine production, while low cAMP concentrations have the opposite effect.Therefore, inhibition of PDE4 upregulates anti-inflammatory cytokines, such as IL-10, and downregulates one or more inflammatory cytokines, such as TNF-α, IFN-γ, IL-5, IL-8, IL-13, IL-17, IL-22, and / or IL-23 (Samrao A et al., Arch Dermatol 2012;148(8):890-897; and Li H et al., "Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases, Front.Pharmacol 2018;9:1048).

[0003] PDE4 inhibitors show potent effects in inflammatory diseases, neurological disorders (e.g., cognitive impairment, depression, psychosis, schizophrenia, and Alzheimer's disease), cancer, metabolic diseases, and skin conditions (Paes et al., “The Molecular Biology of Phosphodiesterase 4 Enzymes as Pharmacological Targets: An Interplay of Isoforms, Conformational States, and Inhibitors”; Pharmacol Rev.2021;73(3):1016-1049; Richter et al., “PDE4 as a target for cognition enhancement”, Expert Opin Ther Targets.2013 Sep;17(9):1011-27; Li et al., above; and Lugnier et al., “Cyclic nucleotide phosphodiesterases: New targets in the metabolic syndrome?” Pharmacol Ther.2020).

[0004] Inhibition of PDE4 has therapeutic potential in the treatment of psoriasis and other skin diseases with immunoinflammatory components (Dastidar et al., see above). In allergic skin diseases, PDE4 inhibitors inhibit the migration of cutaneous dendritic cells, and this inhibition is accompanied by inhibition of matrix metalloproteinase 9 activity in the epidermis and dermis. Furthermore, cytokine secretion from human dendritic cells (tumor necrosis factor [TNF]-α, IL-1β, and IL-12) is inhibited by PDE4 inhibitors, and inhibition of T cell activation has also been shown in vitro. Both T helper (Th)1 and Th2 cytokines are reduced in vitro and in inflammatory mouse skin by PDE4 inhibitors (Jin SL et al., Phosphodiesterase 4 and its inhibitors in inflammatory diseases. Chang Gung Med J. 2012;35(3):197-210).

[0005] Increased cAMP-PDE activity has been reported in patients with atopic dermatitis. Using immunohistochemical staining, PDE4 isoforms PDE4A, PDE4B, PDE4C, and PDE4D have also been observed to be increased in dermal fibroblasts from skin samples of patients with atopic dermatitis. Therefore, PDE4 inhibitors are expected to be useful in the treatment of atopic dermatitis (Guttman-Yassky et al., The role of phosphodiesterase 4 in the pathophysiology of atopic dermatitis and the perspective for its inhibition, Experimental Dermatology, 2019;28:3-10).

[0006] Several PDE4-specific inhibitors are in late-stage clinical development or have recently been marketed. For example, the oral PDE4 inhibitor roflumilast (Daxas® / Daliresp®) is approved in the United States and Europe for reducing the risk of exacerbations in patients with chronic obstructive pulmonary disease and chronic bronchitis (Roflumilast European Product Characteristics). The oral PDE4 inhibitor apremilast (Otezla®) is approved in the United States and Europe for multiple indications, including psoriatic arthritis and psoriasis (Apremilast European Product Characteristics), and is being studied for atopic dermatitis and other chronic inflammatory diseases (Samrao A et al., Arch Dermatol. 2012;148(8):890-897).

[0007] One of the major challenges of effective oral PDE4 therapy is its narrow therapeutic range. Most programs investigating PDE4 inhibitors have failed due to safety issues, and currently only two approved oral PDE4 inhibitors, roflumilast and apremilast, are available. However, both of these therapies have tolerability issues that affect the gastrointestinal (GI) tract, primarily characterized by nausea and diarrhea, but not limited to these. These undesirable GI effects have been consistently observed from the start of treatment, and therefore dose adjustments have been made to reduce or mitigate these undesirable side effects. Apremilast is administered orally twice daily at a starting dose of 10 mg, and the dose is increased to 30 mg twice daily over one week (Apremilast European Product Summary). Roflumilast is administered orally once daily at a starting dose of 250 μg for 28 days, followed by a maintenance dose of 500 μg once daily (Roflumilast European Product Summary). However, despite this dose adjustment, some patients still experience GI side effects such as diarrhea, nausea, and abdominal pain.

[0008] Orismilast, 2-(3,5-dichloro-1-oxidepyridine-1-ium-4-yl)-1-[7-(difluoromethoxy)-1',1'-dioxospiro[1,3-benzodioxol-2,4'-thian]-4-yl]etanone, has the formula: [ka] It is a potent selective PDE4 inhibitor.

[0009] Orismilast, disclosed in international publication brochure 2011 / 160632, is a selective PDE4 inhibitor and a potent inhibitor of PDE4B and PDE4D subtype splice variants in vitro. When tested in vitro, orismilast inhibited tumor necrosis factor α (TNFα) production in human whole blood and human peripheral blood mononuclear cell-mediated microorganisms (PBMCs), as well as the secretion of T helper (Th)1 (TNFα and IFNγ), Th17 (IL-22 and IL-23), and Th2 (IL-4, IL-5, and IL-13) related cytokines in PBMCs. In vivo, orismilast at doses of 10 and 30 mg / kg significantly reduced auricle thickness and inflammatory markers in a mouse model of chronic oxazolone-induced auricular dermatitis (Silverberg JI et al., Pharmacology of orismilast, a potent and selective PDE4 inhibitor. J Eur Acad Dermatol Venereol. 2023;37(4):721-729).

[0010] In a Phase 2a prospective, randomized, double-blind, placebo-controlled clinical trial (NCT02888236), patients with moderate to severe psoriasis were randomized to receive 30 mg twice daily orally for 16 weeks in the form of an immediate-release (IR) formulation or placebo. Treatment with orismilast IR significantly improved the mean psoriasis area severity index score at week 16 compared to placebo (Warren RB et al., Oral orismilast: Efficacy and safety in moderate-to-severe psoriasis and development of modified release tablets; J.Eur.Acad.Dermatol Venereol.2023;37(4):711-720).

[0011] International Publication No. 2020 / 148271 discloses modified-release (MR) formulations, including orisumilast. The safety, tolerability, and pharmacokinetics of orisumilast MR and IR formulations were investigated in a Phase 1 clinical trial (NCT03812198) in healthy volunteers. Participants were randomized (3:1) to receive either orisumilast MR or placebo (n=12). Orisumilast MR was administered twice daily for a total of 17 days. Orisumilast MR was started at 10 mg twice daily on days 1-2, increased to 20 mg twice daily on days 3-4, 30 mg twice daily on days 5-6, 40 mg twice daily on days 7-8, 50 mg twice daily on days 9-10, and finally increased to 60 mg twice daily on days 11-17. Orisumilast MR achieved PK characteristics equivalent to orisumilast IR, but fewer participants in the MR group (16.7%) reported GI impairment compared to the IR group (33.3%) (Warren et al., see above).

[0012] In a Phase IIb trial involving 202 patients with moderate to severe plaque-type psoriasis, patients were randomized and treated for 16 weeks with MR orismilast tablets at doses of 20 mg twice daily (BID), 30 mg BID, and 40 mg BID. A statistically significant therapeutic effect compared to placebo was observed at all doses of orismilast (Warren R et al., Efficacy and Safety of Orismilast in Patients with Moderate-to-Severe Psoriasis: Results from the Phase IIb IASOS Trial. Published at the American Academy of Dermatology 2023 Annual Meeting, March 17-21, New Orleans, LA).

[0013] International Publication No. 2022 / 200339 discloses orismilast for the treatment of hidradenitis suppurativa (HS) and describes a Phase 2a clinical trial of a modified-release formulation of orismilast, which includes dose adjustments over the initial two-week period, with the dose progressively increasing from 10 mg twice daily (BID) to 30 mg BID.

[0014] Despite improvements in gastrointestinal side effects obtained with modified-release formulations of orismilast, improved treatments that enhance the tolerability and / or efficacy of orismilast are still needed. [Overview of the project] [Means for solving the problem]

[0015] As described in detail in the examples herein, analysis of Phase 2b clinical trial data from a study of subjects with moderate to severe psoriasis treated orally with orismilast revealed that subject weight significantly influenced treatment efficacy. Subjects weighing ≥100 kg treated with 30 mg of orismilast twice daily yielded more effective treatment compared to subjects weighing <100 kg treated with the same dose. This was unexpected, as analysis of PK data indicated that subjects weighing <100 kg had higher systemic exposure to orismilast compared to subjects weighing ≥100 kg. While higher systemic exposure in lighter subjects was expected to result in better treatment efficacy than subjects weighing over 100 kg, the opposite was observed.

[0016] Therefore, to optimize therapeutic efficacy and / or tolerability, an orismilast administration regimen correlated with the patient's body weight is required.

[0017] According to a first aspect of the present invention, orismilast is provided for use in a method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject, the method comprising administering orismilast to the subject: (Ai) The initial orisumilast dose is administered to the subject once daily during the initial period, and then; (Aii) The intermediate orisumilast dose is administered to the subject twice daily during the intermediate period, and then; (Aiii) The maintenance dose of orisumilast is administered to the subject twice daily; Here: (a) The initial orisumilast dose and the intermediate orisumilast dose are independently selected from 10 mg to 30 mg of orisumilast, provided that the intermediate orisumilast dose is equal to or greater than the initial orisumilast dose; (b) The initial period is 2 to 8 weeks; (c) The intermediate period is 1 to 8 weeks; (d) If the subject has a body weight above the threshold body weight, the maintenance orismilast dose is greater than the intermediate orismilast dose, and the threshold body weight is at least 90 kg.

[0018] In certain embodiments, the initial period of (Ai) is 2 to 6 weeks. In certain embodiments, the initial period of (Ai) is 2 to 4 weeks. In certain embodiments, the initial period of (Ai) is 2 to a maximum of 4 weeks. In certain embodiments, the initial period of (Ai) is 2 weeks, 4 weeks, or 6 weeks. In certain embodiments, the initial period of (Ai) is 3 weeks. In certain embodiments, the initial period of (Ai) is 4 weeks. Preferably, the initial period of (Ai) is 2 weeks.

[0019] In certain embodiments, the intermediate period of (Aii) is a maximum of 8 weeks. In certain embodiments, the intermediate period of (Aii) is a maximum of 6 weeks. In certain embodiments, the intermediate period of (Aii) is a maximum of 4 weeks. In certain embodiments, the intermediate period of (Aii) is 1 to 8 weeks. In certain embodiments, the intermediate period of (Aii) is 6 to 8 weeks. In certain embodiments, the intermediate period of (Aii) is 1 to 6 weeks. In certain embodiments, the intermediate period of (Aii) is 4 to 6 weeks. In certain embodiments, the intermediate period of (Aii) is 1 to 4 weeks. In certain embodiments, the intermediate period of (Aii) is 1 to 3 weeks. In certain embodiments, the intermediate period of (Aii) is 1 to 2 weeks.

[0020] In certain embodiments, the intermediate period of (Aii) is 2 weeks, 4 weeks, or 6 weeks. In certain embodiments, the intermediate period of (Aii) is 1 week. In certain embodiments, the intermediate period of (Aii) is 2 weeks. In certain embodiments, the intermediate period of (Aii) is 4 weeks. In certain embodiments, the intermediate period of (Aii) is 6 weeks. In certain embodiments, the intermediate period of (Aii) is 8 weeks.

[0021] In certain embodiments, the initial period of (Ai) is 2 weeks, and the intermediate period of (Aii) is 4 to 8 weeks. In certain embodiments, the initial period of (Ai) is 2 weeks, and the intermediate period of (Aii) is up to 8 weeks. In certain embodiments, the initial period of (Ai) is 2 weeks, and the intermediate period of (Aii) is up to 6 weeks. In certain embodiments, the initial period of (Ai) is 2 weeks, and the intermediate period of (Aii) is 4 to 6 weeks. In certain embodiments, the initial period of (Ai) is 2 weeks, and the intermediate period of (Aii) is 6 to 8 weeks. In certain embodiments, the initial period of (Ai) is 2 weeks, and the intermediate period of (Aii) is 1 to 4 weeks. In certain embodiments, the initial period of (Ai) is 2 weeks, and the intermediate period of (Aii) is 2 weeks. In a preferred embodiment, the initial period (Ai) is 2 weeks, and the intermediate period (Aii) is 6 weeks.

[0022] Analysis of clinical data has shown that most adverse events associated with orismilast treatment (e.g., diarrhea, nausea, headache, dizziness, or vomiting) begin during the first four weeks of treatment, with very few instances of these events occurring after eight weeks of treatment. Therefore, in certain embodiments, the total duration of the initial and intermediate periods is 4 to 8 weeks. In certain embodiments, the total duration of the initial and intermediate periods is 4 weeks. In certain embodiments, the total duration of the initial and intermediate periods is 5 weeks. In certain embodiments, the total duration of the initial and intermediate periods is 6 weeks. In certain embodiments, the total duration of the initial and intermediate periods is 7 weeks. In certain embodiments, the total duration of the initial and intermediate periods is 8 weeks.

[0023] An analysis of Phase 2b clinical trial data across all subjects treated with orismilast without stratification based on weight showed that the efficacy of 20 mg orismilast administered twice daily for the first 8 weeks of treatment was equivalent to that of 30 mg orismilast administered twice daily for the treatment of moderate to severe plaque psoriasis. Therefore, dose adjustments during the initial and intermediate periods using lower doses of orismilast (e.g., 10 mg or especially 20 mg) are expected to provide therapeutic efficacy while minimizing undesirable side effects during the initial period of treatment, particularly the first 4–8 weeks or throughout treatment.

[0024] In certain embodiments, the maintenance orismilast dose of (Aiii) is the same as the intermediate orismilast dose if the subject has a body weight below the threshold body weight.

[0025] In certain embodiments, if the subject has a body weight above the threshold body weight, the maintenance orisumilast dose of (Aiii) is up to 40 mg, provided that the maintenance orisumilast dose is greater than the intermediate orisumilast dose. For example, the maintenance orisumilast dose may be 30 mg to 40 mg of orisumilast. Preferably, if the subject has a body weight above the threshold body weight, the maintenance orisumilast dose is 30 mg.

[0026] In certain embodiments, the maintenance orisumilast dose of (Aiii) is 30 mg if the subject has a body weight above the threshold body weight, and the intermediate orisumilast dose is less than 30 mg. For example, the intermediate orisumilast dose is 10 mg to 25 mg of orisumilast. In certain embodiments, the maintenance orisumilast dose is 30 mg of orisumilast, and the intermediate orisumilast dose is 10 mg of orisumilast. In certain embodiments, if the subject has a body weight above the threshold body weight, the maintenance orisumilast dose is 30 mg of orisumilast, and the intermediate orisumilast dose is 20 mg of orisumilast.

[0027] As described in the examples herein, an analysis of Phase 2b clinical data in subjects with moderate to severe psoriasis revealed that subjects with a body weight below threshold weight (e.g., less than 100 kg) treated with orismilast doses greater than 20 mg did not benefit from increased therapeutic efficacy, despite the fact that the subjects had higher systemic exposure to orismilast at higher doses. Furthermore, this data suggests that doses greater than 20 mg in subjects with a body weight below threshold weight may reduce therapeutic efficacy.

[0028] Therefore, in certain embodiments, the intermediate orisumilast dose of (Aii) and the maintenance orisumilast dose of (Aiii) are both 20 mg orisumilast if the subject has a body weight below the threshold body weight. In certain embodiments, the initial orisumilast dose of (Ai) is 10 mg or 20 mg; the intermediate orisumilast dose of (Aii) and the maintenance orisumilast dose of (Aiii) are both 20 mg orisumilast if the subject has a body weight below the threshold body weight. In certain embodiments, the initial orisumilast dose of (Ai), the intermediate orisumilast dose of (Aii), and the maintenance orisumilast dose of (Aiii) are all 20 mg orisumilast if the subject has a body weight below the threshold body weight. In certain embodiments, if the subject has a body weight below the threshold body weight, the initial orisumilast dose of (Ai) is 10 mg, and the intermediate orisumilast dose of (Aii) and the maintenance orisumilast dose of (Aiii) are both 20 mg orisumilast. In certain embodiments, if the subject has a body weight below a threshold body weight, the initial orisumilast dose (Ai) is 10 mg, the intermediate orisumilast dose (Aii) is 10 mg, and the maintenance orisumilast dose (Aiii) is 10 mg orisumilast.

[0029] Based on population PK modeling using clinical data and analysis of efficacy and tolerability data, the inventors identified that 10 mg of orisumilast administered twice daily is expected to be the optimal maintenance dose of orisumilast that maximizes efficacy and tolerability in subjects with a body weight below the lower limit, which is between 50 kg and 75 kg. For example, a subject with a lower limit body weight of 60 kg.

[0030] Therefore, in certain embodiments, if the subject has a body weight below the lower limit, the initial orisumilast dose (Ai), the intermediate orisumilast dose (Aii), and the maintenance orisumilast dose (Aiii) are all 10 mg orisumilast, and the lower limit body weight is 50 kg to 75 kg. For example, the subject has a lower limit body weight of 60 kg.

[0031] In some embodiments, when the subject has a body weight in the range of lower body weight to below threshold body weight, the optimal maintenance dose of orismilast is 20 mg administered twice daily.

[0032] Therefore, in certain embodiments, when the subject has a body weight in the range of lower body weight to below threshold body weight, the initial orisumilast dose (Ai), the intermediate orisumilast dose (Aii), and the maintenance orisumilast dose (Aiii) are all 20 mg orisumilast, and the lower body weight is 50 kg to 75 kg. For example, the subject has a lower body weight of 60 kg.

[0033] In some embodiments of the first aspect of the present invention: (i) If the subject has a body weight below the lower limit, the initial orisumilast dose (Ai), the intermediate orisumilast dose (Aii), and the maintenance orisumilast dose (Aiii) are all 10 mg orisumilast; or (ii) If the subject has a body weight in the range of lower body weight to below threshold body weight, the initial orisumilast dose (Ai), the intermediate orisumilast dose (Aii), and the maintenance orisumilast dose (Aiii) are all 20 mg orisumilast; The lower limit of body weight is 50kg to 75kg. For example, the subject has a lower limit of body weight of 60kg.

[0034] In some embodiments, the lower limit weight is 50 kg. In some embodiments, the lower limit weight is 55 kg. In some embodiments, the lower limit weight is 60 kg. In some embodiments, the lower limit weight is 65 kg. In some embodiments, the lower limit weight is 70 kg. In some embodiments, the lower limit weight is 75 kg.

[0035] In certain embodiments, if the subject has a body weight of less than 75 kg, the initial orisumilast dose (Ai), the intermediate orisumilast dose (Aii), and the maintenance orisumilast dose (Aiii) are all 10 mg orisumilast.

[0036] In certain embodiments, when the subject has a body weight of less than 60 kg, the initial orisumilast dose (Ai), the intermediate orisumilast dose (Aii), and the maintenance orisumilast dose (Aiii) are all 10 mg orisumilast.

[0037] In certain embodiments, if the subject has a body weight of less than 50 kg, the initial orisumilast dose (Ai), the intermediate orisumilast dose (Aii), and the maintenance orisumilast dose (Aiii) are all 10 mg orisumilast.

[0038] In certain embodiments, when the subject has a body weight in the range of 75 kg to less than the threshold body weight, the initial orisumilast dose (Ai), the intermediate orisumilast dose (Aii), and the maintenance orisumilast dose (Aiii) are all 20 mg orisumilast.

[0039] In certain embodiments, when the subject has a body weight in the range of 60 kg to less than the threshold body weight, the initial orisumilast dose (Ai), the intermediate orisumilast dose (Aii), and the maintenance orisumilast dose (Aiii) are all 20 mg orisumilast.

[0040] In certain embodiments, when the subject has a body weight in the range of 50 kg to less than the threshold body weight, the initial orisumilast dose (Ai), the intermediate orisumilast dose (Aii), and the maintenance orisumilast dose (Aiii) are all 20 mg orisumilast.

[0041] As illustrated in the examples herein, analysis of clinical trial data has identified that administration of orismilast according to the dosing regimens described herein provides improved tolerability and / or therapeutic efficacy compared to administration of orismilast in a fixed-dose regimen twice daily. In particular, the inventors have identified that subjects with a body weight above the threshold weight exhibit improved tolerability and / or therapeutic response to orismilast when the maintenance orismilast dose is higher than the intermediate orismilast dose, when administered according to the dosing regimens described herein. More specifically, subjects with a body weight above the threshold weight were found to be less likely to experience adverse events leading to treatment discontinuation when receiving higher maintenance doses compared to lighter subjects with a body weight below the threshold weight.

[0042] Therefore, a second aspect of the present invention provides orismilast for use in a method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight above a threshold body weight, the method comprising administering orismilast to the subject, Here: (Bi) The initial orisumilast dose is administered to the subject once daily during the preliminary period, and then; (Bii) The intermediate orisumilast dose is administered to the subject twice daily during the intermediate period, then; (Biii) The maintenance orisumilast dose is administered to the subject twice daily, and the maintenance orisumilast dose is greater than the intermediate orisumilast dose; Here: (a) The initial orisumilast dose and the intermediate orisumilast dose are independently selected from 10 mg to 30 mg of orisumilast, provided that the intermediate orisumilast dose is equal to or greater than the initial orisumilast dose; (b) The reserve period is a maximum of eight weeks; (c) The intermediate period is 1 to 8 weeks; (d) The threshold body weight is at least 90 kg.

[0043] In certain embodiments, the pre-emptive period for (Bi) is 1 day to 8 weeks. In certain embodiments, the pre-emptive period for (Bi) is 2 days to 8 weeks. In certain embodiments, the pre-emptive period for (Bi) is 4 days to 8 weeks. In certain embodiments, the pre-emptive period for (Bi) is 5 days to 8 weeks. In certain embodiments, the pre-emptive period for (Bi) is 6 days to 8 weeks. In certain embodiments, the pre-emptive period for (Bi) is 1 week to 8 weeks. In certain embodiments, the pre-emptive period for (Bi) is 1 week to 6 weeks. In certain embodiments, the pre-emptive period for (Bi) is 1 week to 4 weeks. In certain embodiments, the pre-emptive period for (Bi) is 1 week to 2 weeks. In certain embodiments, the pre-emptive period for (Bi) is 2 weeks to 8 weeks. In certain embodiments, the pre-emptive period for (Bi) is 1 day. In certain embodiments, the pre-emptive period for (Bi) is 2 days. In certain embodiments, the pre-emptive period for (Bi) is 3 days. In certain embodiments, the reserve period for (Bi) is 4 days. In certain embodiments, the reserve period for (Bi) is 5 days. In certain embodiments, the reserve period for (Bi) is 6 days. In certain embodiments, the reserve period for (Bi) is 1 week, 2 weeks, 3 weeks, or 4 weeks. In certain embodiments, the reserve period for (Bi) is 1 week. In certain embodiments, the reserve period for (Bi) is 2 weeks. In certain embodiments, the reserve period for (Bi) is 3 weeks. In certain embodiments, the reserve period for (Bi) is 4 weeks. In certain embodiments, the reserve period for (Bi) is 5 weeks. In certain embodiments, the reserve period for (Bi) is 6 weeks. In certain embodiments, the reserve period for (Bi) is 7 weeks. In certain embodiments, the reserve period for (Bi) is 8 weeks.

[0044] In certain embodiments, the preparatory period for (Bi) is 2 to 4 weeks. In certain embodiments, the preparatory period for (Bi) is 2 to a maximum of 4 weeks. In certain embodiments, the preparatory period for (Bi) is 2 weeks, 4 weeks, or 6 weeks. Preferably, the preparatory period for (Bi) is 2 weeks.

[0045] In certain embodiments, the intermediate period in (Bii) is one week. In certain embodiments, the intermediate period in (Bii) is two weeks, four weeks, or six weeks. In certain embodiments, the intermediate period in (Bii) is two weeks. In certain embodiments, the intermediate period in (Bii) is four weeks. In certain embodiments, the intermediate period in (Bii) is six weeks. In certain embodiments, the intermediate period in (Bii) is eight weeks.

[0046] In certain embodiments, the intermediate period of (Bii) is up to 8 weeks. In certain embodiments, the intermediate period of (Bii) is up to 6 weeks. In certain embodiments, the intermediate period of (Bii) is up to 4 weeks. In certain embodiments, the intermediate period of (Bii) is 1 to 8 weeks. In certain embodiments, the intermediate period of (Bii) is 6 to 8 weeks. In certain embodiments, the intermediate period of (Bii) is 1 to 6 weeks. In certain embodiments, the intermediate period of (Bii) is 4 to 6 weeks. In certain embodiments, the intermediate period of (Bii) is 1 to 4 weeks. In certain embodiments, the intermediate period of (Bii) is 1 to 3 weeks. In certain embodiments, the intermediate period of (Bii) is 1 to 2 weeks.

[0047] In certain embodiments, the preparatory period for (Bi) is 2 weeks, and the intermediate period for (Bii) is 4 to 8 weeks. In certain embodiments, the preparatory period for (Bi) is 2 weeks, and the intermediate period for (Bii) is up to 8 weeks. In certain embodiments, the preparatory period for (Bi) is 2 weeks, and the intermediate period for (Bii) is up to 6 weeks. In certain embodiments, the preparatory period for (Bi) is 2 weeks, and the intermediate period for (Bii) is 4 to 6 weeks. In certain embodiments, the initial period for (Bi) is 2 weeks, and the intermediate period for (Bii) is 6 to 8 weeks. In certain embodiments, the initial period for (Bi) is 2 weeks, and the intermediate period for (Bii) is 1 to 4 weeks. In certain embodiments, the initial period for (Bi) is 2 weeks, and the intermediate period for (Bii) is 2 weeks. In preferred embodiments, the initial period for (Bi) is 2 weeks, and the intermediate period for (Bii) is 6 weeks.

[0048] As discussed above, most adverse events associated with orismilast generally begin during the first 4–8 weeks of orismilast administration. The frequency of adverse events was generally lower after the first 8 weeks of treatment. In certain embodiments, the total duration of the preparatory and intermediate periods is 4–8 weeks. In certain embodiments, the total duration of the preparatory and intermediate periods is 4 weeks. In certain embodiments, the total duration of the preparatory and intermediate periods is 5 weeks. In certain embodiments, the total duration of the preparatory and intermediate periods is 6 weeks. In certain embodiments, the total duration of the preparatory and intermediate periods is 7 weeks. In certain embodiments, the total duration of the preparatory and intermediate periods is 8 weeks.

[0049] In certain embodiments, the maintenance orisumilast dose of (Biii) is orisumilast up to 40 mg, provided that the maintenance orisumilast dose is greater than the intermediate orisumilast dose. For example, the maintenance orisumilast dose of (Biii) may be 30 mg to 40 mg of orisumilast. In preferred embodiments, the maintenance orisumilast dose of (Biii) is 30 mg of orisumilast.

[0050] In certain embodiments, the maintenance orisumilast dose of (Biii) is 30 mg orisumilast, and the intermediate orisumilast dose of (Bii) is less than 30 mg. For example, the intermediate orisumilast dose of (Bii) is 10 mg to 25 mg orisumilast. In certain embodiments, the maintenance orisumilast dose of (Biii) is 30 mg orisumilast, and the intermediate orisumilast dose of (Bii) is 10 mg orisumilast. In certain embodiments, the maintenance orisumilast dose of (Biii) is 30 mg orisumilast, and the intermediate orisumilast dose of (Bii) is 20 mg orisumilast.

[0051] In a specific embodiment of the second aspect of the present invention, the initial orisumilast dose of (Bi) is 10 mg or 20 mg orisumilast. In a preferred embodiment of the second aspect of the present invention, the initial orisumilast dose of (Bi) is 20 mg orisumilast.

[0052] In a specific embodiment of a second aspect of the present invention, orismilast is provided for use in a method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight above a threshold body weight, the method comprising administering orismilast to the subject, Here: The initial dose of (Bi) 20 mg of orisumilast was administered to the subjects once daily for two weeks, and then; (Bii) The intermediate dose of 20 mg of orisumilast was administered to the subjects twice daily for 1 to 8 weeks, and then; (Biii) A maintenance dose of 30 mg of orisumilast was administered to the subjects twice daily; The threshold body weight is at least 90 kg.

[0053] In a specific embodiment of a second aspect of the present invention, orismilast is provided for use in a method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight above a threshold body weight, the method comprising administering orismilast to the subject, Here: The initial dose of (Bi) 20 mg of orisumilast was administered to the subjects once daily for two weeks, and then; (Bii) The intermediate dose of 20 mg of orisumilast was administered to the subjects twice daily for 2 to 8 weeks, and then; (Biii) A maintenance dose of 30 mg of orisumilast was administered to the subjects twice daily; The threshold body weight is at least 90 kg.

[0054] In a specific embodiment of a second aspect of the present invention, orismilast is provided for use in a method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight above a threshold body weight, the method comprising administering orismilast to the subject, Here: The initial dose of (Bi) 20 mg of orisumilast was administered to the subjects once daily for two weeks, and then; (Bii) The intermediate dose of 20 mg of orisumilast was administered to the subjects twice daily for 6 to 8 weeks, and then; (Biii) A maintenance dose of 30 mg of orisumilast was administered to the subjects twice daily; The threshold body weight is at least 90 kg.

[0055] In a preferred embodiment of a second aspect of the present invention, orismilast is provided for use in a method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight above a threshold body weight, the method comprising administering orismilast to the subject, Here: The initial dose of (Bi) 20 mg of orisumilast was administered to the subjects once daily for two weeks, and then; (Bii) The intermediate dose of 20 mg of orisumilast was administered to the subjects twice daily for 6 weeks, then; (Biii) A maintenance dose of 30 mg of orisumilast was administered to the subjects twice daily; The threshold body weight is at least 90 kg.

[0056] A third aspect of the present invention provides orismilast for use in a method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight above a threshold body weight, the method comprising administering orismilast to the subject, Here: (Ci) The initial orisumilast dose is administered to the subject once daily during the preliminary period, and then; (Cii) The maintenance orisumilast dose is administered to the subject twice daily, and is greater than the initial orisumilast dose; Here: (a) The initial dose of orisumilast is 10 mg to 20 mg of orisumilast; (b) The reserve period is a maximum of eight weeks; (c) The threshold body weight is at least 90 kg.

[0057] A fourth aspect of the present invention provides orismilast for use in a method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject, the method comprising administering orismilast to a subject, wherein: (Di) The initial orisumilast dose is administered to the subject once daily during the initial period, and then; (Dii) The maintenance dose of orisumilast is administered to the subject twice daily; Here: (a) The initial dose and maintenance dose of orisumilast are both 20 mg orisumilast; (b) The initial period is 2 to 8 weeks; (c) Subjects have a body weight between the lower limit and the threshold body weight; The threshold weight is at least 90 kg, and the lower limit is 50 kg to 75 kg.

[0058] In some embodiments of a fourth aspect of the present invention, the lower limit body weight is selected from 50 kg, 55 kg, 60 kg, 65 kg, 70 kg, or 75 kg. Therefore, the lower limit body weight may be 50 kg. The lower limit body weight may be 60 kg. The lower limit body weight may be 75 kg.

[0059] In some embodiments of the fourth aspect of the present invention, the threshold weight is 90 kg. In some embodiments of the fourth aspect of the present invention, the threshold weight is 95 kg. In some embodiments of the fourth aspect of the present invention, the threshold weight is 105 kg. Preferably, in the fourth aspect of the present invention, the threshold weight is 100 kg. For example, in the fourth aspect of the present invention, the threshold weight is 100 kg and the lower limit weight is 50 kg. Appropriately, in the fourth aspect of the present invention, the threshold weight is 100 kg and the lower limit weight is 60 kg.

[0060] As described in the examples herein, a population PK model based on pooled orismilast clinical trial data has revealed that treatment with 20 mg of orismilast twice daily in subjects with a body weight below the threshold weight (e.g., 50 kg) results in higher systemic exposure to orismilast compared to heavier subjects. As discussed above, analysis of psoriasis phase 2b data has shown that increasing systemic exposure beyond what is necessary for initial efficacy may not increase efficacy and may even decrease it. Therefore, specific dosing regimens may be required for lighter subjects, such as adolescents.

[0061] A fifth aspect of the present invention provides orismilast for use in a method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight below a lower limit, the method comprising administering orismilast to the subject, wherein: (Ei) The initial orisumilast dose of 10 mg is administered to the subject once daily during the initial period, and then; (Eii) A maintenance dose of 10 mg of orisumilast was administered to the subjects twice daily; Here, the initial period is 2 to 8 weeks; The lower limit for body weight is 50kg to 75kg.

[0062] In some embodiments of a fifth aspect of the present invention, the lower limit body weight is selected from 50 kg, 55 kg, 60 kg, 65 kg, 70 kg, or 75 kg. Therefore, the lower limit body weight may be 50 kg. The lower limit body weight may be 60 kg. The lower limit body weight may be 75 kg.

[0063] In certain embodiments of any of the dosing regimens disclosed herein, the initial orismilast dose is administered to the subject in the evening. In certain embodiments of any of the dosing regimens disclosed herein, the initial orismilast dose is administered to the subject in the morning.

[0064] In certain embodiments of any of the dosing regimens disclosed herein, when orismilast is administered twice daily (for example, at an intermediate or maintenance orismilast dose), the doses are appropriately administered at intervals of approximately 12 hours. Preferably, one dose is administered in the morning and the other in the evening.

