Dosing regimen of orimilast

Abstract

Provided herein are orimilast for use in treating a disease or disorder ameliorated by inhibition of PDE4 in a subject, wherein the orimilast is administered to the subject according to a specific dosing regimen. Also provided is an orimilast for use in the treatment of pruritus associated with atopic dermatitis.

Description

[0001] This invention relates to orlistat for treating diseases or disorders that improve in subjects by inhibiting PDE4, wherein orlistat 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 intracellular secondary messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate, playing a crucial role in mediating biological responses mediated by a variety of extracellular signals. Eleven PDE enzyme families have been identified, among which the PDE4 family comprises four subtypes (AD) and more than 20 isotypes (Houslay MD, et al., “Keynote review: phosphodiesterase-4 as a therapeutic target”, Drug Discov Today; 2005, 10(22):1503-1519). PDEs represent the only cellular pathway for the degradation of cyclic nucleotides, highlighting their crucial role in regulating intracellular levels of these secondary messengers and thus various cellular functional responses (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 predominant form of PDE, and PDE4 inhibitors increase cAMP levels. High intracellular cAMP levels downregulate inflammatory activity and upregulate anti-inflammatory activity, leading to reduced 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 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 have shown potent effects in inflammatory diseases, neurological disorders (such as cognitive impairment, depression, psychosis, schizophrenia, and Alzheimer's disease), cancer, metabolic diseases, and skin diseases (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 Opinion Ther Targets. Sep 2013;17(9):1011-27; Li et al., ibid.; and Lugnier et al., "Cyclic Nucleotide phosphodiesterases: New targets in the metabolic syndrome? (Pharmacol Ther. 2020)

[0004] Inhibition of PDE4 has therapeutic potential in treating psoriasis and other skin diseases with immune-inflammatory components (Dastidar et al., ibid.). In allergic dermatitis, PDE4 inhibitors inhibit the migration of skin dendritic cells, and this inhibition is accompanied by inhibition of matrix metalloproteinase 9 activity in the epidermis and dermis. In addition, PDE4 inhibitors inhibit the secretion of cytokines (tumor necrosis factor [TNF]-α, IL-1β, and IL-12) from human dendritic cells, and have also demonstrated inhibitory effects on T cell activation in vitro. PDE4 inhibitors reduce T helper cell (Th)1 and Th2 cytokines in vitro and in inflamed mouse skin (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. Immunohistochemical staining also revealed increased levels of PDE4 isoforms PDE4A, PDE4B, PDE4C, and PDE4D in dermal fibroblasts of skin samples from patients with atopic dermatitis. Therefore, PDE4 inhibitors are expected to be used to treat 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 ® Roflumilast is approved in the US and Europe for reducing the risk of exacerbations in patients with chronic obstructive pulmonary disease and chronic bronchitis (summary of Roflumilast product characteristics). Otezlazoline, an oral PDE4 inhibitor, is also approved. ®It has been approved in the United States and Europe for multiple indications, including psoriatic arthritis and psoriasis (Apsir product characteristics summary), and has been investigated for atopic dermatitis and other chronic inflammatory diseases (Samrao A et al., ArchDermatol. [Archives of Dermatology] 2012;148(8):890-897).

[0007] One of the key challenges of effective oral PDE4 therapy is the narrow therapeutic window. Most projects investigating PDE4 inhibitors have failed due to safety concerns, and currently only two approved oral PDE4 inhibitors are available—roflumilast and apremilast. However, both therapies have tolerability issues, primarily but not exclusively affecting the gastrointestinal (GI) tract, characterized by nausea and diarrhea. These undesirable GI effects have been observed since the start of treatment, leading to titration of those drugs if attempts are made to reduce or mitigate these undesirable side effects. Apremilast is administered orally twice daily, starting at a dose of 10 mg, which is increased to 30 mg twice daily over a week (Apremilast Product Characteristics Summary). Roflumilast is administered orally at a starting dose of 250 µg once daily for 28 days, followed by a maintenance dose of 500 µg once daily (Roflumilast Product Characteristics Summary). However, despite dose titration, some patients still experience GI side effects such as diarrhea, nausea, and abdominal pain.

[0008] Oresta 2-(3,5-dichloro-1-oxypyridin-1-onthiol-4-yl)-1-[7-(difluoromethoxy)-1',1'-dioxospiro[1,3-benzodioxane-2,4'-thiane]-4-yl] acetone is a potent and selective PDE4 inhibitor with the following chemical formula:

[0009] Orexate, disclosed in WO 2011 / 160632, is a selective PDE4 inhibitor and a potent in vitro inhibitor of PDE4B and PDE4D subtype splice variants. When tested in vitro, orexate inhibits the production of tumor necrosis factor α (TNFα) from human whole blood and human peripheral blood mononuclear cells (PBMCs), as well as the secretion of Th1 (TNFα and IFNγ), Th17 (IL-22 and IL-23), and Th2 (IL-4, IL-5, and IL-13)-related cytokines from PBMCs. In vivo, 10 and 30 mg / kg doses of orismilast significantly reduced ear thickness and inflammatory markers in a mouse model of oxazolone-induced chronic otodermal inflammation (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 orally twice daily in the form of an immediate-release (IR) formulation or placebo for 16 weeks. Compared with placebo, treatment with orismilast IR significantly improved the mean psoriasis area severity index score at week 16 (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] WO 2020 / 148271 discloses an extended-release (MR) formulation containing osrelastide. The safety, tolerability, and pharmacokinetics (PK) of osrelastide MR and IR formulations were tested in a phase 1 clinical trial (NCT03812198) in healthy volunteers. Participants were randomized (3:1) to receive either osrelastide MR or placebo (n=12). Osrelastide MR was administered twice daily for 17 days. Osrelastide MR was started at 10 mg twice daily on days 1–2, increased to 20 mg twice daily on days 3–4, increased to 30 mg twice daily on days 5–6, increased to 40 mg twice daily on days 7–8, increased to 50 mg twice daily on days 9–10, and finally increased to 60 mg twice daily on days 11–17. Oreste MR formulations achieved PK properties comparable to Oreste IR formulations; however, fewer participants reported GI disorders in the MR formulation group (16.7%) compared to the IR formulation group (33.3%) (Warren et al., ibid.).

[0012] In a phase 2b study, 202 patients with moderate to severe plaque psoriasis were randomly assigned to receive MR orismilast tablet formulations at doses of 20 mg twice daily (BID), 30 mg BID, and 40 mg BID for 16 weeks. All doses of orismilast showed statistically significant therapeutic effects compared to placebo (Warren R et al., Efficacy and Safety of Orismilast in Patients with Moderate-to-Severe Psoriasis: Results from the Phase IIb IASOS Trial. Presented at: American Academy of Dermatology 2023 Annual Meeting; March 17-21, New Orleans, Louisiana).

[0013] WO 2022 / 200339 discloses oliquista for the treatment of hidradenitis suppurativa (HS) and describes a phase 2a clinical trial in which the extended-release formulation of oliquista involved dose titration over the first two weeks, with the dose gradually increased from 10 mg twice daily (BID) to 30 mg BID.

[0014] Although the use of extended-release formulations of orestradiol has improved gastrointestinal side effects, further treatment improvements are needed to enhance orestradiol’s tolerability and / or efficacy. Summary of the Invention

[0015] As described in more detail in the examples herein, analysis of data from a Phase 2b clinical trial investigating subjects with moderate to severe psoriasis treated orally with ospermia revealed that subject weight significantly impacted treatment efficacy. Subjects weighing 100 kg or more, treated with 30 mg ospermia twice daily, achieved more effective treatment compared to subjects weighing less than 100 kg treated with the same dose. This was unexpected, as analysis of pharmacokinetic (PK) data showed that subjects weighing less than 100 kg had higher systemic exposure to ospermia compared to those weighing 100 kg or more. Higher systemic exposure in lighter-weight subjects was expected to result in better treatment efficacy than in subjects weighing over 100 kg, but the opposite was observed.

[0016] Therefore, a weight-related dosing regimen for orestrate is needed to optimize treatment efficacy and / or tolerability.

[0017] According to a first aspect of the invention, osrester is provided for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject, the method comprising administering the osrester to the subject, wherein: (Ai) The initial dose of orexate was administered to the subject once daily for the initial period, and then; (Aii) Administer the transitional dose of orlistat to the subject twice daily during the transition period, then; (Aiii) Administer a maintenance dose of orexusone twice daily to the subject; in: (a) The initial orinexetine dose and the transition orinexetine dose are independently selected from 10 mg to 30 mg of orinexetine, provided that the transition orinexetine dose is greater than or equal to the initial orinexetine dose; (b) The initial time period is two to eight weeks; (c) The transition period is one to eight weeks; and (d) When the subject’s weight is greater than or equal to the threshold weight, the maintenance dose of orexus is greater than the transition dose of orexus, wherein the threshold weight is at least 90 kg.

[0018] In some embodiments, the initial time period in (Ai) is two to six weeks. In some embodiments, the initial time period in (Ai) is two to four weeks. In some embodiments, the initial time period in (Ai) is two weeks to up to four weeks. In some embodiments, the initial time period in (Ai) is two weeks, four weeks, or six weeks. In some embodiments, the initial time period in (Ai) is three weeks. In some embodiments, the initial time period in (Ai) is four weeks. Preferably, the initial time period in (Ai) is two weeks.

[0019] In some embodiments, the transition period in (Aii) is as long as eight weeks. In some embodiments, the transition period in (Aii) is as long as six weeks. In some embodiments, the transition period in (Aii) is as long as four weeks. In some embodiments, the transition period in (Aii) is one to eight weeks. In some embodiments, the transition period in (Aii) is six to eight weeks. In some embodiments, the transition period in (Aii) is one to six weeks. In some embodiments, the transition period in (Aii) is four to six weeks. In some embodiments, the transition period in (Aii) is one to four weeks. In some embodiments, the transition period in (Aii) is one to three weeks. In some embodiments, the transition period in (Aii) is one to two weeks.

[0020] In some embodiments, the transition period in (Aii) is two weeks, four weeks, or six weeks. In some embodiments, the transition period in (Aii) is one week. In some embodiments, the transition period in (Aii) is two weeks. In some embodiments, the transition period in (Aii) is four weeks. In some embodiments, the transition period in (Aii) is six weeks. In some embodiments, the transition period in (Aii) is eight weeks.

[0021] In some embodiments, the initial time period in (Ai) is two weeks, and the transition time period in (Aii) is four to eight weeks. In some embodiments, the initial time period in (Ai) is two weeks, and the transition time period in (Aii) is as long as eight weeks. In some embodiments, the initial time period in (Ai) is two weeks, and the transition time period in (Aii) is as long as six weeks. In some embodiments, the initial time period in (Ai) is two weeks, and the transition time period in (Aii) is four to six weeks. In some embodiments, the initial time period in (Ai) is two weeks, and the transition time period in (Aii) is six to eight weeks. In some embodiments, the initial time period in (Ai) is two weeks, and the transition time period in (Aii) is one to four weeks. In some embodiments, the initial time period in (Ai) is two weeks, and the transition time period in (Aii) is two weeks. In a preferred embodiment, the initial time period in (Ai) is two weeks, and the transition time period in (Aii) is six weeks.

[0022] Clinical data analysis shows that most adverse events related to orlistat treatment (such as diarrhea, nausea, headache, dizziness, or vomiting) occur within the first four weeks of treatment, and a very small number of these events occur after eight weeks of treatment. Therefore, in some embodiments, the total duration of the initial and transition periods is four to eight weeks. In some embodiments, the total duration of the initial and transition periods is four weeks. In some embodiments, the total duration of the initial and transition periods is five weeks. In some embodiments, the total duration of the initial and transition periods is six weeks. In some embodiments, the total duration of the initial and transition periods is seven weeks. In some embodiments, the total duration of the initial and transition periods is eight weeks.

[0023] An analysis of data from a phase 2b clinical trial of osrelastide in all subjects receiving treatment without stratifying patients by weight found that, during the first 8 weeks of treatment for moderate to severe plaque psoriasis, the efficacy of twice-daily administration of 20 mg osrelastide was comparable to that of twice-daily administration of 30 mg osrelastide. Therefore, dose titration with low doses of osrelastide (e.g., 10 mg or particularly 20 mg) during the initial and transitional periods is expected to provide therapeutic efficacy while minimizing undesirable side effects during the initial treatment period, particularly in the first 4 to 8 weeks of treatment.

[0024] In some embodiments, when the subject's weight is less than a threshold weight, the maintenance dose of orexusol in (Aiii) is the same as the transition dose of orexusol.