[0065] In certain embodiments, orismilast is administered to subjects without any restrictions on the subjects' intake of food or beverages. However, gastrointestinal side effects can be further minimized by avoiding large meals and / or high-fat foods before administration of orismilast. Therefore, in some embodiments of any of the administration regimens disclosed herein, orismilast is administered to fasted subjects. For example, orismilast is administered at least 4 hours after a meal. Appropriately, fasting administration requires fasting for 2 hours after administration of orismilast. In certain embodiments of any of the administration regimens disclosed herein, orismilast is administered to subjects in a fed state. For example, orismilast is administered to subjects 30 minutes before a meal and 1 hour after a meal. In certain embodiments, orismilast is administered to subjects 30 minutes before a meal and 1 hour after a meal, and the meal is a low-fat meal (less than 50% of the total calorific value of the meal comes from fat). In certain embodiments, orismilast is administered to subjects 30 minutes before and 1 hour after meals, and the meals are low-calorie (less than approximately 1000 calories). In certain embodiments, orismilast is administered to subjects 30 minutes before and 1 hour after meals, and the meals are low-fat, low-calorie. In certain embodiments of any of the administration regimens disclosed herein, orismilast is administered to subjects without any restriction on food or beverage intake.

[0066] In certain embodiments of any of the dosing regimens disclosed herein, the initial orismilast dose and the intermediate orismilast dose are the same. In certain embodiments, both the initial orismilast dose and the intermediate orismilast dose are 20 mg orismilast.

[0067] In certain embodiments of any of the dosing regimens disclosed herein, the intermediate orismilast dose is greater than the initial orismilast dose. In certain embodiments, the intermediate orismilast dose is 20 mg orismilast, and the intermediate orismilast dose is greater than the initial orismilast dose. For example, the initial orismilast dose is 10 mg and the intermediate orismilast dose is 20 mg.

[0068] In certain embodiments of any of the administration regimens disclosed herein, the threshold body weight is 90 kg.

[0069] In certain embodiments of any of the administration regimens disclosed herein, the threshold body weight is 95 kg.

[0070] In certain embodiments of any of the administration regimens disclosed herein, the threshold body weight is 105 kg.

[0071] In preferred embodiments of any of the administration regimens disclosed herein, the threshold body weight is 100 kg.

[0072] In certain embodiments of any of the administration regimens disclosed herein, the maintenance orismilast dose is administered to the subject twice daily for the remainder of the treatment period. Thus, in certain embodiments, the maintenance orismilast dose is administered to the subject twice daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least one month, at least two months, at least three months, at least four months, at least six months, at least nine months, at least one year, at least eighteen months, or at least two years.

[0073] In certain embodiments, the disease or disorder is selected from: inflammatory diseases, autoimmune diseases, central nervous system diseases, cerebrovascular diseases, diabetes, obesity, metabolic syndromes, wounds, and proliferative disorders.

[0074] In certain embodiments, the disease or disorder is an inflammatory disease, such as an inflammatory lung disease, a skin disease, or a neurological disease.

[0075] In certain embodiments, the disease or disorder is psoriasis (e.g., plaque psoriasis and plaque psoriasis). In certain embodiments, the disease or disorder is moderate to severe psoriasis.

[0076] In certain embodiments, the disease or disorder is atopic dermatitis. In certain embodiments, the disease or disorder is moderate to severe atopic dermatitis.

[0077] In certain embodiments, the disease or disorder is ulcerative colitis.

[0078] In certain embodiments, the disease or disorder is hidradenitis suppurativa.

[0079] As described in the examples herein, an analysis of Phase 2b clinical trial data from subjects with moderate to severe atopic dermatitis treated orally with orismilast revealed that orismilast has a remarkably strong and rapid effect on pruritus associated with atopic dermatitis.

[0080] Accordingly, a sixth aspect of the present invention provides orismilast for use in a method for treating pruritus associated with atopic dermatitis in a subject, the method comprising administering a therapeutically effective dose of orismilast to the subject. Orismilast can be administered to the subject using any suitable route of administration. Preferably, orismilast is administered orally as a pharmaceutical composition, for example, one of the orismilast pharmaceutical compositions described herein. In some embodiments, orismilast is administered orally as a modified-release pharmaceutical composition, for example, one of the modified-release pharmaceutical compositions described herein. Orismilast can be administered to the subject, for example, 10 mg, 20 mg, or 30 mg once or twice daily, using any suitable administration regimen. Therefore, orismilast can be administered to the subject at a dose of 10 mg twice daily. Orismilast can be administered to the subject at a dose of 20 mg twice daily. Orismilast can be administered to the subject at a dose of 30 mg twice daily. However, appropriately, orismilast is administered to the subject according to one of the administration regimens of the first to fifth embodiments.

[0081] In certain embodiments of any of the administration regimens disclosed herein, orismilast is administered orally to the subject.

[0082] In certain embodiments, in any of the orismilast administration regimens or uses disclosed herein, orismilast is administered to the subject in the form of a modified-release formulation containing orismilast. In certain embodiments, the modified-release formulation releases an average amount of orismilast of about 10% to about 70% after 45 minutes and more than about 70% after 180 minutes. In certain embodiments, the modified-release formulation releases an average amount of orismilast of about 11% to about 65% after 45 minutes and more than 75% after 180 minutes. In certain embodiments, the modified-release formulation releases an average amount of orismilast of about 35% to about 65% after 45 minutes and more than 70% after 180 minutes. In certain embodiments, the modified-release formulation releases an average amount of orismilast of about 35% to about 55% after 45 minutes and more than 80% after 180 minutes. In each of the above cases, dissolution is determined using the Ph.Eur.2.9.3 apparatus II with 900 ml of dissolution medium of 0.5% sodium dodecyl in 0.1N HCl, a paddle speed of 75 rpm, and dissolution medium at 37±0.5℃.

[0083] The subject may be a human or an animal. Preferably, the subject is a human. In some embodiments, the subject is a human male. In some embodiments, the subject is a human female.

[0084] In certain embodiments, orismilast is administered to the subject simultaneously with one or more additional therapeutic agents, either separately or sequentially.

[0085] Embodiments of the present invention are further described below with reference to the accompanying drawings. [Brief explanation of the drawing]

[0086] [Figure 1]Figure 1A shows the percentage reduction in psoriasis area and severity index (PASI) score compared to baseline after treatment with orismilast at doses of 20 mg BID, 30 mg BID, and 40 mg BID in the Phase 2b clinical trial described in Example 3. Figure 1A shows the percentage of patients who achieved a 50% reduction in PASI score (PASI-50). Figure 1B shows the percentage of patients who achieved a 75% reduction in PASI score (PASI-75). The y-axis shows the percentage of patients who reached a PASI-50 or PASI-75 score at week 0 (W0), week 4 (W4), week 8 (W8), week 12 (W12), and week 16 (W16). "NRI" in this figure refers to non-responder imputation of missing data. [Figure 2] The total percentage of patients who discontinued treatment in the placebo (Pbo), 20 mg BID, 30 mg BID, and 40 mg BID orismilast treatment arms in the Phase 2b clinical trial described in Example 3, and the breakdown of discontinuations due to adverse events and other reasons, are shown below. [Figure 3] This chart shows the percentage of patients who experienced adverse events during the 0–4, 4–8, 8–12, and 12–16 week treatment periods in patients treated with 20 mg, 30 mg, or 40 mg of orismilast BID. The bar graphs for each treatment period represent patients who experienced diarrhea, nausea, headache, or vomiting. [Figure 4] Panel 4A shows PASI-75 and PASI-90 values ​​for patients weighing less than 100 kg and more than 100 kg treated with 20 mg, 30 mg, or 40 mg orisumilast BID. Panel 4B shows the number of treatment-related adverse events leading to treatment discontinuation in patients weighing less than 100 kg and more than 100 kg in each treatment arm. [Figure 5]Panel 5A shows a post-hoc analysis of patients treated with 20 mg orismilast BID if they weighed less than 100 kg, and patients treated with 30 mg orismilast ("20 / 30 mg BID") if they weighed 100 kg or more. These results are compared to the pre-specified treatment arms (20 mg BID, 30 mg BID, and 40 mg BID) in the clinical trial. Panel 5B shows the percentage of treatment-related adverse events leading to discontinuation in patients treated with 20 / 30 mg BID post-hoc and in the pre-specified 20 mg BID, 30 mg BID, and 40 mg BID treatment arms. Figure 5 shows the results of the post-hoc analysis regarding PASI-75, PASI-90, and PASI-100 responses. [Figure 6] A typical administration regimen according to the present invention is shown, in which 20 mg of orisumilast is administered once daily ("OD") for 2 weeks, followed by 20 mg of orisumilast twice daily for 6 weeks. For subjects with a body weight of ≥100 kg, the orisumilast dose is increased to 30 mg twice daily at the 8th week of treatment, while for subjects with a body weight <100 kg, the dose is maintained at 20 mg of orisumilast twice daily. [Figure 7] The design of the Phase 3 clinical trial described in Example 4 is shown. [Figure 8] The design of the Phase 3 clinical trial described in Example 5 is shown. [Figure 9] (Side view) This shows the X-ray powder diffraction pattern of orismilast crystalline form E measured using CuKα radiation λ=1.5418Å. The x-axis represents the 2θ value, and the y-axis represents the intensity (count). [Figure 10] DSC traces are shown for two different batches of orismilast crystalline morph E, measured at heating rates of 2–10°C / min (two measurements per batch). The x-axis represents temperature, and the y-axis represents heat flow (W / g). Each trace shows the melting onset temperature and enthalpy change for each sample of morph E. [Figure 11] The in vitro dissolution profiles of 10 mg and 30 mg orismilast-modified release tablets, measured using the standard dissolution assay defined herein, are shown. The x-axis represents time, and the y-axis represents the % orismilast released into the dissolution medium. [Figure 12] This shows the two-compartment model of the Orisumi last described in Example 6. [Figure 13] The pcVPC results for the healthy volunteer (HV) modified release (MR) study described in Example 6 are shown. [Figure 14] The pcVPC results for the psoriasis phase IIb MR trial described in Example 6 are shown. [Figure 15] The pcVPC results of the HV MR trial for normal weight and obese patients (psoriasis patients) described in Example 6 are shown. The plot on the left is for subjects with a BMI of 16.9–30 kg / m2. The plot on the right is for obese subjects with a BMI of 30–64.5 kg / m2. [Figure 16(a)] As described in the simulation of Example 6, the steady-state AUCτ-ss of orismilast in adolescents after repeated administration of the MR formulation at doses of 10, 20, 30, and 40 mg bids, compared to adults, is shown. In this figure and other figures, AUCτ refers to the AUC of the dosing interval. [Figure 16(b)] A table providing descriptive statistics of steady-state orismilast AUCτ-ss in adolescents after repeated administration of the MR formulation at doses of 10, 20, 30, and 40 mg bid, as described in the simulation of Example 6. [Figure 17] As described in the simulation of Example 6, the steady-state orismilast AUCτ-ss in body-weight stratified adolescents after repeated administration of the MR formulation at doses of 10, 20, 30, and 40 mg bids is shown. [Figure 18(a)] As described in the simulation of Example 6, the steady-state orismilast Cmax-ss in the entire adolescent population after repeated administration of the MR formulation at doses of 10, 20, 30, and 40 mg bids is shown. [Figure 18(b)] A table providing descriptive statistics of steady-state orismilast Cmax-ss in the entire adolescent population after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg, as described in the simulation of Example 6. [Figure 19(a)] As described in the simulation of Example 6, steady-state orismilast Ctrough-ss in the entire adolescent population after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg is shown. [Figure 19(b)] A table providing descriptive statistics on steady-state orismilast Ctrough-ss in the entire adolescent population after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg, as described in the simulation of Example 6. [Figure 20(a)] As described in the simulation of Example 6, steady-state orismilast Cmax-ss in adolescents after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg are shown by body weight category. [Figure 20(b)] A table providing descriptive statistics of steady-state Cmax-ss (ng / mL) in adolescents after repeated bid administration of MR formulations at doses of 10, 20, 30, and 40 mg, categorized by body weight, as described in the simulation of Example 6. [Figure 21(a)] As described in the simulation of Example 6, steady-state orismilast Ctrough-ss in adolescents after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg is shown by body weight category. [Figure 21(b)] A table providing descriptive statistics of steady-state Ctrough-ss (ng / mL) in adolescents after repeated bid administration of MR formulations at doses of 10, 20, 30, and 40 mg, categorized by body weight, as described in the simulation of Example 6. [Figure 22(a)] As described in the simulation of Example 6, the steady-state AUCτ-ss of orismilast in overweight subjects after repeated administration of the MR formulation at doses of 10, 20, 30, and 40 mg bids is shown. [Figure 22(b)]A table providing descriptive statistics of steady-state orismilast AUCτ-ss in overweight subjects after repeated administration of the MR formulation at doses of 10, 20, 30, and 40 mg bid, as described in the simulation of Example 6. [Figure 23(a)] As described in the simulation of Example 6, the steady-state orismilast Cmax-ss in obese subjects after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg is shown. [Figure 23(b)] A table providing descriptive statistics of steady-state Cmax-ss (ng / mL) in obese subjects after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg, as described in the simulation of Example 6. [Figure 24(a)] As described in the simulation of Example 6, steady-state orismilast Ctrough-ss is shown in obese subjects after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg. [Figure 24(b)] A table providing descriptive statistics of steady-state Ctrough-ss (ng / mL) in obese subjects after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg, as described in the simulation of Example 6. [Figure 25(a)] As described in the simulation of Example 6, the steady-state orismilast AUCτ-ss for the target using the Phase III design is shown. [Figure 25(b)] A table providing descriptive statistics of the steady-state orismilast AUCτ-ss for the subject using the Phase III design, as described in the simulation of Example 6. [Figure 26(a)] As shown in the simulation of Example 6, the steady-state orismilast Cmax-ss for the target using the Phase III design is shown. [Figure 26(b)] A table providing descriptive statistics for the steady-state orismilast Cmax-ss in the subject of the Phase III design, as described in the simulation of Example 6. [Figure 27(a)] As shown in the simulation of Example 6, the steady-state orismilast Ctrough-ss of the target using the Phase III design is shown. [Figure 27(b)] A table providing descriptive statistics for the steady-state orismilast Ctrough-ss in the subject using the Phase III design, as described in the simulation of Example 6. [Figure 28(a)] The percentage of patients who achieved a 50% reduction in PASI score (PASI-50) at weeks 0, 4, 8, 12, and 16 in two subgroups of patients (<100kg and >100kg) based on baseline weight and in the two active drug arms (20mg BID and 30mg BID) in the Phase 2b trial of Example 3 is shown: (a) NRI data. "NRI" refers to non-responder imputation of missing data. [Figure 28(b)] (b) Observational data. "NRI" indicates non-respondent imputation for missing data. [Figure 29(a)] The percentages of patients who achieved a 75% reduction in PASI score (PASI-75) at weeks 0, 4, 8, 12, and 16 in two subgroups of patients based on baseline weight (<100 kg and >100 kg) and in the two active drug arms (20 mg BID and 30 mg BID) in the Phase 2b trial of Example 3 are shown. (a) NRI data. "NRI" refers to non-responder imputation for missing data. [Figure 29(b)] (b) Observational data. "NRI" indicates non-respondent imputation for missing data. [Figure 30(a)] The percentages of patients who achieved a 90% reduction in PASI score (PASI-90) at weeks 0, 4, 8, 12, and 16 are shown for two subgroups of patients (<100kg and >100kg) based on baseline weight and for two active drug arms (20mg BID and 30mg BID) in the Phase 2b trial of Example 3. (a) NRI data. "NRI" refers to non-responder imputation for missing data. [Figure 30(b)] (b) Observational data. "NRI" indicates non-respondent imputation for missing data. [Figure 31] The percentage of patients who achieved a 90% reduction in PASI score (PASI-90) at weeks 0, 4, 8, 12, and 16 is shown: for patients with a body weight of <100 kg at baseline in the 20 mg BID and 30 mg BID arms, and for patients with a body weight of >100 kg at baseline in the 30 mg BID arm, in the Phase 2b trial of Example 3. [Figure 32] The steady-state orismilast exposure (AUC) for different body weights (<100kg and >100kg) is shown, and dose (20mg and 30mg) AUC values ​​were obtained from data obtained in the simulation of Example 6. The figure shows the mean AUC and standard deviation (SD), including exemplary optimal exposure ranges for maximizing efficacy. [Figure 33] Active drug arm: For each of the 20mg BID, 30mg BID, and 40mg BID, as well as placebo, the percentage of subjects with a peak pruritus NRS reduction of ≥4 points at week 2 is shown (MI and NRI data). *p<0.05;**p<0.1;MI=multiple imputation (primary analysis);NRI=non-responder imputation. [Figure 34]The percentages shown represent the percentage of subjects who completed the entire treatment and had severe pruritus (PPNRS > 7) at baseline, and who showed a reduction of ≥ 4 points in (observed) peak pruritus NRS at week 16 for each active drug arm (20 mg BID, 30 mg BID, and 40 mg BID) and placebo. PPNRS = Peak Pruritus Numerical Rating Scale, *p<0.05, **p<0.1; 7 is the median PPNRS at baseline, Obs = observed value. [Figure 35] This shows the log2 ratio changes in selected cytokines compared to placebo in PASI75 responders and non-responders (integrated treatment arms) in a Phase 2b dose-range study evaluating oral orismilast in adults with moderate to severe plaque psoriasis as described in Example 3. W16_L = lesion at week 16, BL_L = lesion at baseline, log2FCH = log2 ratio change, BID = twice daily. Nw16_L = 33 (PASI75 responders), Nw16_L = 25 (PASI75 non-responders), Nw16_L = 27 (placebo). [Figure 36] This shows the skin levels of TARC(log2) in the IIT population in a Phase 2b dose-range study evaluating oral orismilast in adults with moderate to severe atopic dermatitis as described in Example 8, after 16 weeks of treatment. The P-values ​​indicate the comparison of lesion skin levels at week 16 to baseline lesion skin levels (day 1). ***FDR<0.001, **FDR<0.01, *FDR<0.05 for lesion skin at week 16 versus lesion skin at day 1. TARC = thymic and activating modulated chemokine, and CCL17 = chemokine CC motif ligand 17. [Figure 37] This shows the Log2 ratio change in TARC in placebo-controlled adults with moderate to severe atopic dermatitis as described in Example 8, in IGA0 / 1 responders and non-responders (integrated treatment arms). W16_L = 16-week lesion, BL_L = baseline lesion, Nw16_L = 40 (placebo), Nw16_L = 66 (non-responder), Nw16_L = 28 (responder). TARC = thymic and activating modulated chemokine, CCL17 = also known as chemokine CC motif. [Figure 38]This example demonstrates an external visual prediction check using the PopPK model described in Example 6, using orismilast plasma concentration data obtained from the Phase 2b atopic dermatitis clinical trial described in Example 8. The dots and lines correspond to the 5th (bottom), median, and 95th (top) percentiles of the orismilast clinical data. The median shaded area represents the predicted median from the PopPK model. The shades on both sides represent the predicted 95th (top) and 5th (bottom) percentiles. [Figure 39] The design of the Phase 3 clinical trial described in Example 13 is shown. [Modes for carrying out the invention]

[0087] Unless otherwise specified, the following terms used in the specification and claims have the meanings set forth below.

[0088] The terms “treating,” “treatment,” or “effectiveness” refer to any indication of success in treating or improving a disease, condition, or state, including any objective or subjective parameters such as remission; remission; reduction of symptoms or making the condition or state more tolerable to the subject; slowing the rate of degeneration or decline; reducing the debilitation of the final stage of degeneration; or the physical or mental well-being of the subject.

[0089] The reference to the treatment of a disease or disorder that is "recovered by inhibiting PDE4" refers to a PDE4 inhibitor that provides a beneficial therapeutic effect to the disease condition being treated with orismilast.

[0090] The “improvement in tolerability” of orismilast as used herein includes reducing or eliminating an undesirable adverse event associated with the administration of orismilast to a subject. For example, improved tolerability includes reducing or eliminating one or more of the following adverse events associated with the administration of orismilast to a subject: diarrhea, nausea, headache, dizziness, vomiting, or stomach pain. Improved tolerability also includes reducing the frequency and / or severity of adverse events associated with the administration of orismilast to a subject.

[0091] When any compound described in this specification is administered for the treatment of a disorder, the “therapeutic effective dose” is an amount sufficient to reduce or completely alleviate the symptoms or other adverse effects of the disorder; to cure the disorder; to reverse, completely halt or delay the progression of the disorder; or to reduce the risk of the disorder worsening.

[0092] A "one-week" treatment period refers to a 7-day treatment. Therefore, for example, if there is an initial period of 2 weeks, followed by an intermediate period of 6 weeks, followed by the administration of a maintenance dose, this refers to the treatment of the target during the initial period from day 1 to 14, followed by the treatment of the target during the intermediate period from day 15 to 56, and the administration of the maintenance dose starting on day 57 of the treatment regimen.

[0093] References to the treatment period, such as "at week 2" or "at week 16," refer to the end of the treatment period. Therefore, "at week 2" refers to the end of the second week of treatment, and "at week 16" refers to the end of the sixteenth week of treatment.

[0094] The term “pharmaceutically acceptable salt” refers to a salt of a compound described herein that retains the biological efficacy and properties and is not biologically or otherwise undesirable. pharmaceutically acceptable salts are well known to those skilled in the art. The present invention is intended to encompass any pharmaceutically acceptable salt of orismilast. The present invention encompasses all crystalline transformations, polymorphs, and mixtures thereof of the compounds described herein, e.g., orismilast. In some embodiments, treatment involves the administration of polymorph E of orismilast.

[0095] The term “solvate” is intended to include species formed by the interaction between a compound, such as orismilast, and a solvent, such as an alcohol, glycerol, or water, and the species is in solid form. When water is the solvent, the species is referred to as a “hydrate.” This invention is intended to encompass all solvates (e.g., hydrates) of orismilast.

[0096] As used herein, the term "phosphodiesterase" refers to one or more cAMP-selective phosphodiesterases (PDEs): PDE4, PDE7, and PDE8. PDE4 is the most important modulator of cAMP. PDE4 is cAMP-specific and dominant in inflammatory cells. The PDE4 enzyme is encoded by four genes (PDE4A, PDE4B, PDE4C, and PDE4D), each capable of generating numerous isoforms through mRNA splicing and the use of different promoters. Each PDE4 isoform within a particular PDE4 subfamily contains a common core region consisting of a catalytic unit and a C-terminal portion, and is defined by its distinctive N-terminal region. PDE4 isoforms are further classified into long, short, or supershort depending on the presence or absence (or truncation) of two highly conserved sequences: upstream conserved region 1 (UCR1) and upstream conserved region 2 (UCR2). The "long" isoform contains both UCR1 and UCR2; the "short" isoform lacks UCR1; and the "super short" isoform lacks UCR1 and has a truncated UCR2.

[0097] As used herein, the term "PDE4 inhibitor" refers to a substance that inhibits PDE4.

[0098] In this specification, the terms “threshold weight” or “lower limit weight” refer to the subject’s weight immediately prior to the administration of the first dose of orismilast to the subject (i.e., baseline weight).

[0099] Unless otherwise specified herein, the term “moderate to severe atopic dermatitis” refers to subjects with atopic dermatitis having a baseline affected body surface area (BSA) of ≥10%, an IGA-AD grade of ≥3, and an Eczema Area and Severity Index (EASI) score of ≥16.

[0100] Unless otherwise specified herein, the term “moderate atopic dermatitis” refers to subjects with atopic dermatitis having a baseline EASI score of ≥16 to ≤21. Appropriately, subjects with moderate atopic dermatitis have a baseline BSA of ≥10% to ≤28%.

[0101] Unless otherwise specified herein, the term “severe atopic dermatitis” refers to subjects with atopic dermatitis having a baseline EASI score > 21. Appropriately, subjects with severe atopic dermatitis have a baseline BSA > 28%.

[0102] Unless otherwise specified herein, the term “moderate to severe psoriasis” refers to a subject with psoriasis who, at baseline, has a Psoriasis Area and Severity Index (PASI) ≥ 12, Affected Body Surface Area (BSA) ≥ 10%, and a Physician's Static Overall Assessment (sPGA) ≥ 3.

[0103] The term "baseline" refers to the level or score (e.g., PASI or EASI) of a subject before treatment with Orismilast.

[0104] In this specification, references to the terms “investigator-reviewed comprehensive assessment of AD” or “IGA-AD” should be considered equivalent and interchangeable with the terms “verified investigator-reviewed comprehensive assessment of AD” or “vIGA-AD.” Accordingly, references to the “IGA-AD” score encompass and are equivalent to the corresponding “vIGA-AD score.”

[0105] References herein to “Peak Pruritus Numerical Rating Scale,” “Peak Pruritus (NRS),” or “PPNRS” are considered equivalent and interchangeable with references to “Worst Pruritus NRS.” Accordingly, references herein to “PPNRS score” also encompass and are equivalent to the corresponding “Worst Pruritus NRS score.”

[0106] The term "particle size distribution" for powders refers to a value that defines the relative amount of particles present, sorted according to size. The D(50) and D(90) values ​​indicate that 50% and 90% of the measured particles are less than or equal to the stated size. For example, D(50) = 6 μm means that 50% of the particles are 6 μm or smaller. A D(90) ≤ 10 μm means that 90% of the particles have a particle size of 10 μm or smaller. Particle size can be measured using conventional methods such as laser diffraction.

[0107] The term "immediate release" refers to a pharmaceutical composition or formulation that does not significantly delay the release of the active ingredient after oral administration. Generally, immediate release refers to a composition or formulation in which ≥85% of the active ingredient is released within 30 minutes when placed in an aqueous solution.

[0108] The term "modified release" refers to a pharmaceutical formulation or composition in which the rate and / or site of release of the active ingredient differs from that of an orally administered immediate-release formulation. A modified release composition may also be a delayed-release composition in which the release of the active substance is delayed over a period of time after oral administration.

[0109] In this specification, “subject” means human or animal subject. Preferably, the subject is a warm-blooded mammal. More preferably, the subject is human. In some embodiments, the subject is adolescent or adult human, for example, a person at least 12 years of age. In some embodiments, the subject is an adult human 18 years of age or older. In some embodiments, the subject is adolescent human between 12 and 18 years of age.

[0110] In a numerical context, "approximately" is intended to encompass a range of + / - 10%. For example, approximately 20% includes the range of 18% to 22%.

[0111] Throughout this specification and the claims, the words “comprise” and “contain,” and their variations, mean “including but not limited to,” and are not intended (or intended not to exclude) any other parts, additions, components, integers, or processes. Throughout this specification and the claims, singular nouns encompass plural nouns unless the context specifically requires otherwise. In particular, where the indefinite article is used, the specification should be understood to assume both singular and plural nouns unless the context specifically requires otherwise.

[0112] Features, integers, properties, compounds, chemical parts, or groups described in conjunction with specific aspects, embodiments, or examples of the present invention should be understood to be applicable to any other aspects, embodiments, or examples described herein, insofar as they do not conflict. All features disclosed in this specification (including any appended claims, abstract, and drawings) and / or all steps of any method or process so as to be disclosed may be combined in any combination, except for any combination in which at least some of such features and / or steps are mutually exclusive. The present invention is not limited to the details of any of the aforementioned embodiments. The present invention extends to any novel features or any novel combination of features disclosed in this specification (including any appended claims, abstract, and drawings) and any novel steps or any novel combination of any method or process so as to be disclosed.

[0113] Readers should take note of all papers and documents filed concurrently with this specification or prior to this specification in connection with this application and made available to the public together with this specification, the contents of all such papers and documents being incorporated herein by reference.

[0114] Orismirusto The present invention relates to an administration regimen for the compound orismilast, 2-(3,5-dichloro-1-oxidepyridine-1-ium-4-yl)-1-[7-(difluoromethoxy)-1',1'-dioxospiro[1,3-benzodioxol-2,4'-thian]-4-yl]etanone, which is of the formula: [ka] It is a potent and selective PDE4 inhibitor.

[0115] The chemical abstract name of Orismilast is etanone, 2-(3,5-dichloro-1-oxide-4-pyridinyl)-1-[7-(difluoromethoxy)-2',3',5',6'-tetrahydro-1',1'-dioxidespiro[1,3-benzodioxol-2,4'-[4H]thiopyran]-4-yl]; CAS number 1353546-86-7.

[0116] Methods for synthesizing orismilast and its compounds are disclosed in International Publication No. 2011 / 160632, International Publication No. 2015 / 197534, International Publication No. 2017 / 103058, and International Publication No. 2018 / 234299.

[0117] In certain embodiments, orismilast can be administered to a subject as a solid, which may be amorphous, crystalline, or semicrystalline. In some embodiments, orismilast is crystalline. In preferred embodiments, orismilast is in the form of polymorph E. Polymorph E of orismilast ("morph E") is described in International Publication Brochure 2018 / 234299.

[0118] In some embodiments, the orismilast is morphology E characterized by an X-ray diffraction pattern having at least one 2θ peak selected from 8.0, 8.6, 11.8, 14.1, 15.0, 16.0, 16.8, 18.1, 18.5, 20.0, 21.4, 23.4, 25.6, and 29.7°±0.2° when measured using CuKα radiation (λ=1.5418 Å).

[0119] In some embodiments, the orismilast is morphology E characterized by an X-ray diffraction pattern having two 2θ peaks selected from 8.0, 8.6, 11.8, 14.1, 15.0, 16.0, 16.8, 18.1, 18.5, 20.0, 21.4, 23.4, 25.6, and 29.7°±0.2° when measured using CuKα radiation (λ=1.5418 Å).

[0120] In some embodiments, the orismilast is morphology E characterized by an X-ray diffraction pattern having five 2θ peaks selected from 8.0, 8.6, 11.8, 14.1, 15.0, 16.0, 16.8, 18.1, 18.5, 20.0, 21.4, 23.4, 25.6, and 29.7°±0.2° when measured using CuKα radiation (λ=1.5418 Å).

[0121] In some embodiments, the orismilast is morphology E, characterized by an X-ray diffraction pattern having 2θ peaks at 15.0, 16.0, 18.1, 18.5, 21.4, and 23.4°±0.2° when measured using CuKα radiation (λ=1.5418 Å).

[0122] In some embodiments, the orismilast is morphology E characterized by an X-ray diffraction pattern having 2θ peaks at 8.0, 11.8, 15.0, 16.0, 16.8, 18.1, 18.5, 23.4, 25.6, and 29.7°±0.2° when measured using CuKα radiation (λ=1.5418 Å).

[0123] In some embodiments, the orismilast is morphology E characterized by an X-ray diffraction pattern having 2θ peaks at 8.0, 8.6, 11.8, 14.1, 15.0, 16.0, 16.8, 18.1, 18.5, 21.4, 23.4, 25.6 and 29.7°±0.2° when measured using CuKα radiation (λ=1.5418 Å).

[0124] In some embodiments, the orismilast is morphology E, characterized by an X-ray diffraction pattern having at least 10 2θ peaks, as shown in Table X, when measured using CuKα radiation (λ=1.5418 Å).

[0125] In some embodiments, the orismilast is morphology E, characterized by an X-ray diffraction pattern with a 2θ peak as shown in Table X, when measured using CuKα radiation (λ=1.5418 Å).

[0126] [Table 1]

[0127] In some embodiments, the orismilast is morphology E, characterized substantially by the powder X-ray diffraction pattern shown in Figure 9 when measured using CuKα radiation (λ=1.5418 Å).

[0128] In certain embodiments, form E is characterized by having a melting endothermy with an onset temperature of approximately 210°C to approximately 213°C (e.g., approximately 211.6°C) when measured by differential scanning calorimetry (DSC) in a sealed aluminum pan with a perforated lid under a nitrogen atmosphere at a heating rate of 2 to 10°C / min. In certain embodiments, form E has a melting enthalpy change of approximately 80 to 90 J / g when measured under the above DSC conditions. In certain embodiments, form E has substantially the DSC curve shown in Figure 10.

[0129] Form E can be obtained by crystallization from one or more suitable solvents, such as ethanol, isopropanol, dimethyl sulfoxide, acetonitrile, and acetone. In some embodiments, the solvent is acetone or ethanol. Crystallization of Form E can be obtained, for example, by dissolving Orismilast in a high-temperature solvent (e.g., at 50°C) to form a solution, and then cooling the resulting solution to room temperature.

[0130] Orisumilast is a selective and efficient inhibitor of PDE4. Orisumilast has been found to be a selective inhibitor of PDE4D and PDE4B. In some embodiments, orisumilast is a selective inhibitor of PDE4B. In some embodiments, orisumilast is a selective inhibitor of PDE4D. In some embodiments, orisumilast is a selective inhibitor of PDE4B1, PDE4B2, PDE4B3, PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5 and / or PDE4D7. In some embodiments, orisumilast is a selective inhibitor of PDE4B2, PDE4B3, PDE4D2, PDE4D3, PDE4D4, PDE4D5 and / or PDE4D7. In some embodiments, orisumilast is a selective inhibitor of PDE4B2, PDE4B3, PDE4D5 and PDE4D7. In some embodiments, orismilast is a selective inhibitor of PDE4B3, PDE4D5, and PDE4D7. In particular, orismilast has been found to be a selective inhibitor of PDE4 isoforms PDE4D3 and PDE4B2. In addition, orismilast has been found to potently inhibit the secretion of two cytokines highly associated with inflammation: TNF-α and IL-1β. This compound also inhibits IFN-γ, a T-cell-derived Th1 cytokine that plays a role in the Th1 immune response. Significantly, orismilast has been shown to be molarly 23-fold more potent than apremilast in both LPS and SEB-induced TNF-α secretion from human whole blood. The ability of orismilast to inhibit cytokines involved in inflammation supports its use in the treatment of inflammatory conditions such as psoriasis, atopic dermatitis, ulcerative colitis, asthma, COPD, and hidradenitis suppurativa (HS).

[0131] Administration regimen The present invention relates to an administration regimen using orismilast. The reference herein to a method of treating a disease or disorder that is restored by inhibiting PDE4 is also intended to include: (i) orismilast for use in the treatment of a disease or disorder; and / or (ii) the use of orismilast for the manufacture of a medicament for the treatment of a disease or condition according to the administration regimen described herein.

[0132] Administration regimen A (First aspect of the present invention) Analysis of clinical trial data from subjects with moderate to severe plaque-type psoriasis confirmed that when orismilast was administered to subjects using regimens of 20 mg, 30 mg, or 40 mg orismilast twice daily, several adverse events, such as diarrhea, nausea, headache, dizziness, vomiting, and stomach pain, were observed. Most adverse events occurred during the first four weeks of treatment, with very few occurring after eight weeks of treatment. Furthermore, subjects with a body weight above the threshold weight treated with high doses of orismilast were found to show improved therapeutic efficacy without a significant increase in undesirable adverse events leading to treatment discontinuation. Moreover, treatment with high intermediate or maintenance doses in subjects with a body weight below the threshold weight may not improve efficacy and may result in increased adverse events. Dosage regimen A is expected to provide reduced adverse events in the early stages of treatment, improved efficacy and / or tolerability in subjects with a higher maintenance dose of orismilast, and optimized efficacy and / or tolerability in subjects with a body weight below the threshold weight.

[0133] Therefore, orismilast is provided for use in a method of treating a disease or disorder that is restored by inhibiting PDE4 in a subject, the method comprising administering orismilast to the subject: (Ai) The initial orisumilast dose is administered to the subject once daily during the initial period, and then; (Aii) The intermediate orisumilast dose is administered to the subject twice daily during the intermediate period, and then; (Aiii) The maintenance dose of orisumilast is administered to the subject twice daily; Here: (a) The initial orisumilast dose and the intermediate orisumilast dose are independently selected from 10 mg to 30 mg of orisumilast, provided that the intermediate orisumilast dose is equal to or greater than the initial orisumilast dose; (b) The initial period is 2 to 8 weeks; (c) The intermediate period is 1 to 8 weeks; (d) If the subject has a body weight above the threshold body weight, the maintenance orismilast dose is greater than the intermediate orismilast dose, and the threshold body weight is at least 90 kg.

[0134] A method for treating a disease or disorder that is restored by inhibiting PDE4 in a subject is also provided, the method comprising administering orismilast to the subject according to the above-described dosing regimens (Ai), (Aii), and (Aiii). Therefore, a method for treating a disease or disorder that is restored by inhibiting PDE4 in a subject is provided, the method comprising administering orismilast to the subject: (Ai) The initial orisumilast dose is administered to the subject once daily during the initial period, and then; (Aii) The intermediate orisumilast dose is administered to the subject twice daily during the intermediate period, and then; (Aiii) The maintenance dose of orisumilast is administered to the subject twice daily; Here: (a) The initial orisumilast dose and the intermediate orisumilast dose are independently selected from 10 mg to 30 mg of orisumilast, provided that the intermediate orisumilast dose is equal to or greater than the initial orisumilast dose; (b) The initial period is 2 to 8 weeks; (c) The intermediate period is 1 to 8 weeks; (d) If the subject has a body weight above the threshold body weight, the maintenance orismilast dose is greater than the intermediate orismilast dose, and the threshold body weight is at least 90 kg.

[0135] The use of orismilast for the manufacture of a medicament for the treatment of a disease or disorder that is restored by inhibiting PDE4 in a subject is also provided, the method comprising administering orismilast to a subject in accordance with the above-described dosing regimens (Ai), (Aii), and (Aiii).

[0136] In certain embodiments of administration regimen A, the intermediate orismilast dose is 10-20 mg of orismilast. In certain embodiments, the intermediate orismilast dose is 10 mg of orismilast. In certain embodiments, the intermediate orismilast dose is 20 mg of orismilast.

[0137] In certain embodiments of administration regimen A, if the subject has a body weight below the threshold body weight, the maintenance orismilast dose is the same as the intermediate orismilast dose. Therefore, in some embodiments, if the subject has a body weight below the threshold body weight, the intermediate orismilast dose is 20 mg BID and the maintenance dose is 20 mg BID. In some embodiments, if the subject has a body weight below the threshold body weight, the intermediate orismilast dose is 10 mg BID and the maintenance dose is 10 mg BID.

[0138] In administration regimen A, if the subject has a body weight above the threshold body weight, the maintenance orisumilast dose is greater than the intermediate orisumilast dose. Appropriately, the maintenance orisumilast dose for subjects with a body weight above the threshold body weight is up to 40 mg of orisumilast, for example, the maintenance orisumilast dose is up to 35 mg or up to 30 mg, provided that the maintenance orisumilast dose is greater than the intermediate orisumilast dose. In some embodiments, the maintenance orisumilast dose is selected from 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 mg of orisumilast, provided that the maintenance orisumilast dose is greater than the intermediate orisumilast dose. In a preferred embodiment, the maintenance orisumilast dose is 30 mg of orisumilast, provided that the maintenance orisumilast dose is greater than the intermediate orisumilast dose.

[0139] Embodiment A1 In a specific embodiment of administration regimen A, the administration regimen includes: (Ai) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Aii) The intermediate dose of orisumilast is 20 mg of orisumilast administered to the subject twice daily for 1 to 8 weeks; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is 20 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orisumilast is 30 mg orisumilast administered twice daily.

[0140] Embodiment A2 In a specific embodiment of administration regimen A, the administration regimen includes: (Ai) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Aii) The intermediate dose of orisumilast is 20 mg of orisumilast administered to the subject twice daily for two weeks; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is 20 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orisumilast is 30 mg orisumilast administered twice daily.

[0141] Embodiment A3 In a specific embodiment of administration regimen A, the administration regimen includes: (Ai) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Aii) The intermediate dose of orisumilast is 20 mg of orisumilast administered to the subject twice daily for two weeks; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is 20 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orisumilast is 30 mg orisumilast administered twice daily.

[0142] Embodiment A4 In a specific embodiment of administration regimen A, the administration regimen includes: (Ai) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Aii) The intermediate dose of orisumilast is 20 mg of orisumilast administered twice daily for 4 weeks to the subject; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is 20 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orisumilast is 30 mg orisumilast administered twice daily.

[0143] Embodiment A5 In a specific embodiment of administration regimen A, the administration regimen includes: (Ai) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Aii) The intermediate dose of orisumilast is 20 mg of orisumilast administered twice daily for 6 weeks to the subject; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is 20 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orisumilast is 30 mg orisumilast administered twice daily.

[0144] Embodiment A6 In a specific embodiment of administration regimen A, the administration regimen includes: (Ai) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Aii) The intermediate dose of orisumilast is 20 mg of orisumilast administered to the subject twice daily for 8 weeks; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is 20 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orisumilast is 30 mg orisumilast administered twice daily.

[0145] Embodiment A7 In a specific embodiment of administration regimen A, the administration regimen includes: (Ai) The initial dose of orisumilast is 10 mg of orisumilast administered once daily for two weeks to the subject; (Aii) The intermediate dose of orisumilast is 10 mg of orisumilast administered to the subject twice daily for 1 to 8 weeks; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is 10 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orisumilast is 20 mg orisumilast administered twice daily.

[0146] Embodiment A8 In a specific embodiment of administration regimen A, the administration regimen includes: (Ai) The initial dose of orisumilast is 10 mg of orisumilast administered once daily for two weeks to the subject; (Aii) The intermediate dose of orisumilast is 10 mg of orisumilast administered to the subject twice daily for two weeks; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is 10 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orisumilast is 20 mg orisumilast administered twice daily.

[0147] Embodiment A9 In a specific embodiment of administration regimen A, the administration regimen includes: (Ai) The initial dose of orisumilast is 10 mg of orisumilast administered once daily for two weeks to the subject; (Aii) The intermediate dose of orisumilast is 10 mg of orisumilast administered to the subject twice daily for two weeks; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is 10 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orisumilast is 20 mg orisumilast administered twice daily.

[0148] Embodiment A10 In a specific embodiment of administration regimen A, the administration regimen includes: (Ai) The initial dose of orisumilast is 10 mg of orisumilast administered once daily for two weeks to the subject; (Aii) The intermediate dose of orisumilast is 10 mg of orisumilast administered twice daily for 4 weeks to the subject; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is 10 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orisumilast is 20 mg orisumilast administered twice daily.

[0149] Embodiment A11 In a specific embodiment of administration regimen A, the administration regimen includes: (Ai) The initial dose of orisumilast is 10 mg of orisumilast administered once daily for two weeks to the subject; (Aii) The intermediate dose of orisumilast is 10 mg of orisumilast administered twice daily for 6 weeks to the subject; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is 10 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orisumilast is 20 mg orisumilast administered twice daily.

[0150] Embodiment A12 In a specific embodiment of administration regimen A, the administration regimen includes: (Ai) The initial dose of orisumilast is 10 mg of orisumilast administered once daily for two weeks to the subject; (Aii) The intermediate dose of orisumilast is 10 mg of orisumilast administered to the subject twice daily for 8 weeks; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is 10 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orisumilast is 20 mg orisumilast administered twice daily.

[0151] Embodiment A13 In a specific embodiment of administration regimen A, the administration regimen includes: (Ai) If the subject has a body weight below the lower limit, the initial orisumilast dose is 10 mg orisumilast administered once daily for 2 to 4 weeks, or If the subject has a body weight between the lower limit and below the threshold body weight, the initial orisumilast dose is 20 mg of orisumilast administered once daily for 2 to 8 weeks; (Aii) If the subject has a body weight below the lower limit, the intermediate orisumilast dose is 10 mg of orisumilast administered to the subject twice daily for 1 to 8 weeks; or If the subject has a body weight between the lower limit and below the threshold body weight, the intermediate orismilast dose is 20 mg of orismilast administered twice daily for 1 to 8 weeks; (Aiii) If the subject has a body weight below the lower limit, the maintenance dose of orisumilast is 10 mg orisumilast administered to the subject twice daily, or If the subject has a body weight between the lower limit and the threshold body weight, the maintenance orisumilast dose is 20 mg orisumilast administered to the subject twice daily, or If the subject has a body weight above the threshold weight, the maintenance dose of orismilast is 30 mg of orismilast administered twice daily to the subject; The lower limit for body weight here is 50kg to 75kg.

[0152] In some embodiments of Embodiment A13, the intermediate orismilast dose is administered to the subject twice daily for 1 to 4 weeks. In some embodiments of Embodiment A13, the intermediate orismilast dose is administered to the subject twice daily for 2 to 8 weeks. In some embodiments of Embodiment A13, the intermediate orismilast dose is administered to the subject twice daily for 4 to 8 weeks. In some embodiments of Embodiment A13, the intermediate orismilast dose is administered to the subject twice daily for 2 weeks. In some embodiments of Embodiment A13, the intermediate orismilast dose is administered to the subject twice daily for 4 weeks. In some embodiments of Embodiment A13, the intermediate orismilast dose is administered to the subject twice daily for 6 weeks.

[0153] Embodiment A14 In a specific embodiment of administration regimen A, the administration regimen includes: (Ai) If the subject has a body weight below the lower limit, the initial orisumilast dose is 10 mg orisumilast administered once daily for 2 to 4 weeks, or If the subject has a body weight between the lower limit and below the threshold body weight, the initial orisumilast dose is 20 mg of orisumilast administered once daily for 2 to 4 weeks; (Aii) If the subject has a body weight below the lower limit, the intermediate orisumilast dose is 10 mg orisumilast administered to the subject twice daily for 6 to 8 weeks, or If the subject has a body weight between the lower limit and below the threshold body weight, the intermediate orismilast dose is 20 mg of orismilast administered twice daily for 6 to 8 weeks; (Aiii) If the subject has a body weight below the lower limit, the maintenance dose of orisumilast is 10 mg orisumilast administered to the subject twice daily; or If the subject has a body weight between the lower limit and the threshold body weight, the maintenance orisumilast dose is 20 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orismilast is 30 mg of orismilast administered twice daily to the subject; The lower limit for body weight is 50kg to 75kg.

[0154] Embodiment A15 In a specific embodiment of administration regimen A, the administration regimen includes: (Ai) If the subject has a body weight below the lower limit, the initial orisumilast dose is 10 mg orisumilast administered once daily for two weeks, or If the subject has a body weight between the lower limit and below the threshold body weight, the initial orisumilast dose is 20 mg of orisumilast administered once daily for two weeks; (Aii) If the subject has a body weight below the lower limit, the intermediate orisumilast dose is 10 mg orisumilast administered to the subject twice daily for two weeks, or If the subject has a weight between the lower limit and below the threshold weight, the intermediate orismilast dose is 20 mg of orismilast administered twice daily for two weeks; (Aiii) If the subject has a body weight below the lower limit, the maintenance dose of orisumilast is 10 mg orisumilast administered to the subject twice daily, or If the subject has a body weight between the lower limit and the threshold body weight, the maintenance orisumilast dose is 20 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orismilast is 30 mg of orismilast administered twice daily to the subject; The lower limit for body weight is 50kg to 75kg.

[0155] Embodiment A16 In certain embodiments of dosing regimen A, the dosing regimen includes the following: (Ai) If the subject has a weight less than the lower weight limit, the initial orlistat dose is 10 mg of orlistat administered once daily to the subject for 2 weeks, or If the subject has a weight between the lower weight limit and less than the threshold weight, the initial orlistat dose is 20 mg of orlistat administered once daily to the subject for 2 weeks; (Aii) If the subject has a weight less than the lower weight limit, the intermediate orlistat dose is 10 mg of orlistat administered twice daily to the subject for 4 weeks, or If the subject has a weight between the lower weight limit and less than the threshold weight, the intermediate orlistat dose is 20 mg of orlistat administered twice daily to the subject for 4 weeks; (Aiii) If the subject has a weight less than the lower weight limit, the maintenance orlistat dose is 10 mg of orlistat administered twice daily to the subject, or If the subject has a weight between the lower weight limit and less than the threshold weight, the maintenance orlistat dose is 20 mg of orlistat administered twice daily to the subject; or If the subject has a weight greater than or equal to the threshold weight, the maintenance orlistat dose is 30 mg of orlistat administered twice daily to the subject; The lower weight limit is 50 kg to 75 kg.

[0156] Embodiment A17 In certain embodiments of dosing regimen A, the dosing regimen includes the following: (Ai) If the subject has a weight less than the lower weight limit, the initial orlistat dose is 10 mg of orlistat administered once daily to the subject for 2 weeks, or If the subject has a weight between the lower weight limit and less than the threshold weight, the initial orlistat dose is 20 mg of orlistat administered once daily to the subject for 2 weeks; (Aii) If the subject has a weight less than the lower weight limit, the intermediate orlistat dose is 10 mg of orlistat administered twice daily to the subject for 6 weeks, or If the subject has a weight between the lower limit and below the threshold weight, the intermediate orismilast dose is 20 mg of orismilast administered twice daily for 6 weeks; (Aiii) If the subject has a body weight below the lower limit, the maintenance dose of orisumilast is 10 mg orisumilast administered to the subject twice daily, or If the subject has a body weight between the lower limit and the threshold body weight, the maintenance orisumilast dose is 20 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orismilast is 30 mg of orismilast administered twice daily to the subject; The lower limit for body weight is 50kg to 75kg.

[0157] Embodiment A18 In a specific embodiment of administration regimen A, the administration regimen includes: (Ai) If the subject has a body weight below the lower limit, the initial orisumilast dose is 10 mg orisumilast administered once daily for two weeks, or If the subject has a body weight between the lower limit and below the threshold body weight, the initial orisumilast dose is 20 mg of orisumilast administered once daily for two weeks; (Aii) If the subject has a body weight below the lower limit, the intermediate orisumilast dose is 10 mg orisumilast administered to the subject twice daily for 8 weeks, or If the subject has a body weight between the lower limit and below the threshold body weight, the intermediate orismilast dose is 20 mg of orismilast administered twice daily for 8 weeks; (Aiii) If the subject has a body weight below the lower limit, the maintenance dose of orisumilast is 10 mg orisumilast administered to the subject twice daily, or If the subject has a body weight between the lower limit and the threshold body weight, the maintenance orisumilast dose is 20 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orismilast is 30 mg of orismilast administered twice daily to the subject; The lower limit of body weight is 50kg to 75kg.

[0158] In any one of embodiments A13 to A18, the lower limit body weight can be selected from 50 kg, 55 kg, 60 kg, 65 kg, 70 kg, and 75 kg. The lower limit body weight may be 50 kg. The lower limit body weight may be 60 kg. The lower limit body weight may be 70 kg. The lower limit body weight may be 75 kg.

[0159] The administration regimen described in Administration Regimen A (including any of Embodiments A1 to A18) is particularly suitable for the treatment of psoriasis, for example, moderate to severe psoriasis. Psoriasis may be plaque-type psoriasis. Preferably, the administration regimen is for the treatment of moderate to severe plaque-type psoriasis.

[0160] In some embodiments, the administration regimen described in administration regimen A (including any of embodiments A1 to A18) is for the treatment of atopic dermatitis. In some embodiments, the administration regimen is for the treatment of moderate to severe atopic dermatitis. In some embodiments, the administration regimen is for the treatment of severe atopic dermatitis. In some embodiments, the administration regimen is for the treatment of moderate atopic dermatitis.

[0161] In some embodiments, the administration regimen described in administration regimen A (including any of embodiments A1 to A18) is for the treatment of hidradenitis suppurativa (HS). In some embodiments, the administration regimen is for the treatment of mild to severe HS. In some embodiments, the administration regimen is for the treatment of moderate to severe HS. In some embodiments, the administration regimen is for the treatment of severe HS. In some embodiments, the administration regimen is for the treatment of moderate HS.

[0162] Administration regimen B (Second aspect of the present invention) As discussed above with respect to administration regimen A, subjects with a body weight above the threshold weight are expected to show improved efficacy and / or tolerability when treated with a higher maintenance dose of orismilast. Administration regimen B described herein is for the treatment of subjects with a body weight above the threshold weight.

[0163] Therefore, orismilast is also provided for use in a method of treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight above a threshold body weight, the method comprising administering orismilast to the subject, Here: (Bi) The initial orisumilast dose is administered to the subject once daily during the preliminary period, and then; (Bii) The intermediate orisumilast dose is administered to the subject twice daily during the intermediate period, then; (Biii) The maintenance orisumilast dose is administered to the subject twice daily, and the maintenance orisumilast dose is greater than the intermediate orisumilast dose; Here: (a) The initial orisumilast dose and the intermediate orisumilast dose are independently selected from 10 mg to 30 mg of orisumilast, provided that the intermediate orisumilast dose is equal to or greater than the initial orisumilast dose; (b) The reserve period is a maximum of eight weeks; (c) The intermediate period is 1 to 8 weeks; (d) The threshold body weight is at least 90 kg.

[0164] A method for treating diseases or disorders that are cured by inhibiting PDE4 in subjects with a body weight above a threshold body weight is also provided, the method comprising administering orismilast to the subject according to the above-described dosing regimens (Bi), (Bii), and (Biii).

[0165] The use of olisthilast for the manufacture of a medicament for the treatment of a disease or disorder that is restored by inhibiting PDE4 in a subject having a weight above a threshold also is provided, the method including administering olisthilast to the subject according to the dosing regimens (Bi), (Bii) and (Biii) described above.

[0166] In certain embodiments of dosing regimen B, the intermediate olisthilast dose is 10 to 20 mg of olisthilast. In certain embodiments, the intermediate olisthilast dose is 10 mg of olisthilast. In certain embodiments, the intermediate olisthilast dose is 20 mg of olisthilast.

[0167] Administration of the initial and intermediate olisthilast doses of (Bi) and (Bii) is expected to improve subject tolerance to olisthilast by reducing the number and / or severity of side effects such as diarrhea, nausea, headache, dizziness or vomiting.

[0168] In dosing regimen B, when the subject has a weight above the threshold weight, the maintenance olisthilast dose is greater than the intermediate olisthilast dose. Suitably, the maintenance olisthilast dose for a subject having a weight above the threshold weight is up to 40 mg of olisthilast, for example, the maintenance olisthilast dose is up to 35 mg of olisthilast, or up to 30 mg of olisthilast, provided that the maintenance olisthilast dose is greater than the intermediate olisthilast dose. In some embodiments, the maintenance olisthilast dose is selected from 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 mg of olisthilast, provided that the maintenance olisthilast dose is greater than the intermediate olisthilast dose.

[0169] In certain embodiments of dosing regimen B, the dosing regimen includes: (Bi) The initial olisthilast dose is 20 mg of olisthilast administered once daily to the subject for 1 week; (Bii) The intermediate olisthilast dose is 20 mg of olisthilast administered twice daily to the subject for 1 to 8 weeks; (Biii) The maintenance dose of orisumilast is 30 mg of orisumilast administered twice daily to the subject.

[0170] Therefore, the intermediate dose of orisumilast may be administered to subjects twice daily for 2 to 8 weeks. The intermediate dose of orisumilast may be administered to subjects twice daily for 1 to 4 weeks. The intermediate dose of orisumilast may be administered to subjects twice daily for 4 to 8 weeks. The intermediate dose of orisumilast may be administered to subjects twice daily for 6 to 8 weeks.

[0171] Embodiment B1 In a specific embodiment of administration regimen B, the administration regimen includes: (Bi) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for one week to the subject; (Bii) The intermediate dose of orisumilast is 20 mg of orisumilast administered to the subject twice daily for two weeks; (Biii) The maintenance dose of orisumilast is 30 mg of orisumilast administered twice daily to the subject.

[0172] Embodiment B2 In a specific embodiment of administration regimen B, the administration regimen includes: (Bi) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for one week to the subject; (Bii) The intermediate dose of orisumilast is 20 mg of orisumilast administered twice daily for 4 weeks to the subject; (Biii) The maintenance dose of orisumilast is 30 mg of orisumilast administered twice daily to the subject.

[0173] Embodiment B3 In a specific embodiment of administration regimen B, the administration regimen includes: (Bi) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for one week to the subject; (Bii) The intermediate dose of orisumilast is 20 mg of orisumilast administered twice daily for 6 weeks to the subject; (Biii) The maintenance dose of orisumilast is 30 mg of orisumilast administered twice daily to the subject.

[0174] Embodiment B4 In a specific embodiment of administration regimen B, the administration regimen includes: (Bi) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for one week to the subject; (Bii) The intermediate dose of orisumilast is 20 mg of orisumilast administered twice daily for 8 weeks to the subject; (Biii) The maintenance dose of orisumilast is 30 mg of orisumilast administered twice daily to the subject.

[0175] Embodiment B5 In a specific embodiment of administration regimen B, the administration regimen includes: (Bi) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Bii) The intermediate dose of orisumilast is 20 mg of orisumilast administered to the subject twice daily for 1 to 8 weeks; (Biii) The maintenance dose of orisumilast is 30 mg of orisumilast administered twice daily to the subject.

[0176] Therefore, the intermediate dose of orisumilast may be administered to subjects twice daily for 2 to 8 weeks. The intermediate dose of orisumilast may be administered to subjects twice daily for 1 to 4 weeks. The intermediate dose of orisumilast may be administered to subjects twice daily for 4 to 8 weeks. The intermediate dose of orisumilast may be administered to subjects twice daily for 6 to 8 weeks.

[0177] Embodiment B6 In a specific embodiment of administration regimen B, the administration regimen includes: (Bi) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Bii) The intermediate dose of orisumilast is 20 mg of orisumilast administered to the subject twice daily for two weeks; (Biii) The maintenance dose of orisumilast is 30 mg of orisumilast administered twice daily to the subject.

[0178] Embodiment B7 In a specific embodiment of administration regimen B, the administration regimen includes: (Bi) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Bii) The intermediate dose of orisumilast is 20 mg of orisumilast administered twice daily for 4 weeks to the subject; (Biii) The maintenance dose of orisumilast is 30 mg of orisumilast administered twice daily to the subject.

[0179] Embodiment B8 In a specific embodiment of administration regimen B, the administration regimen includes: (Bi) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Bii) The intermediate dose of orisumilast is 20 mg of orisumilast administered twice daily for 6 weeks to the subject; (Biii) The maintenance dose of orisumilast is 30 mg of orisumilast administered twice daily to the subject.

[0180] Embodiment B9 In a specific embodiment of administration regimen B, the administration regimen includes: (Bi) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Bii) The intermediate dose of orisumilast is 20 mg of orisumilast administered twice daily for 8 weeks to the subject; (Biii) The maintenance dose of orisumilast is 30 mg of orisumilast administered twice daily to the subject.

[0181] The dosing regimen described in Dosing Regimen B (including any of Embodiments B1 to B9) is particularly suitable for the treatment of psoriasis, for example, moderate to severe psoriasis. Psoriasis may be plaque-type psoriasis. Preferably, the dosing regimen is for the treatment of moderate to severe plaque-type psoriasis.

[0182] In some embodiments, the administration regimen described in Administration Regimen B (including any of Embodiments B1 to B9) is for the treatment of atopic dermatitis. The administration regimen may be for the treatment of moderate to severe atopic dermatitis. The administration regimen may be for the treatment of moderate atopic dermatitis. The administration regimen may be for the treatment of severe atopic dermatitis.

[0183] In certain embodiments, the threshold body weight is 90 kg in administration regimen A and administration regimen B. In certain embodiments, the threshold body weight is 95 kg in administration regimen A and administration regimen B. In certain embodiments, the threshold body weight is 105 kg in administration regimen A and administration regimen B. In preferred embodiments, the threshold body weight is 100 kg in administration regimen A and administration regimen B.

[0184] The improved tolerability and / or efficacy provided by the administration regimens described herein also provide improved patient adherence to medication, thereby enhancing the effectiveness of orismilast treatment.

[0185] In certain embodiments, the initial / preparatory period, initial orismilast dose, intermediate period, and intermediate orismilast dose used in administration regimen A or administration regimen B are any one of the administration regimens in Table 1. In Table 1, the initial period used in administration regimen A is any of the regimens in Table 1 in which the initial period is 2 to 8 weeks according to administration regimen A.

[0186] [Table 2]

[0187] Table 3

[0188] Table 4

[0189] Table 5

[0190] Table 6

[0191] Table 7

[0192] Table 8

[0193] Table 9

[0194] Table 10

[0195] Table 11

[0196] Table 12

[0197] Table 13

[0198] Table 14

[0199] Table 15

[0200] Table 16

[0201] Table 17

[0202] Table 18

[0203] Table 19

[0204] Table 20

[0205] Table 21

[0206] Table 22

[0207] Table 23

[0208] Table 24

[0209] Table 25

[0210] Table 26

[0211] Table 27

[0212] Table 28

[0213] Table 29

[0214] Table 30

[0215] Table 31

[0216] Table 32

[0217] Table 33

[0218] [Table 34]

[0219] If Table 1 shows the intermediate orismilast dose as a range, it should be understood that the intermediate dose is selected to be greater than or equal to the initial or reserve orismilast dose, according to administration regimens A and B.

[0220] In each of the administration regimens shown in Table 1, the maintenance orismilast dose administered to the subject after the interim period may be any of the maintenance orismilast doses described herein.

[0221] Therefore, in the case of the administration regimens according to administration regimens A and B in Table 1, the maintenance orismilast dose exceeds the intermediate orismilast dose if the subject has a body weight above the threshold body weight. In a preferred embodiment, the maintenance orismilast dose is 30-40 mg orismilast if the subject has a body weight above the threshold body weight, and the maintenance dose is higher than the intermediate dose. More preferably, the maintenance orismilast dose is 30 mg orismilast if the subject has a body weight above the threshold body weight, and the maintenance dose is higher than the intermediate dose. When the subject has a body weight above the threshold body weight, a particular embodiment of administration regimens A and B is the administration regimen in Table 1 in which the intermediate orismilast dose is 10 or 20 mg orismilast (e.g., 20 mg orismilast) and the maintenance orismilast dose is 30 mg.

[0222] Appropriately, in the administration regimen A shown in Table 1, if the subject has a body weight below the threshold weight, the maintenance orismilast dose is the same as the intermediate orismilast dose. For example, in the preferred administration regimen A shown in Table 1, the intermediate orismilast dose and the maintenance orismilast dose are the same and in the range of 10 to 20 mg for subjects with a body weight below the threshold weight. In a specific embodiment of administration regimen A shown in Table 1, the intermediate orismilast dose and the maintenance orismilast dose are the same and in the range of 10 to 20 mg for subjects with a body weight below the threshold weight. In the preferred embodiment of administration regimen A shown in Table 1, both the intermediate orismilast dose and the maintenance orismilast dose are 20 mg for subjects with a body weight below the threshold weight.

[0223] A preferred embodiment in Table 1 is a dosing regimen in which the total duration of the initial / preparatory period and the intermediate period is 4 to 8 weeks. Therefore, the dosing regimen may be the dosing regimen in Table 1 in which the total duration of the initial / preparatory period and the intermediate period is 4 weeks. The dosing regimen may be the dosing regimen in Table 1 in which the total duration of the initial / preparatory period and the intermediate period is 6 weeks. The dosing regimen may be the dosing regimen in Table 1 in which the total duration of the initial / preparatory period and the intermediate period is 8 weeks.

[0224] Preferably, in any of the embodiments described in Table 1, the threshold weight is 90 kg. Preferably, in any of the embodiments described in Table 1, the threshold weight is 95 kg. Preferably, in any of the embodiments described in Table 1, the threshold weight is 105 kg. Preferably, in any of the embodiments described in Table 1, the threshold weight is 100 kg.

[0225] Administration regimen C (third aspect of the present invention) A dosage regimen is also being considered in which subjects with a body weight above the threshold weight transition to a maintenance dose immediately after the completion of initial dose adjustments.

[0226] Therefore, in some embodiments, orismilast is provided for use in methods of treating diseases or disorders that are cured by inhibiting PDE4 in subjects having a body weight above a threshold body weight, the method comprising administering orismilast to the subject, Here: (Ci) The initial orisumilast dose is administered to the subject once daily during the preliminary period, and then; (Cii) The maintenance orisumilast dose is administered to the subject twice daily, and is greater than the initial orisumilast dose; Here: (a) The initial dose of orisumilast is 10 mg to 20 mg of orisumilast; (b) The reserve period is a maximum of eight weeks; (c) The threshold body weight is at least 90 kg.

[0227] A method is also provided for treating a disease or disorder that is cured by inhibiting PDE4 in subjects with a body weight above a threshold body weight, the method comprising administering orismilast to the subject according to the above-described dosing regimens (Ci) and (Cii), wherein the threshold body weight is at least 90 kg.

[0228] Orismilast is also provided for the manufacture of a medicament for the treatment of a disease or disorder that is cured by inhibiting PDE4 in subjects having a body weight above a threshold body weight, the method comprising administering orismilast to a subject according to the above-described dosing regimens (Ci) and (Cii), the threshold body weight being at least 90 kg.

[0229] In certain embodiments, the preparatory period for (Ci) is 1 to 4 weeks. In certain embodiments, the preparatory period for (Ci) is 1 to 3 weeks. In certain embodiments, the preparatory period for (Ci) is 1 to 2 weeks. In certain embodiments, the preparatory period for (Ci) is 2 to 4 weeks. In certain embodiments, the preparatory period for (Ci) is 2 weeks to a maximum of 4 weeks. In certain embodiments, the preparatory period for (Ci) is 1 week. In certain embodiments, the preparatory period for (Ci) is 3 weeks. In certain embodiments, the preparatory period for (Ci) is 4 weeks. Preferably, the preparatory period for (Ci) is 2 weeks.

[0230] In a preferred embodiment, the initial orisumilast dose of (Ci) is 20 mg orisumilast.

[0231] In certain embodiments, the maintenance orisumilast dose of (Ciii) is orisumilast up to 40 mg, provided that the maintenance orisumilast dose is greater than the initial orisumilast dose. For example, the maintenance orisumilast dose may be 30 mg to 40 mg of orisumilast. In preferred embodiments, the maintenance orisumilast dose of (Ciii) is 30 mg of orisumilast.

[0232] In a preferred embodiment, the initial orisumilast dose of (Ci) is 20 mg orisumilast, and the maintenance orisumilast dose of (Ciii) is 30 mg orisumilast.

[0233] In another embodiment, the initial orisumilast dose of (Ci) is 20 mg orisumilast, the reserve period of (Ci) is 2 to 4 weeks, and the maintenance orisumilast dose of (Ciii) is 30 mg orisumilast.

[0234] In another embodiment, the initial orisumilast dose of (Ci) is 20 mg orisumilast, the reserve period of (Ci) is 2 weeks, and the maintenance orisumilast dose of (Ciii) is 30 mg orisumilast.

[0235] In a particular embodiment of administration regimen C, the threshold body weight is 90 kg. In a particular embodiment of administration regimen C, the threshold body weight is 95 kg. In a particular embodiment of administration regimen C, the threshold body weight is 105 kg. Preferably, in administration regimen C, the threshold body weight is 100 kg.

[0236] Variations of administration regimens A, B, and C A subset of subjects with a body weight above the threshold weight may exhibit a favorable clinical response during the intermediate period ("weight-based responsive subjects"). Such weight-based responsive subjects may not require a maintenance orismilast dose exceeding the intermediate orismilast dose and may instead be administered a maintenance orismilast dose equal to the intermediate dose. This weight-based stratification of patients can maximize the therapeutic response to orismilast while minimizing the frequency and / or severity of undesirable side effects.

[0237] Therefore, any variation of any one of the administration regimens A, B, and C described herein is also contemplated, where: (i) In subjects with a body weight above the threshold weight, if the subject shows a good therapeutic response during the intermediate period, the subject will be administered the same maintenance dose as the intermediate dose of orisumilast; (ii) In subjects with a body weight above the threshold body weight who do not show a favorable therapeutic response during the intermediate period, the subject will be administered a maintenance dose of orisumilast exceeding the intermediate dose.