[0025] In some embodiments, when the subject's weight is greater than or equal to the threshold weight, the maintenance orelastide dose in (Aiii) is up to 40 mg, provided that the maintenance orelastide dose is greater than the transition orelastide dose. For example, the maintenance orelastide dose may be 30 mg to 40 mg of orelastide. Preferably, when the subject's weight is greater than or equal to the threshold weight, the maintenance orelastide dose is 30 mg.

[0026] In some embodiments, when the subject's weight is greater than or equal to a threshold weight and the transition orelastide dose is less than 30 mg, the maintenance orelastide dose in (Aiii) is 30 mg orelastide. For example, the transition orelastide dose is 10 mg to 25 mg orelastide. In some embodiments, the maintenance orelastide dose is 30 mg orelastide and the transition orelastide dose is 10 mg orelastide. In some embodiments, when the subject's weight is greater than or equal to a threshold weight, the maintenance orelastide dose is 30 mg orelastide and the transition orelastide dose is 20 mg orelastide.

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

[0028] Therefore, in some embodiments, when the subject's weight is less than a threshold weight, the transition orelastide dose in (Aii) and the maintenance orelastide dose in (Aiii) are both 20 mg orelastide. In some embodiments, when the subject's weight is less than a threshold weight, the initial orelastide dose in (Ai) is 10 mg or 20 mg; the transition orelastide dose in (Aii) and the maintenance orelastide dose in (Aiii) are both 20 mg orelastide. In some embodiments, when the subject's weight is less than a threshold weight, the initial orelastide dose in (Ai), the transition orelastide dose in (Aii), and the maintenance orelastide dose in (Aiii) are all 20 mg orelastide. In some embodiments, when the subject's weight is less than a threshold weight, the initial orelastide dose in (Ai) is 10 mg, and the transition orelastide dose in (Aii) and the maintenance orelastide dose in (Aiii) are both 20 mg orelastide. In some embodiments, when the subject's weight is less than a threshold weight, the initial orelastide dose in (Ai) is 10 mg, the transition orelastide dose in (Aii) is 10 mg, and the maintenance orelastide dose in (Aiii) is 10 mg orelastide.

[0029] Through population pharmacokinetic (PK) modeling based on clinical data and analysis of efficacy and tolerability data, the inventors have determined that twice-daily administration of 10 mg of orexusite is expected to be the optimal maintenance dose of orexusite to maximize efficacy and tolerability in subjects with a lower weight limit of 50 kg to 75 kg. For example, the lower weight limit for a subject is 60 kg.

[0030] Therefore, in some embodiments, when the subject's weight is below a lower limit weight, the initial orelastide dose in (Ai), the transition orelastide dose in (Aii), and the maintenance orelastide dose in (Aiii) are all 10 mg orelastide, where the lower limit weight is 50 kg to 75 kg. For example, the subject's lower limit weight is 60 kg.

[0031] In some embodiments, when the subject's weight is within the lower limit to below the threshold weight range, the optimal maintenance dose of orestradiol is 20 mg twice daily.

[0032] Therefore, in some embodiments, when the subject's weight is within the lower limit weight to below the threshold weight range, the initial orelastide dose in (Ai), the transition orelastide dose in (Aii), and the maintenance orelastide dose in (Aiii) are all 20 mg orelastide, where the lower limit weight is 50 kg to 75 kg. For example, the subject's lower limit weight is 60 kg.

[0033] In some embodiments of the first aspect of the invention: (i) When the subject's weight is below the lower limit, the initial orelastide dose in (Ai), the transition orelastide dose in (Aii), and the maintenance orelastide dose in (Aiii) are all 10 mg orelastide; or (ii) When the subject's weight is within the range of the lower limit weight to less than the threshold weight, the initial orelastide dose in (Ai), the transition orelastide dose in (Aii), and the maintenance orelastide dose in (Aiii) are all 20 mg orelastide; The lower limit of this weight ranges from 50 kg to 75 kg. For example, the lower limit for a subject is 60 kg.

[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 some embodiments, when the subject's weight is less than 75 kg, the initial orelastide dose in (Ai), the transition orelastide dose in (Aii), and the maintenance orelastide dose in (Aiii) are all 10 mg orelastide.

[0036] In some embodiments, when the subject's weight is less than 60 kg, the initial orelastide dose in (Ai), the transition orelastide dose in (Aii), and the maintenance orelastide dose in (Aiii) are all 10 mg orelastide.

[0037] In some embodiments, when the subject's weight is less than 50 kg, the initial orelastide dose in (Ai), the transition orelastide dose in (Aii), and the maintenance orelastide dose in (Aiii) are all 10 mg orelastide.

[0038] In some embodiments, when the subject's weight is in the range of 75 kg to less than the threshold weight, the initial orelastide dose in (Ai), the transition orelastide dose in (Aii), and the maintenance orelastide dose in (Aiii) are all 20 mg orelastide.

[0039] In some embodiments, when the subject's weight is in the range of 60 kg to less than the threshold weight, the initial orelastide dose in (Ai), the transition orelastide dose in (Aii), and the maintenance orelastide dose in (Aiii) are all 20 mg orelastide.

[0040] In some embodiments, when the subject's weight is in the range of 50 kg to less than the threshold weight, the initial orelastide dose in (Ai), the transition orelastide dose in (Aii), and the maintenance orelastide dose in (Aiii) are all 20 mg orelastide.

[0041] As illustrated in the examples herein, analysis of clinical trial data has determined that administration of orelastide according to the dosing regimen described herein improves tolerability and / or therapeutic efficacy compared to administration of orelastide at a fixed twice-daily dose. Specifically, the inventors have determined that, when following the dosing regimen described herein, subjects weighing greater than or equal to a threshold weight exhibit improved tolerability and / or therapeutic response to orelastide when the maintenance dose is higher than the transitional orelastide dose. More specifically, it has been found that subjects weighing greater than the threshold weight are less likely to experience side effects leading to treatment discontinuation when receiving higher maintenance doses compared to lighter subjects weighing less than the threshold weight.

[0042] Therefore, a second aspect of the invention provides osrester for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject whose weight is greater than or equal to a threshold weight, the method comprising administering osrester to the subject. in: (Bi) The initial dose of orlistat was administered to the subject once daily for the initial period, and then; (Bii) Administer the transitional dose of orlistat to the subject twice daily during the transition period, then; (Biii) The subject was given a maintenance dose of orinelast twice daily, wherein the maintenance dose of orinelast was greater than the transition dose of orinelast. in: (a) The initial orinexetine dose and the transition orinexetine dose are independently selected from 10 mg to 30 mg of orinexetine, provided that the transition orinexetine dose is greater than or equal to the initial orinexetine dose; (b) This initial timeframe lasted eight weeks; (c) The transition period is one to eight weeks; and (d) The threshold weight is at least 90 kg.

[0043] In some embodiments, the initial time period in (Bi) is one day to eight weeks. In some embodiments, the initial time period in (Bi) is two days to eight weeks. In some embodiments, the initial time period in (Bi) is four days to eight weeks. In some embodiments, the initial time period in (Bi) is five days to eight weeks. In some embodiments, the initial time period in (Bi) is six days to eight weeks. In some embodiments, the initial time period in (Bi) is one week to eight weeks. In some embodiments, the initial time period in (Bi) is one week to six weeks. In some embodiments, the initial time period in (Bi) is one week to four weeks. In some embodiments, the initial time period in (Bi) is one week to two weeks. In some embodiments, the initial time period in (Bi) is two days to eight weeks. In some embodiments, the initial time period in (Bi) is one day. In some embodiments, the initial time period in (Bi) is two days. In some embodiments, the initial time period in (Bi) is three days. In some embodiments, the initial time period in (Bi) is four days. In some embodiments, the initial time period in (Bi) is five days. In some embodiments, the initial time period in (Bi) is six days. In some embodiments, the initial time period in (Bi) is one week, two weeks, three weeks, or four weeks. In some embodiments, the initial time period in (Bi) is one week. In some embodiments, the initial time period in (Bi) is two weeks. In some embodiments, the initial time period in (Bi) is three weeks. In some embodiments, the initial time period in (Bi) is four weeks. In some embodiments, the initial time period in (Bi) is five weeks. In some embodiments, the initial time period in (Bi) is six weeks. In some embodiments, the initial time period in (Bi) is seven weeks. In some embodiments, the initial time period in (Bi) is eight weeks.

[0044] In some embodiments, the initial time period in (Bi) is two to four weeks. In some embodiments, the initial time period in (Bi) is two weeks to up to four weeks. In some embodiments, the initial time period in (Bi) is two weeks, four weeks, or six weeks. Preferably, the initial time period in (Bi) is two weeks.

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

[0046] In some embodiments, the transition period in (Bii) is as long as eight weeks. In some embodiments, the transition period in (Bii) is as long as six weeks. In some embodiments, the transition period in (Bii) is as long as four weeks. In some embodiments, the transition period in (Bii) is one to eight weeks. In some embodiments, the transition period in (Bii) is six to eight weeks. In some embodiments, the transition period in (Bii) is one to six weeks. In some embodiments, the transition period in (Bii) is four to six weeks. In some embodiments, the transition period in (Bii) is one to four weeks. In some embodiments, the transition period in (Bii) is one to three weeks. In some embodiments, the transition period in (Bii) is one to two weeks.

[0047] In some embodiments, the initial time period in (Bi) is two weeks, and the transition time period in (Bii) is four to eight weeks. In some embodiments, the initial time period in (Bi) is two weeks, and the transition time period in (Bii) is as long as eight weeks. In some embodiments, the initial time period in (Bi) is two weeks, and the transition time period in (Bii) is as long as six weeks. In some embodiments, the initial time period in (Bi) is two weeks, and the transition time period in (Bii) is four to six weeks. In some embodiments, the initial time period in (Bi) is two weeks, and the transition time period in (Bii) is six to eight weeks. In some embodiments, the initial time period in (Bi) is two weeks, and the transition time period in (Bii) is one to four weeks. In some embodiments, the initial time period in (Bi) is two weeks, and the transition time period in (Bii) is two weeks. In a preferred embodiment, the initial time period in (Bi) is two weeks, and the transition time period in (Bii) is six weeks.

[0048] As described above, most adverse events associated with orlistat typically occur within the first four to eight weeks of orlistat administration. The incidence of adverse events is generally low after the first eight weeks of treatment. In some embodiments, the total duration of the initial and transition periods is four to eight weeks. In some embodiments, the total duration of the initial and transition periods is four weeks. In some embodiments, the total duration of the initial and transition periods is five weeks. In some embodiments, the total duration of the initial and transition periods is six weeks. In some embodiments, the total duration of the initial and transition periods is seven weeks. In some embodiments, the total duration of the initial and transition periods is eight weeks.

[0049] In some embodiments, the maintenance orelastine dose in (Biii) is up to 40 mg orelastine, provided that the maintenance orelastine dose is greater than the transition orelastine dose. For example, the maintenance orelastine dose in (Biii) may be 30 mg to 40 mg orelastine. In a preferred embodiment, the maintenance orelastine dose in (Biii) is 30 mg orelastine.

[0050] In some embodiments, the maintenance orelastine dose in (Biii) is 30 mg orelastine, and the transition orelastine dose in (Bii) is less than 30 mg. For example, the transition orelastine dose in (Bii) is 10 mg to 25 mg orelastine. In some embodiments, the maintenance orelastine dose in (Biii) is 30 mg orelastine, and the transition orelastine dose in (Bii) is 10 mg orelastine. In some embodiments, the maintenance orelastine dose in (Biii) is 30 mg orelastine, and the transition orelastine dose in (Bii) is 20 mg orelastine.

[0051] In some embodiments of the second aspect of the invention, the initial dose of orlistat in (Bi) is 10 mg or 20 mg of orlistat. In a preferred embodiment of the second aspect of the invention, the initial dose of orlistat in (Bi) is 20 mg of orlistat.

[0052] In certain embodiments of the second aspect of the invention, osrester is provided for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject whose weight is greater than or equal to a threshold weight, the method comprising administering osrester to the subject. in: (Bi) Subjects were given an initial dose of 20 mg of orestradiol once daily for two weeks, and then; (Bii) Administer a transitional dose of 20 mg of orestradiol to subjects twice daily for one to eight weeks, then; (Biii) Administer a maintenance dose of 30 mg of orestradiol to the subject twice daily; The threshold weight is at least 90 kg.

[0053] In certain embodiments of the second aspect of the invention, osrester is provided for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject whose weight is greater than or equal to a threshold weight, the method comprising administering osrester to the subject. in: (Bi) Subjects were given an initial dose of 20 mg of orestradiol once daily for two weeks, and then; (Bii) Administer a transitional dose of 20 mg of orestradiol to subjects twice daily for two to eight weeks, then; (Biii) Administer a maintenance dose of 30 mg of orestradiol to the subject twice daily; The threshold weight is at least 90 kg.

[0054] In certain embodiments of the second aspect of the invention, osrester is provided for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject whose weight is greater than or equal to a threshold weight, the method comprising administering osrester to the subject. in: (Bi) Subjects were given an initial dose of 20 mg of orestradiol once daily for two weeks, and then; (Bii) Subjects were given a transitional dose of 20 mg of orestradiol twice daily for six to eight weeks, and then; (Biii) Administer a maintenance dose of 30 mg of orestradiol to the subject twice daily; The threshold weight is at least 90 kg.

[0055] In a preferred embodiment of a second aspect of the invention, osrester is provided for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject whose weight is greater than or equal to a threshold weight, the method comprising administering osrester to the subject. in: (Bi) Subjects were given an initial dose of 20 mg of orestradiol once daily for two weeks, and then; (Bii) Subjects were given a transitional dose of 20 mg of orestradiol twice daily for six weeks, then; (Biii) Administer a maintenance dose of 30 mg of orestradiol to the subject twice daily; The threshold weight is at least 90 kg.

[0056] In a third aspect of the invention, osrester is provided for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject whose weight is greater than or equal to a threshold weight, the method comprising administering osrester to the subject. in: (Ci) The initial dose of orlistat was administered to the subject once daily for the initial period, and then; (Cii) The subject was given a maintenance dose of orinelast twice daily, wherein the maintenance dose of orinelast was greater than the initial dose of orinelast. in: (a) The initial dose of orexaminase is 10 mg to 20 mg orexaminase; (b) This initial period lasted eight weeks; and (c) The threshold weight is at least 90 kg.

[0057] In a fourth aspect of the invention, osrester is provided for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject, the method comprising administering osrester to the subject, wherein: (Di) Administer the initial dose of orlistat to the subject once daily for the initial period, then; (Dii) Administer a maintenance dose of orexate to the subject twice daily; in: (a) The initial dose of orinelast and the maintenance dose of orinelast are both 20 mg orinelast; (b) The initial time period is two to eight weeks; and (c) The subject's weight is between the lower limit and below the threshold weight; The threshold weight is at least 90 kg, and the lower limit weight is between 50 kg and 75 kg.

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

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

[0060] As illustrated in the examples in this article, population pharmacokinetic (PK) models based on pooled osrelastide clinical trial data have determined that treatment with 20 mg osrelastide twice daily in subjects weighing less than a threshold weight (e.g., 50 kg) resulted in higher systemic exposure to osrelastide compared to heavier subjects. As stated above, analysis of the psoriasis phase 2b data showed that increasing systemic exposure beyond what was initially required to improve efficacy may not improve it and could potentially decrease it. Therefore, specific dosing regimens may be necessary for lighter subjects, such as adolescents.

[0061] In a fifth aspect of the invention, osrester is provided for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject, the subject having a weight less than a lower limit of body weight, the method comprising administering osrester to the subject, wherein: (Ei) The subject was given an initial dose of 10 mg of orestradiol once daily for the initial period, and then; (Eii) The subject was given a maintenance dose of 10 mg of orestradiol twice daily; The initial time period is two to eight weeks; The lower limit of this weight ranges from 50 kg to 75 kg.

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

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

[0064] In some embodiments of any of the dosing regimens disclosed herein, when orlistat is administered twice daily (e.g., for transitional and maintenance doses), the doses are appropriately spaced approximately 12 hours apart. Suitably, one dose is administered in the morning and another in the evening.

[0065] In some embodiments, oliquista is administered to the subject without restricting the subject's intake of food or beverages. However, gastrointestinal side effects can be further minimized by avoiding large meals and / or fatty foods prior to administration of oliquista. Therefore, in some embodiments of any of the dosing regimens disclosed herein, oliquista is administered to the subject in a fasting state. For example, oliquista is administered at least 4 hours after a meal. Suitably, administration in a fasting state also requires the subject to fast for two hours after administration of oliquista. In some embodiments of any of the dosing regimens disclosed herein, oliquista is administered to the subject in a eating state. For example, oliquista is administered to the subject within a timeframe of 30 minutes before and 1 hour after a meal. In some embodiments, oliquista is administered to the subject within a timeframe of 30 minutes before and 1 hour after a meal, wherein the meal is a low-fat meal (less than 50% of the total calories of the meal comes from fat). In some embodiments, oliquista is administered to the subject within a timeframe of 30 minutes before and 1 hour after a meal, wherein the meal is a low-calorie meal (less than about 1000 calories). In some embodiments, orlistat is administered to the subject 30 minutes before and 1 hour after a meal, wherein the meal is a low-fat, low-calorie meal. In some embodiments of any of the dosing regimens disclosed herein, orlistat is administered to the subject without restriction of food or beverage intake.

[0066] In some embodiments of any of the dosing regimens disclosed herein, the initial olisitol dose and the transition olisitol dose are the same. In some embodiments, both the initial olisitol dose and the transition olisitol dose are 20 mg olisitol.

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

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

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

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

[0071] In a preferred embodiment of any dosing regimen disclosed herein, the threshold body weight is 100 kg.

[0072] In some embodiments of any of the dosing regimens disclosed herein, a maintenance dose of orexusone is administered to the subject twice daily for the remainder of the treatment period. Thus, in some embodiments, a maintenance dose of orexusone 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 18 months, or at least two years.

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

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

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

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

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

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

[0079] As illustrated in this example, analysis of Phase 2b clinical trial data from a study of subjects with moderate to severe atopic dermatitis treated with oral ospermia revealed that ospermia has a surprisingly strong and rapid effect on pruritus / itch associated with atopic dermatitis.

[0080] Therefore, a sixth aspect of the invention provides osrelastide for use in a method of treating pruritus associated with atopic dermatitis in a subject, the method comprising administering a therapeutically effective amount of osrelastide to the subject. Osrelastide can be administered to the subject using any suitable route of administration. Suitably, osrelastide is administered orally as a pharmaceutical composition, such as any osrelastide pharmaceutical composition described herein. In some embodiments, osrelastide is administered orally as a sustained-release pharmaceutical composition, such as any sustained-release pharmaceutical composition described herein. Osrelastide can be administered to the subject using any suitable dosing regimen, such as 10 mg, 20 mg, or 30 mg, once or twice daily. Thus, osrelastide can be administered to the subject twice daily at a dose of 10 mg. Osrelastide can be administered to the subject twice daily at a dose of 20 mg. Osrelastide can be administered to the subject twice daily at a dose of 30 mg. However, suitably, osrelastide is administered to the subject using the dosing regimen described in any one of the first to fifth aspects of the invention.

[0081] In some embodiments of any of the dosing regimens disclosed herein, orlistat is administered orally to the subject.

[0082] In some embodiments of any of the oxiracetam dosing regimens or uses disclosed herein, oxiracetam is administered to the subject in the form of a sustained-release formulation comprising oxiracetam. In some embodiments, the sustained-release formulation releases an average amount of about 10% to about 70% of oxiracetam after 45 minutes and more than about 70% after 180 minutes. In some embodiments, the sustained-release formulation releases an average amount of about 11% to about 65% of oxiracetam after 45 minutes and more than 75% of oxiracetam after 180 minutes. In some embodiments, the sustained-release formulation releases an average amount of about 35% to about 65% of oxiracetam after 45 minutes and more than 70% of oxiracetam after 180 minutes. In some embodiments, the sustained-release formulation releases an average amount of about 35% to about 55% of oxiracetam after 45 minutes and more than about 80% of oxiracetam after 180 minutes. In each of the above cases, dissolution was determined using the European Pharmacopoeia 2.9.3 Method II (Apparatus II, paddle method), wherein the dissolution medium was 900 ml of 0.5% sodium dodecyl sulfate solution in 0.1 N HCl, the paddle speed was 75 rpm, and the dissolution medium was at 37°C ± 0.5°C.

[0083] The subject can 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 some embodiments, orestradiol is administered to the subject simultaneously, alone, or sequentially with one or more additional therapeutic agents. Attached Figure Description