[0238] Therefore, in some embodiments, orismilast is provided for use in methods of treating diseases or disorders that are cured by inhibiting PDE4 in a subject, the method comprising administering orismilast to the subject: The initial dose of (Ai) 20 mg of orisumilast was administered to the subjects once daily for an initial period of two weeks, and then; (Aii) An intermediate dose of 20 mg of orisumilast is administered to the subject twice daily for an intermediate period of 1 to 8 weeks (e.g., 1 to 4 weeks, 2 to 8 weeks, or 6 to 8 weeks), and then; (Aiii-a) If the subject has a body weight below the threshold body weight, a maintenance dose of 20 mg of orisumilast is administered to the subject twice daily; or (Aiii-b) If the subject has a body weight above the threshold body weight and shows a good clinical response during the interim period, the subject is given a maintenance dose of 20 mg of orisumilast twice daily; or (Aiii-c) If the subject has a body weight above the threshold weight and does not show a favorable clinical response during the interim period, the subject will be administered a maintenance dose of 30 mg of orisumilast twice daily; The threshold body weight is at least 90 kg.

[0239] Preferably, the threshold body weight is 100 kg.

[0240] In some embodiments, orismilast is provided for use in a method of treating a disease or disorder that is cured by inhibiting PDE4 in a subject, the method comprising administering orismilast to the subject, wherein: The initial dose of (Ai) 20 mg of orisumilast was administered to the subjects once daily for an initial period of two weeks, and then; (Aii) An intermediate dose of 20 mg of orisumilast was administered to the subjects twice daily for an intermediate period of 6 weeks, and then; (Aiii-a) If the subject has a body weight below the threshold body weight, a maintenance dose of 20 mg of orisumilast is administered to the subject twice daily; or (Aiii-b) If the subject has a body weight above the threshold body weight and shows a good clinical response during the interim period, the subject is administered a maintenance dose of 20 mg of orisumilast twice daily; or (Aiii-c) If the subject has a body weight above the threshold weight and does not show a favorable clinical response during the interim period, the subject will be administered a maintenance dose of 30 mg of orisumilast twice daily; the threshold weight is at least 90 kg.

[0241] Preferably, the threshold body weight is 100 kg.

[0242] In some embodiments, orismilast is provided for use in a method of treating a disease or disorder that is cured by inhibiting PDE4 in a subject, the method comprising administering orismilast to the subject, wherein: The initial dose of (Ai) 20 mg of orisumilast was administered to the subjects once daily for an initial period of two weeks, and then; (Aii) An intermediate dose of 20 mg of orisumilast was administered to the subjects twice daily for an intermediate period of 4 weeks, and then; (Aiii-a) If the subject has a body weight below the threshold body weight, a maintenance dose of 20 mg of orisumilast is administered to the subject twice daily; or (Aiii-b) If the subject has a body weight above the threshold body weight and shows a good clinical response during the interim period, the subject is given a maintenance dose of 20 mg of orisumilast twice daily; or (Aiii-c) If the subject has a body weight above the threshold weight and does not show a favorable clinical response during the interim period, a maintenance dose of 30 mg of orisumilast is administered to the subject twice daily; the threshold weight is at least 90 kg.

[0243] Preferably, the threshold body weight is 100 kg.

[0244] In some embodiments, orismilast is provided for use in a method of treating a disease or disorder that is cured by inhibiting PDE4 in a subject, the method comprising administering orismilast to the subject, wherein: The initial dose of (Ai) 20 mg of orisumilast was administered to the subjects once daily for an initial period of two weeks, and then; (Aii) An intermediate dose of 20 mg of orisumilast was administered to the subjects twice daily for an intermediate period of two weeks, and then; (Aiii-a) If the subject has a body weight below the threshold body weight, a maintenance dose of 20 mg of orisumilast is administered to the subject twice daily; or (Aiii-b) If the subject has a body weight above the threshold body weight and shows a good clinical response during the interim period, the subject is given a maintenance dose of 20 mg of orisumilast twice daily; or (Aiii-c) If the subject has a body weight above the threshold weight and does not show a favorable clinical response during the interim period, a maintenance dose of 30 mg of orisumilast is administered to the subject twice daily; the threshold weight is at least 90 kg.

[0245] Preferably, the threshold body weight is 100 kg.

[0246] In some embodiments, orismilast is provided for use in a method of treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight above a threshold body weight, the method comprising administering orismilast to the subject, Here: The initial dose of (Bi) 20 mg of orisumilast was administered to the subjects once daily for a 2-week preliminary period, and then; (Bii) An intermediate dose of 20 mg of orisumilast was administered to the subjects twice daily for an intermediate period of 1 to 8 weeks, and then; (Biii-a) If the subject shows a favorable clinical response during the interim period, a maintenance dose of 20 mg of orisumilast is administered to the subject twice daily; or (Biii-b) If the subject does not show a favorable clinical response during the interim period, a maintenance dose of 30 mg of orisumilast is administered to the subject twice daily; the threshold body weight is at least 90 kg.

[0247] Preferably, the threshold body weight is 100 kg.

[0248] In some embodiments, orismilast is provided for use in a method of treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight above a threshold body weight, the method comprising administering orismilast to the subject, Here: The initial dose of (Bi) 20 mg of orisumilast was administered to the subjects once daily for a 2-week preliminary period, and then; (Bii) An intermediate dose of 20 mg of orisumilast was administered to the subjects twice daily for an intermediate period of 6 weeks, and then; (Biii-a) If the subject shows a favorable clinical response during the interim period, a maintenance dose of 20 mg of orisumilast is administered to the subject twice daily; or (Biii-b) If the subject does not show a favorable clinical response during the interim period, a maintenance dose of 30 mg of orisumilast will be administered to the subject twice daily; The threshold body weight is at least 90 kg.

[0249] Preferably, the threshold body weight is 100 kg.

[0250] Therefore, in some embodiments, orismilast is also provided for use in methods of treating diseases or disorders that are cured by inhibiting PDE4 in subjects having a body weight above a threshold body weight, the method comprising administering orismilast to the subject, Here: The initial orisumilast dose of (Ci) 20 mg was administered to the subject once daily during the preliminary period, and then; (Cii-a) If the subject shows a favorable clinical response during the preliminary period, a maintenance dose of 20 mg of orisumilast is administered to the subject twice daily; or (Cii-b) If the subject does not show a favorable clinical response during the preliminary period, a maintenance dose of 30 mg of orisumilast will be administered to the subject twice daily; The threshold weight is at least 90 kg; the reserve period is 1 to 4 weeks.

[0251] Preferably, the threshold body weight is 100 kg. Preferably, the reserve period is 2 weeks.

[0252] In the variations of the above administration regimens A, B, and C, “good clinical response” refers to one or more reductions in one or more signs and symptoms of the disease, depending on the disease or disorder being treated, and is readily determined by the physician.

[0253] In some embodiments where the disease or disorder is psoriasis, a good clinical response during the interim period may be one or more of the following: A decrease from baseline in the Psoriasis Area and Severity Index (PASI) score (e.g., a decrease of 50% (PASI 50) or more, a decrease of 75% (PASI 75) or more, a decrease of 90% (PASI 90) or more, or a decrease of 100% (PASI 100) or more); A decrease from baseline in the Investigator's Overall Assessment (IGA) score (e.g., a score of clear (0) or near clear (1), and an improvement of at least 2 points in the IGA); Achieving an IGA score of 0; A decrease from baseline in the physician's static overall assessment (sPGA) score; A decrease in the Total Psoriasis Symptom Scale (PSS) score from baseline; Reduction in affected body surface area (BSA) from baseline; A decrease from baseline in the Dermatological Quality of Life Index (DLQI) score; Decrease from baseline in the overall assessment (ss-IGA) score by a scalp specialist clinical trial investigator; A decrease from baseline in the overall assessment score (ScPGA) by a scalp specialist; A decrease from baseline in the static overall assessment (sPGA-G®) score by a reproductive physician; Baseline reduction in the Physician-Assessed Comprehensive Assessment (PPPGA) of Palmoplantar Psoriasis; A decrease from baseline in the physician's overall assessment (PGA-F) score for onychopsoriasis; A decrease from baseline in the Numerical Rating Scale (NRS) for generalized itchiness; A decrease in pain NRS score from baseline; A decrease from baseline in the Numerical Rating Scale (NRS) score for scalp itchiness; and / or Improvement from baseline in EuroQol Quality of Life 5D-5Level (EQ-5D-5L®) score.

[0254] In some embodiments where the disease is psoriasis (e.g., moderate to severe psoriasis), a good clinical response during the interim period may be at least a 75% reduction in the PASI score from baseline (PASI75) or sPGA of 0 or 1.

[0255] In some embodiments where the disease is psoriasis (e.g., moderate to severe psoriasis), a good clinical response during the interim period may be a primary, secondary, or tertiary endpoint in the psoriasis clinical trials disclosed in Examples 3, 4, and 5 of this specification.

[0256] In some embodiments where the disease is atopic dermatitis (e.g., moderate to severe atopic dermatitis), a good clinical response during the intermediate period may be one or more of the following: A decrease from baseline in the Eczema Area and Severity Index (EASI) score (e.g., a decrease of 50% or more (EASI50), a decrease of 75% or more (EASI75), a decrease of 90% or more (EASI90), or a decrease of 100% or more (EASI100)); A decrease from baseline in the Investigator-Assessed Overall Assessment (IGA-AD) score for Alzheimer's Disease (e.g., a score of clear (0) or near clear (1), and subjects achieving an improvement of at least 2 points in IGA-AD); Achievement of IGA-AD 0; A reduction from baseline in the investigator-reviewed comprehensive assessment (vIGA-AD) score for validated Alzheimer's disease (e.g., a score of clear (0) or nearly clear (1) and an improvement of at least 2 points in the vIGA-AD score); Achievement of vIGA-AD 0; A decrease from baseline in the Peak Itch Numerical Rating Scale (NRS); A decrease from baseline in the worst pruritus numerical rating scale (NRS); Reduction in affected body surface area (BSA) from baseline; A decrease from baseline in the dermatological quality of life index score; A decrease from baseline in patient-oriented eczema measurement scores; A decrease from baseline in the patient's overall impression regarding severity; Patient's overall impression score regarding change: 1 or 2; A decrease from baseline in the NRS score for sleep disorders; A decrease from baseline in the NRS score for skin pain; or Changes from baseline in skin biomarkers, such as a decrease in TARC (thymic and activating regulatory chemokines, also known as CCL17) or C6A6.

[0257] In some embodiments where the disease is atopic dermatitis (e.g., moderate to severe atopic dermatitis), a good clinical response during the intermediate period may be the primary, secondary, or tertiary endpoint in the atopic dermatitis clinical trials disclosed in Examples 8 and 13 of this specification.

[0258] In some embodiments where the disease is hidradenitis suppurativa (HS), a good clinical response during the intermediate period may be one or more of the following: Decrease in the number of abscesses and nodules (AN count) from baseline A decrease from baseline in the International Hidradenitis Severity Score System (IHS4) score; A decrease from baseline in the Clinical Response (HiSCR) score for hidradenitis suppurativa; A decrease from baseline in the Quality of Life (HiSQoL) score for hidradenitis suppurativa; A decrease from baseline in the physician's overall assessment of disease severity (HS-PGA); A decrease from baseline in the Dermatological Quality of Life Index (DLQI) score; A decrease from baseline in the overall NRS score of patients with skin pain; Decrease in C-reactive protein levels from baseline

[0259] Administration regimen D (fourth aspect of the present invention) A fourth aspect of the present invention provides an administration regimen optimized for subjects having a body weight between a lower limit and a threshold body weight, where the lower limit is between 50 kg and 75 kg.

[0260] Therefore, orismilast is provided for use in a method of treating a disease or disorder that is restored by inhibiting PDE4 in a subject, the method comprising administering orismilast to the subject, wherein: (Di) The initial orisumilast dose is administered to the subject once daily during the initial period, and then; (Dii) The maintenance dose of orisumilast is administered to the subject twice daily; Here: (a) The initial dose and maintenance dose of orisumilast are both 20 mg orisumilast; (b) The initial period is 2 to 8 weeks; (c) The subjects have a body weight between the lower limit and the threshold weight, with the threshold weight being at least 90 kg and the lower limit being between 50 kg and 75 kg.

[0261] A method is also provided for treating diseases or disorders that are cured by inhibiting PDE4 in subjects having a body weight between the lower limit and below the threshold body weight, the method comprising administering orismilast to the subject according to the above-described dosing regimens (Di) and (Dii), where the threshold body weight is at least 90 kg and the lower limit body weight is between 50 kg and 75 kg.

[0262] The use of orismilast for the manufacture of a medicament for the treatment of a disease or disorder that is cured by inhibiting PDE4 in subjects having a weight between the lower limit and below the threshold weight is also provided, the method comprising administering orismilast to a subject according to the above-described dosing regimens (Di) and (Dii), wherein the threshold weight is at least 90 kg and the lower limit weight is between 50 kg and 75 kg.

[0263] In certain embodiments, the initial period of (Di) is 2 to 6 weeks. In certain embodiments, the initial period of (Di) is 2 to 4 weeks. In certain embodiments, the initial period of (Di) is 2 to a maximum of 4 weeks. In certain embodiments, the initial period of (Di) is 3 weeks. In certain embodiments, the initial period of (Di) is 4 weeks. Preferably, the initial period of (Di) is 2 weeks.

[0264] In a particular embodiment of the fourth aspect, the threshold weight is 90 kg. In a particular embodiment of the fourth aspect, the threshold weight is 90 kg. In a particular embodiment of the fourth aspect, the threshold weight is 95 kg. In a preferred embodiment of the fourth aspect, the threshold weight is 100 kg.

[0265] In a specific embodiment of the fourth aspect, the lower limit weight is selected from 50 kg, 55 kg, 60 kg, 65 kg, 70 kg, and 75 kg. In a specific embodiment of the fourth aspect, the lower limit weight is 50 kg. In a specific embodiment of the fourth aspect, the lower limit weight is 60 kg. In a specific embodiment of the fourth aspect, the lower limit weight is 70 kg. In a specific embodiment of the fourth aspect, the lower limit weight is 75 kg.

[0266] Therefore, the subjects may have a weight of 50 kg to less than 100 kg. In some embodiments, the subjects have a weight of 60 kg to less than 100 kg. The subjects have a weight of 70 kg to less than 100 kg.

[0267] In one embodiment of the fourth aspect, orismilast is provided for use in a method for treating a disease or disorder that is restored by inhibiting PDE4 in a subject, the method comprising administering orismilast to the subject, wherein: The initial dose of (Di) 20 mg of orisumilast is administered to the subject once daily for two weeks, then; (Dii) The maintenance dose of 20 mg of orisumilast is administered to the subject twice daily; The subjects are individuals weighing between 75kg and less than 100kg.

[0268] In a fourth embodiment, orismilast is provided for use in a method of treating a disease or disorder that is restored by inhibiting PDE4 in a subject, the method comprising administering orismilast to the subject, wherein: The initial dose of (Di) 20 mg of orisumilast is administered to the subject once daily for two weeks, then; (Dii) Maintenance dose of orisumilast: 20 mg. Orisumilast is administered to subjects twice daily; The subjects are individuals weighing between 60kg and less than 100kg.

[0269] In another embodiment of the fourth aspect, orismilast is provided for use in a method of treating a disease or disorder that is restored by inhibiting PDE4 in a subject, the method comprising administering orismilast to the subject, wherein: The initial dose of (Di) 20 mg of orisumilast is administered to the subject once daily for two weeks, then; (Dii) Maintenance dose of orisumilast: 20 mg. Orisumilast is administered to subjects twice daily; The subjects are individuals weighing between 50kg and less than 100kg.

[0270] Administration regimen E (Fifth aspect of the present invention) As described in the examples herein, a population PK model based on pooled orismilast clinical trial data confirms that treatment of low-body weight subjects, e.g., under 50 kg (e.g., adolescent patients), with 20 mg of orismilast twice daily results in higher systemic exposure to orismilast compared to heavier subjects. As discussed above, analysis of Phase 2b data for psoriasis indicates that increased systemic exposure beyond what is necessary for initial efficacy may not increase efficacy, but rather decrease it. Therefore, specific dosing regimens may be necessary for lighter subjects.

[0271] A fifth aspect of the present invention provides orismilast for use in a method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight below a lower limit, the method comprising administering orismilast to the subject, wherein: (Ei) The initial orisumilast dose of 10 mg is administered to the subject once daily during the initial period, and then; (Eii) A maintenance dose of 10 mg of orisumilast was administered to the subjects twice daily; The initial period here is 2 to 8 weeks, and the lower limit of body weight is 50 kg to 75 kg.

[0272] A method for treating a disease or disorder that is cured by inhibiting PDE4 in subjects with a body weight below the lower limit is also provided, the method comprising administering orismilast to the subject according to the above-described dosing regimens (Ei) and (Eii), where the lower limit is 50 kg to 75 kg.

[0273] The use of orismilast for the manufacture of a medicament for the treatment of a disease or disorder that is cured by inhibiting PDE4 in subjects having a body weight below the lower limit is also provided, the method comprising administering orismilast to a subject according to the above-described dosing regimens (Ei) and (Eii), where the lower limit is 50 kg to 75 kg.

[0274] In certain embodiments, the initial period of (Ei) is 2 to 6 weeks. In certain embodiments, the initial period of (Ei) is 2 to 4 weeks. In certain embodiments, the initial period of (Ei) is 2 to a maximum of 4 weeks. In certain embodiments, the initial period of (Ei) is 3 weeks. In certain embodiments, the initial period of (Ei) is 4 weeks. Preferably, the initial period of (Ei) is 2 weeks.

[0275] In some embodiments of a fifth aspect of the present invention, orismilast is provided for use in a method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight below a lower limit, the method comprising administering orismilast to the subject, wherein: (Ei) The initial dose of orisumilast, 10 mg, was administered to the subject once daily for two weeks, and then; (Eii) A maintenance dose of 10 mg of orisumilast was administered to the subjects twice daily; The lower limit for body weight here is 50kg to 75kg.

[0276] In some embodiments of a fifth aspect of the present invention, the lower limit weight is selected from 50 kg, 55 kg, 60 kg, 65 kg, 70 kg, and 75 kg. In a particular embodiment of the fifth aspect, the lower limit weight is 50 kg. In a particular embodiment of the fifth aspect, the lower limit weight is 60 kg. In a particular embodiment of the fifth aspect, the limit weight is 70 kg. In a particular embodiment of the fifth aspect, the lower limit weight is 75 kg.

[0277] Alternative initial dose adjustment Modifications of any of the administration regimens A, B, C, D, or E described herein are also intended, in which the initial orismilast dose, administration frequency, and / or initial or preliminary period are changed from once daily administration as described in administration regimens A, B, C, D, or E.

[0278] Accordingly, variations of administration regimens A, B, C, D, or E are also provided, in (Ai), (Bi), (Ci), (Di), or (Ei), in which an initial orisumilast dose (e.g., 10 mg or 20 mg) is administered to the subject once or twice daily during an initial or preliminary period (e.g., 2 weeks) prior to the administration of an intermediate or maintenance orisumilast dose twice daily. Variations of administration regimens A, B, C, D, or E are also provided, in which (Ai), (Bi), (Ci), (Di), or (Ei) an initial dose of 10 mg of orisumilast is administered twice daily to the subject during an initial or preliminary period of one or two weeks prior to the administration of the intermediate or maintenance orisumilast dose twice daily. Variations of administration regimens A, B, C, D, or E are also provided, in which (Ai), (Bi), (Ci), (Di), or (Ei) an initial dose of 20 mg of orisumilast is administered once or twice daily to the subject during an initial or preliminary period of one or two weeks prior to the administration of the intermediate or maintenance orisumilast dose twice daily. Variations of administration regimens A, B, C, D, or E are also provided, in which an initial dose of 20 mg of orisumilast is administered twice daily to the subject during an initial or preliminary period of one or two weeks, prior to the administration of an intermediate or maintenance dose of orisumilast twice daily.

[0279] In some embodiments of alternative initial dose adjustments, in any of the administration regimens A, B, C, D, or E described herein, steps (Ai), (Bi), (Ci), (Di), or (Ei) are each replaced for the first 14 days of treatment with one of the variations 1, 2, or 3 shown in the table below.

[0280] [Table 35]

[0281] After completion of the initial 14 days of treatment, subjects are subsequently treated with an intermediate orisumilast dose initiated on day 15 of treatment, as described in either administration regimen A or B, or a maintenance orisumilast dose as described in either administration regimen C, D, or E.

[0282] In some embodiments of alternative initial dose adjustments, in any of the dosing regimens A, B, C, D, or E described herein, steps (Ai), (Bi), (Ci), (Di), or (Ei) are replaced by the initial dose adjustments shown in Table 5 of Example 3, respectively. After completion of the initial 14 days of treatment, the subject is then treated with an intermediate orismilast dose initiated on day 15 of treatment, as described in either dosing regimen A or B, or a maintenance orismilast dose described in either dosing regimen C, D, or E.

[0283] Pharmaceutical composition Orismilast may be included in pharmaceutical compositions. Therefore, the present invention also includes pharmaceutical compositions containing orismilast for use in any of the administration regimens described herein.

[0284] Pharmaceutical compositions containing orismilast may optionally further contain one or more viscosity modifiers, carriers (e.g., mannitol, lactose, microcrystalline cellulose, or trehalose), emulsifiers, surfactants, hydrating agents, oils, waxes, polymers, preservatives, pH adjusters (e.g., suitable acids or bases, e.g., organic acids or organic amine bases), buffers, stabilizers, electrolyte antioxidants (e.g., butylated hydroxyanisole or butylated hydroxytoluene), crystallization inhibitors (e.g., cellulose derivatives such as hydroxypropyl methylcellulose or polyvinylpyrrolidone), colorants, fragrances, and taste masking agents. Such excipients are well known and are listed, for example, in Handbook of Pharmaceutical Excipients, 10th Edition, Sheskey et al.

[0285] In some embodiments, orisumilast is present in the pharmaceutical composition in an amount of about 0.01 to 50% by weight of the composition. Thus, orisumilast may be present in the solid composition in an amount of about 0.05 to 40%, 0.1 to 30%, 0.2 to 20%, 0.3 to 15%, 0.4 to 12%, 0.5 to 11%, 1 to 10%, 1.5 to 9.5%, 2 to 9%, 2.5 to 8.5%, 3 to 8%, 3.5 to 7.5%, 4 to 7%, 4.5 to 6.5%, or about 5 to 6%, for example, about 5.5%, where % is by weight relative to the weight of the composition.

[0286] Pharmaceutical compositions for oral administration In some embodiments, pharmaceutical compositions containing orismilast are suitable for oral administration. Preferably, the pharmaceutical composition is a solid pharmaceutical composition, preferably a solid pharmaceutical composition suitable for oral administration. The pharmaceutical composition containing orismilast may be in the form of individual units such as capsules, medicine bags, tablets, lozenges, or granules, each containing a predetermined amount of orismilast. Individual units may include compositions in the form of powders or granules, aqueous or non-aqueous liquids, such as solutions or suspensions in ethanol or glycerol, or oil-in-water emulsions or water-in-oil emulsions. Such oils may be edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil. Suitable dispersants or suspending agents for aqueous turbidities include synthetic or natural rubbers, such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomer, and polyvinylpyrrolidone. The formulation may also be administered in the form of boluses, licks, or pastes.

[0287] The powder can be prepared using well-known methods, for example, by grinding, blending, micro-precipitation, freeze-drying or spray-drying a solution containing orismilast.

[0288] The amount of orismilast in each oral dosage form (e.g., tablets, capsules, medicine bags, or lozenges) may range from about 1 mg to about 40 mg. The amount of orismilast may range from, for example, 5 mg to 40 mg, 10 mg to 40 mg, 15 mg to 35 mg, 20 to 30 mg, 25 mg to 30 mg, 5 mg to 30 mg, or 10 mg to 30 mg. In some embodiments, the amount of orismilast in each oral dosage form (e.g., tablets, capsules, medicine bags, or lozenges) is 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg.

[0289] In certain embodiments, particles containing orismilast can be prepared by precipitating, freeze-drying, or spray-freezing a solution containing orismilast and a suitable carrier to provide powder particles containing orismilast and a carrier as composite particles. Suitable carriers include inert carriers such as starch and sugars (e.g., mannitol, lactose, microcrystalline cellulose, or trehalose).

[0290] In some embodiments, orismilast exists in the composition as a pulverized powder, for example, a pulverized crystalline powder (e.g., pulverized crystalline form E of orismilast). Therefore, the particle size distribution of orismilast in the composition may have D(50) ≤ 25 μm, for example, D(50) ≤ 20 μm, D(50) ≤ 10 μm, D(50) ≤ 5 μm, or D(50) ≤ 3 μm. In some embodiments, the particle size distribution of orismilast in the composition has D(90) ≤ 10 μm. In some embodiments, the particle size distribution of orismilast in the composition has D(50) from about 1 μm to about 6 μm.

[0291] The powder containing orismilast described herein may be dissolved or suspended in a suitable solvent (preferably water) before administration (e.g., by spraying or applying a gel). Alternatively, the powder or granules containing orismilast may be sprinkled on food or dispersed in a liquid before administration.

[0292] Tablets may be produced by compressing or molding a composition, sometimes together with one or more auxiliary components. Compressed tablets may be prepared by compressing a free-flowing formulation, such as a powder or granules mixed with a binder, such as lactose, glucose, starch, gelatin, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, or wax; a lubricant, such as sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, or sodium chloride; a tablet disintegrant, such as starch, methylcellulose, agar, bentonite, croscarmellose sodium, sodium starch glycolate, or crospovidone, or a dispersant, such as polysorbate 80, in a suitable tablet press.

[0293] Molded tablets can be manufactured by molding. Techniques suitable for molded tablets are well known in the art. For example, a mixture of powdered active ingredients and a suitable carrier may be moistened with an inert liquid diluent in a suitable machine. In some embodiments, molded tablets may be manufactured by dispersing a water-soluble excipient together with powdered orismilast in a suitable solvent such as water, alcohol, or an organic solvent (e.g., acetone, hydrocarbon). Alternatively, molded tablets may be manufactured using a thermoplastic polymer (e.g., polyethylene oxide or polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer) without the use of an inert liquid diluent.

[0294] Table 2 shows typical examples of oral pharmaceutical compositions containing orismilast.

[0295] [Table 36]

[0296] modified release composition In some embodiments, orismilast is included in modified-release composition formulations, such as modified-release compositions for oral administration. Thus, orismilast may be included in modified-release tablet compositions for oral administration. The use of modified-release compositions can control the release of the therapeutic agent, thereby controlling the absorption of orismilast from the gastrointestinal tract. Beneficial effects associated with improved tolerability and maintained systemic exposure to gastrointestinal adverse events can be achieved by formulating orismilast in modified-release tablet formulations, where in vitro release is faster compared to delayed or sustained-release oral release profiles, but still not as fast as immediate-release tablets, which have shown major tolerability issues, as previously described by the applicant (in a PCT application published as International Publication 2020 / 148271).

[0297] It is understood that the dissolution rate of modified-release compositions is determined by several factors, such as the excipients and properties of the composition, the particle size of the components used in the composition, particularly the particle size of orismilast, and the use of coatings or capsules to regulate the release of orismilast from the composition. The target dissolution range in Figure 1 of International Publication No. 2020 / 0148271 shows that a suitable dissolution profile for compositions containing modified-release orismilast can be appropriately determined in vitro using Ph.Eur.2.9.3 Apparatus II with 900 ml of dissolution medium of 0.5% sodium dodecyl sulfate in 0.1N HCl, a paddle speed of 75 rpm, and a dissolution medium at 37±0.5℃, which is referred to herein as the “standard dissolution assay”.

[0298] In some embodiments, orismilast is formulated as a modified-release formulation as described in International Publication No. 2020 / 0148271, which is incorporated herein by reference.

[0299] Compositions containing other modified release orismilasts are also intended. For example, orismilasts may be dispersed, dissolved, or conjugated (e.g., complexed) in a polymer matrix. The polymer matrix may be hydrophobic or hydrophilic, but is preferably hydrophilic. In some embodiments, the composition comprises orismilast and a polymer matrix, where the polymer is one or more polymers selected from hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene oxide, polyethylene glycol; polyethylene oxide and polypropylene oxide block copolymers (e.g., poloxamer), cellulose phthalate acetate, hydroxypropyl methylcellulose phthalate, polyvinylpyrrolidone (PVP), copolymers of PVP and vinyl acetate, poly(ethylene-vinyl acetate), polyvinyl alcohol, sugar alcohols (e.g., xylitol or sorbitol), and biodegradable polymers (e.g., poly(lactide-co-glycolide)).

[0300] Orismilast can also be dissolved, dispersed, or conjugated in one or more protein-based polymers, such as collagen, albumin, gelatin, and polysaccharides, such as agarose, alginate, carrageenan, hyaluronic acid (HA), dextran, chitosan, galactomannan, guar gum; locust bean gum; gum arabic; karaya gum, agar, or cyclodextrin.

[0301] In some embodiments, the polymer matrix is ​​present in the composition in an amount of 10 to 40% by weight, for example, 15 to 30% by weight of the composition. The composition containing the modified release orismilast may further contain one or more fillers, binders, or flow enhancers. Such additional excipients are well known to those skilled in the art.

[0302] In some embodiments, orismilast may be dissolved or dispersed in a polymer matrix by melt extrusion. Alternatively, orismilast may be dispersed or dissolved in a polymer matrix by wet or dry granulation after blending with excipients, and / or by pressing the composition into a suitable dosage form such as a tablet. Orismilast may also be dispersed or dissolved in a gel matrix, such as a hydrogel system containing a gel-forming polymer.

[0303] Compositions containing modified release orismilast can also be prepared as nanoparticle compositions. For example, nanoparticles containing orismilast and a biodegradable polymer such as poly(lactide-co-glycolide), or orismilast conjugated with a suitable polymer carrier.

[0304] In some embodiments, the composition containing orismilast is a solid dispersion, where orismilast is present in an amorphous matrix (typically a polymer matrix). Examples of amorphous solid dispersions are disclosed in Jain S et al. Solubility and dissolution enhancement strategies: Current understanding and recent trends. Drug Dev. Ind. Pharm. 2015;41:875-887. Solid dispersions can be prepared by known methods, such as hot-melt extrusion.

[0305] Modified release of orismilast can also be achieved through the use of a coating on a core composition containing orismilast (e.g., a tablet core), or orismilast may be present in a coating applied to a suitable substrate (e.g., an inert core such as a sugar or polymer core) to provide a layer containing orismilast on the core. Suitable coatings that can provide modified release of orismilast include, for example, modified cellulose, polymethacrylate, polyvinylpyrrolidone, polyvinyl phthalate acetate, zein and / or shellac or natural rubber, such as carrageenan. For example, coatings containing water-soluble polymers, such as low viscosity hydroxypropyl methylcellulose, hydroxypropylcellulose or PVA polymer.

[0306] A core composition containing orismilast, for example, a coating applied to a core containing orismilast and a polymer matrix as described herein, is also intended. The coating may be any of the coatings described herein and acts to further regulate the release of orismilast from the composition. In a particular embodiment, the composition comprises a core containing orismilast, and the core is coated with a coating containing orismilast. In this embodiment, orismilast is released from both the coating and the core.

[0307] Compositions containing modified release orismilast may also be formulated as lipid-based compositions, for example, liposomes, emulsions or microemulsions, self-emulsifying drug delivery systems, nano-emulsions, lipid-drug conjugates, solid-lipid nanoparticles, or solid lipid microparticles. Therefore, the composition may be, for example, a self-emulsifying drug delivery (SEDD) composition, a self-microemulsifying drug delivery (SMEDD) composition, or a self-nanoemulsifying drug delivery (SNEDD) composition.Lipids include, for example, mono-, di-, or triglycerides (e.g., medium-chain triglycerides). Lipid emulsifiers include, for example, phosphatidylcholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), hydrogenated soybean phosphatidylcholine (HSPC), 1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine (MSPC), 1-hexadecenyl-2-oleoyl-sn-glycero-3-phosphocholine (HOPC), 1,2- Dipalmitoyl-sn-glycero-3-phosphatidylglycerol (DPPG), 1,2-distearoyl-sn-glycero-3-phosphatidylglycerol (DSPG), 1,2-dimiristoyl-sn-glycero-3-phosphatidylglycerol (DMPG), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000](DSPE-PEG2000), 1,2-dimiristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), unsaturated polyglycolized glycerides (e.g., oleoyl macrogol glyceride or linoleoyl macrogol glyceride), sorbitan esters (e.g., sorbitan monooleate, sorbitan monostearate, sorbitan monolaurate or sorbitan monopalmitate), polyoxyethylene sorbitan esters (e.g., polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), polyoxyl castor The lipid preparation may also be an oil derivative (e.g., polyoxyl 35 castor oil or polyoxyl 40 hydrogenated castor oil), a polyoxyethylene polyoxypropylene block copolymer (e.g., poloxamer 188 or poloxamer 407), a saturated polyglycolized glyceride (e.g., lauroyl macrogol glyceride or stearoyl macrogol glyceride), a PEGylated capryl / caprin glyceride (e.g., caprylocaproyl macrogol glyceride), or a vitamin E derivative (e.g., D-tocophenyl polyethylene glycol succinate). The lipid preparation may further contain one or more surfactants and / or cosolvents.Lipid-based drug delivery systems are described as examples of emulsifiers in Rahim MA et al., Recent Advancements in Stimuli Responsive Drug Delivery Platforms for Active and Passive Cancer Targeting. Cancers (Basel). 2021 Feb 7;13(4):670; and Yingchoncharoen et al., Lipid-Based Drug Delivery Systems in Cancer Therapy: What Is Available and What Is Yet to Come. Pharmacol Rev. 2016 Jul;68(3):701-87.

[0308] An osmotic release drug delivery system is also envisioned, comprising an orismilast composition and an osmotic agent, enclosed in a semipermeable membrane capsule containing a small orifice. During use, water is drawn in through the semipermeable membrane by the osmotic agent, causing the osmotic agent to hydrate and expand, and the drug is pushed out through the orifice of the capsule.

[0309] In some embodiments, the modified-release formulation releases less than 40% orismilast after 12 minutes. In some embodiments, the modified-release formulation releases less than 20% orismilast after 12 minutes. In some embodiments, the modified-release composition releases less than 40% orismilast after 30 minutes. In some embodiments, the modified-release composition releases less than 35% orismilast after 30 minutes. In some embodiments, the modified-release composition releases about 20% to about 40% orismilast after 30 minutes. In some embodiments, the modified-release composition releases about 25% to about 35% orismilast after 30 minutes. In some embodiments, the modified-release composition releases about 25% to about 50% orismilast after 30 minutes. In some embodiments, the modified-release composition releases about 25% to about 45% orismilast after 30 minutes. In some embodiments, the modified-release composition releases about 24% to about 36% orismilast after 30 minutes. In some embodiments, the modified release composition releases about 11% to about 65% orisumilast after 45 minutes. In some embodiments, the modified release composition releases about 25% to about 60% orisumilast after 45 minutes. In some embodiments, the modified release composition releases about 35% to about 55% orisumilast after 45 minutes. In some embodiments, the modified release composition releases about 30% to about 45% orisumilast after 45 minutes. In some embodiments, the modified release composition releases about 30% to about 46% orisumilast after 45 minutes. In some embodiments, the modified release composition releases about 40% to about 65% orisumilast after 60 minutes. In some embodiments, the modified release composition releases about 40% to about 55% orisumilast after 60 minutes. In some embodiments, the modified release composition releases more than about 60% orisumilast after 60 minutes. In some embodiments, the modified release composition releases more than 40% orismilast after 60 minutes. In some embodiments, the modified release composition releases more than 60% orismilast after 60 minutes. In some embodiments, the modified release composition releases about 35% to about 65% orismilast after 60 minutes.In some embodiments, the modified release composition releases about 35% to about 50% orisumilast after 60 minutes. In some embodiments, the modified release composition releases about 40% to about 50% orisumilast after 60 minutes. In some embodiments, the modified release composition releases about 35% to about 53% orisumilast after 60 minutes. In some embodiments, the modified release composition releases about 50% to about 75% orisumilast after 90 minutes. In some embodiments, the modified release composition releases about 50% to about 60% orisumilast after 90 minutes. In some embodiments, the modified release composition releases about 44% to about 66% orisumilast after 90 minutes. In some embodiments, the modified release composition releases about 60% to about 80% orisumilast after 120 minutes. In some embodiments, the modified release composition releases about 65% to about 80% orisumilast after 120 minutes. In some embodiments, the modified release composition releases about 60% to about 70% of orisumilast after 120 minutes. In some embodiments, the modified release composition releases about 52% to about 78% of orisumilast after 120 minutes. In some embodiments, the modified release composition releases more than 70% of orisumilast after 180 minutes. In some embodiments, the modified release composition releases more than 80% of orisumilast after 180 minutes. In some embodiments, the modified release composition releases about 66% to about 100% of orisumilast after 180 minutes. In some embodiments, the modified release composition releases about 70% to about 100% of orisumilast after 180 minutes. In some embodiments, the modified release composition releases about 80% to about 100% of orisumilast after 180 minutes. In some embodiments, the modified release composition releases about 85% to about 100% of orisumilast after 180 minutes. In some embodiments, the modified release composition releases about 90% to about 100% of orismilast after 180 minutes. In some embodiments, the modified release composition releases about 95% to about 100% of orismilast after 180 minutes.

[0310] In certain embodiments, the modified release composition releases about 11% to about 65% orisumilast after 45 minutes and more than 80% orisumilast after 180 minutes. In certain embodiments, the modified release composition releases about 25% to about 65% orisumilast after 45 minutes and at least 75% orisumilast after 180 minutes. In certain embodiments, the modified release composition releases about 30% to about 50% orisumilast after 45 minutes and at least 75% orisumilast after 180 minutes. In some embodiments, the modified release composition releases about 30% to about 55% orisumilast after 45 minutes and at least 80% orisumilast after 180 minutes.

[0311] In some embodiments, the modified release composition releases about 30% to about 46% orisumilast after 45 minutes and at least 80% orisumilast after 180 minutes. In certain embodiments, the modified release composition releases about 30% to about 50% orisumilast after 45 minutes and about 80% to about 100% orisumilast after 180 minutes. In some embodiments, the modified release composition releases about 30% to about 55% orisumilast after 45 minutes, about 44% to about 66% after 90 minutes, and at least 80% orisumilast after 180 minutes.

[0312] In some embodiments, the modified release composition releases about 50% of orisumilast between about 60 and 100 minutes. In some embodiments, the modified release composition releases about 80% of orisumilast between about 120 and 180 minutes. In some embodiments, the modified release composition releases less than 40% of orisumilast after 30 minutes; 50% between 60 and 100 minutes; and 80% between 115 and 180 minutes. In some embodiments, the modified release composition releases about 30% to about 46% of orisumilast after 45 minutes; about 52% to about 78% after 120 minutes; and at least about 80% of orisumilast after 180 minutes.

[0313] In any of the embodiments described in the four paragraphs above, the modified release composition releases, for example, less than 40% orismilast after 30 minutes, or, for example, less than approximately 30% orismilast after 30 minutes. In any of the embodiments described in the four paragraphs above, the modified release composition releases, for example, less than 20% orismilast after 12 minutes.

[0314] In each case described in the above paragraph and elsewhere in this specification, the release of orismilast refers to in vitro release measured using the “standard dissolution assay” as defined herein.

[0315] In the above paragraph, the reference to “release of orismilast” from the composition refers to the weight percentage of the orismilast compound initially present in the modified release composition and released into the dissolution medium at a specified time, as measured using a standard dissolution assay. The amount of orismilast present in the dissolution medium can be determined by reverse-phase, homogeneous solvent HPLC using a C18 column and UV detection at 272 nm. Preferably, the % release value of the orismilast compound is the average value obtained by measuring the release profiles of two or more samples of the modified release composition, thereby reducing the effects of inter-batch or intra-batch variability. The average release % can be obtained, for example, by measuring the release from 6, 12, or 24 samples of the modified release composition.

[0316] The modified release composition may be, for example, any of the modified release compositions described herein that provide the release profile described herein.

[0317] In some embodiments, compositions containing orismilast have an in vitro release profile similar to the release profile shown in Figure 11, measured using a standard lysis assay. References to a “similar” release profile mean a release profile considered similar from a regulatory standpoint, such as those shown in the FDA Dissolution Testing of Immediate Release Solid Oral Dosage Forms.Guidance for Industry August 1997, available online at https: / / www.fda.gov / downloads / drugs / guidances / ucm070237.pdf, or the EMA Guideline on the Investigation of Bioequivalence 2010, available online at https: / / www.ema.europa.eu / en / documents / scientific-guideline / guideline-investigation-bioequivalence-rev1_en.pdf.

[0318] Therefore, in some embodiments, compositions containing orismilast have an in vitro release profile with a similarity coefficient f2 of 50 to 100 compared to the release profile in Figure 11, where:

number

[0319] Appropriately, in accordance with the FDA guidelines above, the following conditions apply to the f2 value: (1) Dissolution tests will be performed under the same conditions for both products; (2) A minimum of three time points (excluding time zero) are considered for both products; (3) The time at which dissolution is measured is the same for both products; (4) At least 12 individual dose units are used for both products; (5) For any product, there is at most one average percentage value exceeding 85%; (6) The coefficient of variation (CV) of both products must be less than 20% at the first (non-zero) time point and less than 10% at subsequent time points.

[0320] In some embodiments, compositions containing orismilast have an in vitro release profile with a difference factor f1 of 0 to 15 compared to the release profile in Figure 11, where

number

[0321] In some embodiments, the composition containing orismilast has an in vitro release profile corresponding to the release profile shown in Table C of Example 1, where the % orismilast released at each time point corresponds to ±20% of the value shown in Table C for a 30 mg composition, as measured using a standard dissolution assay. For illustrative purposes, at 45 minutes, the 30 mg tablet released 39% orismilast in 45 minutes. Therefore, in this embodiment, the composition containing orismilast releases ±20% of that value in 45 minutes, i.e., 31.2% to 46.8% of orismilast is released in 45 minutes. The same ±20% values ​​apply to the other time points shown in Table C.

[0322] In some embodiments, the modified release composition comprises orismilast and a pharmaceutically acceptable hydrophilic matrix-forming agent (e.g., HPMC). In some embodiments, the modified release composition comprises orismilast; a pharmaceutically acceptable hydrophilic matrix-forming agent (e.g., HPMC); and a filler (e.g., lactose monohydrate). In some embodiments, the modified release composition comprises orismilast; and 15% w / w to 30% w / w of a pharmaceutically acceptable hydrophilic matrix-forming agent (e.g., HPMC). In some embodiments, the modified release composition comprises a compound of orismilast; and 15% w / w to 25% w / w of HPMC.

[0323] In some embodiments, the modified release composition comprises orismilast; and 15% w / w to 20% w / w of HPMC.

[0324] In some embodiments, the modified release composition includes a core comprising the following: (i) Orisumilast; (ii) one or more pharmaceutically acceptable hydrophilic matrix-forming agents; (iii) as applicable, one or more pharmaceutically acceptable excipients selected from the group consisting of fillers, flow promoters and lubricants; and (iv) A pharmaceutically acceptable coating system on the core, if applicable.

[0325] In some embodiments, the hydrophilic matrix-forming agent in the modified release composition includes hydroxypropyl methylcellulose or hydroxypropylcellulose, or a mixture thereof.

[0326] In some embodiments, one or more pharmaceutically acceptable excipients present in the modified release composition include fillers selected from lactose monohydrate, microcrystalline cellulose, and mixtures thereof. In some embodiments, the fillers are present at concentrations of about 30% to about 78% w / w of lactose monohydrate and 0% to about 40% w / w of microcrystalline cellulose based on the weight of the core. In some embodiments, the filler is lactose monohydrate. In some embodiments, the filler is lactose monohydrate and is present at a concentration of about 30% to about 78% w / w based on the weight of the core. Thus, lactose monohydrate may be present at a concentration of about 71% w / w based on the weight of the core. In this specification, "% w / w based on the weight of the core" refers to the weight percentage of the core components before application of the coating system.

[0327] In some embodiments, the modified emission composition includes a coating on the core, such as a PVA-based coating system.

[0328] In some embodiments, the modified release composition includes a core comprising the following: (i) Orisumilast; (ii) Hydrophilic matrix-forming agent, where the hydrophilic matrix-forming agent is present at a concentration of approximately 15% w / w to approximately 25% w / w hydroxypropyl methylcellulose based on the weight of the core; (iii) Approximately 30% w / w to approximately 78% w / w lactose monohydrate based on the weight of the core; and (iv) If applicable, one or more pharmaceutically acceptable excipients selected from the group consisting of flow promoters and lubricants; In some cases, the composition further includes a pharmaceutically acceptable coating system on the core.

[0329] In some embodiments, the modified release composition comprises an orismilast core containing about 0.5% w / w colloidal silicon dioxide and about 1.0% w / w magnesium stearate based on the weight of the core; and optionally a PVA-based coating system on the core.

[0330] In some embodiments, the modified release composition comprises a core containing orismilast, about 17.5% w / w HPMC, about 71.0% w / w lactose monohydrate, about 0.5% w / w colloidal silicon dioxide, and about 1.0% w / w magnesium stearate based on the weight of the core; and optionally, a PVA-based coating system on the core.

[0331] In some embodiments, orisumilast is present in the modified release composition in an amount of about 1% w / w to about 40% w / w. In some embodiments, orisumilast is present in the modified release composition in an amount of about 1% w / w to about 30% w / w. In some embodiments, orisumilast is present in the modified release composition in an amount of about 1% w / w to about 20% w / w. In some embodiments, orisumilast is present in the modified release composition in an amount of about 2% w / w to about 15% w / w. In some embodiments, orisumilast is present in the modified release composition in an amount of about 2% w / w to about 5% w / w. In some embodiments, orisumilast is present in the modified release composition in an amount of about 8% w / w to about 12% w / w.

[0332] In some embodiments, orismilast is present in the modified release composition in amounts of about 5 mg to about 60 mg; about 10 mg to about 50 mg. For example, about 10 mg or about 30 mg.

[0333] In some embodiments, orisumilast is uniformly distributed in the pharmaceutical composition. In some embodiments, the orisumilast in the pharmaceutical composition is pulverized. In some embodiments, the orisumilast in the pharmaceutical composition is crystalline. In some embodiments, the orisumilast present in the pharmaceutical composition is crystalline and pulverized.

[0334] In some embodiments, the pharmaceutical composition comprises polymorph E of orisumilast. In some embodiments, polymorph E of orisumilast is micronized. In some embodiments, polymorph E of orisumilast is crystalline and micronized.

[0335] The hydrophilic matrix-forming agent may be hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), or a mixture thereof. For example, the hydrophilic matrix-forming agent may be hydroxypropyl methylcellulose and a mixture thereof. The hydrophilic matrix-forming agent may be present in various concentrations and combinations of HPMC from about 10% w / w to about 30% w / w. In some embodiments, the hydrophilic matrix-forming agent is present in an amount of about 15% w / w to about 25% w / w HPMC. In some embodiments, the hydrophilic matrix-forming agent is present in an amount of about 15% w / w to about 20% w / w HPMC. In some embodiments, the hydrophilic matrix-forming agent is present in an amount of 17.5% w / w HPC.

[0336] In some embodiments, the hydrophilic matrix-forming agent in the modified release composition comprises hydroxypropyl methylcellulose (HPMC). In some embodiments, the hydrophilic matrix-forming agent in the modified release composition consists of HPMC. In some embodiments, the HPMC has a viscosity of 30 to 150 mPa.s. In some embodiments, the HPMC has a viscosity of 35 to 130 mPa.s. In some embodiments, the HPMC has a viscosity of 40 to 60 mPa.s. In some embodiments, the HPMC has a viscosity of 80 to 120 mPa.s. References to the viscosity of HPMC herein refer to the viscosity of a 2% (w / w) aqueous solution of HPMC at 20°C according to the United States Pharmacopeia (USP XXIII).

[0337] In some embodiments, the hydrophilic matrix-forming agent in the modified release composition comprises HPMC having a methoxyl substitution rate of about 5% to about 35%. In some embodiments, the HPMC has a methoxyl substitution rate of about 15% to about 30%. In some embodiments, the HPMC has a methoxyl substitution rate of about 19% to about 24%. In some embodiments, the HPMC has a methoxyl substitution rate of about 25% to about 35%. In some embodiments, the HPMC has a methoxyl substitution rate of about 28% to about 30%. In some embodiments, the HPMC has a methoxyl substitution rate of about 22% to about 24%.

[0338] In some embodiments, the hydrophilic matrix-forming agent in the modified release composition comprises HPMC having a hydroxypropyl substitution rate of about 4% to about 15%. In some embodiments, the hydrophilic matrix-forming agent in the modified release composition comprises HPMC having a hydroxypropyl substitution rate of about 4% to about 12%. In some embodiments, the hydrophilic matrix-forming agent in the modified release composition comprises HPMC having a hydroxypropyl substitution rate of about 7% to about 12%. In some embodiments, the hydrophilic matrix-forming agent in the modified release composition comprises HPMC having a hydroxypropyl substitution rate of about 7.5% to about 9.5%.

[0339] In some embodiments, the hydrophilic matrix-forming agent in the modified release composition comprises HPMC having a methoxyl substitution rate of about 19% to about 24% and a hydroxypropyl substitution rate of about 4% to about 12%.

[0340] In some embodiments, the hydrophilic matrix-forming agent in the modified release composition comprises HPMC having a methoxyl substitution rate of about 19% to about 24% and a hydroxypropyl substitution rate of about 7% to about 12%.

[0341] In some embodiments, the hydrophilic matrix-forming agent in the modified release composition comprises HPMC having a methoxyl substitution rate of about 28% to about 30% and a hydroxypropyl substitution rate of about 7% to about 12%.

[0342] In some embodiments, the hydrophilic matrix-forming agent in the modified release composition comprises HPMC having a methoxyl substitution rate of about 22% to about 24% and a hydroxypropyl substitution rate of about 7.5% to about 9.5%.

[0343] Appropriately, in any of the six paragraphs above, HPMC has a viscosity of 80–120 mPa·s. The reference for the viscosity of HPMC is the viscosity of a 2% (w / w) aqueous solution of HPMC at 20°C according to the United States Pharmacopeia (USP XXIII).

[0344] In some embodiments, hydroxypropyl methylcellulose is hypromellose 2910, hypromellose 2208, Methocel K100, or a mixture thereof.

[0345] Appropriately, the hydrophilic matrix-forming agent is present at a concentration of about 10% w / w to about 30% w / w based on the weight of the hydroxypropyl methylcellulose core. Therefore, the hydrophilic matrix-forming agent may be present at a concentration of about 15% w / w to about 25% w / w based on the weight of the hydroxypropyl methylcellulose core. For example, the hydrophilic matrix-forming agent is present at a concentration of 17.5% w / w based on the weight of the hydroxypropyl methylcellulose core. The hydroxypropyl methylcellulose may be, for example, any of the grades of hydroxypropyl methylcellulose disclosed herein (e.g., hypromellose 2910, hypromellose 2208, Methocel K100, or a mixture thereof).

[0346] In some embodiments, the modified release composition comprises one or more fillers and / or binders. The term “filler” as used herein may also function as a binder. The filler or binder may be selected from lactose monohydrate, hydrated or anhydrous lactose, microcrystalline cellulose, mannitol, isomalt, and mixtures thereof. For example, the filler may be lactose monohydrate. The filler may be present in various concentrations from about 30% w / w to about 78% w / w. For example, the filler may consist of lactose monohydrate in an amount of about 30% w / w to about 78% w / w and microcrystalline cellulose in an amount of about 0% to about 40% w / w. For example, the filler may be lactose monohydrate in an amount of about 71% w / w.

[0347] In some embodiments, the modified release composition (e.g., a modified release tablet composition) comprises one or more flow promoters. As used herein, the term “flow promoter” includes colloidal silicon dioxide, talc, and the like. For example, the flow promoter may be colloidal silicon dioxide. The flow promoter may be present at various concentrations from about 0.1% w / w to about 2% w / w, for example, from about 0.2% w / w to about 1% w / w, for example, about 0.5% w / w.

[0348] In some embodiments, the modified-release composition (e.g., a modified-release tablet composition) further comprises one or more lubricants. As used herein, the term “lubricant” includes magnesium stearate, sodium stearyl fumarate, talc, and the like. For example, the lubricant may be magnesium stearate. The lubricant may be present at various concentrations from about 0.1% w / w to about 2% w / w, for example, from about 0.5% w / w to about 1.5% w / w, or for example, about 1.0% w / w.

[0349] The %w / w of the components constituting a modified release composition (e.g., a modified release tablet composition, (e.g., including orismilast, a hydrophilic matrix-forming agent, a filler, a flow enhancer, and / or a lubricant)) refers to the %w / w before the optional coating is added to the composition (e.g., onto a core containing orismilast and other excipients). Thus, as those skilled in the art will understand, in embodiments in which a modified release composition (e.g., a tablet) is coated, the %w / w of each component in the coated composition, based on the total weight of the coated composition, is smaller than the %w / w based on the uncoated composition due to the additional weight of the coating.

[0350] In some embodiments, the modified release composition includes a film coating on the core. A suitable coating may be a PVA-based coating system. As used herein, the term “coating system” includes HPMC-based coating systems, PVA-based coating systems (polyvinyl alcohol), PVA-PEG-based coating systems (polyethylene glycol), or ethylcellulose-based functional barrier film coating systems. For example, the coating system may be a PVA-based coating system. For example, the coating system may be Opadry® II. For example, the coating system may be present in an amount of about 3% to about 5% weight gain of the core composition, for example, 4% weight gain of the core.

[0351] In some embodiments, the composition containing Orismilast is a core composition comprising core 1, core 2, or core 3 selected from Table A, or core 4, core 5, or core 6 selected from Table B.

[0352] [Table 37]

[0353] Here, the core is coated with a water-soluble film coating in an amount that provides approximately 3% to 5% of the core's weight gain.

[0354] [Table 38]

[0355] Appropriately, the film coatings on the cores in Tables A and B are PVA-based coatings. Preferably, the film coatings contain polyvinyl alcohol (Ph.Eur. 1961), macrogol (Ph.Eur. 1444), titanium dioxide (Ph.Eur. 0150), talc (Ph.Eur. 0438), and optionally a colorant. For example, the film coating may be Opadry® II.

[0356] Appropriately, lactose monohydrate in the compositions described herein, including those in Tables A and B, conforms to the European Pharmacopoeia (Ph.Eur.) 0187. Appropriately, anhydrous colloidal silica in the compositions described herein, including those in Tables A and B, conforms to Ph.Eur. 0434. Appropriately, magnesium stearate in the compositions described herein, including those in Tables A and B, conforms to Ph.Eur. 0229. Appropriately, hydroxymethylcellulose (HPMC, hypromellose) in the compositions described herein, including those in Tables A and B, conforms to Ph.Eur. 0348.

[0357] Suitablely, the HPMCs in Tables A and B include HPMCs having a methoxyl substitution rate of about 22% to about 24%; and a hydroxypropyl substitution rate of about 7.5% to about 9.5%. Suitablely, the HPMCs have a viscosity of 80 to 120 mPa.s. The references herein to the viscosity of HPMCs refer to the viscosity of a 2% (w / w) aqueous solution of HPMC at 20°C according to the United States Pharmacopeia (USP XXIII). For example, the HPMCs are Methocel® K100 or mixtures thereof.

[0358] Modified release compositions containing hydrophilic matrices such as HPMC, as described herein, including the compositions of Tables A and B, can be prepared using well-known methods, for example, by blending and sieving orismilast and excipients, followed by direct compression, or by roller compaction, followed by compression. The water-soluble coating is then applied to the core, for example, using a spray coater.

[0359] In preferred embodiments, the composition comprising modified-release orismilast described herein is a modified-release tablet comprising orismilast. In some embodiments, the composition comprising modified-release orismilast is a modified-release tablet comprising orismilast as described in the examples herein.

[0360] In some embodiments, the particle size distribution of orismilast present in a pharmaceutical composition (e.g., a tablet composition) may be D(50) ≤ 25 μm, for example, D(50) ≤ 20 μm, D(50) ≤ 10 μm, D(50) ≤ 5 μm, D(50) ≤ 3 μm, and / or D(90) ≤ 10 μm. For example, in the compositions of Tables A and B, the orismilast particle size distribution may be D(90) ≤ 10 μm and D(50) < 1 to 6 μm.

[0361] In some embodiments, compositions containing pharmaceutical orismilast are formulated in unit dosage forms, such as tablets or capsules. The amount of orismilast in each unit dose (e.g., tablet) may range from about 1 mg to about 40 mg, about 5 mg to about 35 mg, 5 mg to 30 mg, 10 mg to 30 mg, or 10 to 20 mg. In some embodiments, the amount of orismilast in each unit dosage form (e.g., tablet) may be about 10 to about 30 mg. In some embodiments, the amount of orismilast in each unit dosage form (e.g., tablet) is 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg. In some embodiments, the amount of orismilast in each unit dosage form (e.g., tablet) is 10 mg. In some embodiments, the amount of orismilast in each unit dosage form (e.g., tablet) is 20 mg. In some embodiments, the amount of orismilast in each unit dosage form (e.g., tablet) is 30 mg. In some embodiments, the amount of orismilast in each unit dosage form (e.g., tablet) is 40 mg.

[0362] In some embodiments, Orismilast is included in the granulated blend composition. The granulated blend composition may include: - Orismilast; and - One or more pharmaceutically acceptable hydrophilic matrix-forming agents; - One or more pharmaceutically acceptable excipients selected from the group consisting of fillers, binders, flow promoters and lubricants; and - Shell material for hard capsules.

[0363] The hydrophilic matrix-forming agent may be hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), or a mixture thereof. The hydrophilic matrix-forming agent may be present in various concentrations and combinations of HPMC, ranging from about 10% w / w to about 20% w / w.

[0364] The filler / binder may be selected from lactose monohydrate, hydrated lactose, or microcrystalline cellulose, and mixtures thereof. The filler / binder may be present in various concentrations of lactose monohydrate from about 20% w / w to about 75% w / w and microcrystalline cellulose from 0% w / w to about 50% w / w. The flow enhancer may be colloidal silicon dioxide, present in various concentrations from about 0.1% w / w to about 2% w / w.

[0365] The lubricant can be magnesium stearate, which can be present in various concentrations ranging from approximately 0.1% w / w to approximately 2% w / w.

[0366] In some embodiments, orismilast is present in the granulated blend composition in an amount of about 1% w / w to about 40% w / w, for example, about 1% w / w to about 30% w / w, about 1% w / w to about 20% w / w, or about 2% w / w to about 15% w / w.

[0367] The blended composition can be dispensed into hard capsules. The capsule shell material for the hard capsules can be made from and applied from several materials, such as gelatin (pork, cow, fish, etc.), hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol, starch, and pullulan.

[0368] In some embodiments, the granulated blend composition is formulated as a unit dosage form (e.g., a capsule composition). The amount of orismilast in each unit dosage form may range from about 1 mg to about 40 mg, or from about 5 mg to about 30 mg. The amount of the compound may range, for example, from 10 mg to 30 mg. In some embodiments, the amount of the compound in a unit dosage form containing the granulated blend composition may range from about 10 mg to about 30 mg. In some embodiments, the amount of orismilast in each unit dosage form is 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg.

[0369] The granulated blend composition may be prepared by blending and sieving the active pharmaceutical ingredient and excipients, followed by granulation, such as roller compaction and encapsulation.

[0370] Diseases and Disabilities Orismilast administration according to the dosing regimen described herein can be used to treat or prevent diseases or disorders that are restored by inhibiting PDE4.

[0371] In certain embodiments, the diseases or disorders treated with orismilast according to the administration regimen are selected from: inflammatory diseases, autoimmune diseases, central nervous system diseases, cerebrovascular diseases, diabetes, obesity, metabolic syndromes, wounds, and proliferative disorders.

[0372] Inhibition of PDE4 is expected to be beneficial for a wide range of diseases with inflammatory components. Therefore, in a preferred embodiment, the disease or disorder treated with orismilast is an inflammatory disease.

[0373] In certain embodiments, the diseases or disorders treated with orismilast according to the administration regimen include inflammatory diseases, e.g., inflammatory airway diseases (e.g., asthma or COPD), allergic rhinitis, acute lung injury, acute respiratory distress syndrome, allergic diseases, nephritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, inflammatory bowel disease, colitis (e.g., ulcerative colitis), lupus (e.g., systemic lupus erythematosus or plaque lupus erythematosus), depression, amnesia, cognitive impairment, dementia, Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, and acute diabetes (e.g., insulin-resistant diabetes). Or chronic wound disorders (e.g., wound healing), vulvar pain, cancer, inflammatory or proliferative skin disorders (e.g., psoriasis (including psoriasis vulgaris and plaque psoriasis), epithelial inflammation, acne, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritus, eczema, neutrophilic skin diseases (e.g., pyoderma gangrenosum, prurigo nodosa), alopecia, skin atrophy, steroid-induced skin atrophy, skin aging, photoaging, vitiligo, lichen planus, organ damage associated with ischemic reflux (e.g., due to heart failure, shock, and cerebrovascular disease, etc.), uveitis, and Behçet's disease (e.g., oral ulcers associated with Behçet's disease).

[0374] In certain embodiments, diseases or disorders treated with orismilast according to the administration regimen include: dermatitis, contact dermatitis including atopic dermatitis, seborrheic dermatitis, irritant contact dermatitis and allergic contact dermatitis, hand dermatitis, psoriasis, psoriasis vulgaris, plaque psoriasis, reverse psoriasis, nail psoriasis, psoriatic arthritis, spondyloarthritis, epithelial inflammation, alopecia, alopecia areata, rosacea, skin atrophy, steroid-induced skin atrophy, photodermatological aging, SAPHO syndrome, (synovial membrane (Inflammation, acne, pustulosis, osteoporosis and osteitis), acne vulgaris, hidradenitis suppurativa (HS), urticaria, pruritus, eczema, and neutrophilic skin diseases (e.g., pyoderma gangrenosum (PG), pustular PG, atypical / bullous PG, proliferative PG, pathergeese PG, necrotizing fasciitis-like PG, peristoma PG, and postoperative PG), Sweet's syndrome (SS, also known as acute febrile neutrophilic dermatosis, bullous SS, pustular SS, giant cellulitis-like SS, necrotizing fasciitis-like SS, (Including drug-induced suppurative syphilis and subcutaneous suppurative syphilis), Sneddon-Wilkinson disease (also known as subcorneal pustular dermatosis), Behçet's disease, neutrophilic panniculitis, neutrophilic eccrine hidradenitis, persistent erythema elevata, neutrophilic urticaria, IgA neutrophilic cutaneous diseases, bacterial pustulosis of the folds, persistent acrodermatitis of Hallopeau, acute systemic exanthematous pustulosis, infantile acropustulosis, sterile abscess, PASH syndrome (pyoderma gangrenosum, acne and HS) The following conditions are selected: PAPA syndrome (pyoderma gangrenosum, acne and septic arthritis), PASS syndrome (PG, acne clusters, HS, seroporacoarthropathy), PAPASH syndrome (PG, septic arthritis, acne, HS), PsAPASH (psoriatic arthritis, PG, acne, HS), histiocytic neutrophilic dermatitis, neutrophilic dermatitis of the back of the hand, intestinal bypass syndrome (intestinal-associated dermatitis-arthritis syndrome), palisade neutrophilic granulomatous dermatitis, and VEXAS syndrome.

[0375] psoriasis In certain embodiments, the disease or disorder treated with orismilast according to the administration regimen is psoriasis. In some embodiments, psoriasis is plaque psoriasis or plaque psoriasis. Psoriasis can be mild, moderate, or severe. The severity of psoriasis in a subject can be assessed, for example, using the following known methods: • Physiologist-administered static overall assessment (sPGA) to determine the severity of psoriasis at a single point in time, using a 5-point scale: clear (0), mostly clear (1), mild (2), moderate (3), or severe (4). Body surface area (BSA) is used to estimate the extent of psoriasis-related disease or skin lesions and is expressed as a percentage of the body surface. Mild psoriasis is considered to affect <3% of the body, moderate psoriasis 3–10%, and severe psoriasis >10%. The Psoriasis Area and Severity Index (PASI) score ranges from 0 to 72, with higher scores reflecting higher disease severity (Fredriksson et al., Dermatologica. 1978; 157(4): 238-244). Erythema, induration / thickness, and scaling are scored on a scale of 0 (none) to 4 (very severe) for four anatomical regions of the body: head, trunk, upper extremities, and lower extremities. The degree of lesions in each of the four anatomical regions is scored on a scale of 0 (no lesions) to 6 (90% to 100% lesions). The total quantitative score (sum of erythema, thickness, and scaling scores) is multiplied by the degree of lesions in each anatomical region, and then by a constant. The scores for each anatomical region are summed to obtain the final PASI. • Investigator-Assessed Global Assessment (IGA) for Psoriasis: The IGA is a scale used by physicians to determine the overall severity of a patient's disease. A static version (Langley et al., J Dermatolog Treat. 2015, Feb;26(1):23-31) will be used in this trial to measure at a single time point as shown in the assessment schedule. The investigator will assess the severity of the patient's psoriasis on a 5-point scale ranging from 0 (clear) to 4 (severe).

[0376] Details of sPGA, BSA, PASI, and IGA for psoriasis are provided in the examples.

[0377] Disease severity is defined as the severity at baseline (i.e., before treatment with orismilast).

[0378] In some embodiments, the psoriasis may be moderate or severe, where the subject has a PASI ≥ 12, BSA ≥ 10%, and sPGA ≥ 3 prior to treatment with orismilast.

[0379] In some embodiments, the psoriasis is moderate, for example, the subject here has 3 IGAs of psoriasis prior to treatment with orismilast.

[0380] In some embodiments, the psoriasis is severe psoriasis, for example, the subject here has 4 IGAs of psoriasis prior to treatment with orismilast.

[0381] In some embodiments, treatment with orismilast according to the administration regimen reduces the psoriasis area and severity index (PASI) score from baseline. In some embodiments, the PASI score decreases by 50% or more (PASI50) at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, PASI50 or higher at week 16 of treatment. In some embodiments, the PASI score decreases by 75% or more (PASI75) at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, PASI75 or higher at week 16 of treatment. In some embodiments, the PASI score decreases by 90% or more (PASI90) at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, PASI90 or higher at week 16 of treatment. In some embodiments, the PASI score decreases by 100% (PASI100) at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, PASI100 is administered at week 16 of treatment. Details of the PASI evaluation are provided in Example 4 of this specification.

[0382] In some embodiments, treatment with orismilast according to the dosing regimen provides a clear (0) or near-clear (1) score and at least a 2-point improvement in the Investigator's Overall Assessment (IGA). In some embodiments, treatment with orismilast according to the dosing regimen provides a clear (0) or near-clear (1) score and at least a 2-point improvement in the IGA at weeks 4, 8, 12, 16, or 20 of treatment. In some embodiments, treatment with orismilast according to the dosing regimen provides a clear (0) score and at least a 2-point improvement in the IGA at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen provides an IGA of 0 or 1 at week 16 of treatment. Details of the IGA are provided in Example 3.

[0383] In some embodiments, treatment with orismilast according to a dosing regimen reduces the total psoriasis symptom scale (PSS) score from baseline. In some embodiments, treatment with orismilast according to a dosing regimen reduces the total PSS score from baseline at weeks 4, 8, 12, 16, or 20 of treatment. For example, treatment may reduce the total PSS by 1, 2, or 3 points. Details of the PSS are provided in Example 3.