[0085] Embodiments of the present invention will be further described below with reference to the accompanying drawings, wherein: Figure 1 This demonstrates the reduction in Psoriasis Area and Severity Index (PASI) scores relative to baseline after treatment with orlistat at doses of 20 mg BID, 30 mg BID, and 40 mg BID in the phase 2b clinical trial described in Example 3. Figure 1 A shows patients with a 50% reduction in PASI score (PASI-50). Figure 1 B shows the percentage of patients with a 75% reduction in PASI score (PASI-75). The y-axis shows the percentage of patients who achieved PASI-50 or PASI-75 scores at weeks 0 (W0), 4 (W4), 8 (W8), 12 (W12), and 16 (W16). "NRI" in this figure refers to imputation of non-responder data. Figure 2 The total number of patients who discontinued treatment and discontinued splits due to adverse events and other reasons in the Phase 2b clinical trial described in Example 3, in the placebo (Pbo), 20 mg BID, 30 mg BID, and 40 mg BID orexaminase treatment groups is shown. Figure 3 The chart shows the proportion of patients who experienced adverse events during treatment periods of 0–4 weeks, 4–8 weeks, 8–12 weeks, and 12–16 weeks for patients treated with 20 mg, 30 mg, or 40 mg orexine BID. Bar graphs for each treatment period show patients who experienced diarrhea, nausea, headache, or vomiting. Figure 4 point Figure 4 A shows the PASI-75 and PASI-90 values ​​for patients weighing less than 100 kg and greater than 100 kg who were treated with 20 mg, 30 mg, or 40 mg orexine BID. Figure 4 B shows the number of treatment-related adverse events leading to patient discontinuation in each treatment group for patients weighing less than 100 kg and greater than 100 kg. Figure 5 point Figure 5 A shows a post-hoc analysis, illustrating patients treated with 20 mg orelastide BID if they weighed less than 100 kg, and patients treated with 30 mg orelastide if they weighed 100 kg or more (“20 / 30 mg BID”). These results were compared to pre-specified treatment groups (20 mg BID, 30 mg BID, and 40 mg BID) in the clinical trial. Figure 5B shows the percentage of treatment-related adverse events leading to discontinuation in patients treated with post-treatment 20 / 30 mg BID and in the pre-specified 20 mg BID, 30 mg BID, and 40 mg BID treatment groups. Figure 5 The results of post-hoc analysis of the PASI-75, PASI-90, and PASI-100 reactions are shown. Figure 6 A representative dosing regimen according to the invention is shown, wherein 20 mg of orexine was administered once daily (“OD”) for 2 weeks, followed by 20 mg of orexine twice daily for 6 weeks. At week 8 of treatment, for subjects weighing ≥ 100 kg, the orexine dose was increased to 30 mg twice daily, while subjects weighing < 100 kg maintained a dose of 20 mg orexine 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 (Horizontal) shows the X-ray powder diffraction pattern of oreste crystal form E measured using CuKα radiation at λ = 1.5418 Å. The x-axis shows the 2θ values, and the y-axis shows the intensity (count). Figure 10 DSC traces of two different batches of Oreste crystal form E, measured at heating rates from 2 to 10°C / min (two measurements per batch), are shown. The x-axis represents temperature, and the y-axis represents heat flux (W / g). Each trace shows the melt initiation temperature and enthalpy change for each sample of crystal form E. Figure 11 The in vitro dissolution profiles of 10 mg and 30 mg orexate extended-release tablets, measured using standard dissolution assays as defined herein, are shown. The x-axis represents time, and the y-axis represents orexate released into the dissolution medium. Figure 12 The two-chamber model of Oreste described in Example 6 is shown. Figure 13 The pcVPC results of the sustained-release (MR) study in healthy volunteers (HV) described in Example 6 are shown. Figure 14 The pcVPC results of the stage IIb MR study of psoriasis described in Example 6 are shown. Figure 15 The pcVPC results of the HV MR study described in Example 6 for normal-weight and obese patients (psoriasis patients) are shown. The left panel is for BMIs ranging from 16.9 to 30 kg / m². 2The right figure shows subjects with a BMI of 30 to 64.5 kg / m². 2 Obese subjects. Figure 16(a) shows the steady-state AUCτ of osresterol in adolescents compared to adults described in the simulation in Example 6, after repeated administration of the MR formulation at doses of 10, 20, 30, and 40 mg b.id. -ss In this and other figures, AUCtau refers to the AUC of the dosing interval. Figure 16(b) provides the steady-state AUCτ of osrester in adolescents after repeated administration of the MR formulation at doses of 10, 20, 30, and 40 mg bid, as described in the simulation in Example 6. -ss Descriptive statistics. Figure 17 The simulation in Example 6 shows the steady-state AUCτ of orestrate in body-stratified adolescents after repeated BID administration of the MR formulation at doses of 10, 20, 30, and 40 mg bid, as described in the simulation. -ss . Figure 18(a) shows the overall steady-state results of orestrate C in the adolescent population after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg, as described in the simulation in Example 6. max-ss . Figure 18(b) provides the overall steady-state results of orexus C in the adolescent population after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg, as described in the simulation in Example 6. max-ss Descriptive statistics. Figure 19(a) shows the overall steady-state results of orestrate C in the adolescent population after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg bid, as described in the simulation in Example 6. trough-ss . Figure 19(b) provides the overall steady-state results of orexus C in the adolescent population after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg, as described in the simulation in Example 6. trough-ss Descriptive statistics. Figure 20(a) shows the steady-state results of loratadine C in adolescents after repeated bid administration of MR formulation at doses of 10, 20, 30, and 40 mg (by weight), as described in the simulation in Example 6. max-ss . Table 20(b) provides the steady-state Cg of adolescents after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg (by weight), as described in the simulation in Example 6. max-ss Descriptive statistics (ng / mL). Figure 21(a) shows the steady-state results of loratadine C in adolescents after repeated bid administration of MR formulation at doses of 10, 20, 30, and 40 mg (by weight), as described in the simulation in Example 6. trough-ss . Figure 21(b) provides the steady-state Cg of adolescents after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg (by weight), as described in the simulation in Example 6. trough-ss Descriptive statistics (ng / mL). Figure 22(a) shows the steady-state AUCτ of orexusone 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 in Example 6. -ss . Figure 22(b) shows the steady-state AUCτ of orexusone 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 in Example 6. -ss Descriptive statistics. Figure 23(a) shows the steady-state results of orestradiol C 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 in Example 6. max-ss . Table 23(b) provides the steady-state C-values ​​of obese subjects after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg, as described in the simulation in Example 6. max-ss Descriptive statistics (ng / mL). Figure 24(a) shows the steady-state results of orestradiol C 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 in Example 6. trough-ss . Table 24(b) provides the steady-state C-values ​​of obese subjects after repeated bid administration of the MR formulation at doses of 10, 20, 30, and 40 mg, as described in the simulation in Example 6. trough-ss Descriptive statistics (ng / mL). Figure 25(a) shows the steady-state AUCτ of the subjects according to the phase III design described in the simulation in Example 6. -ss . Figure 25(b) shows the steady-state AUCτ of the subjects according to the Phase III design described in the simulation in Example 6. -ss Descriptive statistics. Figure 26(a) shows the subjects in steady state with orestrate C according to the phase III design described in the simulation in Example 6. max-ss . Figure 26(b) shows the subjects' steady-state status with orestradiol C according to the phase III design described in the simulation in Example 6. max-ss Descriptive statistics. Figure 27(a) shows the subjects in steady state with orestrate C according to the phase III design described in the simulation in Example 6. trough-ss . Figure 27(b) shows the steady-state results of subjects receiving orlistat C according to the phase III design described in the simulation in Example 6. trough-ss Descriptive statistics. Figure 28 shows the percentage of patients with a 50% reduction in PASI score (PASI-50) at weeks 0, 4, 8, 12, and 16 for two patient subgroups based on baseline weight (< 100 kg and > 100 kg) and two active groups (20 mg BID and 30 mg BID) in the phase 2b study in Example 3: (a) NRI data; and (b) observed data. “NRI” refers to nonresponder imputation for missing data. Figure 29 shows the percentage of patients with a 75% reduction in PASI score (PASI-75) at weeks 0, 4, 8, 12, and 16 for two patient subgroups based on baseline weight (< 100 kg and > 100 kg) and two active groups (20 mg BID and 30 mg BID) in the phase 2b study in Example 3. (a) NRI data; and (b) observed data. “NRI” refers to nonresponder imputation for missing data. Figure 30 shows the percentage of patients with a 90% reduction in PASI score (PASI-90) at weeks 0, 4, 8, 12, and 16 for two patient subgroups based on baseline weight (< 100 kg and > 100 kg) and two active groups (20 mg BID and 30 mg BID) in the phase 2b study in Example 3. (a) NRI data; and (b) observed data. “NRI” refers to imputation of non-responder with missing data. Figure 31The 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 baseline weight < 100 kg in the 20 mg BID and 30 mg BID groups; and for patients with a baseline weight > 100 kg in the 30 mg BID group in the phase 2b study in Example 3. Figure 32 The figure shows the orexate exposure (AUC) at steady state for different body weights (< 100 kg and > 100 kg) and doses (20 mg and 30 mg). AUC values ​​were obtained from simulations in Example 6. The figure shows the mean AUC and standard deviation (SD) and includes an illustrative optimal exposure range to maximize efficacy. Figure 33 The percentage of subjects with a ≥ 4-point reduction in peak pruritus NRS (MI and NRI data) at week 2 is shown for each active group: 20 mg BID, 30 mg BID, and 40 mg BID, as well as placebo. p < 0.05; p < 0.1; MI = multiple interpolation (preliminary analysis); NRI = non-responder interpolation. Figure 34 This shows the percentage of subjects with severe pruritus (PPNRS > 7) at all finishers and baseline, for each active group (20 mg BID, 30 mg BID, and 40 mg BID) and placebo group, who had an observed reduction of ≥ 4 points in peak pruritus NRS at week 16. PPNRS = Peak Pruritus Numerical Rating Scale. p < 0.05, p < 0.1; 7 is the median PPNRS at baseline, Obs = observation. Figure 35 This shows the log2 fold change in selected cytokines compared to placebo in PASI75 responders and nonresponders (combined treatment group) in a phase 2b dose-range study evaluating oral osrelastase in adults with moderate to severe plaque psoriasis, as described in Example 3. W16_L = lesions at week 16, BL_L = baseline lesions, log2FCH = log2 fold change, BID = twice daily. N w16_L = 33 (PASI75 respondents), N w16_L = 25 (PASI75 nonresponders), N w16_L = 27 (placebo). Figure 36This shows the skin level (log2) of TARC in the IIT population after 16 weeks of treatment in a phase 2b dose-range study evaluating oral orlistat in adults with moderate to severe atopic dermatitis, as described in Example 8. The p-value represents a comparison of the lesion skin level at week 16 with the baseline lesion skin level (day 1). The lesion skin level at week 16 compared to the lesion skin level on day 1... FDR < 0.001, FDR < 0.01, FDR < 0.05. TARC = Thymus activation regulatory chemokine, also known as CCL17 = chemokine CC motif ligand 17. Figure 37 The Log2 fold change in TARC between IGA0 / 1 responders and non-responders (combined treatment group) with moderate to severe atopic dermatitis, as described in Example 8, is shown. W16_L = lesions at week 16, BL_L = baseline lesions, N w16_L = 40 (placebo), N w16_L = 66 (non-responders), N w16_L = 28 (responders). TARC = Thymus activation regulatory chemokine, also known as CCL17 = chemokine CC motif. Figure 38 The diagram shows an external visual prediction examination using the PopPK model described in Example 6, based on orlistat plasma concentration data obtained from the phase 2b atopic dermatitis trial described in Example 8. The dots and lines correspond to the 5th percentile (bottom), median (middle), and 95th percentile (top) of the orlistat clinical data. The central shaded area represents the predicted median from the PopPK model. The flank shades represent the predicted 95th percentile (top shade) and 5th percentile (bottom shade). Figure 39 The design of the phase 3 clinical study described in Example 13 is shown. Detailed Implementation

[0086] Unless otherwise stated, the following terms used in the specification and claims have the same meanings as stated below.

[0087] The terms “treating” or “treatment” refer to any indication of the successful treatment or improvement of a disease, symptom, or condition, including any objective or subjective parameters such as the elimination, relief, or reduction of symptoms or making the symptom or condition more tolerable for the subject; slowing the rate of degeneration or decline; making the degenerative endpoint less debilitating; or improving the physical or mental health of the subject.

[0088] Referring to the treatment of diseases or disorders "improved by inhibiting PDE4" means that inhibiting PDE4 provides a beneficial therapeutic effect on the disease or condition treated with orlistat.

[0089] This article mentions that improving the "tolerability" of orlistat includes reducing or eliminating undesirable side effects associated with administering orlistat to a subject. For example, improving tolerability includes reducing or eliminating one or more of the following associated with administering orlistat to a subject: diarrhea, nausea, headache, dizziness, vomiting, or stomach pain. Improving tolerability also includes reducing the frequency and / or severity of side effects associated with administering orlistat to a subject.

[0090] When the compounds described in this specification are administered to treat a disorder, a “therapeutic effective amount” is an amount sufficient to have the following effects: reduce or completely alleviate the symptoms or other adverse effects of the disorder; cure the disorder; reverse, completely stop or slow the progression of the disorder; or reduce the risk of the disorder worsening.

[0091] The term "one week" in the treatment period refers to 7 days of treatment. Therefore, for example, when the initial period is two weeks, followed by a six-week transition period, and then the maintenance dose is administered, this means treating the subject during the initial period from day 1 to day 14, then during the transition period from day 15 to day 56, and finally administering the maintenance dose starting from day 57 of the dosing regimen.

[0092] Referring to a treatment period, such as "week 2" or "week 16," indicates the end of that treatment period. Therefore, "week 2" means the end of the second week of treatment, and "week 16" means the end of the sixteenth week of treatment.

[0093] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of the compounds described herein and is not biologically or otherwise undesirable. Pharmaceutically acceptable salts are well known to those skilled in the art. This invention is intended to cover any pharmaceutically acceptable salt of orestradiol. This invention covers all crystal variants, polymorphs, and mixtures thereof of compounds described herein, such as orestradiol. In some embodiments, treatment comprises administration of polymorph E of orestradiol.

[0094] The term "solvent" is intended to refer to a substance formed through the interaction between a compound (e.g., orex) and a solvent (e.g., alcohol, glycerol, or water), wherein the substance is in solid form. When water is the solvent, the substance is referred to as a "hydrate." This invention aims to cover all solvates (e.g., hydrates) of orex.

[0095] As used herein, the term "phosphodiesterase" refers to one or more phosphodiesterases (PDEs), with PDE4, PDE7, and PDE8 being cAMP-selective. PDE4 is the most important regulator of cAMP. PDE4 is cAMP-specific and is the dominant PDE in inflammatory cells. The PDE4 enzyme is encoded by four genes (PDE4A, PDE4B, PDE4C, and PDE4D), each capable of producing multiple isoforms via mRNA splicing and the use of different promoters. Each PDE4 isoform within a specific PDE4 subfamily contains a common core region consisting of a catalytic unit and a C-terminal portion, and is defined by its unique N-terminal region. PDE4 isoforms are further classified as long, short, or ultra-short, 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” isotype contains both UCR1 and UCR2; the “short” isotype lacks UCR1, and the “ultra-short” isotype lacks UCR1 and has a truncated UCR2.

[0096] As used in this article, the phrase "PDE4 inhibitor" refers to a substance that inhibits PDE4.

[0097] The term “threshold weight” or “lower limit weight” in this article refers to the subject’s weight (i.e., baseline weight) before administering the first dose of orestradiol to the subject.

[0098] Unless otherwise stated herein, “moderate to severe atopic dermatitis” refers to a subject having atopic dermatitis with the following characteristics: affected body surface area (BSA) ≥ 10% at baseline, IGA-AD grade ≥ 3, and Eczema Area and Severity Index (EASI) score ≥ 16.

[0099] Unless otherwise stated herein, “moderate atopic dermatitis” refers to atopic dermatitis in which the subject has an EASI score ≥ 16 to ≤ 21 at baseline. Appropriately, subjects with moderate atopic dermatitis have a baseline BSA of ≥ 10% to ≤ 28%.

[0100] Unless otherwise stated herein, “severe atopic dermatitis” refers to atopic dermatitis in which the subject has an EASI score >21 at baseline. Appropriately, subjects with severe atopic dermatitis have a baseline BSA >28%.

[0101] Unless otherwise stated herein, “moderate to severe psoriasis” refers to subjects with the following psoriasis conditions: a Psoriasis Area and Severity Index (PASI) ≥ 12 at baseline, an Affected Body Surface Area (BSA) ≥ 10%, and a Static Physician Overall Assessment (sPGA) ≥ 3.