[0384] In some embodiments, treatment with orismilast according to the dosing regimen provides a physician-mediated static overall assessment (sPGA) of 0 (clear) or 1 (nearly clear). In some embodiments, treatment with orismilast according to the dosing regimen provides an sPGA of 0 or 1 at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen provides an sPGA of 0 or 1 at week 16 of treatment. Details of the sPGA are provided in Example 4.

[0385] In some embodiments, treatment with orismilast according to the dosing regimen reduces the affected body surface area (BSA) compared to baseline. In some embodiments, the dosing regimen reduces BSA by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to baseline. In some embodiments, the dosing regimen reduces BSA by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to baseline at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen reduces BSA by 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to baseline at week 16 of treatment. Details of BSA are provided in Example 3.

[0386] In some embodiments, treatment with orismilast according to a dosing regimen provides a reduction in the Dermatological Quality of Life Index (DLQI) score from baseline. In certain embodiments, the dosing regimen provides a reduction of ≥4 points in the DLQI score compared to baseline at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen provides a reduction of ≥4 points in the DLQI score compared to baseline at week 16 of treatment. In certain embodiments, the dosing regimen provides a DLQI score of 0 or 1 at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen provides a DLQI score of 0 or 1 at week 16 of treatment. Details of the DLQI are provided in Example 4.

[0387] In some embodiments, treatment with orismilast according to the dosing regimen provides a 0 (clear) or 1 (nearly clear) ScPGA (Science Peritoneal Prognosis). In some embodiments, treatment with orismilast according to the dosing regimen provides a 0 or 1 ScPGA at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen provides a 0 or 1 ScPGA at week 16 of treatment. Details of the ScPGA are provided in Example 4.

[0388] In some embodiments, treatment with orismilast according to the dosing regimen provides a scalp specialist investigator overall assessment (ss-IGA) of 0 (clear) or 1 (nearly clear). In some embodiments, treatment with orismilast according to the dosing regimen provides an ss-IGA of 0 or 1 at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen provides an ss-IGA of 0 or 1 at week 16 of treatment. Details of the ss-IGA are provided in Example 3.

[0389] In some embodiments, treatment with orismilast according to the administration regimen provides a physician-mediated static overall assessment (sPGA-G) of 0 (clear) or 1 (minimum) of the genitals. In some embodiments, treatment with orismilast according to the administration regimen provides an sPGA-G of 0 or 1 at weeks 4, 8, 12, 16, or 20 of treatment, preferably at week 16. Details of the sPGA-G are provided in Example 4.

[0390] In some embodiments, treatment with orismilast according to the dosing regimen provides a physician-generated overall assessment (PPPGA) of 0 (clear) or 1 (nearly clear) of palmoplantar psoriasis. In some embodiments, treatment with orismilast according to the dosing regimen provides a PPPGA of 0 or 1 at weeks 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment. Details of the PPPGA are provided in Example 4.

[0391] In some embodiments, treatment with orismilast according to the administration regimen preferably provides a physician's overall assessment (PGA-F) score of 0 or 1 for onychopsoriasis at week 16 of treatment. Details of the PGA-F are provided in Example 3.

[0392] In some embodiments, treatment with orismilast according to a dosing regimen provides a reduction from baseline in the Numerical Rating Scale (NRS) for generalized pruritus. For example, the dosing regimen provides a reduction of ≥4 points from baseline in the NRS for generalized pruritus. In some embodiments, the dosing regimen provides a reduction of ≥4 points from baseline in the NRS for generalized pruritus at weeks 2, 8, 12, or 16 of treatment. Details of the NRS for generalized pruritus are provided in Example 4.

[0393] In some embodiments, treatment with orismilast according to a dosing regimen provides a reduction from baseline in the Numerical Rating Scale (NRS). For example, the dosing regimen provides a reduction of ≥4 points from baseline in the pain NRS. In some embodiments, the dosing regimen provides a reduction of ≥4 points from baseline in the pain NRS at weeks 2, 8, 12, or 16 of treatment. Details of the pain NRS are provided in Example 4.

[0394] In some embodiments, treatment with orismilast according to a dosing regimen provides a reduction from baseline in the Numerical Rating Scale (NRS) of scalp itchiness. For example, the dosing regimen provides a reduction of ≥4 points from baseline in the scalp itchiness NRS. In some embodiments, the dosing regimen provides a reduction of ≥4 points from baseline in the scalp itchiness NRS at weeks 2, 8, 12, or 16 of treatment. Details of the scalp itchiness NRS are provided in Example 4.

[0395] In some embodiments, treatment with Orismilast according to a dosing regimen provides an increase from baseline in the EuroQol Quality of Life 5-Dimensional-5 Level (EQ-5D-5L™) score. Appropriately, the EQ-5D-5L™ score increases by at least 50%, e.g., at least 75%, or e.g., at least 90%. In some embodiments, the dosing regimen provides an increase of at least (least) 50%, at least 75%, or at least 90% from baseline in the EQ-5D-5L™ score at weeks 2, 8, 12, or 16 of treatment. Details of EQ-5D-5L™ are provided in Example 4.

[0396] In some embodiments, treatment with orismilast according to a dosing regimen provides an increase from baseline in the World Health Organization's Five-Item Well-being Index (WHO-5) score. Appropriately, the WHO-5 score increases by at least 50%, e.g., at least 75%, or e.g., at least 90%. In some embodiments, the dosing regimen provides an increase from baseline of at least (least) 50%, at least 75%, or at least 90% in the WHO-5 score at weeks 2, 8, 12, or 16 of treatment.

[0397] In some embodiments, treatment with orismilast according to a dosing regimen provides a weight loss from the subject's baseline. In some embodiments, the dosing regimen provides a weight loss of 5%, 10%, or 15% from the subject's baseline. In some embodiments, the dosing regimen provides a weight loss of 5%, 10%, or 15% from the subject's baseline at 16 weeks of treatment. In some embodiments, the dosing regimen provides a weight loss of ≥5% from the subject's baseline, where the subject has a baseline BMI of ≥30. In some embodiments, the dosing regimen provides a weight loss of ≥5% from the subject's baseline at 16 weeks of treatment, where the subject has a baseline BMI of ≥30.

[0398] In some embodiments, treatment with orismilast according to a dosage regimen reduces or eliminates one or more symptoms of psoriasis, such as erythema, induration (plaque elevation), scaling, psoriasis-related pain or itching, or lesion size (area).

[0399] In some embodiments, subjects with psoriasis have comorbidities, such as obesity, metabolic syndrome, diabetes, inflammatory bowel disease, spondyloarthritis, or any combination thereof. In certain embodiments, subjects with psoriasis are obese.

[0400] In some embodiments, treatment with orismilast according to a dosing regimen is for use in reducing inflammation caused by or associated with psoriasis. In some embodiments, orismilast is for use in reducing inflammation caused by or associated with psoriasis, where treatment with orismilast reduces one or more psoriasis-related inflammatory biomarkers in the subject, for example, any of the psoriasis-related inflammatory biomarkers described in the examples. Thus, the dosing regimen may reduce C-reactive protein from baseline. In some embodiments, the dosing regimen reduces psoriasis-related inflammatory biomarkers by at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% compared to baseline.

[0401] In some embodiments, treatment with orismilast according to the administration regimen satisfies any one of the primary, secondary, or tertiary endpoints described in the psoriasis clinical trials disclosed in Examples 3, 4, and 5 of this specification.

[0402] Atopic dermatitis In certain embodiments, the disease or disorder treated with orismilast according to the administration regimen is atopic dermatitis. In some embodiments, atopic dermatitis is mild, moderate, severe, or very severe. The severity of atopic dermatitis can be assessed using established methods, such as the Eczema Area and Severity Index (EASI) score. The EASI assessment integrates the intensity of the body surface and lesioned skin into a single composite score. The final EASI score is the sum of four area scores ranging from 0 to 72. A score of 0 indicates clear or no eczema, 0.1–1.0 indicates nearly clear, 1.1–7 indicates mild disease, 7.1–21 indicates moderate disease, 21.1–50 indicates severe disease, and over 51 indicates very severe disease (Leshem YA et al., What the Eczema Area and Severity Index score tells us about the severity of atopic dermatitis: an interpretability study. Br J Dermatol 2015;172(5):1353-1357).

[0403] In certain embodiments, atopic dermatitis is moderate to severe atopic dermatitis. Therefore, subjects may have moderate to severe atopic dermatitis with a baseline EASI score of ≥16. Appropriately, subjects with moderate to severe atopic dermatitis have a baseline BSA of ≥10% affected body surface area (BSA). Appropriately, subjects with moderate to severe atopic dermatitis have a baseline IGD-AD of ≥3. Appropriately, subjects with moderate to severe atopic dermatitis have a baseline peak pruritus NRS of ≥4. Appropriately, subjects with moderate to severe atopic dermatitis have a baseline weekly mean peak pruritus NRS of ≥4.

[0404] In certain embodiments, atopic dermatitis is moderate atopic dermatitis. Therefore, subjects may have moderate atopic dermatitis with a baseline EASI score of ≥16 to ≤21. Appropriately, subjects with moderate atopic dermatitis have a baseline BSA of ≥10% to ≤28%. Appropriately, subjects with severe atopic dermatitis have a baseline peak pruritus NRS of ≥4 to ≤7. Appropriately, subjects with moderate to severe atopic dermatitis have a baseline weekly mean peak pruritus NRS of ≥4 to ≤7.

[0405] In certain embodiments, atopic dermatitis is severe atopic dermatitis. Therefore, a subject may have severe atopic dermatitis with a baseline EASI score > 21. Appropriately, a subject with severe atopic dermatitis has a baseline BSA > 28%. Appropriately, a subject with severe atopic dermatitis has a baseline peak pruritus NRS > 7. Appropriately, a subject with moderate to severe atopic dermatitis has a baseline weekly mean peak pruritus NRS > 7. In some embodiments, treatment with orismilast according to the administration regimen reduces or eliminates one or more symptoms of atopic dermatitis, such as erythema, edema, papulogenesis, exfoliation, pruritus, and lichenification size (area of ​​lesions).

[0406] In some embodiments, treatment with orismilast according to a dosing regimen is for use in reducing inflammation caused by or associated with atopic dermatitis. In some embodiments, orismilast is for use in reducing inflammation caused by or associated with atopic dermatitis, where treatment with orismilast reduces one or more inflammatory biomarkers associated with atopic dermatitis in the subject. For example, orismilast may reduce C-reactive protein. In some embodiments, the dosing regimen reduces TARC (thymic and activating modulated chemokine, also known as CCL17) compared to baseline. In some embodiments, the dosing regimen reduces C6A6 compared to baseline. In some embodiments, the dosing regimen reduces inflammatory biomarkers associated with atopic dermatitis by at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% compared to baseline. In some embodiments, the dosing regimen increases anti-inflammatory biomarkers in the skin compared to baseline. In some embodiments, the dosing regimen increases anti-inflammatory biomarkers in the blood (e.g., plasma or serum) compared to baseline. In some embodiments, the dosing regimen decreases anti-inflammatory biomarkers associated with atopic dermatitis by at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% compared to baseline. In some embodiments, the dosing regimen results in a change in biomarkers at weeks 1, 2, 4, 8, 12, 16, or 20. Skin biomarkers can be collected using tape stripping and analyzed using well-known proteomics methods.

[0407] In some embodiments, treatment with orismilast according to the administration regimen reduces the Eczema Area and Severity Index (EASI) score from baseline. In some embodiments, the EASI score decreases by 50% (EASI50) at weeks 2, 4, 8, 12, 16, or 20 of treatment. Preferably, EASI50 is reached at week 16 of treatment. In some embodiments, the EASI score decreases by 75% (EASI75) at weeks 2, 4, 8, 12, 16, or 20 of treatment. Preferably, EASI75 is reached at week 16 of treatment. In some embodiments, the EASI score decreases by 90% (EASI90) at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, EASI90 is reached at week 16 of treatment. In some embodiments, the EASI score decreases by 100% (EASI100) at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, EASI100 is reached at week 16 of treatment. Details of the PASI evaluation are provided in Example 8 of this specification.

[0408] In some embodiments, treatment with orismilast according to a dosing regimen reduces the investigator-assessed overall assessment (IGA-AD) of atopic dermatitis from baseline. In some embodiments, treatment with orismilast according to a dosing regimen provides a clear (0) or nearly clear (1) IGA-AD score and an improvement of at least 2 points from baseline. In some embodiments, treatment with orismilast according to a dosing regimen provides a clear (0) or nearly clear (1) IGA-AD score and an improvement of at least 2 points at weeks 2, 4, 8, 12, 16, or 20 of treatment. In some embodiments, treatment with orismilast according to a dosing regimen provides a clear (0) or nearly clear (1) IGA-AD score at weeks 2, 4, 8, 12, 16, or 20 of treatment. In some embodiments, treatment with orismilast according to a dosing regimen provides a clear (0) IGA-AD score at weeks 2, 4, 8, 12, 16, or 20 of treatment. Preferably, the administration regimen provides 0 or 1 IGA-AD at week 16 of treatment. Details of IGA-AD are provided in Example 8.

[0409] In some embodiments, treatment with orismilast according to a dosing regimen reduces the Peak Pruritation Numerical Rating Scale (PPNRS) score from baseline in subjects with atopic dermatitis. In some embodiments, treatment with orismilast according to a dosing regimen reduces the PPNRS by ≥4 points from baseline. In some embodiments, treatment with orismilast according to a dosing regimen reduces the PPNRS by ≥4 points from baseline at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment. Preferably, treatment with orismilast according to a dosing regimen reduces the PPNRS by ≥4 points from baseline at week 1 of treatment. Preferably, treatment with orismilast according to a dosing regimen reduces the PPNRS by ≥4 points from baseline at week 2 of treatment. In some embodiments, treatment with orismilast according to a dosing regimen reduces the PPNRS score by ≥4 points from baseline and reduces one or more of the following compared to baseline, as described herein: EASI, IGA-AD, BSA, DLQI, POEM, PGIS, PGIC, sleep disorder NRS, and skin pain NRS. In some embodiments, treatment with orismilast according to a dosing regimen reduces the PPNRS score by ≥4 points from baseline and the EASI score by 50% or more (EASI50) at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment. In some embodiments, treatment with orismilast according to a dosing regimen reduces the PPNRS score by ≥4 points from baseline and the EASI score by 75% or more (EASI75) at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment. In some embodiments, treatment with orismilast according to the dosing regimen reduces the PPNRS score by ≥4 points from baseline and the EASI score by 90% or more (EASI90) at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment. In some embodiments, treatment with orismilast according to the dosing regimen reduces the PPNRS score by ≥4 points from baseline and the EASI score by 100% (EASI100) at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment.In some embodiments, treatment with orismilast according to the dosing regimen reduces the PPNRS score by ≥4 points from baseline at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment, and subjects achieve a clear (0) or nearly clear (1) IGA-AD score. In some embodiments, treatment with orismilast according to the dosing regimen reduces the PPNRS score by ≥4 points from baseline at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment, and subjects achieve a clear (0) IGA-AD score. In any of the embodiments described above, treatment with orismilast can reduce the PPNRS score from baseline by, for example, 4, 5, 6, 7, or 8 points from baseline. For example, treatment with orismilast can reduce the PPNRS to 4 or less, for example, ≤3, ≤2, or ≤1. For example, treatment with orismilast can reduce the PPNRS to 3, 2, 1, or 0.

[0410] In any of the embodiments described in the above paragraphs, the baseline PPNRS may be ≥ 4. In some embodiments, subjects have a baseline PPNRS of at least 4, 5, 6, 7, or 8. In some embodiments, subjects may have a baseline PPNRS of 4, 5, 6, 7, or 8. Analysis of Phase 2b clinical data for atopic dermatitis suggests that subjects with more severe baseline PPNRS may respond particularly well to treatment with orismilast and show a rapid decline in PPNRS scores (see Example 9). Therefore, in any of the embodiments described in the above paragraphs, subjects may have a baseline PPNRS of ≥ 7.

[0411] Details of the peak pruritus NRS are provided in Examples 8 and 9, where subjects record their peak pruritus NRS for the previous day (i.e., the past 24 hours). Alternatively, the peak pruritus NRS is the weekly average peak pruritus NRS. "Weekly average peak pruritus NRS" refers to the PPNRS score obtained by having subjects record their peak pruritus score for the previous day each day for a week, and then calculating the weekly average of the PPNRS scores for each subject.

[0412] In some embodiments, treatment with orismilast according to the dosing regimen reduces the affected body surface area (BSA) compared to baseline. In some embodiments, the dosing regimen reduces BSA by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% compared to baseline. In some embodiments, the dosing regimen reduces BSA by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% compared to baseline at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen reduces BSA by 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% compared to baseline at week 16 of treatment. Details of BSA are provided in Example 8.

[0413] In some embodiments, treatment with orismilast according to the dosing regimen reduces the dermatological quality of life index (DLQI) compared to baseline. In certain embodiments, the dosing regimen provides a reduction of ≥4 points in the DLQI score compared to baseline at weeks 8, 16, or 20 of treatment. Preferably, the dosing regimen provides a reduction of ≥4 points in the DLQI score compared to baseline at week 16 of treatment. In certain embodiments, the dosing regimen provides a DLQI score of 0 or 1 at weeks 8, 16, or 20 of treatment. Preferably, the dosing regimen provides a DLQI score of 0 or 1 at week 16 of treatment. Details of the DLQI are provided in Example 8.

[0414] In some embodiments, treatment with orismilast according to a dosing regimen reduces the Patient-Oriented Eczema Measure (POEM) score compared to baseline. In certain embodiments, the dosing regimen provides a reduction of ≥4 points in the POEM score compared to baseline at weeks 2, 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen provides a reduction of ≥4 points in the POEM score compared to baseline at week 16 of treatment. In certain embodiments, the dosing regimen provides a POEM score of 0 or 1 at weeks 2, 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen provides a POEM score of 0 or 1 at week 16 of treatment. Details of the POEM are provided in Example 8.

[0415] In some embodiments, treatment with orismilast according to the dosing regimen reduces the patient's Global Impression of Severity (PGIS) score compared to baseline. In certain embodiments, the dosing regimen provides a PGIS score of 0 or 1 at weeks 2, 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen provides a PGIS score of 0 or 1 at week 16 of treatment. Details of the PGIS are provided in Example 8.

[0416] In some embodiments, treatment with orismilast according to the dosing regimen reduces the patient's Global Impression of Change (PGIC) score by 1 or 2 compared to baseline. In certain embodiments, the dosing regimen provides a PGIC score of 1 or 2 at weeks 2, 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen provides a PGIC score of 1 or 2 at week 16 of treatment. Details of the PGIC are provided in Example 8.

[0417] In some embodiments, treatment with orismilast according to a dosing regimen reduces the sleep disorder NRS score compared to baseline. In certain embodiments, the dosing regimen provides a reduction of ≥4 points in the sleep disorder NRS score compared to baseline at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen provides a reduction of ≥4 points in the sleep disorder NRS score compared to baseline at week 16 of treatment. In certain embodiments, the dosing regimen provides a sleep disorder NRS score of 0 or 1 at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen provides a sleep disorder NRS score of 0 or 1 at week 16 of treatment. Details of the sleep disorder NRS score are provided in Example 8.

[0418] In some embodiments, treatment with orismilast according to the dosing regimen reduces the skin pain NRS score compared to baseline. In certain embodiments, the dosing regimen provides a reduction of ≥4 points in the skin pain NRS score compared to baseline at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen provides a reduction of ≥4 points in the skin pain NRS score compared to baseline at week 16 of treatment. In certain embodiments, the dosing regimen provides a skin pain NRS score of 0 or 1 at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen provides a skin pain NRS score of 0 or 1 at week 16 of treatment. Details of the skin pain NRS score are provided in Example 8.

[0419] With respect to atopic dermatitis, in any of the clinical scoring or efficacy measures described above and herein, the reference to the “IGA-AD” score is equivalent to the “vIGA-AD” score described in Example 13. Therefore, the reference to an IGA-AD score of 0 or 1 is equivalent to a vIGA-AD score of 0 or 1. Thus, the terms “IGA-AD” and “vIGA-AD” herein are equivalent and interchangeable. Similarly, the reference to the “peak pruritus NRS” score is equivalent and interchangeable to the “worst pruritus NRS,” which is described in Example 13.

[0420] In some embodiments, treatment with orismilast according to the administration regimen satisfies any one of the primary, secondary, or tertiary endpoints described in the atopic dermatitis clinical trials disclosed in Examples 8 and 13 of this specification.

[0421] Hidradenitis suppurativa In certain embodiments, the disease or disorder treated with orismilast according to the administration regimen is hidradenitis suppurativa (HS).

[0422] The subject may have mild, moderate, or severe HS. In some embodiments, the subject has mild HS. In some embodiments, the subject has moderate HS. In some embodiments, the subject has severe HS.

[0423] The severity of hidradenitis suppurativa (HS) can be assessed using known scoring methods. For example, severity (also referred to as disease state or progression) can be defined according to the International Hidradenitis Suppurativa Severity Score System (IHS4), a validated international clinical laboratory scale (Zouboulis et al., Br J Dermatol. 2017;177(5):1401-1409). The score is based on the count of inflammatory lesions. The resulting IHS4 score is calculated by the number of nodules (×1) + the number of abscesses (×2) + the number of drainage tracts (×4). A total score of 4 or less indicates mild disease, 4-10 indicates moderate disease, and 11 or more indicates severe disease. In some embodiments, subjects with HS have comorbidities selected from obesity, metabolic syndromes, inflammatory bowel disease, spondyloarthropathy, or any combination thereof.

[0424] In some embodiments, the subjects have been previously treated with antibodies or other biological therapies for HS. In some embodiments, the subjects have not been previously treated with TNF-α inhibitors (e.g., adalimumab).

[0425] In other embodiments, the subject has been previously treated with an antibody or other biological therapy for HS. In some embodiments, the subject has been previously treated with an anti-inflammatory antibody. In some embodiments, the subject has been previously treated with a TNF-α inhibitor (e.g., adalimumab). The subject may be unresponsive or refractory to prior treatment of HS with antibody therapy, for example, the subject may be unresponsive or refractory to treatment with a TNF-α inhibitor (e.g., adalimumab). The references herein to “biological therapies for HS” include anti-TNF-α biological agents (e.g., adalimumab, certolizumab, infliximab, etanercept, or golimumab); anti-IL-17 biological agents (e.g., bimekizumab, brodalumab, CJM112, ixekizumab, or secukinumab); anti-IL-12 / 23 biological agents (e.g., ustekinumab); anti-IL-23 biological agents (e.g., guselkumab, risankizumab, or tildrakizumab); anti-IL-1 biological agents (e.g., anakinra, bermkimab, or canakinumab); anti-CD (e.g., iscarimab); or anti-IL-36 biological agents (e.g., spesolimab or ismidolimab); anti-CXCR1 / CXCR2 biological agents (e.g., LY3041658); or complement C5a inhibitors, or any combination thereof. In some embodiments, the biological therapy for HS is an anti-TNF-α biological agent (e.g., adalimumab or infliximab). In some embodiments, the biological therapy for HS is adalimumab.

[0426] In some embodiments, treatment with orismilast according to the administration regimen treats the symptoms of HS. For example, the compound may be used for the elimination or reduction of the number, severity, and / or spread of inflammatory nodules, abscesses, comedones and / or sinuses. In some embodiments, the compound of the present invention is used for the elimination or reduction of abscesses, nodules and / or draining fistulas caused by or associated with HS. In some embodiments, the compound of the present invention is used for the elimination or reduction of abscesses and / or nodules caused by or associated with HS.

[0427] In some embodiments, treatment with orismilast according to a dosing regimen reduces inflammation caused by or associated with HS. In some embodiments, orismilast is used for reducing inflammation caused by or associated with HS, where the compound reduces one or more HS-related inflammatory biomarkers in the subject. For example, orismilast may reduce one or more of the following compared to baseline levels before treatment with orismilast: C-reactive protein (e.g., high-sensitivity C-reactive protein (hs-CRP)); erythrocyte sedimentation rate; white blood cell count; or platelet count.

[0428] In some embodiments, treatment with orismilast according to the administration regimen reduces the total number of abscesses and nodules (AN count) compared to the baseline. For example, the AN count decreases by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to baseline. In some embodiments, the AN count decreases by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to baseline at weeks 2, 4, 8, 12, 16, or 20 of treatment. In some embodiments, the AN count decreases by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to baseline at week 16 of treatment.

[0429] In some embodiments, treatment with orismilast according to the administration regimen eliminates or reduces itching caused by or associated with HS.

[0430] In some embodiments, orismilast therapy according to a dosage regimen is used for the elimination or reduction of swelling caused by or associated with HS. For example, orismilast may reduce the swelling of HS lesions.

[0431] In some embodiments, orismilast treatment according to an administration regimen is for use in the elimination or reduction of scars caused by or associated with HS.

[0432] In some embodiments, orismilast therapy according to a dosage regimen is intended for use in reducing the size of lesions associated with HS. For example, the compound may be used for reducing or eliminating lesions associated with HS.

[0433] In some embodiments, orismilast treatment according to an administration regimen is for use in reducing pain caused by or associated with HS.

[0434] Pain can be assessed according to the Numerical Rating Scale (NRS) of 0-10 (0 = no pain, 10 = worst pain imaginable) for patients with cutaneous pain (Newton et al., J Patient Rep Outcomes. 2019;3(1):42). Appropriately, the NRS should decrease by at least 30% compared to baseline. Other well-known pain scoring systems can be used to assess the reduction in HS-related pain. For example, pain reduction can also be assessed using the Visual Analog Scale of Pain (VAS pain), which also assesses pain on a visual scale from 0 (no pain) to 10 (worst pain imaginable).

[0435] Pain can also be assessed according to the McGill Pain Questionnaire. The McGill Pain Questionnaire can be used to assess the sensation, intensity, and changes in experienced pain over time. This can be used to monitor pain over time or to determine the effectiveness of interventions (Melzack, Pain: September 1975, Volume 1, Issue 3, pp. 277-299).

[0436] In some embodiments, HS-related pain is reduced by at least approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the baseline pain level before treatment of HS with orismilast, using an appropriate pain scoring method (e.g., one of the scoring methods described herein). In some embodiments, HS-related pain is reduced by at least approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to baseline at weeks 2, 4, 8, 12, 16, or 20 of treatment. In some embodiments, HS-related pain is reduced by at least approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to baseline at week 16 of treatment.

[0437] In some embodiments, the total quality of life (HisQoL) score of patients treated with the compound decreases during the treatment period. In some embodiments, the HisQoL of the subject decreases by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the baseline level before treatment of HS with orismilast. Preferably, the patient's HisQoL decreases by at least 50%, for example, at least 75%, or for example, at least 90%. In some embodiments, the patient's HisQoL decreases by at least 50%, for example, at least 75%, or for example, at least 90% at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment.

[0438] HiSQOL is based on the results of the Hidradenitis SuppuraTiva core outcomes set International Collaboration (HISTORIC). HiSQOL is a systematically developed and validated 17-item questionnaire that includes HS-specific items such as pus discharge and odor, in addition to general skin-specific items. HiSQOL is an HS-specific questionnaire designed to assess HRQOL in clinical trials (Thorlacius et al., Skin Appendage Disord. 2019 Jun;5(4):221-229; Kirby et al., Br J Dermatol. 2020 Aug;183(2):340-348). It has a 7-day recall period and consists of 17 items divided into three domains: 4 symptom questions, 5 psychosocial questions, and 8 activity adaptation questions. Each item is scored from 0 to 4, with higher scores indicating a greater negative impact on HRQOL. In some embodiments, the subject's HRQOL decreases by at least approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to baseline levels before treatment with orismilast for HS. In some embodiments, the subject's HRQOL decreases by at least approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to baseline at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment.

[0439] In some embodiments, the clinical response (HiSCR) of hidradenitis suppurativa (HS) in patients treated with the compound decreases during the treatment period. In some embodiments, the HiSCR of the subject decreases by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the baseline level before treatment of HS with orismilast. In some embodiments, the patient's HiSCR decreases by at least 50%, for example, at least 75%, or for example, at least 90%, compared to baseline. In some embodiments, the patient's HiSCR decreases by at least 50%, for example, at least 75%, or for example, at least 90%, compared to baseline at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment.

[0440] HiSCR is a treatment goal based on the correlation between changes in lesion counts and PROM (pain and HRQoL). Clinical response to hidradenitis suppurativa (HiSCR; ≥50% decrease from baseline in abscess and inflammatory nodule counts, and no increase in abscess or purulent fistula counts) (Kimball et al., Ann Intern Med. 2012 Dec 18;157(12):846-55; Kimball et al., J Eur Acad Dermatol Venereol. 2016 Jun;30(6):989-94). Subsequent modifications for further differentiation: HiSCR75; ≥75% decrease from baseline in abscess and inflammatory nodule counts, and no increase in abscess or purulent fistula counts), and HiSCR-90; ≥90% decrease from baseline in abscess and inflammatory nodule counts, and no increase in abscess or purulent fistula counts).

[0441] In some embodiments, the physician's overall assessment of disease severity (HS-PGA) in patients treated with orismilast decreases during the treatment period. Appropriately, the HS-PGA of patients during or after treatment decreases to a score of 0 or 1. In some embodiments, the dosing regimen provides an HS-PGA of 0 or 1 at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16.

[0442] HS-PGA ranges from clear to very severe (Kimball et al., Ann Intern Med. 2012 Dec 18;157(12):846-55). It is used in clinical trials to measure clinical improvement of inflammatory nodules, abscesses, and draining fistulas. There are six stages; Clear: No inflammation or non-inflammatory nodules. Minimum: Only the presence of non-inflammatory nodules. Mild: Fewer than 5 inflammatory nodules or 1 abscess or draining fistula, and no inflammatory nodules. Moderate: Fewer than 5 inflammatory nodules, or 1 abscess or draining fistula and 1 or more inflammatory nodules, or 2 to 5 abscesses or draining fistulas and fewer than 10 inflammatory nodules. Severe: 2-5 abscesses or draining fistulas and 10 or more inflammatory nodules. Very severe: More than 5 abscesses or pus discharges That is the case.

[0443] In some embodiments, the treatment regimen reduces the severity of HS in the subject. For example, the treatment regimen may reduce severity by an HS-PGA level of 1 or more (e.g., 1, 2, or 3). Thus, the treatment regimen may reduce the severity of HS from very severe to severe, moderate, or mild HS. In some embodiments, the treatment regimen reduces the severity of HS from very severe to severe, moderate, or mild at week 16 of treatment.

[0444] In some embodiments, the compound reduces the amount of C-reactive protein (e.g., high-sensitivity C-reactive protein (hs-CRP)) in the subject treated with the compound. Preferably, the amount of C-reactive protein (e.g., hs-CRP) in the patient is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to baseline levels before treatment of HS with the compound. For example, the amount of C-reactive protein (e.g., hs-CRP) is reduced by at least 50%, for example, at least 75%, or for example, at least 90%. In some embodiments, the administration regimen reduces C-reactive protein by at least 50%, for example, at least 75%, or for example, at least 90% at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment.

[0445] In some embodiments, the dermatological quality of life index (DLQI) of the subject treated with the compound decreases during the treatment period. In some embodiments, the subject's DLQI decreases by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the baseline level before treatment of HS with the compound. In some embodiments, the subject's DLQI decreases by at least 50%, for example, at least 75%, or for example, at least 90%. In some embodiments, the dosing regimen reduces the DLQI by at least 50%, for example, at least 75%, or for example, at least 90% at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment.

[0446] The DLQI is a questionnaire consisting of 10 questions about a patient's perception of the impact of skin disease on various aspects of their health-related quality of life over the past week. Each question is scored on a 4-point scale (0-3), resulting in a range of 0-30 points (0 = disease does not affect quality of life, 30 = disease has the greatest impact on quality of life). The validated scale was first introduced by Finlay and Khan, Clin. Exp. Dermatol., 19 (1994), pp. 210-216.

[0447] In some embodiments, the Work Productivity and Activity Inventory (WPAI) disability percentage of patients treated with the compound decreases during the treatment period. Preferably, the patient's disability score decreases by at least 50%, for example, at least 75%, or for example, at least 90%. In some embodiments, the patient's disability score decreases by at least 50%, for example, at least 75%, or for example, at least 90% at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment.

[0448] The Workplace Activity Inventory (WAPI) is a questionnaire used to describe work-related disabilities caused by specific diseases. Outcomes are expressed as disability percentages, with higher numbers indicating greater disability and lower productivity (Reilly et al., Pharmacoeconomics. 1993 Nov;4(5):353-65).

[0449] In some embodiments, the anxiety and depression (HADS) score of the subject treated with the administration regimen decreases compared to baseline. Preferably, the patient's HADS score decreases by at least 50%, for example, at least 75%, or for example, at least 90%. In some embodiments, the administration regimen reduces the HADS score by at least 50%, for example, at least 75%, or for example, at least 90% at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment.

[0450] The HADS is a questionnaire that includes seven questions about anxiety and seven questions about depression. Each question is associated with four responses that score between 0 and 3 points. For each condition, 0-7 points corresponds to a normal case; 8-10 to a borderline abnormal case; and 11-21 to an abnormal case (Zigmond and Snaith, Acta Psychiatrica Scandinavica (1983), 67(6):361-370).

[0451] In some embodiments, the European Quality of Life-5 Dimension (EQ-5D) score of subjects treated with the dosing regimen increases during treatment compared to baseline. Preferably, the patient's EQ-5D score increases by at least 50%, e.g., at least 75%, or e.g., at least 90%. In some embodiments, the dosing regimen increases the EQ-5D score by at least 50%, e.g., at least 75%, or e.g., at least 90% compared to baseline at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment.

[0452] The EQ-5D is a standardized assessment scale for measuring general health status across five dimensions: mobility, self-care, daily living activities, pain / discomfort, and anxiety / depression. Each dimension is assigned a value from 1 to 5, resulting in 55 different health states. The score is combined with a patient's overall health rating from 0 to 100, where 0 is the worst health imaginable and 100 is the best health imaginable. This scale was further developed from the original EQ-5D by Herdman et al., Qual Life Res. 2011 Dec;20(10):1727-36.