[0102] The term “baseline” refers to a subject’s level or score (e.g., PASI or EASI) prior to treatment with orestradiol.

[0103] This article refers to the term “Investigator Overall Assessment of AD” or “IGA-AD” as equivalent to the term “Empirical Evidenced Investigator Overall Assessment of AD” or “vIGA-AD”, and they are interchangeable. Therefore, this article refers to “IGA-AD” scores as encompassing and equivalent to the corresponding “vIGA-AD scores”.

[0104] In this article, the terms "peak pruritus numerical rating scale," "peak pruritus (NRS)," or "PPNRS" are considered equivalent to and interchangeable with "most severe pruritus NRS." Therefore, the "PPNRS score" mentioned in this article also encompasses and is equivalent to the corresponding "most severe pruritus NRS score."

[0105] The term "particle size distribution" in powder refers to the value defining the relative amount of particles present, categorized according to size. D(50) and D(90) values ​​indicate that 50% and 90% of the measured particles are smaller than or equal to the stated size. For example, D(50) = 6 µm means that 50% of the particles are smaller than or equal to 6 μm. D(90) ≤ 10 µm means that 90% of the particles have a particle size less than or equal to 10 µm. Particle size can be measured using conventional methods such as laser diffraction techniques.

[0106] 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. Typically, immediate release means a composition or formulation in which ≥ 85% of the active ingredient is released within 30 minutes when placed in an aqueous dissolution medium.

[0107] The term "sustained release" refers to a pharmaceutical formulation or composition in which the release rate and / or site of release of the active ingredient differs from that of an immediately released dosage form administered orally. Sustained-release compositions may be delayed-release compositions in which the release of the active substance is delayed for a period of time after oral administration.

[0108] The term "subject" as used herein refers to a human or animal subject. Preferably, the subject is a warm-blooded mammal. More preferably, the subject is a human. In some embodiments, the subject is an adolescent or an adult, such as a person at least 12 years of age or older. In some embodiments, the subject is an adult 18 years of age or older. In some embodiments, the subject is an adolescent aged 12 to up to 18 years of age.

[0109] In the context of numbers, the use of "about" is intended to include values ​​plus or minus 10%. For example, about 20% includes a range of 18% to 22%.

[0110] Throughout the description and claims of this specification, the words “comprising” and “including”, and variations thereof, mean “including but not limited to,” and are not intended (and do not) exclude other parts, additives, components, integers, or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context requires otherwise. In particular, when the indefinite article is used, this specification should be understood to take into account both the plural and the singular unless the context requires otherwise.

[0111] Features, integers, characteristics, compounds, chemical parts, or groups described in conjunction with specific aspects, embodiments, or examples of the invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless incompatible with it. All features disclosed in this specification (including any appended claims, abstract, and drawings) and / or all steps of any method or process so disclosed may be combined in any combination, except for at least some mutually exclusive combinations of such features and / or steps. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification (including any appended claims, abstract, and drawings), or to any novel step or any novel combination of steps of any method or process so disclosed.

[0112] The reader’s focus is on all papers and documents that were filed together with this application at the same time as or prior to this specification and that were made available to the public for examination, and the contents of all such papers and documents are incorporated herein by reference. Oreste

[0113] This invention relates to a dosing regimen for the compound orestrate 2-(3,5-dichloro-1-oxypyridin-1-onthiol-4-yl)-1-[7-(difluoromethoxy)-1',1'-dioxospiro[1,3-benzodioxane-2,4'-thiane]-4-yl]acetone, a potent and selective PDE4 inhibitor, with the chemical formula:

[0114] The chemical abstract name of Oreste is acetone, 2-(3,5-dichloro-1-oxy-4-pyridyl)-1-[7-(difluoromethoxy)-2',3',5',6'-tetrahydro-1',1'-dioxospiro[1,3-benzodioxane-2,4'-[4H]thiaran]-4-yl]; CAS number 1353546-86-7.

[0115] Oreste and the method for synthesizing the compound are disclosed in WO 2011 / 160632, WO 2015 / 197534, WO2017 / 103058 and WO 2018 / 234299.

[0116] In some embodiments, orexant may be administered to a subject as a solid, which may be amorphous, crystalline, or semi-crystalline. In some embodiments, orexant is crystalline. In a preferred embodiment, orexant is in the form of polymorph E. Polymorph E of orexant (“Form E”) is described in WO 2018 / 234299.

[0117] In some embodiments, oreste is of form E, characterized in that, when measured using CuKα radiation (λ = 1.5418 Å), the powder X-ray diffraction pattern has at least one 2θ peak selected from the following: 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°.

[0118] In some embodiments, oreste is of form E, characterized in that, when measured using CuKα radiation (λ = 1.5418 Å), the powder X-ray diffraction pattern has two 2θ peaks selected from the following: 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°.

[0119] In some embodiments, oreste is of form E, characterized in that, when measured using CuKα radiation (λ = 1.5418 Å), the powder X-ray diffraction pattern has five 2θ peaks selected from the following: 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°.

[0120] In some embodiments, oreste is of form E, characterized in that when measured using CuKα radiation (λ = 1.5418 Å), the powder X-ray diffraction pattern has 2θ peaks at 15.0, 16.0, 18.1, 18.5, 21.4, and 23.4° ± 0.2°.

[0121] In some embodiments, oreste is of form E, characterized by powder X-ray diffraction patterns 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).

[0122] In some embodiments, oreste is of form E, characterized in that, when measured using CuKα radiation (λ = 1.5418 Å), the powder X-ray diffraction pattern has 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°.

[0123] In some embodiments, oreste is of form E, characterized in that, when measured using CuKα radiation (λ = 1.5418 Å), the powder X-ray diffraction pattern has at least 10 of the 2θ peaks shown in Table X.

[0124] In some embodiments, oreste is of form E, characterized in that when measured using CuKα radiation (λ = 1.5418 Å), the powder X-ray diffraction pattern has the 2θ peak shown in Table X. Table X

[0125] In some embodiments, oreste is of form E, characterized in that, when measured using CuKα radiation (λ = 1.5418 Å), the powder X-ray diffraction pattern is substantially as follows: Figure 9 As shown.

[0126] In some embodiments, form E is characterized by having an endothermic melt with an initial temperature of about 210°C to about 213°C (e.g., about 211.6°C) when measured by differential scanning calorimetry (DSC) at a heating rate of 2 to 10°C / min in a sealed aluminum dish with a perforated cap under a nitrogen atmosphere. In some embodiments, form E has a melting enthalpy change of about 80 to 90 J / g when measured under the above-described DSC conditions. In some embodiments, form E has substantially the following characteristics: Figure 10 The DSC curve shown.

[0127] Form E can be obtained by crystallization from a suitable solvent, such as one or more solvents selected from 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 orestradiol in a hot solvent (e.g., at 50°C) to form a solution and then cooling the resulting solution to room temperature.

[0128] Orelaste is a selective and potent PDE4 inhibitor. Orelaste has been found to be a selective inhibitor of PDE4D and PDE4B. In some embodiments, osrelaste is a selective inhibitor of PDE4B. In some embodiments, osrelaste is a selective inhibitor of PDE4D. In some embodiments, osrelaste is a selective inhibitor of PDE4B1, PDE4B2, PDE4B3, PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, and / or PDE4D7. In some embodiments, osrelaste is a selective inhibitor of PDE4B2, PDE4B3, PDE4D2, PDE4D3, PDE4D4, PDE4D5, and / or PDE4D7. In some embodiments, osrelaste is a selective inhibitor of PDE4B2, PDE4B3, PDE4D5, and PDE4D7. In some embodiments, osrelastide is a selective inhibitor of PDE4B3, PDE4D5, and PDE4D7. Specifically, osrelastide has been found to be a selective inhibitor of the PDE4 isoforms PDE4D3 and PDE4B2. Additionally, osrelastide has been found to potently inhibit the secretion of TNF-α and IL-1β (two cytokines highly associated with inflammation). The compound also inhibits IFN-γ. IFN-γ is a T-cell-derived Th1 cytokine that plays a role in Th1 immune responses. Significantly, in LPS and SEB-induced TNF-α secretion in human whole blood, osrelastide has been shown to be on average 23 times more potent than aprelastide on a molar basis. The ability of osrelastide 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). Dosing regimen

[0129] This invention relates to dosing regimens using osrelastide. Methods of treating diseases or disorders that are improved by inhibiting PDE4, as described herein, are also intended to cover: (i) osrelastide for treating such disease or disorder; and / or (ii) the use of osrelastide in the manufacture of a medicament for treating the disease or condition according to the dosing regimens described herein. Dosing regimen A (first aspect of the invention)

[0130] Analysis of clinical trial data from studies in subjects with moderate to severe plaque psoriasis has identified several side effects, such as diarrhea, nausea, headache, dizziness, vomiting, and stomach pain, when administered orally with 20 mg, 30 mg, or 40 mg of orexaminase at twice-daily doses. Most side effects occurred during the first 4 weeks of treatment, with fewer occurring after 8 weeks. Furthermore, subjects weighing ≥100% of a threshold weight showed improved treatment efficacy with higher doses of orexaminase, but without a significant increase in adverse side effects leading to treatment discontinuation. Further, treatment with higher transition or maintenance doses in subjects weighing <100% of a threshold weight may not improve efficacy and may lead to increased side effects. Regimen A reduces side effects in the initial phase of treatment and is also expected to provide improved efficacy and / or tolerability in heavier subjects treated with higher maintenance doses of orexaminase, and optimized efficacy and / or tolerability in subjects weighing <100% of a threshold weight.

[0131] Therefore, osrester is provided for use in a method of treating a disease or disorder that improves by inhibiting PDE4 in a subject, the method comprising administering osrester to the subject, wherein: (Ai) The initial dose of orexate was administered to the subject once daily for the initial period, and then; (Aii) Administer the transitional dose of orlistat to the subject twice daily during the transition period, then; (Aiii) Administer a maintenance dose of orexusone twice daily to the subject; in: (a) The initial orinexetine dose and the transition orinexetine dose are independently selected from 10 mg to 30 mg of orinexetine, provided that the transition orinexetine dose is greater than or equal to the initial orinexetine dose; (b) The initial time period is two to eight weeks; (c) The transition period is one to eight weeks; and (d) When the subject’s weight is greater than or equal to the threshold weight, the maintenance dose of orexus is greater than the transition dose of orexus, wherein the threshold weight is at least 90 kg.

[0132] A method for treating a disease or disorder in a subject that improves by inhibiting PDE4 is also provided, the method comprising administering osrelastide to the subject according to the dosing regimens (Ai), (Aii), and (Aiii) described above. Therefore, a method for treating a disease or disorder in a subject that improves by inhibiting PDE4 is provided, the method comprising administering osrelastide to the subject, wherein: (Ai) The initial dose of orexate was administered to the subject once daily for the initial period, and then; (Aii) Administer the transitional dose of orlistat to the subject twice daily during the transition period, then; (Aiii) Administer a maintenance dose of orexusone twice daily to the subject; in: (a) The initial orinexetine dose and the transition orinexetine dose are independently selected from 10 mg to 30 mg of orinexetine, provided that the transition orinexetine dose is greater than or equal to the initial orinexetine dose; (b) The initial time period is two to eight weeks; (c) The transition period is one to eight weeks; and (d) When the subject’s weight is greater than or equal to the threshold weight, the maintenance dose of orexus is greater than the transition dose of orexus, wherein the threshold weight is at least 90 kg.

[0133] It also provides the use of orestrate in the manufacture of a medicament for treating a disease or disorder in a subject that is improved by inhibiting PDE4, the method comprising administering orestrate to the subject according to the dosing regimens (Ai), (Aii) and (Aiii) described above.

[0134] In some embodiments of dosing regimen A, the transitional olivator dose is 10 to 20 mg olivator. In some embodiments, the transitional olivator dose is 10 mg olivator. In some embodiments, the transitional olivator dose is 20 mg olivator.

[0135] In some embodiments of dosing regimen A, when the subject's weight is below a threshold weight, the maintenance orelastide dose is the same as the transition orelastide dose. Therefore, in some embodiments, when the subject's weight is below the threshold weight, the transition orelastide dose is 20 mg BID, and the maintenance dose is 20 mg BID. In some embodiments, when the subject's weight is below the threshold weight, the transition orelastide dose is 10 mg BID, and the maintenance dose is 10 mg BID.

[0136] In dosing regimen A, when the subject's weight is greater than or equal to a threshold weight, the maintenance orelastide dose is greater than the transition orelastide dose. Suitably, for subjects with a weight greater than or equal to the threshold weight, the maintenance orelastide dose is up to 40 mg orelastide, for example, up to 35 mg orelastide, or up to 30 mg orelastide, provided that the maintenance orelastide dose is greater than the transition orelastide dose. In some embodiments, the maintenance orelastide dose is selected from 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 mg orelastide, provided that the maintenance orelastide dose is greater than the transition orelastide dose. In a preferred embodiment, the maintenance orelastide dose is 30 mg orelastide, provided that the maintenance orelastide dose is greater than the transition orelastide dose. Example A1

[0137] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) The initial dose of olivrazine was 20 mg olivrazine, administered to the subject once daily for two weeks; (Aii) The transitional dose of osrelastide was 20 mg osrelastide administered twice daily to the subject for one to eight weeks; and (Aiii) If the subject's weight is below the threshold weight, the maintenance dose of orexate is 20 mg orexate twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexate is 30 mg orexate, administered to the subject twice daily. Example A2

[0138] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) The initial dose of olivrazine was 20 mg olivrazine, administered to the subject once daily for two weeks; (Aii) The transitional dose of olivrazine was 20 mg olivrazine administered to the subject twice daily for two weeks; and (Aiii) If the subject's weight is below the threshold weight, the maintenance dose of orexate is 20 mg orexate twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexate is 30 mg orexate, administered to the subject twice daily. Example A3

[0139] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) The initial dose of olivrazine was 20 mg olivrazine, administered to the subject once daily for two weeks; (Aii) The transitional dose of olivrazine was 20 mg olivrazine administered to the subject twice daily for two weeks; and (Aiii) If the subject's weight is below the threshold weight, the maintenance dose of orexate is 20 mg orexate twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexate is 30 mg orexate, administered to the subject twice daily. Example A4

[0140] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) The initial dose of olivrazine was 20 mg olivrazine, administered to the subject once daily for two weeks; (Aii) The transitional dose of olivrazide was 20 mg olivrazide administered to the subject twice daily for four weeks; and (Aiii) If the subject's weight is below the threshold weight, the maintenance dose of orexate is 20 mg orexate twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexate is 30 mg orexate, administered to the subject twice daily. Example A5

[0141] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) The initial dose of olivrazine was 20 mg olivrazine, administered to the subject once daily for two weeks; (Aii) The transitional dose of orexusone was 20 mg orexusone administered to the subject twice daily for six weeks; (Aiii) If the subject's weight is below the threshold weight, the maintenance dose of orexate is 20 mg orexate twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexate is 30 mg orexate, administered to the subject twice daily. Example A6

[0142] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) The initial dose of olivrazine was 20 mg olivrazine, administered to the subject once daily for two weeks; (Aii) The transitional dose of orexusone was 20 mg orexusone administered to the subject twice daily for eight weeks; (Aiii) If the subject's weight is below the threshold weight, the maintenance dose of orexate is 20 mg orexate twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexate is 30 mg orexate, administered to the subject twice daily. Example A7

[0143] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) The initial dose of olivrazine was 10 mg olivrazine, administered to the subject once daily for two weeks; (Aii) The transitional dose of osrelastide was 10 mg osrelastide administered twice daily to the subject for one to eight weeks; and (Aiii) If the subject's weight is below the threshold weight, the maintenance dose of orexate is 10 mg orexate twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orestradiol is 20 mg orestradiol, administered to the subject twice daily. Example A8

[0144] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) The initial dose of olivrazine was 10 mg olivrazine, administered to the subject once daily for two weeks; (Aii) The transitional dose of olivrazine was 10 mg olivrazine administered to the subject twice daily for two weeks; and (Aiii) If the subject's weight is below the threshold weight, the maintenance dose of orexate is 10 mg orexate twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orestradiol is 20 mg orestradiol, administered to the subject twice daily. Example A9

[0145] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) The initial dose of olivrazine was 10 mg olivrazine, administered to the subject once daily for two weeks; (Aii) The transitional dose of olivrazine was 10 mg olivrazine administered to the subject twice daily for two weeks; and (Aiii) If the subject's weight is below the threshold weight, the maintenance dose of orexate is 10 mg orexate twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orestradiol is 20 mg orestradiol, administered to the subject twice daily. Example A10

[0146] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) The initial dose of olivrazine was 10 mg olivrazine, administered to the subject once daily for two weeks; (Aii) The transitional dose of olivrazide was 10 mg olivrazide administered to the subject twice daily for four weeks; and (Aiii) If the subject's weight is below the threshold weight, the maintenance dose of orexate is 10 mg orexate twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orestradiol is 20 mg orestradiol, administered to the subject twice daily. Example A11

[0147] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) The initial dose of olivrazine was 10 mg olivrazine, administered to the subject once daily for two weeks; (Aii) The transitional dose of orexusone was 10 mg orexusone administered to the subject twice daily for six weeks; (Aiii) If the subject's weight is below the threshold weight, the maintenance dose of orexate is 10 mg orexate twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orestradiol is 20 mg orestradiol, administered to the subject twice daily. Example A12

[0148] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) The initial dose of olivrazine was 10 mg olivrazine, administered to the subject once daily for two weeks; (Aii) The transitional dose of orexusone was 10 mg orexusone administered to the subject twice daily for eight weeks; (Aiii) If the subject's weight is below the threshold weight, the maintenance dose of orexate is 10 mg orexate twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orestradiol is 20 mg orestradiol, administered to the subject twice daily. Example A13

[0149] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) If the subject's weight is below the lower limit, the initial dose of osrelastide is 10 mg osrelastide administered once daily for two to four weeks, or If the subject's weight is between the lower limit and the threshold, the initial dose of orexusone is 20 mg orexusone, administered to the subject once daily for two to eight weeks. (Aii) If the subject's weight is below the lower limit, the transitional dose of orexusone is 10 mg orexusone twice daily for one to eight weeks; or If the subject's weight is between the lower limit and below the threshold, the transitional olivate dose is 20 mg olivate administered twice daily for one to eight weeks; and (Aiii) If the subject's weight is below the lower limit, the maintenance dose of olivaster is 10 mg olivaster administered to the subject twice daily, or If the subject's weight is between the lower limit and the threshold, the maintenance dose of orexate is 20 mg orexate, administered to the subject twice daily. If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexusone is 30 mg orexusone, administered to the subject twice daily. The lower limit of this weight ranges from 50 kg to 75 kg.

[0150] In some embodiments of Example A13, the transitional dose of osrelastide was administered to the subject twice daily for one to four weeks. In some embodiments of Example A13, the transitional dose of osrelastide was administered to the subject twice daily for two to eight weeks. In some embodiments of Example A13, the transitional dose of osrelastide was administered to the subject twice daily for four to eight weeks. In some embodiments of Example A13, the transitional dose of osrelastide was administered to the subject twice daily for two weeks. In some embodiments of Example A13, the transitional dose of osrelastide was administered to the subject twice daily for four weeks. In some embodiments of Example A13, the transitional dose of osrelastide was administered to the subject twice daily for six weeks. Example A14

[0151] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) If the subject's weight is below the lower limit, the initial dose of osrelastide is 10 mg osrelastide administered once daily for two to four weeks, or If the subject's weight is between the lower limit and the threshold, the initial dose of orexusone is 20 mg orexusone, administered to the subject once daily for two to four weeks. (Aii) If the subject's weight is below the lower limit, the transitional dose of orexusone is 10 mg orexusone twice daily for six to eight weeks, or If the subject's weight is between the lower limit and below the threshold, the transitional dose of orexusone is 20 mg orexusone, administered twice daily for six to eight weeks; and (Aiii) If the subject's weight is below the lower limit, the maintenance dose of olivraz is 10 mg olivraz, administered to the subject twice daily; or If the subject's weight is between the lower limit and below the threshold, the maintenance dose of orexamin is 20 mg orexamin administered twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexusone is 30 mg orexusone, administered to the subject twice daily. The lower limit of this weight ranges from 50 kg to 75 kg. Example A15

[0152] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) If the subject's weight is below the lower limit, the initial dose of olivaster is 10 mg olivaster administered once daily for two weeks, or If the subject's weight is between the lower limit and the threshold, the initial dose of orexusone is 20 mg orexusone, administered to the subject once daily for two weeks. (Aii) If the subject's weight is below the lower limit, the transitional dose of orexusone is 10 mg orexusone twice daily for two weeks, or If the subject's weight is between the lower limit and below the threshold, the transitional dose of orexusone is 20 mg orexusone, administered twice daily for two weeks; and (Aiii) If the subject's weight is below the lower limit, the maintenance dose of olivaster is 10 mg olivaster administered to the subject twice daily, or If the subject's weight is between the lower limit and below the threshold, the maintenance dose of orexamin is 20 mg orexamin administered twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexusone is 30 mg orexusone, administered to the subject twice daily. The lower limit of this weight ranges from 50 kg to 75 kg. Example A16

[0153] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) If the subject's weight is below the lower limit, the initial dose of olivaster is 10 mg olivaster administered once daily for two weeks, or If the subject's weight is between the lower limit and the threshold, the initial dose of orexusone is 20 mg orexusone, administered to the subject once daily for two weeks. (Aii) If the subject's weight is below the lower limit, the transitional dose of orexusone is 10 mg orexusone twice daily for four weeks, or If the subject's weight is between the lower limit and below the threshold, the transitional dose of orexusone is 20 mg orexusone, administered twice daily for four weeks; and (Aiii) If the subject's weight is below the lower limit, the maintenance dose of olivaster is 10 mg olivaster administered to the subject twice daily, or If the subject's weight is between the lower limit and below the threshold, the maintenance dose of orexamin is 20 mg orexamin administered twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexusone is 30 mg orexusone, administered to the subject twice daily. The lower limit of this weight ranges from 50 kg to 75 kg. Example A17

[0154] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) If the subject's weight is below the lower limit, the initial dose of olivaster is 10 mg olivaster administered once daily for two weeks, or If the subject's weight is between the lower limit and the threshold, the initial dose of orexusone is 20 mg orexusone, administered to the subject once daily for two weeks. (Aii) If the subject's weight is below the lower limit, the transitional dose of orexusone is 10 mg orexusone twice daily for six weeks, or If the subject's weight is between the lower limit and below the threshold, the transitional olivate dose is 20 mg olivate administered twice daily for six weeks; and (Aiii) If the subject's weight is below the lower limit, the maintenance dose of olivaster is 10 mg olivaster administered to the subject twice daily, or If the subject's weight is between the lower limit and below the threshold, the maintenance dose of orexamin is 20 mg orexamin administered twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexusone is 30 mg orexusone, administered to the subject twice daily. The lower limit of this weight ranges from 50 kg to 75 kg. Example A18

[0155] In some embodiments of dosing regimen A, the dosing regimen includes: (Ai) If the subject's weight is below the lower limit, the initial dose of olivaster is 10 mg olivaster administered once daily for two weeks, or If the subject's weight is between the lower limit and the threshold, the initial dose of orexusone is 20 mg orexusone, administered to the subject once daily for two weeks. (Aii) If the subject's weight is below the lower limit, the transitional dose of orexusone is 10 mg orexusone twice daily for eight weeks, or If the subject's weight is between the lower limit and below the threshold, the transitional olivate dose is 20 mg olivate administered twice daily for eight weeks; and (Aiii) If the subject's weight is below the lower limit, the maintenance dose of olivaster is 10 mg olivaster administered to the subject twice daily, or If the subject's weight is between the lower limit and below the threshold, the maintenance dose of orexamin is 20 mg orexamin administered twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexusone is 30 mg orexusone, administered to the subject twice daily. The lower limit of this weight ranges from 50 kg to 75 kg.

[0156] In any of Examples A13 to A18, the lower limit weight may be selected from 50 kg, 55 kg, 60 kg, 65 kg, 70 kg, and 75 kg. The lower limit weight may be 50 kg. The lower limit weight may be 60 kg. The lower limit weight may be 70 kg. The lower limit weight may be 75 kg.

[0157] The dosing regimen described in dosing regimen A (including any of Examples A1 to A18) is particularly suitable for treating psoriasis, such as moderate to severe psoriasis. The psoriasis may be plaque psoriasis. Preferably, this dosing regimen is used to treat moderate to severe plaque psoriasis.