[0453] In some embodiments, the Multidimensional Fatigue Inventory 20 (MFI-20) response of patients treated with the administration regimen improves compared to baseline. The MFI-20 was invented by Smets et al., J Psychosom Res 1995;39:315-25. It consists of 20 items describing five subscales of fatigue: general fatigue (GF), physical fatigue (PF), decreased motivation (RM), decreased activity (RA), and mental fatigue (MF). For each item, respondents are required to indicate the degree to which a particular description relates to them on a 5-point scale ranging from yes (true) to no (false).

[0454] In some embodiments, orismilast treatment according to a dosing regimen is for use in the prevention or reduction of HS flares in subjects. In some embodiments, orismilast is for use in the reduction of the severity of HS flares in subjects. In some embodiments, orismilast treatment according to a dosing regimen is for use in the reduction of the frequency of HS flares in subjects. In some embodiments, orismilast treatment according to a dosing regimen is for use in the reduction of both the frequency and severity of HS flares in subjects.

[0455] Colitis In certain embodiments, the disease or disorder treated with orismilast according to the administration regimen is colitis, for example, ulcerative colitis.

[0456] Pruritus associated with atopic dermatitis (Sixth aspect of the present invention) Analysis of Phase 2b clinical trial data from a study of subjects with moderate to severe atopic dermatitis treated orally with orismilast, as described in the examples herein, revealed that orismilast has a remarkably strong and rapid effect on pruritus. All active-treatment arms of the study showed a significant ≥4-point reduction in peak pruritus NRS (PPNRS) from baseline at 2 weeks of treatment with orismilast (MI p<0.05 compared to placebo). In subjects with PPNRS > 7 at baseline, all active-treatment arms of the clinical trial showed a statistically significant ≥4-point reduction in PPNRS improvement from baseline at 16 weeks (observational p<0.05 or p<0.1 compared to placebo).

[0457] Pruritus is a particularly significant symptom in individuals with atopic dermatitis. Interestingly, the effectiveness of known treatments for atopic dermatitis against pruritus does not necessarily correlate with their effectiveness against atopic dermatitis (Rodriguez-Le Roy Y et al., Efficacy of topical and systemic treatments for atopic dermatitis on pruritus: A systematic literature review and meta-analysis. Front Med (Lausanne). 2022 Dec 22;9:1079323.doi:10.3389 / fmed.2022.1079323.PMID:36619624;PMCID:PMC9814490). Therefore, new treatments for pruritus associated with atopic dermatitis are needed.

[0458] Accordingly, a sixth aspect of the present invention provides orismilast for use in a method for treating pruritus associated with atopic dermatitis in a subject, the method comprising administering a therapeutically effective amount of orismilast to the subject.

[0459] A method for treating pruritus associated with atopic dermatitis in the subjects is also provided, which includes administering a therapeutically effective dose of orismilast to the subjects.

[0460] The use of orismilast for the manufacture of a medicament for the treatment of pruritus associated with atopic dermatitis in subjects is also provided, the treatment comprising administering a therapeutically effective amount of orismilast to the subjects.

[0461] In some embodiments of the sixth aspect of the present invention, atopic dermatitis is mild, moderate, severe, or very severe atopic dermatitis as described herein. In some embodiments, the subject has moderate to severe atopic dermatitis. In some embodiments, the subject has severe atopic dermatitis as described herein. For example, the subject may have at least 10% affected body surface area (BSA), at least 3 IGA-AD grades, and an eczema area and severity index (EASI) score of ≥16 at baseline. In some embodiments, the subject has a baseline EASI score >21.

[0462] In some embodiments of the sixth aspect of the present invention, the subject has a baseline PPNRS of at least 4. For example, the subject may have a baseline PPNRS of at least 4, 5, 6, 7, or 8. In some embodiments, the subject may have a baseline PPNRS of 4, 5, 6, 7, or 8. In some embodiments, the subject has a baseline PPNRS of >7. In some embodiments, the subject has severe itching at baseline and has a baseline PPNRS of, for example, >7.

[0463] Details of PPNRS are provided in Example 8. As described, the severity of itching (pruritus) can be assessed using a horizontal 11-point NRS. Subjects may be asked to rate the “worst itching caused by AD over the past 24 hours” on an NRS scale set with terms “no itching” (0) and “worst possible itching” (10). In some embodiments, PPNRS is the average PPNRS for the day prior to the measurement point. In some embodiments, PPNRS is the weekly average of the daily PPNRS scores determined in this manner.

[0464] Typically, treatment with orismilast results in a decrease in PPNRS in the subject. For example, treatment can reduce PPNRS by at least 4 points from baseline, e.g., at least 5 or 6 points from baseline. In some embodiments, treatment with orismilast results in a decrease of 4, 5 or 6 points from baseline in PPNRS. In some embodiments, treatment with orismilast can reduce absolute PPNRS to 4 or less, e.g., ≤3, ≤2 or ≤1. For example, treatment with orismilast can reduce absolute PPNRS to 3, 2, 1 or 0.

[0465] Treatment with orisumilast may reduce PPNRS at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment, for example, at weeks 1, 2, 8, or 16. As described in Example 9, treatment with orisumilast results in a rapid reduction of PPNRS. Therefore, in some embodiments of the sixth aspect of the present invention, treatment with orisumilast reduces PPNRS at week 2 of treatment. In some embodiments, treatment with orisumilast reduces PPNRS at week 1 of treatment.

[0466] In some embodiments of the sixth aspect of the present invention, treatment with orisumilast reduces the PPNRS by ≥4 points from baseline at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment. Preferably, treatment with orisumilast reduces the PPNRS by ≥4 points from baseline at weeks 2 or 16 of treatment. In some embodiments, orisumilast reduces the PPNRS by ≥4 points from baseline at week 1 of treatment. Preferably, orisumilast reduces the PPNRS by ≥4 points from baseline at week 2 of treatment.

[0467] In some embodiments of a sixth aspect of the present invention, treatment with orismilast also results in improvement in one or more additional efficacy measures of atopic dermatitis treatment. For example, treatment may also reduce one or more of the additional atopic dermatitis measures described herein compared to baseline. In some embodiments, treatment with orismilast may reduce one or more of the following compared to baseline, as described herein: EASI, IGA-AD, BSA, DLQI, POEM, PGIS, PGIC, sleep disorder NRS, and skin pain NRS. In some embodiments, treatment with orismilast reduces PPNRS compared to baseline (e.g., reduces PPNRS by ≥4 points at week 2 or week 16 of treatment), and also reduces one or more of EASI and IGA-D compared to baseline, as described herein. In some embodiments, treatment reduces PPNRS compared to baseline (e.g., reduces PPNRS by ≥4 points at week 2 or week 16 of treatment), and also provides an IGA-AD of 0 or 1 at week 16 of treatment. Treatment with orismilast may cause changes in one or more biomarkers in the skin, such as a decrease in TARC compared to baseline, as described herein. In some embodiments, treatment with orismilast may reduce TARC by at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% compared to baseline at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment (e.g., at week 16 of treatment).

[0468] In some embodiments of the sixth aspect of the present invention, treatment with orismilast reduces the PPNRS score by ≥4 points from baseline and the EASI score by 50% or more (EASI50) at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment (e.g., week 16 of treatment). In some embodiments, treatment with orismilast reduces the PPNRS score by ≥4 points from baseline and the EASI score by 75% or more (EASI75) at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment (e.g., week 16 of treatment). In some embodiments, treatment with orismilast reduces the PPNRS score by ≥4 points from baseline and the EASI score by 90% or more (EASI90) at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment (e.g., week 16 of treatment). In some embodiments, at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment (e.g., week 16 of treatment), treatment with orisumilast reduces the PPNRS score by ≥4 points from baseline and reduces the EASI score by 100% (EASI100). In some embodiments, at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment (e.g., week 16 of treatment), treatment with orisumilast reduces the PPNRS score by ≥4 points from baseline and the subject achieves a clear (0) or nearly clear (1) IGA-AD score. In some embodiments, at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment (e.g., week 16 of treatment), treatment with orisumilast reduces the PPNRS score by ≥4 points from baseline and the subject achieves a clear (0) IGA-AD score. In any of the embodiments described above, treatment with Orismilast can reduce the PPNRS score from baseline by, for example, 4, 5, 6, 7, or 8 points from baseline.

[0469] In any embodiment of the sixth aspect of the present invention, the baseline PPNRS may be ≥ 4. In some embodiments, the subject has a baseline PPNRS of at least 4, 5, 6, 7, or 8. In some embodiments, the subject may have a baseline PPNRS of 4, 5, 6, 7, or 8.

[0470] Analysis of Phase 2b clinical data in atopic dermatitis suggests that subjects with more severe baseline PPNRS scores respond particularly well to treatment with orismilast and may show a rapid decline in PPNRS scores (see Example 9). Therefore, in any embodiment of the sixth aspect of the present invention, the baseline PPNRS may be ≥ 7.

[0471] In some embodiments of the sixth aspect of the present invention, the subject is treated with orismilast according to any of the administration regimens and variations thereof described herein, in accordance with the first to fifth aspects of the present invention.

[0472] In some embodiments of the sixth aspect of the present invention, the subject is treated as described in other aspects of the present invention, for example, with respect to orismilast, pharmaceutical compositions, and combination therapies.

[0473] In a sixth aspect of the present invention, a reference to the “IGA-AD” score is equivalent to the “vIGA-AD” score described in Example 13. Thus, a reference to an IGA-AD score of 0 or 1 is equivalent to a vIGA-AD score of 0 or 1. Therefore, the terms “IGA-AD” and “vIGA-AD” are equivalent and interchangeable herein. Similarly, a reference to the “peak pruritus NRS” score is equivalent and interchangeable to the “worst pruritus NRS,” which is described in Example 13.

[0474] Combination therapy Orismilast, or formulations or compositions containing its compounds, can be used alone to provide therapeutic effects. Orismilast, or formulations or compositions containing its compounds, can also be used in combination with further therapies.

[0475] In some embodiments, further therapies include antiandrogens, hormones, antibiotics (e.g., dapsone, doxycycline, clindamycin, rifampin, or carbapenems (e.g., ertapenem)), retinoids, vitamin D analogues, anti-inflammatory agents (including steroids (e.g., budesonide, prednisolone)), nonsteroidal anti-inflammatory drugs, colchicine, mycophenolate, thioguanine, hydroxyurea, sulfasalazine, azathioprine, or fumarate esters, and PDE4 inhibitors other than orismilast. Analgesics, immunosuppressants (e.g., tacrolimus, pimecrolimus, sirolimus, or cyclosporine), methotrexate, anthraline / ditranol, metformin, nutritional supplements (e.g., zinc gluconate), TNF-α inhibitors (e.g., adalimumab, etanercept, infliximab, or certolizumab pegol), and IL-1 inhibitors (e.g., anakinra), anti-IL-17 (and IL-17A, IL-17F, and IL-17AF) drugs (e.g., secukinumab, bimekizumab, brodalumab, or ixeki Anti-IL-23 drugs (e.g., risankizumab, tildrakizumab, or guselkumab), anti-IL-12 / 23 drugs (e.g., ustekinumab), anti-IL-12 drugs, anti-IL-23 drugs (e.g., guselkumab, Janus kinase (JAK) inhibitors (e.g., baricitinib, abrocitinib, tofacitinib, poborcitinib (also known as INCB054707), or upadacitinib), anti-IL-4 / 13 drugs (e.g., dupilumab), tyrosine kinase 2 (TYK2) inhibitors (e.g., duk Treatment may be selected from labacitinib, TYK2 / JAK1 inhibitors (e.g., PF-06700841), complement C5a inhibitors (e.g., avacopan), leukotriene A4 hydrolase inhibitors (e.g., LYS006), IRAK4 degraders (e.g., KT-474), IRAK4 inhibitors (e.g., PF-06650833), phototherapy (e.g., ultraviolet B [UVB], psoralen, and ultraviolet A [PUVA] radiation), surgery, or any combination thereof.

[0476] In some embodiments, further therapies include topical steroids, such as amcinonides, clobetasol (e.g., clobetasol propionate or clobetazone butyrate), betamethasone (e.g., betamethasone dipropionate or betamethasone valerate), desonide, desoxymethasone, diflorasone diacetate, diflucortolone (e.g., diflucortolone valerate), fluocinolone acetonide, fluocinonide, flulandrenolide, fluticasone (e.g., propio The topical steroid is selected from fluticasone (fluticasone acid), halcinonide, halobetasol propionate, halomethasone, hydrocortisone (e.g., hydrocortisone, hydrocortisone butyrate, hydrocortisone acetate, or hydrocortisone valerate), mometasone (e.g., mometasone furoate), methylprednisolone (e.g., methylprednisolone aceponate), and triamcinolone (e.g., triamcinolone acetonide), or a combination of two or more of these.

[0477] Such combination therapy can be achieved by simultaneous, sequential, or separate administration of the individual components of the treatment. Such combination products utilize the orismilast administration regimen of the present invention and its approved dosage range for other pharmaceutically active agents.

[0478] Where the term “combination” is used herein, it should be understood that it refers to simultaneous, separate, or sequential administration. In one aspect of the present invention, “combination” refers to simultaneous administration. In another aspect of the present invention, “combination” refers to separate administrations. In a further aspect of the present invention, “combination” refers to sequential administrations. When administration is sequential or separate, delays in the administration of the second component should not result in a loss of the beneficial effect of the combination.

[0479] Embodiment The following numbered embodiments further illustrate the present invention.

[0480] A1. A method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject, the method comprising administering orismilast to the subject, (Ai) The initial orisumilast dose is administered to the subject once daily during the initial period, and then; (Aii) The intermediate orisumilast dose is administered to the subject twice daily during the intermediate period, and then; (Aiii) The maintenance dose of orisumilast is administered to the subject twice daily; Here: (a) The initial orisumilast dose and the intermediate orisumilast dose are independently selected from 10 mg to 30 mg of orisumilast, provided that the intermediate orisumilast dose is equal to or greater than the initial orisumilast dose; (b) The initial period is 2 to 8 weeks; (c) The intermediate period is 1 to 8 weeks; (d) If the subject has a body weight above the threshold body weight, the maintenance orismilast dose is greater than the intermediate orismilast dose, and the threshold body weight is at least 90 kg.

[0481] A2. The initial orismilast dose and the intermediate orismilast dose are the same; The method according to Embodiment A1, wherein, in some cases, both the initial orisumilast dose and the intermediate orisumilast dose are 20 mg orisumilast.

[0482] A3. The method according to Embodiment A1 or Embodiment A2, wherein if the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is the same as the intermediate orisumilast dose.

[0483] A4. The method according to any one of Embodiments A1 to A3, wherein, if the subject has a body weight above the threshold body weight, the maintenance orisumilast dose is orisumilast up to 40 mg, provided that the maintenance orisumilast dose is greater than the intermediate orisumilast dose.

[0484] A5. The method according to any one of Embodiments A1 to A4, wherein if the subject has a body weight above the threshold body weight, the maintenance orisumilast dose is 30 mg orisumilast.

[0485] A6. The initial period is 2 to 6 weeks; The method according to any one of Embodiments A1 to A5, wherein the initial period is, in some cases, two weeks, four weeks, or six weeks.

[0486] A7. The method according to any one of embodiments A1 to A5, wherein the initial period is two weeks.

[0487] A8. The intermediate period is between 1 and 6 weeks; Depending on the circumstances, the intermediate period may be two weeks, four weeks, or six weeks; Furthermore, the method according to any one of embodiments A1 to A7, wherein the intermediate period is two weeks in some cases.

[0488] A9. The total duration of the initial and intermediate periods is 4 to 8 weeks; The method according to any one of Embodiments A1 to A7, wherein, in some cases, the total duration of the initial and intermediate periods is 8 weeks.

[0489] A10. (i) If the subject has a body weight below the lower limit, the initial orisumilast dose (Ai), the intermediate orisumilast dose (Aii), and the maintenance orisumilast dose (Aiii) are all 10 mg orisumilast; or (ii) If the subject has a body weight in the range of lower body weight to below threshold body weight, the initial orisumilast dose (Ai), the intermediate orisumilast dose (Aii), and the maintenance orisumilast dose (Aiii) are all 20 mg orisumilast; The lower limit for body weight here is 50kg to 75kg. The method according to any one of embodiments A1 to A12.

[0490] A11. If the subject has a body weight below the lower limit, the initial orisumilast dose, intermediate orisumilast dose, and maintenance orisumilast dose are all 10 mg orisumilast; The lower limit of body weight is 50kg to 75kg; In some cases, if the subject has a body weight of less than 60 kg, the initial orisumilast dose, the intermediate orisumilast dose, and the maintenance orisumilast dose are all 10 mg orisumilast, according to any one of Embodiments A1 to A12.

[0491] A12. If the subject's weight is within the range of lower body weight to below threshold body weight, the initial orisumilast dose, intermediate orisumilast dose, and maintenance orisumilast dose are all 20 mg orisumilast; The lower limit of body weight is 50kg to 75kg; In some cases, if the subject has a body weight in the range of 60 kg to less than the threshold body weight, the initial orisumilast dose, the intermediate orisumilast dose, and the maintenance orisumilast dose are all 20 mg orisumilast, according to Embodiment 1.

[0492] A13. (Ai) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Aii) The intermediate dose of orisumilast is 20 mg of orisumilast administered to the subject twice daily for two weeks; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is 20 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orisumilast is 30 mg orisumilast administered twice daily. The method according to Embodiment A1.

[0493] A14. (Ai) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Aii) The intermediate dose of orisumilast is 20 mg of orisumilast administered twice daily for 4 weeks to the subject; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is 20 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orisumilast is 30 mg orisumilast administered twice daily. The method according to Embodiment A1.

[0494] A15. (Ai) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Aii) The intermediate dose of orisumilast is 20 mg of orisumilast administered twice daily for 6 weeks to the subject; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is 20 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orisumilast is 30 mg orisumilast administered twice daily. The method according to Embodiment A1.

[0495] A16. (Ai) If the subject has a body weight below the lower limit, the initial orisumilast dose is 10 mg orisumilast administered once daily for 2 to 4 weeks, or If the subject has a body weight between the lower limit and below the threshold body weight, the initial orisumilast dose is 20 mg of orisumilast administered once daily for 2 to 4 weeks; (Aii) If the subject has a body weight below the lower limit, the intermediate orisumilast dose is 10 mg of orisumilast administered to the subject twice daily for 1 to 8 weeks; or If the subject has a body weight between the lower limit and below the threshold body weight, the intermediate orismilast dose is 20 mg of orismilast administered twice daily for 1 to 8 weeks; (Aiii) If the subject has a body weight below the lower limit, the maintenance dose of orisumilast is 10 mg orisumilast administered to the subject twice daily; or If the subject has a body weight between the lower limit and the threshold body weight, the maintenance orisumilast dose is 20 mg orisumilast administered to the subject twice daily; or If the subject has a body weight above the threshold weight, the maintenance dose of orismilast is 30 mg of orismilast administered twice daily to the subject; The lower limit of body weight is 50kg to 75kg. The method according to Embodiment 1.

[0496] A17. The lower limit of body weight is selected from 50kg, 55kg, 60kg, 65kg, 70kg, and 75kg; In some cases, the minimum weight is 50 kg; The method according to embodiment A16, wherein the lower limit body weight is 60 kg in some cases.

[0497] A18. The method according to any one of embodiments A1 to A17, wherein the threshold body weight is 90 kg.

[0498] A19. The method according to any one of embodiments A1 to A17, wherein the threshold body weight is 95 kg.

[0499] A20. The method according to any one of embodiments A1 to A17, wherein the threshold body weight is 100 kg.

[0500] A21. The method according to any one of embodiments A1 to A17, wherein the threshold body weight is 105 kg.

[0501] A22. The initial orisumilast dose according to any one of Embodiments A1 to A21, administered to the subject in the evening.

[0502] A22. The initial orisumilast dose is administered to the subject in the morning, according to any one of Embodiments A1 to A21.

[0503] A23. The method according to any one of Embodiments A1 to A22, wherein the maintenance orisumilast dose is administered to the subject twice daily for at least one week, for example, at least one month, at least six months, or at least one year.

[0504] A24. A method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight above a threshold body weight, the method comprising administering orismilast to the subject, (Bi) The initial orisumilast dose is administered to the subject once daily during the preliminary period, and then; (Bii) The intermediate orisumilast dose is administered to the subject twice daily during the intermediate period, then; (Biii) The maintenance orisumilast dose is administered to the subject twice daily, and the maintenance orisumilast dose is greater than the intermediate orisumilast dose; Here: (a) The initial orisumilast dose and the intermediate orisumilast dose are independently selected from 10 mg to 30 mg of orisumilast, provided that the intermediate orisumilast dose is equal to or greater than the initial orisumilast dose; (b) The reserve period is 1 to 8 weeks; (c) The interim period is a maximum of 8 weeks; (d) The threshold body weight is at least 90 kg, by method.

[0505] A25. The initial orismilast dose and the intermediate orismilast dose are the same; The method according to Embodiment A24, wherein, in some cases, both the initial orisumilast dose and the intermediate orisumilast dose are 20 mg orisumilast.

[0506] A26. The method according to Embodiment A24 or Embodiment A25, wherein the maintenance orisumilast dose is orisumilast up to 40 mg, provided that the maintenance orisumilast dose is greater than the intermediate orisumilast dose.

[0507] A27. The method according to any one of embodiments A24 to A26, wherein the maintenance orisumilast dose is 30 mg.

[0508] A28. The reserve period is 1 day to 8 weeks; Depending on the circumstances, there may be a buffer period: (i) 2 days to 8 weeks (ii) 1 to 8 weeks; (iii) 1 to 6 weeks; (iv) 2 to 4 weeks; (v) 1 week; (vi) 2 weeks; (vii) 4 weeks; or (viii) The method according to any one of embodiments A24 to A27, wherein the duration is 6 weeks.

[0509] A29. The method according to any one of embodiments A24 to A28, wherein the reserve period is two weeks.

[0510] A30. The intermediate period is between 1 and 8 weeks; Depending on the circumstances, the intermediate period may be between one and six weeks; Depending on the circumstances, the intermediate period may be 1 to 2 weeks. Depending on the circumstances, the intermediate period may be 2 to 4 weeks; The method according to any one of embodiments A24 to A29, wherein the intermediate period is 2 weeks, 4 weeks, or 6 weeks, depending on the circumstances.

[0511] A31. The total duration of the reserve and intermediate periods is 4 to 8 weeks; The method according to any one of embodiments A24 to A30, wherein, in some cases, the total duration of the reserve period and the intermediate period is 8 weeks.

[0512] A32. (Bi) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Bii) The intermediate dose of orisumilast is 20 mg of orisumilast administered to the subject twice daily for 1 to 8 weeks; and (Biii) The maintenance dose of orisumilast is 30 mg orisumilast administered twice daily to the subject. The method described in Embodiment A24.

[0513] A33. (Bi) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for one week to the subject; (Bii) The intermediate dose of orisumilast is 20 mg of orisumilast administered to the subject twice daily for two weeks; (Biii) The maintenance dose of orisumilast is 30 mg orisumilast administered twice daily to the subject. The method described in Embodiment A24.

[0514] A34. (Bi) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Bii) The intermediate dose of orisumilast is 20 mg of orisumilast administered to the subject twice daily for two weeks; (Biii) The maintenance dose of orisumilast is 30 mg orisumilast administered twice daily to the subject. The method described in Embodiment A24.

[0515] A35. (Bi) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Bii) The intermediate dose of orisumilast is 20 mg of orisumilast administered twice daily for 4 weeks to the subject; (Biii) The maintenance dose of orisumilast is 30 mg orisumilast administered twice daily to the subject. The method described in Embodiment A24.

[0516] A36. (Bi) The initial dose of orisumilast is 20 mg of orisumilast administered once daily for two weeks to the subject; (Bii) The intermediate dose of orisumilast is 20 mg of orisumilast administered twice daily for 6 weeks to the subject; (Biii) The maintenance dose of orisumilast is 30 mg orisumilast administered twice daily to the subject. The method described in Embodiment A24.

[0517] A37. The method according to any one of embodiments A24 to A36, wherein the threshold body weight is 90 kg.

[0518] A38. The method according to any one of the practical embodiments A24 to A36, wherein the threshold body weight is 95 kg.

[0519] A39. The method according to any one of the practical embodiments A24 to A36, wherein the threshold body weight is 100 kg.

[0520] A40. The method according to any one of the practical embodiments A24 to A36, wherein the threshold body weight is 105 kg.

[0521] A41. The initial orisumilast dose is administered to the subject in the evening, according to any one of embodiments A24 to A40.

[0522] A42. The initial orisumilast dose is administered to the subject in the morning, according to any one of Embodiments A24 to A40.

[0523] A43. The maintenance orisumilast dose is administered to the subject twice daily for at least one week, for example, at least one month, at least six months, or at least one year, according to any one embodiment A24 to A42.

[0524] A44. A method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight above a threshold body weight, the method comprising administering orismilast to the subject, Here: (Ci) The initial orisumilast dose is administered to the subject once daily during the preliminary period, and then; (Cii) The maintenance orisumilast dose is administered to the subject twice daily, and is greater than the initial orisumilast dose; Here: (a) The initial dose of orisumilast is 10 mg to 20 mg of orisumilast; (b) The reserve period is a maximum of eight weeks; (c) The threshold weight is at least 90 kg (for example, the threshold weight is 100 kg), method.

[0525] A45. A method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight below the lower limit, the method comprising administering orismilast to the subject, wherein: (Ei) The initial orisumilast dose of 10 mg is administered to the subject once daily during the initial period, and then; (Eii) The maintenance dose of 10 mg of orisumilast was administered twice daily to the patient; Here: The initial period is 2 to 8 weeks. The lower limit of body weight is 50kg to 75kg; In some cases, the minimum weight is 50 kg; In some cases, the lower limit of body weight is 60 kg.

[0526] A46. A method for treating pruritus associated with atopic dermatitis in a subject, comprising administering a therapeutically effective dose of orismilast to the subject.

[0527] A47. The method according to Embodiment A46, wherein the subject has a baseline PPNRS of ≥ 4.

[0528] A48. The method according to Embodiment A46, wherein the subject has a baseline PPNRS of >7.

[0529] A49. The method according to any one of embodiments A46 to A48, which reduces the baseline peak pruritus NRS (PPNRS) by ≥ 4 points.

[0530] A50. The method according to any one of embodiments A46 to A49, which reduces the baseline peak pruritus NRS (PPNRS) by ≥4 points two weeks after treatment.

[0531] A51. The method according to any one of embodiments A46 to A50, wherein the subject has moderate to severe atopic dermatitis.

[0532] A52. The method according to any one of Embodiments A1 to A51, wherein orisumilast is administered orally to the target.

[0533] A53. The method according to any one of Embodiments A1 to A51, wherein orisumilast is administered orally to the subject in the form of a modified release formulation containing orisumilast.

[0534] A55. The method according to Embodiment A53, wherein the modified release formulation, when measured in vitro using the standard dissolution assay described in the specification, releases an average amount of orismilast of approximately 10% to approximately 70% after 45 minutes and more than approximately 70% after 180 minutes.

[0535] A56. The method according to any one of Embodiments A1 to A55, wherein orisumilast is administered to the subject simultaneously with or concurrently with one or more additional therapeutic agents in a therapeutically effective amount, either separately or sequentially. [Examples]

[0536] The present invention is further illustrated by the following embodiments.

[0537] Example 1: Orally modified-release tablet formulation 10 mg and 30 mg orisumilast and placebo oral modified-release tablets were prepared according to Table 3.

[0538] [Table 39]

[0539] Tablets were prepared by blending the excipients and orismilast together and compressing them into tablets using a rotary press to provide a tablet core. The tablet core was then coated with a PVA-based coating (Opadry II).

[0540] The average dissolution profiles of 10 mg and 30 mg modified-release tablets were measured using the standard dissolution assay described in the specification, giving the results shown in Table C, where the % values ​​refer to the percentage of orismilast in the dissolution medium at each time point.

[0541] [Table 40]

[0542] The dissolution profile is shown in Figure 11.

[0543] Characteristics of Orismilast The orismilast used in the modified-release tablet formulation was orismilast crystalline morph E. The powder X-ray diffraction pattern (XRPD) of morph E is shown in Figure 9. The XRPD consisted of transmission geometry and was obtained using a PANalytical X'pert PRO MPD diffractometer equipped with a PIXcel detector. A continuous 2θ scan range of 3–45° was used with a CuKα radiation source λ=1.5418 Å and generator powers of 40 mA and 45 kV. A 2θ step size of 0.0070° / step with a step time of 148.92 s was used. For transmission measurements, the sample was gently placed flat on a well in a 96-well plate. The well plate was moved back and forth in the x-direction, and all experiments were performed at room temperature. The 2θ peak values ​​of the XRPD for orismilast morph E are shown in Table C.

[0544] [Table 41]

[0545] Morphology E was also characterized using DSC with the TA instrument Q20 system. Several mg of sample were gently placed and weighed into the pan. A lid with pre-punched pinholes was used and pressed onto the pan. Both modulated and conventional temperature profiles were used with various heating temperatures from 2 to 10 °C / min. Figure 10 shows the DSC traces (average of two measurements) of two batches of orismilast. Morphology E showed endothermic melting with starting temperatures of 211.6 °C and 211.7 °C and enthalpy changes of 83 J / g and 85 J / g. No glass transition was observed in the modulated DSCs of the two samples, indicating that morphology E is crystalline with no detectable amorphous material present.

[0546] Example 2: Theoretical basis for dosage The modified-release formulation was tested in a clinical trial (LP0058-1442) involving a total of 36 healthy volunteers: 18 in Part 1, 9 in Part 2, and 9 in Part 3. 27 healthy volunteers received a single dose of 30 mg orisumilast, while 9 subjects received multiple doses over a 17-day period, with up-dose adjustments up to a maximum of 60 mg BID. Part 1 of this trial aimed to evaluate the key PK parameters of the novel modified-release formulation compared to an immediate-release reference capsule formulation. Orisumilast was rapidly absorbed from both formulations, with a median tmax of 3.00 hours post-administration for the immediate-release capsule and a median tmax of 2.52 hours post-administration for the modified-release tablet. Individual tmax ranges were approximately 1–6 hours post-administration for the immediate-release capsule and 1–4 hours post-administration for the modified-release tablet. After tmax, plasma concentrations of orisumilast decreased in a biphasic manner for both the modified-release tablets and the immediate-release capsules, with geometric mean terminal half-lives (t1 / 2) of 6.48 and 6.67 hours, respectively. 0-∞ The geometric mean was 507 ng.h / mL, and systemic exposure to orismilast after administration of the modified-release tablets was equivalent to that of one of the immediate-release capsules (506 ng.h / mL). Statistical analysis comparing the major PK parameters of orismilast for both formulations showed no significant differences, leading to the conclusion that systemic exposure after administration of the modified-release formulation was no different from that after administration of the immediate-release formulation. Therefore, it can be reasonably assumed that the safety profile arising from systemic effects can be extrapolated from studies investigating the immediate-release formulation, particularly from study LP0058-1072, a Phase 2a trial involving 36 patients with moderate to severe psoriasis vulgaris.

[0547] In the trial, patients received either orisumilast 30 mg BID immediate-release or placebo for 16 weeks. Efficacy in psoriasis was confirmed at each predefined endpoint. No significant safety issues were identified during the trial, and no adverse reactions not previously seen with PDE4 inhibitors were reported. However, high levels of intolerance were present in the orisumilast group. Most patients treated with orisumilast experienced treatment-induced adverse events related to gastric function, primarily nausea and diarrhea, throughout the treatment period. These tolerability issues led to half of the patients in the orisumilast group withdrawing from the trial. The hypothesis is that the high incidence of these gastric side effects is related to the high local concentration of orisumilast in the stomach, and therefore, the formulation worked to identify a delayed-release formulation that would reduce the local concentration of the active compound in the stomach while preserving similar systemic exposure to maintain efficacy. The trial LP0058-1442 in healthy volunteers confirmed these characteristics by showing a similar PK profile and an improved safety profile. After multiple doses up to 60 mg BID, orismilast modified-release tablets were safe and well-tolerated. There were no clinically relevant findings on vital signs, laboratory assessments, 12-lead ECG parameters, or physical examination in any of the subjects, and there were no deaths or SAEs during any part of the trial. A total of 113 adverse events (Ae) were reported: 12 Ae in 3 subjects randomized to placebo, and 101 Ae in 9 subjects after administration of orismilast BID-modified-release tablets up to 60 mg. Headache, nausea, dizziness, severe pain, and diarrhea were the most frequently reported Ae. Of the 14 pain-related adverse events reported in subjects receiving orismilast, 6 occurred at the 40 mg dose level. Dizziness was reported only after administration of 30 mg or more of orismilast. Nausea was reported in 5 subjects receiving orismilast, with the majority of events occurring at the 60 mg dose level. Despite continued administration and dose adjustments, only two participants experienced nausea at doses of 40 mg or less, and these side effects lasted approximately one day before spontaneously resolving. Therefore, it was concluded that 40 mg BID is the maximum tolerated dose, and 30 mg BID is the target dose for further development.

[0548] Orismilast-modified release tablet formulation used in clinical trials The following orismilast-modified release tablet formulations were used in the clinical trials described in Examples 3, 4, 5, 8 and 13 of this specification.

[0549] [Table 42]

[0550] Example 3: A randomized, double-blind, placebo-controlled, parallel-group, phase 2b dose-range study to evaluate the efficacy and safety of orismilast in adults with moderate to severe plaque-type psoriasis. The following Phase 2b clinical trial was conducted.

[0551] Primary purpose: To evaluate the efficacy and safety of modified-release orismilast tablets versus placebo in adults with moderate to severe plaque-type psoriasis.