[0158] In some embodiments, the dosing regimen described in dosing regimen A (including any of Examples A1 to A18) is used to treat atopic dermatitis. In some embodiments, the dosing regimen is used to treat moderate to severe atopic dermatitis. In some embodiments, the dosing regimen is used to treat severe atopic dermatitis. In some embodiments, the dosing regimen is used to treat moderate atopic dermatitis.

[0159] In some embodiments, the dosing regimen described in dosing regimen A (including any of Examples A1 to A18) is used to treat hidradenitis suppurativa (HS). In some embodiments, the dosing regimen is used to treat mild to severe HS. In some embodiments, the dosing regimen is used to treat moderate to severe HS. In some embodiments, the dosing regimen is used to treat severe HS. In some embodiments, the dosing regimen is used to treat moderate HS. Dosing regimen B (second aspect of the invention)

[0160] As discussed above regarding dosing regimen A, subjects weighing greater than or equal to the threshold weight are expected to show improved efficacy and / or tolerability when treated with a higher maintenance dose of orexusol. Dosing regimen B described herein is for treating subjects weighing greater than or equal to the threshold weight.

[0161] Therefore, orestradiol is also provided for use in a method of treating a disease or disorder that improves by inhibiting PDE4 in a subject whose weight is greater than or equal to a threshold weight, the method comprising administering orestradiol to the subject. in: (Bi) The initial dose of orlistat was administered to the subject once daily for the initial period, and then; (Bii) Administer the transitional dose of orlistat to the subject twice daily during the transition period, then; (Biii) The subject was given a maintenance dose of orinelast twice daily, wherein the maintenance dose of orinelast was greater than the transition dose of orinelast. in: (a) The initial orinexetine dose and the transition orinexetine dose are independently selected from 10 mg to 30 mg of orinexetine, provided that the transition orinexetine dose is greater than or equal to the initial orinexetine dose; (b) This initial timeframe lasted eight weeks; (c) The transition period is one to eight weeks; and (d) The threshold weight is at least 90 kg.

[0162] A method is also provided for treating a disease or disorder in a subject whose weight is greater than or equal to a threshold weight by inhibiting PDE4, the method comprising administering orlistat to the subject according to the dosing regimens (Bi), (Bii), and (Biii) described above.

[0163] Also provided is the use of orestradiol in the manufacture of a medicament for treating a disease or disorder that improves by inhibiting PDE4 in a subject whose weight is greater than or equal to a threshold weight, the method comprising administering orestradiol to the subject according to the dosing regimens (Bi), (Bii), and (Biii) described above.

[0164] In some embodiments of dosing regimen B, the transitional olivator dose is 10 to 20 mg olivator. In some embodiments, the transitional olivator dose is 10 mg olivator. In some embodiments, the transitional olivator dose is 20 mg olivator.

[0165] The administration of initial and transitional orlistat doses in (Bi) and (Bii) is intended to improve the subject’s tolerability to orlistat by reducing the number and / or severity of side effects such as diarrhea, nausea, headache, dizziness or vomiting.

[0166] In dosing regimen B, when a subject's weight is greater than or equal to a threshold weight, the maintenance orelastide dose is greater than the transition orelastide dose. Suitably, for subjects whose weight is greater than or equal to the threshold weight, the maintenance orelastide dose is up to 40 mg orelastide, for example, up to 35 mg orelastide, or up to 30 mg orelastide, provided that the maintenance orelastide dose is greater than the transition orelastide dose. In some embodiments, the maintenance orelastide dose is selected from 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 mg orelastide, provided that the maintenance orelastide dose is greater than the transition orelastide dose.

[0167] In some embodiments of dosing regimen B, the dosing regimen includes: (Bi) The initial dose of olivrazine was 20 mg olivrazine, administered to the subject once daily for one week; (Bii) The transitional dose of orexusone was 20 mg orexusone, administered to the subject twice daily for one to eight weeks; (Biii) The maintenance dose of orestradiol was 30 mg orestradiol, administered to the subject twice daily.

[0168] Therefore, the transitional dose of orexusone may be administered to the subject twice daily for two to eight weeks. The transitional dose of orexusone may be administered to the subject twice daily for one to four weeks. The transitional dose of orexusone may be administered to the subject twice daily for four to eight weeks. The transitional dose of orexusone may be administered to the subject twice daily for six to eight weeks. Example B1

[0169] In some embodiments of dosing regimen B, the dosing regimen includes: (Bi) The initial dose of olivrazine was 20 mg olivrazine, administered to the subject once daily for one week; (Bii) The transitional dose of orexusone was 20 mg orexusone administered to the subject twice daily for two weeks; (Biii) The maintenance dose of orestradiol was 30 mg orestradiol, administered to the subject twice daily. Example B2

[0170] In some embodiments of dosing regimen B, the dosing regimen includes: (Bi) The initial dose of olivrazine was 20 mg olivrazine, administered to the subject once daily for one week; (Bii) The transitional dose of orexusone was 20 mg orexusone, administered to the subject twice daily for four weeks; (Biii) The maintenance dose of orestradiol was 30 mg orestradiol, administered to the subject twice daily. Example B3

[0171] In some embodiments of dosing regimen B, the dosing regimen includes: (Bi) The initial dose of olivrazine was 20 mg olivrazine, administered to the subject once daily for one week; (Bii) The transitional dose of orexusone was 20 mg orexusone administered to the subject twice daily for six weeks; (Biii) The maintenance dose of orestradiol was 30 mg orestradiol, administered to the subject twice daily. Example B4

[0172] In some embodiments of dosing regimen B, the dosing regimen includes: (Bi) The initial dose of olivrazine was 20 mg olivrazine, administered to the subject once daily for one week; (Bii) The transitional dose of orexusone was 20 mg orexusone administered to the subject twice daily for eight weeks; (Biii) The maintenance dose of orestradiol was 30 mg orestradiol, administered to the subject twice daily. Example B5

[0173] In some embodiments of dosing regimen B, the dosing regimen includes: (Bi) The initial dose of orinester was 20 mg orinester, administered to the subject once daily for two weeks; (Bii) The transitional dose of orexusone was 20 mg orexusone, administered to the subject twice daily for one to eight weeks; (Biii) The maintenance dose of orestradiol was 30 mg orestradiol, administered to the subject twice daily.

[0174] Therefore, the transitional dose of orexusone may be administered to the subject twice daily for two to eight weeks. The transitional dose of orexusone may be administered to the subject twice daily for one to four weeks. The transitional dose of orexusone may be administered to the subject twice daily for four to eight weeks. The transitional dose of orexusone may be administered to the subject twice daily for six to eight weeks. Example B6

[0175] In some embodiments of dosing regimen B, the dosing regimen includes: (Bi) The initial dose of orinester was 20 mg orinester, administered to the subject once daily for two weeks; (Bii) The transitional dose of orexusone was 20 mg orexusone administered to the subject twice daily for two weeks; (Biii) The maintenance dose of orestradiol was 30 mg orestradiol, administered to the subject twice daily. Example B7

[0176] In some embodiments of dosing regimen B, the dosing regimen includes: (Bi) The initial dose of orinester was 20 mg orinester, administered to the subject once daily for two weeks; (Bii) The transitional dose of orexusone was 20 mg orexusone, administered to the subject twice daily for four weeks; (Biii) The maintenance dose of orestradiol was 30 mg orestradiol, administered to the subject twice daily. Example B8

[0177] In some embodiments of dosing regimen B, the dosing regimen includes: (Bi) The initial dose of orinester was 20 mg orinester, administered to the subject once daily for two weeks; (Bii) The transitional dose of orexusone was 20 mg orexusone administered to the subject twice daily for six weeks; (Biii) The maintenance dose of orestradiol was 30 mg orestradiol, administered to the subject twice daily. Example B9

[0178] In some embodiments of dosing regimen B, the dosing regimen includes: (Bi) The initial dose of orinester was 20 mg orinester, administered to the subject once daily for two weeks; (Bii) The transitional dose of orexusone was 20 mg orexusone administered to the subject twice daily for eight weeks; (Biii) The maintenance dose of orestradiol was 30 mg orestradiol, administered to the subject twice daily.

[0179] The dosing regimen described in dosing regimen B (including any of Examples B1 to B9) is particularly suitable for treating psoriasis, such as moderate to severe psoriasis. This psoriasis may be plaque psoriasis. Preferably, this dosing regimen is used to treat moderate to severe plaque psoriasis.

[0180] In some embodiments, the dosing regimen described in dosing regimen B (including any of Examples B1 to B9) is used to treat atopic dermatitis. This dosing regimen may be used to treat moderate to severe atopic dermatitis. This dosing regimen may be used to treat moderate atopic dermatitis. This dosing regimen may be used to treat severe atopic dermatitis.

[0181] In some embodiments of dosing regimen A and dosing regimen B, the threshold weight is 90 kg. In some embodiments of dosing regimen A and dosing regimen B, the threshold weight is 95 kg. In some embodiments of dosing regimen A and dosing regimen B, the threshold weight is 105 kg. In a preferred embodiment of dosing regimen A and dosing regimen B, the threshold weight is 100 kg.

[0182] The improved tolerability and / or efficacy provided by the dosing regimen described in this article can also improve patient adherence to treatment, thereby enhancing the effectiveness of orestradiol treatment.

[0183] In some embodiments, the initial time period / preliminary time period, initial olivaster dose, transition time period, and transition olivaster dose used in dosing regimen A or dosing regimen B are any of the dosing regimens in Table 1. In Table 1, the initial time period used in dosing regimen A is any of the regimens in Table 1, wherein the initial time period is 2 to 8 weeks according to dosing regimen A. Table 1

[0184] It should be understood that when Table 1 shows the transitional orelaste dose in range, the transitional dose is selected to be greater than or equal to the initial or preliminary orelaste dose, depending on dosing regimen A and dosing regimen B.

[0185] The maintenance dose of orestrate administered to the subject after the transition period in each dosing regimen shown in Table 1 can be any maintenance dose of orestrate described herein.

[0186] Therefore, for dosing regimens A and B according to Table 1, when the subject's weight is greater than or equal to the threshold weight, the maintenance orelastide dose is greater than the transition orelastide dose. In a preferred embodiment, when the subject's weight is greater than or equal to the threshold weight, the maintenance orelastide dose is 30 to 40 mg orelastide, wherein the maintenance dose is higher than the transition dose. More preferably, when the subject's weight is greater than or equal to the threshold weight, the maintenance orelastide dose is 30 mg orelastide, wherein the maintenance dose is higher than the transition dose. Specific embodiments of dosing regimens A and B when the subject's weight is greater than or equal to the threshold weight are the dosing regimens in Table 1, wherein the transition orelastide dose is 10 or 20 mg orelastide (e.g., 20 mg orelastide) and the maintenance orelastide dose is 30 mg.

[0187] Suitablely, in the dosing regimen according to dosing regimen A in Table 1, when the subject's weight is below the threshold weight, the maintenance orelastide dose and the transition orelastide dose are the same. For example, in a preferred dosing regimen according to dosing regimen A in Table 1, for subjects with a weight below the threshold weight, the transition orelastide dose and the maintenance orelastide dose are the same and in the range of 10 to 20 mg. A particular embodiment of dosing regimen A in Table 1 is the embodiment in which the transition orelastide dose and the maintenance orelastide dose are the same and in the range of 10 to 20 mg for subjects with a weight below the threshold weight. In a preferred embodiment of dosing regimen A in Table 1, for subjects with a weight below the threshold weight, both the transition orelastide dose and the maintenance orelastide dose are 20 mg.

[0188] The preferred embodiments in Table 1 are dosing regimens in which the total duration of the initial / preliminary period and the transition period is 4 to 8 weeks. Therefore, this dosing regimen could be one of the dosing regimens in Table 1, where the total duration of the initial / preliminary period and the transition period is 4 weeks. This dosing regimen could be one of the dosing regimens in Table 1, where the total duration of the initial / preliminary period and the transition period is 6 weeks. This dosing regimen could be one of the dosing regimens in Table 1, where the total duration of the initial / preliminary period and the transition period is 8 weeks.

[0189] Suitably, in any of the embodiments described in Table 1, the threshold weight is 90 kg. Suitably, in any of the embodiments described in Table 1, the threshold weight is 95 kg. Suitably, 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. Dosing regimen C (third aspect of the invention)

[0190] Another dosing regimen was considered, in which subjects with a weight greater than or equal to a threshold weight transitioned to a maintenance dose immediately after completing the initial dose titration.