[0552] Primary endpoint: • Percentage change in psoriasis activity and Psoriasis Severity Index (PASI) score from baseline at week 16.

[0553] Primary secondary endpoints • Patients who achieved a 75% reduction in PASI response (PASI75) at week 16. Patients who achieved a clear (0) or near-clear (1) score on the Investigator's Overall Assessment (IGA) at week 16, and an improvement of at least 2 points.

[0554] Other secondary endpoints Patients who achieved a clear (0) or nearly clear (1) IGA score and / or an improvement of at least 2 points at weeks 4, 8, 12, and 20. Patients who achieved a PASI75 response at weeks 4, 8, 12, and 20. Patients who achieved a 50% reduction in PASI (PASI50) and a 90% reduction in PASI response (PASI90) at weeks 4, 8, 12, 16, and 20. • Changes from baseline in PASI at weeks 4, 8, 12, and 20. • Change from baseline in the total psoriasis symptom scale (PSS) score at weeks 4, 8, 12, 16, and 20. • Changes from baseline in each individual item of the PSS at weeks 4, 8, 12, 16, and 20. • Changes in affected body surface area (BSA) from baseline at weeks 4, 8, 12, 16, and 20. • Change from baseline in the Dermatological Quality of Life Index (DLQI) score at weeks 16 and 20. Patients who, by week 20, have experienced a psoriasis rebound defined as a baseline PASI ≥ 125%, or new systemic pustular, erythrodermic, or more inflammatory psoriasis.

[0555] Safety endpoint: • Incidence, severity, and severity of treatment-related adverse events (TEAEs) reported during the 16-week treatment period and the 4-week follow-up period. • Changes from baseline in physical examination measurements; vital signs measurements (body temperature, respiratory rate, heart rate, and systolic and diastolic blood pressure measurements); and body weight over a 16-week treatment period and a 4-week follow-up period. • Changes in electrocardiogram (ECG) findings from baseline over a 16-week treatment period and a 4-week follow-up period. • Changes from baseline in safety laboratory values ​​(hematology, serology, and urinalysis) over a 16-week treatment period and a 4-week follow-up period. • Hospital anxiety and depression scales at each visit, excluding the second week. • Columbia Suicide Severity Scale (C-SSRS) at each visit, excluding weeks 1 and 2.

[0556] Exploratory endpoints: • Change from baseline in the physician's overall assessment of the nail (PGA-F) at 16 weeks. • Change from baseline in the overall assessment (ss-IGA) by a scalp specialist investigator at week 16 in a subgroup of patients with at least a baseline score of 2 (mild scalp psoriasis). • Change from baseline in the Numerical Rating Scale (NRS) of scalp itchiness at week 16 in a subgroup of patients with a baseline score of at least 4 on the 11-point NRS. • Change from baseline in arthralgia NRS at week 16 in patients with psoriatic arthritis (PsA) and a baseline arthralgia score of at least 4. • Changes in cardiovascular risk factors at week 16. The following parameters are collected: weight, body weight index, waist and hip circumference, blood pressure, fasting serum glucose, triglycerides, cholesterol (total and high-density lipoprotein / low-density lipoprotein fractions), and C-reactive protein. • Changes from baseline at week 16 of skin biomarkers collected via tape stripping and analyzed using proteomics methods. • Plasma levels of drugs and their metabolites at scheduled hospital visits.

[0557] Test design A multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2b dose-range trial designed to evaluate the efficacy and safety of modified-release orisumilast compared to placebo in adult patients with moderate to severe plaque-type psoriasis. Efficacy and safety outcomes will be evaluated to select the appropriate orisumilast dose for subsequent phase 3 trials.

[0558] Following a screening visit within 28 days prior to baseline, 202 patients were randomly assigned in a 1:1:1:1 ratio to receive one of three orisumilast doses (20 mg, 30 mg, or 40 mg) or placebo twice daily (BID) for 16 weeks, with 4 weeks of follow-up visits. Dosage was initiated at baseline with a dose adjustment period. The maximum duration of participation in the study was approximately 24 weeks.

[0559] Patients visited the study site at screening, baseline (day 1), and at weeks 1, 2, 4, 8, 12, and 16 (completion of treatment visits), and at week 20 (follow-up visit, 4 weeks after treatment completion or discontinuation). Visits at weeks 1 and 2 could be conducted via telemedicine procedures at the discretion of the principal investigator.

[0560] PASI, BSA, IGA, and PSS were assessed at baseline and at each visit from week 4 onward. Quality of life was assessed by performing the DLQI at baseline and at weeks 16 and 20. Additional efficacy parameters included ss-IGA for those diagnosed with PsA, physician-reported comprehensive assessment of onychopsoriasis (PGA-F), and patient arthralgia NRS. These parameters were assessed at baseline and at weeks 16 and 20. Safety assessments included adverse events (Ae), laboratory and vital sign assessments, physical examination, and patient-reported mood changes (hospital anxiety and depression scales) and investigator-reported suicidal ideation (C-SSRS). A panel of cardiovascular risk factors was assessed at baseline and at week 16.

[0561] Blood samples were collected at baseline and before administration of the study drug at weeks 4, 8, and 16 to determine the concentration of orismilast. In addition, non-invasive surface skin sampling using tape stripping was performed on target lesions at baseline and at week 16 for all-patient proteomics analysis.

[0562] Inclusion Criteria A patient is eligible for inclusion in the study only if all of the following criteria are met: 1. Signed informed consent may be given, including compliance with the requirements and limitations listed in the Informed Consent Form (ICF) and the Protocol. 2. Male and female patients who were ≥18 years old at the time of signing the ICF. 3. Weight > 40kg at the time of signing the ICF. 4. Diagnosis of chronic, stable plaque-type psoriasis at least two months prior to the screening visit. If the patient is diagnosed with psoriatic arthritis, the arthritis must be stable. 5. Moderate to severe plaque-type psoriasis as defined by PASI ≥ 12, BSA ≥ 10%, and IGA ≥ 3 at screening and baseline visit. 6. Candidates for systemic antipsoriasis treatment or phototherapy. 7. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at the screening visit and a negative urine pregnancy test at the baseline visit. In addition, sexually active WOCBPs must agree to use a highly effective method of contraception for at least four weeks after the experimental treatment.

[0563] Exclusion criteria Patients will be excluded from the trial if any of the following criteria apply: 1. Treatment-resistant psoriasis defined as ≥2 treatment failures due to insufficient efficacy within the past 5 years of any biotherapy (including, but not limited to, etanercept adalimumab, infliximab, certolizumab pegol, guselkumab, secukinumab, risankizumab, ixekizumab, tildrakizumab, or ustekinumab) administered in sufficient dose and duration in accordance with the label or regional / national guidelines (patients who discontinued systemic treatment for reasons unrelated to lack of efficacy are not excluded). 2. Unstable psoriasis or PsA with acute exacerbation within 4 weeks of the screening visit. 3. A history of allergies or hypersensitivity to any component of the experimental treatment. 4. An active infection (e.g., bacterial, viral, or fungal) requiring treatment with systemic antibiotics within four weeks of the cleaning visit. 5. A history of malignant tumors other than treated (i.e., cured) basal cell carcinoma. 6. A current diagnosis of predominant guttate, erythrodermic, exfoliative, or pustular psoriasis, or drug-induced psoriasis, or, in the judgment of the principal investigator, any other skin condition that may interfere with the assessment of psoriasis vulgaris (e.g., Alzheimer's disease, lupus). 7. Any recurrent medical condition associated with a serious GI disease, such as inflammatory bowel disease. 8. Any medical or mental condition (e.g., current major depression with a HADS score of ≥15 at baseline, schizophrenia, suicidal behavior, or psychiatric hospitalization within the past year) that, in the opinion of the principal investigator, would prevent the patient from following the protocol, completing the trial in accordance with the protocol, and / or place the patient at an unacceptable risk to receiving the investigational therapy. 9. Any therapy or systemic treatment that does not adhere to the indicated washout interval. 10. Failure of any prior treatment with orisumilast or apremilast or any other systemic PDE4 inhibitor. 11. Any condition, including abnormalities in laboratory tests or ECG, that places the patient at an unacceptable risk to participation in the study or that impairs their ability to interpret data from the study. 12. Severe hepatic impairment based on medical history and laboratory abnormalities (e.g., low albumin and abnormal bilirubin). 13. Any abnormalities in clinical tests at screening (low neutrophil count, low hemoglobin, low platelet count, low absolute lymphocyte count, high bilirubin, high alanine transferase or aspartate aminotransferase or high serum creatine). 14. History or evidence of hepatitis B virus (HBV) infection at the time of screening. Patients with a positive hepatitis B surface antigen (HbsAg) test are excluded. In patients with a positive anti-hepatitis B core antibody (HbcAb) test alone, the hepatitis B surface antibody (HbsAb) result must also be positive for this test to be considered. 15. History of hepatitis C virus (HCV) antibody testing indicating an ongoing infection or a positive test result at the time of screening. Confirmatory HCV RNA testing will be performed on patients with a positive test result. Patients with a negative HCV RNA result are eligible to participate in the study. 16. A history of positive HIV, or a congenital or acquired immunodeficiency disorder (e.g., unclassified immunodeficiency). Patients who test positive for HIV antibodies (HIV-1 or HIV-2) at the time of screening will be excluded from the study. 17. Suicidal ideation or behavior in the past 12 months, as indicated by a positive response (yes) to question 4 or 5 of the C-SSRS completed at the screening visit or at the baseline visit. 18. Pregnant or breastfeeding. 19. A history of alcohol or substance abuse within six months prior to baseline will result in exclusion from the study at the discretion of the principal investigator. 20. Detained by court order or by local authority.

[0564] treatment The tablets are taken approximately every 12 hours, in the morning and evening. The minimum time interval between two consecutive doses is 6 hours. The first dose of the study drug is taken in the evening of day 1. The administration schedule used is shown in Table 4.

[0565] [Table 43]

[0566] Dose adjustment The orismilast-modified release tablet dose should be adjusted over a period of up to two weeks according to the schedule shown in Table 5.

[0567] [Table 44]

[0568] Effectiveness evaluation The Psoriasis Area and Severity Index (PASI) is a measure of psoriatic disease severity that takes into account qualitative lesion characteristics (erythema, induration, and desquamation) and the percentage of skin surface area in defined anatomical regions. PASI is a validated assessment index and is the most widely used tool for measuring the severity of psoriasis. The Psoriasis Area and Severity Index score ranges from 0 to 72, with higher scores reflecting greater disease severity (Fredriksson et al., Dermatologica. 1978;157(4):238-244). Erythema, induration / thickness, and scaling are scored on a scale of 0 (none) to 4 (very severe) in four anatomical regions of the body: head, trunk, upper extremities, and lower extremities. The degree of lesions in each of the four anatomical regions is scored on a scale of 0 (no lesions) to 6 (90% to 100% lesions). The total quantitative score (sum of erythema, thickness, and scaling scores) is multiplied by the degree of lesion in each anatomical region, and then by a constant. The scores for each anatomical region are then combined to obtain the final PASI.

[0569] Comprehensive Assessment by the Principal Investigator: IGA is a scale used by physicians to determine...

Claims

1. Orismilast for use in a method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject, wherein the method comprises administering the orismilast to the subject: (Ai) The initial dose of orisumilast is administered to the subject once daily during the initial period, and then; (Aii) The intermediate orisumilast dose is administered to the subjects twice a day during the intermediate period, and then; (Aiii) The maintenance orisumilast dose is administered to the subjects twice daily; Here: (a) The initial orisumilast dose and the intermediate orisumilast dose are independently selected from 10 mg to 30 mg of orisumilast, provided that the intermediate orisumilast dose is equal to or greater than the initial orisumilast dose; (b) The initial period is 2 to 8 weeks; (c) The aforementioned intermediate period is 1 to 8 weeks; (d) Orismilast, wherein if the subject has a body weight equal to or greater than the threshold body weight, the maintenance orismilast dose is greater than the intermediate orismilast dose, and the threshold body weight is at least 90 kg.

2. The initial orismilast dose and the intermediate orismilast dose are the same; Orisumilast for use according to claim 1, wherein, in some cases, both the initial orisumilast dose and the intermediate orisumilast dose are 20 mg orisumilast.

3. Orisumilast for use according to claim 1 or 2, wherein if the subject has a body weight below the threshold body weight, the maintenance orisumilast dose is the same as the intermediate orisumilast dose.

4. Orisumilast for use according to any one of claims 1 to 3, wherein if the subject has a body weight equal to or greater than the threshold body weight, the maintenance orisumilast dose is up to 40 mg, provided that the maintenance orisumilast dose is greater than the intermediate orisumilast dose.

5. Orisumilast for use according to any one of claims 1 to 4, wherein if the subject has a body weight equal to or greater than the threshold body weight, the maintenance orisumilast dose is 30 mg orisumilast.

6. Orisumilast for use according to any one of claims 1 to 5, wherein the initial period is 2 weeks to 4 weeks.

7. Orisumilast for use according to any one of claims 1 to 5, wherein the initial period is two weeks.

8. Orisumilast for use according to any one of claims 1 to 7, wherein the intermediate period is 6 to 8 weeks.

9. Orisumilast for use according to any one of claims 1 to 7, wherein the intermediate period is one to four weeks.

10. Orisumilast for use according to any one of claims 1 to 7, wherein the intermediate period is two weeks.

11. Orisumilast for use according to any one of claims 1 to 7, wherein the aforementioned intermediate period is 6 weeks.

12. The total duration of the aforementioned initial period and the aforementioned intermediate period is 4 to 8 weeks; Orisumilast for use according to any one of claims 1 to 7, wherein, in some cases, the total duration of the initial period and the intermediate period is 8 weeks.

13. (i) If the subject has a body weight below the lower limit, the initial orisumilast dose of (Ai), the intermediate orisumilast dose of (Aiii), and the maintenance orisumilast dose of (Aiiii) are all 10 mg orisumilast; or (ii) If the subject has a body weight in the range of lower body weight to less than the threshold body weight, the initial orisumilast dose of (Ai), the intermediate orisumilast dose of (Aiii), and the maintenance orisumilast dose of (Aiii) are all 20 mg orisumilast; The aforementioned lower limit of body weight is 50 kg to 75 kg; In some cases, the lower limit of body weight is 60 kg. Orisumilast for use according to any one of claims 1 to 12.

14. If the subject has a body weight below the lower limit, the initial orismilast dose, the intermediate orismilast dose, and the maintenance orismilast dose are all 10 mg orismilast; The aforementioned lower limit of body weight is 50 kg to 75 kg; In some cases, if the subject has a body weight of less than 60 kg, the initial orisumilast dose, the intermediate orisumilast dose, and the maintenance orisumilast dose are all 10 mg orisumilast. Orisumilast for use according to any one of claims 1 to 12.

15. If the subject has a body weight in the range of lower body weight to less than the threshold body weight, the initial orismilast dose, the intermediate orismilast dose, and the maintenance orismilast dose are all 20 mg orismilast; The aforementioned lower limit of body weight is 50 kg to 75 kg; In some cases, if the subject has a body weight in the range of 60 kg to less than the threshold body weight, the initial orismilast dose, the intermediate orismilast dose, and the maintenance orismilast dose are all 20 mg orismilast. Orisumilast for use according to any one of claims 1 to 12.

16. (Ai) The initial orisumilast dose is 20 mg of orisumilast administered to the subject once daily for two weeks; (Aii) The intermediate dose of orisumilast is 20 mg of orisumilast administered to the subject twice a day for 1 to 8 weeks; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orismilast dose is 20 mg orismilast administered to the subject twice daily; or If the subject has a body weight equal to or greater than the threshold body weight, the maintenance orisumilast dose is 30 mg orisumilast administered to the subject twice daily. Orisumilast for use as described in claim 1.

17. The aforementioned intermediate orisumilast dose is administered to the subject twice a day for 2 to 8 weeks; Orisumilast for use according to claim 16, wherein, in some cases, the intermediate dose of orisumilast is administered to the subject twice a day for 6 to 8 weeks.

18. (Ai) The initial orisumilast dose is 20 mg of orisumilast administered to the subject once daily for two weeks; (Aii) The intermediate dose of orisumilast is 20 mg of orisumilast administered to the subject twice a day for two weeks; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orismilast dose is 20 mg orismilast administered to the subject twice daily; or If the subject has a body weight equal to or greater than the threshold body weight, the maintenance orisumilast dose is 30 mg orisumilast administered to the subject twice daily. Orisumilast for use as described in claim 1.

19. (Ai) The initial orisumilast dose is 20 mg of orisumilast administered to the subject once daily for two weeks; (Aii) The intermediate dose of orisumilast is 20 mg of orisumilast administered to the subject twice a day for 6 weeks; (Aiii) If the subject has a body weight below the threshold body weight, the maintenance orismilast dose is 20 mg orismilast administered to the subject twice daily; or If the subject has a body weight equal to or greater than the threshold body weight, the maintenance orisumilast dose is 30 mg orisumilast administered to the subject twice daily. Orisumilast for use as described in claim 1.

20. (Ai) If the subject has a body weight below the lower limit, the initial orisumilast dose is 10 mg orisumilast administered to the subject once daily for 2 to 4 weeks, or If the subject has a body weight between the lower limit body weight and the threshold body weight, the initial orisumilast dose is 20 mg of orisumilast administered to the subject once daily for 2 to 4 weeks; (Aii) If the subject has a body weight below the lower limit, the intermediate orisumilast dose is 10 mg orisumilast administered to the subject twice daily for 1 to 8 weeks; or If the subject has a body weight between the lower limit body weight and the threshold body weight, the intermediate orismilast dose is 20 mg of orismilast administered to the subject twice a day for 1 to 8 weeks; (Aiii) If the subject has a body weight below the lower limit, the maintenance orisumilast dose is 10 mg orisumilast administered to the subject twice daily; or If the subject has a body weight between the lower limit body weight and the threshold body weight, the maintenance orismilast dose is 20 mg orismilast administered to the subject twice daily; or If the subject has a body weight equal to or greater than the threshold body weight, the maintenance orismilast dose is 30 mg orismilast administered to the subject twice daily; The aforementioned lower limit of body weight is 50 kg to 75 kg. Orisumilast for use as described in claim 1.

21. Orisumilast for use according to claim 20, wherein the lower limit body weight is selected from 50 kg, 55 kg, 60 kg, 65 kg, 70 kg, and 75 kg.

22. Orisumilast for use according to claim 20, wherein the lower limit body weight is 60 kg.

23. The aforementioned intermediate orisumilast dose is administered to the subject twice a day for 2 to 8 weeks; Orisumilast for use according to any one of claims 20 to 22, wherein, in some cases, the intermediate dose of orisumilast is administered to the subject twice a day for 6 to 8 weeks.

24. (Ai) If the subject has a body weight of less than 60 kg, the initial orisumilast dose is 10 mg of orisumilast administered to the subject once daily for two weeks; or If the subject has a body weight between 60 kg and the threshold body weight, the initial orisumilast dose is 20 mg of orisumilast administered to the subject once daily for two weeks; (Aii) If the subject has a body weight of less than 60 kg, the intermediate dose of orisumilast is 10 mg of orisumilast administered to the subject twice daily for 6 weeks; or If the subject has a body weight between 60 kg and the threshold body weight, the intermediate orismilast dose is 20 mg of orismilast administered to the subject twice daily for 6 weeks; (Aiii) If the subject has a body weight of less than 60 kg, the maintenance orismilast dose is 10 mg orismilast administered to the subject twice daily; or If the subject has a body weight of 60 kg or less than the threshold body weight, the maintenance orismilast dose is 20 mg orismilast administered to the subject twice daily; or If the subject has a body weight equal to or greater than the threshold body weight, the maintenance orismilast dose is 30 mg orismilast administered to the subject twice daily. Orisumilast for use as described in claim 1.

25. Orisumilast for use according to any one of claims 1 to 24, wherein the threshold body weight is 90 kg.

26. Orisumilast for use according to any one of claims 1 to 24, wherein the threshold body weight is 95 kg.

27. Orisumilast for use according to any one of claims 1 to 24, wherein the threshold body weight is 100 kg.

28. Orisumilast for use according to any one of claims 1 to 24, wherein the threshold body weight is 105 kg.

29. Orisumilast for use according to any one of claims 1 to 28, wherein the initial orisumilast dose is administered to the subject in the evening.

30. Orisumilast for use according to any one of claims 1 to 28, wherein the initial orisumilast dose is administered to the subject in the morning.

31. Orisumilast for use according to any one of claims 1 to 30, wherein the maintenance orisumilast dose is administered to the subject twice daily for at least one week, for example, at least one month, at least six months, or at least one year.

32. Orismilast for use in a method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight above a threshold body weight, wherein the method comprises administering the orismilast to the subject: (Bi) The initial orisumilast dose is administered to the subjects once daily during the preliminary period, and then; (Bii) The intermediate orisumilast dose is administered to the subjects twice a day during the intermediate period, and then; (Biiii) The maintenance orisumilast dose is administered to the subject twice daily and is greater than the intermediate orisumilast dose; Here: (a) The initial orisumilast dose and the intermediate orisumilast dose are independently selected from 10 mg to 30 mg of orisumilast, provided that the intermediate orisumilast dose is equal to or greater than the initial orisumilast dose; (b) The reserve period is one to eight weeks; (c) The aforementioned intermediate period is a maximum of eight weeks; (d) The threshold body weight is at least 90 kg, Orismilast.

33. The initial orismilast dose and the intermediate orismilast dose are the same; Orisumilast for use according to claim 32, wherein, in some cases, both the initial orisumilast dose and the intermediate orisumilast dose are 20 mg orisumilast.

34. Orisumilast for use according to claim 32 or claim 33, wherein the maintenance orisumilast dose is up to 40 mg, provided that the maintenance orisumilast dose is greater than the intermediate orisumilast dose.

35. Orisumilast for use according to any one of claims 32 to 34, wherein the maintenance orisumilast dose is 30 mg.

36. Orisumilast for use according to any one of claims 32 to 35, wherein the aforementioned reserve period is two to four weeks.

37. Orisumilast for use according to any one of claims 32 to 36, wherein the aforementioned reserve period is two weeks.

38. Orisumilast for use according to any one of claims 32 to 37, wherein the aforementioned intermediate period is 6 to 8 weeks.

39. Orisumilast for use according to any one of claims 32 to 37, wherein the intermediate period is one to four weeks.

40. Orisumilast for use according to any one of claims 32 to 37, wherein the aforementioned intermediate period is two weeks.

41. Orisumilast for use according to any one of claims 32 to 37, wherein the aforementioned intermediate period is six weeks.

42. The total duration of the aforementioned reserve period and the aforementioned intermediate period is 4 to 8 weeks; Orisumilast for use according to any one of claims 32 to 38, wherein, in some cases, the total duration of the preparatory period and the intermediate period is eight weeks.

43. (Bi) The initial dose of orisumilast is 20 mg of orisumilast administered to the subject once daily for two weeks; (Bii) The intermediate dose of orisumilast is 20 mg of orisumilast administered to the subject twice a day for 1 to 8 weeks; (Biiii) The maintenance dose of orisumilast is 30 mg of orisumilast administered to the subject twice a day. Orisumilast for use as described in claim 32.

44. (Bi) The initial dose of orisumilast is 20 mg of orisumilast administered to the subject once daily for two weeks; (Bii) The intermediate dose of orisumilast is 20 mg of orisumilast administered to the subject twice daily for 6 weeks; (Biiii) The maintenance dose of orisumilast is 30 mg of orisumilast administered to the subject twice a day. Orisumilast for use as described in claim 32.

45. Orisumilast for use according to any one of claims 32 to 44, wherein the threshold body weight is 90 kg.

46. Orisumilast for use according to any one of claims 32 to 44, wherein the threshold body weight is 95 kg.

47. Orisumilast for use according to any one of claims 32 to 44, wherein the threshold body weight is 100 kg.

48. The method according to any one of claims 32 to 44, wherein the threshold body weight is 105 kg.

49. Orisumilast for use according to any one of claims 32 to 48, wherein the initial orisumilast dose is administered to the subject in the evening.

50. The initial orisumilast dose is administered to the subject in the morning. Orisumilast for use according to any one of claims 32 to 48.

51. Orisumilast for use according to any one of claims 32 to 50, wherein the maintenance orisumilast dose is administered to the subject twice a day for at least one week, for example, at least one month, at least six months, or at least one year.

52. Orismilast for use in a method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight above a threshold body weight, wherein the method comprises administering the orismilast to the subject. Here: (Ci) The initial orisumilast dose is administered to the subjects once daily during the preliminary period, and then; (Cii) The maintenance orisumilast dose is administered to the subject twice daily, and the maintenance orisumilast dose is greater than the initial orisumilast dose; Here: (a) The initial dose of orisumilast is 10 mg to 20 mg of orisumilast; (b) The reserve period is a maximum of eight weeks; (c) The threshold body weight is at least 90 kg, Orismilast.

53. Orismilast for use in a method for treating a disease or disorder that is cured by inhibiting PDE4 in a subject, wherein the method comprises administering the orismilast to the subject: (Di) The initial orisumilast dose is administered to the subject once daily during the initial period, and then; (Dii) The maintenance orisumilast dose is administered to the subjects twice daily; Here: (a) The initial orisumilast dose and the maintenance orisumilast dose are both 20 mg orisumilast; (b) The initial period is 2 to 8 weeks; (c) The subject has a weight between the lower limit weight and the threshold weight; The aforementioned threshold body weight is at least 90 kg. The aforementioned lower limit of body weight is 50 kg to 75 kg; In some cases, the lower limit of body weight is 60 kg, Orisumilast.

54. Orisumilast for use according to claim 53, wherein the threshold body weight is 100 kg.

55. Orismilast for use in a method of treating a disease or disorder that is cured by inhibiting PDE4 in a subject having a body weight below the lower limit, wherein the method comprises administering the orismilast to the subject: (Ei) An initial dose of 10 mg of orisumilast is administered to the subject once daily during the initial period, and then; (Eiii) A maintenance dose of 10 mg of orisumilast is administered to the subjects twice daily; Here: The aforementioned initial period is 2 to 8 weeks. The aforementioned lower limit of body weight is 50 kg to 75 kg; In some cases, the lower limit of body weight is 60 kg, Orisumilast.

56. Orismilast for use according to any one of claims 1 to 55, wherein the disease or disorder is selected from: inflammatory diseases, autoimmune diseases, central nervous system diseases, cerebrovascular diseases, diabetes mellitus, obesity, metabolic syndromes, wounds, and proliferative disorders.

57. The aforementioned diseases or disorders include: inflammatory diseases, e.g., inflammatory airway diseases (e.g., asthma or COPD), allergic rhinitis, acute lung injury, acute respiratory distress syndrome, allergic diseases, nephritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, inflammatory bowel disease, colitis (e.g., ulcerative colitis), lupus (e.g., systemic lupus erythematosus or plaque lupus erythematosus), depression, amnesia, cognitive impairment, dementia, Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, diabetes (e.g., insulin-resistant diabetes), acute or chronic wound disorders (e.g., wound healing), vulvodynia, cancer, inflammatory or proliferative Orismilast for use according to any one of claims 1 to 55, selected from skin disorders (e.g., psoriasis (including psoriasis vulgaris and plaque psoriasis), epithelial inflammation, acne, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritus, eczema, neutrophilic skin diseases (e.g., pyoderma gangrenosum, prurigo nodosa), alopecia, skin atrophy, steroid-induced skin atrophy, skin aging, photoaging, vitiligo, lichen planus, organ damage associated with ischemic reflux (e.g., due to heart failure, shock, and cerebrovascular disease, etc.), uveitis, and Behçet's disease (e.g., oral ulcers associated with Behçet's disease).

58. The aforementioned diseases or disorders include: dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis including irritant contact dermatitis and allergic contact dermatitis, hand dermatitis, psoriasis, psoriasis vulgaris, plaque psoriasis, reverse psoriasis, onychopsoriasis, psoriatic arthritis, spondyloarthritis, epithelial inflammation, alopecia, alopecia areata, rosacea, skin atrophy, steroid-induced skin atrophy, photodermatitis, SAPHO syndrome (synovitis, acne, pustulosis, osteoporosis and osteitis), acne vulgaris, and hidradenitis suppurativa. (HS), urticaria, pruritus, eczema, and neutrophilic skin diseases (e.g., pyoderma gangrenosum (PG), pustular PG, atypical / bullous PG, proliferative PG, pathergian PG, necrotizing fasciitis-like PG, peristomatal PG, and postoperative PG), Sweet's syndrome (SS, also known as acute febrile neutrophilic dermatosis, including bullous SS, pustular SS, giant cellulitis-like SS, necrotizing fasciitis-like SS, drug-induced SS, and subcutaneous SS), Sneddon-Wilki Nson's disease (also known as subkeratotic pustular dermatosis), Behçet's disease, neutrophilic panniculitis, neutrophilic eccrine hidradenitis, persistent erythema elevata, neutrophilic urticaria, IgA neutrophilic cutaneous diseases, bacterial pustulosis of the folds, persistent acrodermatitis of Hallopeau, acute systemic exanthematous pustulosis, infantile acropustulosis, sterile abscess, PASH syndrome (pyoderma gangrenosum, acne and HS), PAPA syndrome (pyoderma gangrenosum, acne and septic arthritis), PAS Orisumilast for use according to any one of claims 1 to 55, selected from S syndrome (PG, acne clusters, HS, seropocystosis), PAPASH syndrome (PG, septic arthritis, acne, HS), PsAPASH (psoriatic arthritis, PG, acne, HS), histiocytic neutrophilic dermatitis, neutrophilic dermatitis of the back of the hand, intestinal bypass syndrome (intestinal-associated dermatitis-arthritis syndrome), palisade neutrophilic granulomatous dermatitis, or VEXAS syndrome).

59. The aforementioned disease or disorder is psoriasis; Depending on the situation: (i) The disease or disorder is moderate to severe psoriasis; (ii) The disease or disorder is psoriasis vulgaris or plaque psoriasis; or (iii) The disease or disorder is moderate to severe plaque psoriasis, Orisumilast for use according to any one of claims 1 to 55.

60. Orismilast for use according to any one of claims 1 to 55, wherein the disease or disorder is moderate to severe psoriasis (e.g., moderate to severe plaque psoriasis), and the subject has a 75% reduction in PASI from baseline (PASI 75) after 16 weeks of treatment.

61. The disease or disorder is moderate to severe psoriasis (e.g., moderate to severe plaque psoriasis): (i) The subject has a 90% reduction in PASI from baseline (PASI90) after 16 weeks of treatment; or (ii) The subject has a 100% reduction in PASI from baseline (PASI 100) after 16 weeks of treatment; or (iii) The subject achieves an Investigator's Overall Assessment (IGA) of clear (0) or nearly clear (1) after 16 weeks of treatment. Orisumilast for use according to any one of claims 1 to 55.

62. The aforementioned disease or disorder is atopic dermatitis; In some cases, the aforementioned disease or disorder may be moderate to severe atopic dermatitis. Orisumilast for use according to any one of claims 1 to 55.

63. The aforementioned disease or disorder is moderate to severe atopic dermatitis: (i) The subject has a 75% reduction in EASI from baseline (EASI75) after 16 weeks of treatment; or (ii) The subject has a 90% reduction in EASI from baseline (EASI90) after 16 weeks of treatment; or (iii) The subject has a 100% reduction in EASI from baseline (EASI 100) after 16 weeks of treatment; or (iv) The subject achieves, after 16 weeks of treatment, an investigator-assessed comprehensive (IGA-AD) score of clear (0) or nearly clear (1) AD, and an improvement of at least 2 points from baseline in IGA-AD; or (v) The subject achieves a physician-reviewed comprehensive assessment (IGA-AD) score of clear (0) AD after 16 weeks of treatment. Orisumilast for use according to any one of claims 1 to 55.

64. The disease or disorder is moderate to severe atopic dermatitis, and the treatment reduces the baseline peak pruritus numerical rating scale (PPNRS) by ≥4 points; Preferably, the treatment reduces the baseline PPNRS by ≥ 4 points after two weeks of treatment. Orisumilast for use according to any one of claims 1 to 55.

65. Orisumilast for use according to any one of claims 1 to 55, wherein the disease or disorder is ulcerative colitis.

66. Orisumilast for use according to any one of claims 1 to 55, wherein the disease or disorder is hidradenitis suppurativa.

67. Orismilast for use in a method for treating pruritus associated with atopic dermatitis in a subject, wherein the method comprises administering a therapeutically effective amount of orismilast to the subject.

68. Orisumilast for use according to claim 67, wherein the subject has a baseline peak pruritus numerical rating scale (PPNRS) of ≥ 4.

69. Orisumilast for use according to claim 67, wherein the subject has a baseline PPNRS of >7.

70. Orisumilast for use according to any one of claims 67 to 69, wherein the method reduces the baseline PPNRS by ≥ 4 points.

71. Orisumilast for use according to any one of claims 67 to 69, wherein the method reduces the baseline PPNRS by ≥ 4 points two weeks after treatment.

72. Orisumilast for use according to any one of claims 67 to 71, wherein the subject has moderate to severe atopic dermatitis.

73. Orisumilast for use according to any one of claims 1 to 72, wherein the orisumilast is administered orally to the subject.

74. Orisumilast for use according to any one of claims 1 to 72, wherein the orisumilast is administered orally to the subject in the form of a modified-release formulation (e.g., an orally modified-release tablet formulation) containing the orisumilast.

75. Orisumilast for use according to claim 74, wherein the modified release formulation, when measured in vitro using the standard dissolution assay described in the specification, releases an average amount of orisumilast of about 10% to about 70% after 45 minutes and more than 70% after 180 minutes.

76. Orisumilast for use according to any one of claims 1 to 75, wherein the orisumilast is administered to the subject separately or consecutively at the same time as one or more additional therapeutic agents in a therapeutically effective amount.

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