[0191] Therefore, in some embodiments, osrester is provided for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject whose weight is greater than or equal to a threshold weight, the method comprising administering osrester to the subject. in: (Ci) The initial dose of orlistat was administered to the subject once daily for the initial period, and then; (Cii) The subject was given a maintenance dose of orinelast twice daily, wherein the maintenance dose of orinelast was greater than the initial dose of orinelast. in: (a) The initial dose of orexaminase is 10 mg to 20 mg orexaminase; (b) This initial period lasted eight weeks; and (c) The threshold weight is at least 90 kg.

[0192] A method is also provided for treating a disease or disorder in a subject whose weight is greater than or equal to a threshold weight by inhibiting PDE4, the method comprising administering orlistat to the subject according to the dosing regimens (Ci) and (Cii) described above, wherein the threshold weight is at least 90 kg.

[0193] Also provided is the use of orestradiol in the manufacture of a medicament for treating a disease or disorder that improves in a subject by inhibiting PDE4, the subject having a weight greater than or equal to a threshold weight, the method comprising administering orestradiol to the subject according to the dosing regimens (Ci) and (Cii) described above, wherein the threshold weight is at least 90 kg.

[0194] In some embodiments, the initial time period in (Ci) is one to four weeks. In some embodiments, the initial time period in (Ci) is one to three weeks. In some embodiments, the initial time period in (Ci) is one to two weeks. In some embodiments, the initial time period in (Ci) is two weeks to four weeks. In some embodiments, the initial time period in (Ci) is two weeks to up to four weeks. In some embodiments, the initial time period in (Ci) is one week. In some embodiments, the initial time period in (Ci) is three weeks. In some embodiments, the initial time period in (Ci) is four weeks. Preferably, the initial time period in (Ci) is two weeks.

[0195] In a preferred embodiment, the initial dose of orexusone in (Ci) is 20 mg of orexusone.

[0196] In some embodiments, the maintenance dose of orelastide in (Ciii) is up to 40 mg of orelastide, provided that the maintenance dose of orelastide is greater than the initial dose of orelastide. For example, the maintenance dose of orelastide may be 30 mg to 40 mg of orelastide. In a preferred embodiment, the maintenance dose of orelastide in (Ciii) is 30 mg of orelastide.

[0197] In a preferred embodiment, the initial oxiracetam dose in (Ci) is 20 mg oxiracetam, and the maintenance oxiracetam dose in (Ciii) is 30 mg oxiracetam.

[0198] In another embodiment, the initial oxiracetam dose in (Ci) is 20 mg oxiracetam, the initial time period in (Ci) is two to four weeks, and the maintenance oxiracetam dose in (Ciii) is 30 mg oxiracetam.

[0199] In another embodiment, the initial oxiracetam dose in (Ci) is 20 mg oxiracetam, the initial time period in (Ci) is two weeks, and the maintenance oxiracetam dose in (Ciii) is 30 mg oxiracetam.

[0200] In some embodiments of dosing regimen C, the threshold body weight is 90 kg. In some embodiments of dosing regimen C, the threshold body weight is 95 kg. In some embodiments of dosing regimen C, the threshold body weight is 105 kg. Preferably, in dosing regimen C, the threshold body weight is 100 kg. Variations of dosing regimens A, B, and C

[0201] A subset of subjects weighing at or above the threshold weight may demonstrate a satisfactory clinical response during the transition period (“heavier responders”). These heavier responders may not require a maintenance dose of orelastide higher than the transition dose, but may instead be administered the same maintenance dose as the transition dose. This stratified dosing for heavier patients may maximize the therapeutic response to orelastide while further minimizing the frequency and / or severity of undesirable side effects.

[0202] Therefore, variations of any of the dosing regimens A, B, and C described herein are also considered, wherein: (i) If the subject's weight is greater than or equal to the threshold weight and the subject shows a satisfactory treatment response during the transition period, the subject is given the same maintenance dose of orelastide as the transition dose; and (ii) If the subject’s weight is greater than or equal to the threshold weight and the subject does not show a satisfactory treatment response during the transition period, the subject is given a maintenance dose of orexusite greater than the transition dose.

[0203] Therefore, in some embodiments, osrester is provided for use in a method of treating a disease or disorder that is improved by inhibiting PDE4 in a subject, the method comprising administering osrester to the subject, wherein: (Ai) During the initial two-week period, subjects were given an initial dose of 20 mg of orestradiol once daily, and then; (Aii) During the transition period of one to eight weeks (e.g., one to four weeks, two to eight weeks, or six to eight weeks), administer a transitional dose of 20 mg of orexate twice daily to the subject, and then; (Aiii-a) If the subject's weight is below the threshold weight, administer a maintenance dose of 20 mg of orexate twice daily; or (Aiii-b) If the subject's weight is greater than or equal to the threshold weight and the subject demonstrates a satisfactory clinical response during the transition period, administer a maintenance dose of 20 mg of orexate twice daily; or (Aiii-c) If the subject's weight is greater than or equal to the threshold weight and the subject does not show a satisfactory clinical response during the transition period, a maintenance dose of 30 mg of orexate should be administered to the subject twice daily; and The threshold weight is at least 90 kg.

[0204] Preferably, the threshold weight is 100 kg.

[0205] In some embodiments, orlistat is provided for use in a method of treating a disease or disorder that improves by inhibiting PDE4 in a subject, the method comprising administering orlistat to the subject, wherein: (Ai) During the initial two-week period, subjects were given an initial dose of 20 mg of orestradiol once daily, and then; (Aii) During the six-week transition period, subjects were given a transitional dose of 20 mg of orestradiol twice daily, and then; (Aiii-a) If the subject's weight is below the threshold weight, administer a maintenance dose of 20 mg of orexate twice daily; or (Aiii-b) If the subject's weight is greater than or equal to the threshold weight and the subject demonstrates a satisfactory clinical response during the transition period, administer a maintenance dose of 20 mg of orexate twice daily; or (Aiii-c) If the subject’s weight is greater than or equal to the threshold weight and the subject does not show a satisfactory clinical response during the transition period, the subject shall be given a maintenance dose of 30 mg of orexate twice daily; and the threshold weight is at least 90 kg.

[0206] Preferably, the threshold weight is 100 kg.

[0207] In some embodiments, orlistat is provided for use in a method of treating a disease or disorder that improves by inhibiting PDE4 in a subject, the method comprising administering orlistat to the subject, wherein: (Ai) During the initial two-week period, subjects were given an initial dose of 20 mg of orestradiol once daily, and then; (Aii) During the four-week transition period, subjects were given a transitional dose of 20 mg of orestradiol twice daily, and then; (Aiii-a) If the subject's weight is below the threshold weight, administer a maintenance dose of 20 mg of orexate twice daily; or (Aiii-b) If the subject's weight is greater than or equal to the threshold weight and the subject demonstrates a satisfactory clinical response during the transition period, administer a maintenance dose of 20 mg of orexate twice daily; or (Aiii-c) If the subject’s weight is greater than or equal to the threshold weight and the subject does not show a satisfactory clinical response during the transition period, the subject shall be given a maintenance dose of 30 mg of orexate twice daily; and the threshold weight is at least 90 kg.

[0208] Preferably, the threshold weight is 100 kg.

[0209] In some embodiments, orlistat is provided for use in a method of treating a disease or disorder that improves by inhibiting PDE4 in a subject, the method comprising administering orlistat to the subject, wherein: (Ai) During the initial two-week period, subjects were given an initial dose of 20 mg of orestradiol once daily, and then; (Aii) During the two-week transition period, subjects were given a transitional dose of 20 mg of orestradiol twice daily, and then; (Aiii-a) If the subject's weight is below the threshold weight, administer a maintenance dose of 20 mg of orexate twice daily; or (Aiii-b) If the subject's weight is greater than or equal to the threshold weight and the subject demonstrates a satisfactory clinical response during the transition period, administer a maintenance dose of 20 mg of orexate twice daily; or (Aiii-c) If the subject’s weight is greater than or equal to the threshold weight and the subject does not show a satisfactory clinical response during the transition period, the subject shall be given a maintenance dose of 30 mg of orexate twice daily; and the threshold weight is at least 90 kg.

[0210] Preferably, the threshold weight is 100 kg.

[0211] In some embodiments, orexine is provided for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject whose weight is greater than or equal to a threshold weight, the method comprising administering orexine to the subject. in: (Bi) During the initial two-week period, subjects were given an initial dose of 20 mg of orestradiol once daily, followed by... (Bii) During the transition period of one to eight weeks, subjects were given a transitional dose of 20 mg of orestradiol twice daily, and then; (Biii-a) If the subject demonstrates a satisfactory clinical response during the transition period, administer a maintenance dose of 20 mg of orexate twice daily; or (Biii-b) If the subject does not show a satisfactory clinical response during the transition period, a maintenance dose of 30 mg of orestradiol shall be administered to the subject twice daily; wherein the threshold body weight is at least 90 kg.

[0212] Preferably, the threshold weight is 100 kg.

[0213] In some embodiments, orexine is provided for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject whose weight is greater than or equal to a threshold weight, the method comprising administering orexine to the subject. in: (Bi) During the initial two-week period, subjects were given an initial dose of 20 mg of orestradiol once daily, followed by... (Bii) During the six-week transition period, subjects were given a transitional dose of 20 mg of orestradiol twice daily, and then; (Biii-a) If the subject demonstrates a satisfactory clinical response during the transition period, administer a maintenance dose of 20 mg of orexate twice daily; or (Biii-b) If the subject does not show a satisfactory clinical response during the transition period, a maintenance dose of 30 mg of orlistat shall be administered to the subject twice daily; and The threshold weight is at least 90 kg.

[0214] Preferably, the threshold weight is 100 kg.

[0215] Therefore, in some embodiments, orestrate is also provided for use in a method of treating a disease or disorder that is improved by inhibiting PDE4 in a subject whose weight is greater than or equal to a threshold weight, the method comprising administering orestrate to the subject. in: (Ci) Administer an initial dose of 20 mg of orlistat once daily to the subjects during the initial time period, then; (Cii-a) If the subject demonstrates a satisfactory clinical response during the initial time period, administer a maintenance dose of 20 mg of orexate twice daily; or (Cii-b) If the subject does not show a satisfactory clinical response during the initial period, administer a maintenance dose of 30 mg of orestradiol twice daily to the subject; The threshold weight is at least 90 kg; and the initial time period is one to four weeks.

[0216] Preferably, the threshold weight is 100 kg. Preferably, the initial time period is two weeks.

[0217] The “satisfactory clinical response” mentioned in the variations of dosing regimens A, B, and C above will depend on the disease or disorder being treated and may be one or more reductions in one or more signs and symptoms of the disease, which will be readily determined by the physician.

[0218] In some embodiments where the disease or disorder is psoriasis, a satisfactory clinical response during the transition period may be one or more of the following: A decrease in the Psoriasis Area and Severity Index (PASI) score relative to baseline (e.g., a decrease of 50% (PASI50) or more, a decrease of 75% (PASI75) or more, a decrease of 90% (PASI90) or more, or a decrease of 100% (PASI100) or more). The Investigator Global Assessment (IGA) score decreased relative to baseline (e.g., the subject achieved a clear (0) or nearly clear (1) IGA score and improved by at least 2 points). Achieve an IGA score of 0; The static physician overall assessment (sPGA) score decreased relative to baseline; The total Psoriasis Symptom Scale (PSS) score decreased relative to baseline; The affected body surface area (BSA) decreased relative to baseline; The Dermatology Quality of Life Index (DLQI) score decreased relative to baseline; The Scalp-Specific Investigator Global Assessment (SS-IGA) score decreased relative to baseline; The scalp-specific physician overall assessment (ScPGA) score decreased relative to baseline; The static physician overall assessment (sPGA-G™) score of the genitals decreased relative to baseline; Physician Overall Assessment (PPPGA) for palmoplantar psoriasis decreased relative to baseline; The Physician’s Overall Assessment of Nail Psoriasis (PGA-F) score decreased relative to baseline; The numerical rating scale (NRS) for generalized pruritus decreased relative to baseline; The pain NRS decreased relative to baseline; A decrease in the Numerical Rating Scale (NRS) score for pruritus scalp relative to baseline; and / or EuroQol Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L) TM The score increased relative to the baseline.

[0219] In some embodiments where the disease is psoriasis (e.g., moderate to severe psoriasis), a satisfactory clinical response during the transition period can be a PASI score that is at least 75% lower than baseline (PASI75) or an sPGA of 0 or 1.

[0220] In some embodiments where the disease is psoriasis (e.g., moderate to severe psoriasis), a satisfactory clinical response during the transition period can be a primary, secondary, or tertiary endpoint in the psoriasis clinical trials disclosed in Examples 3, 4, and 5 of this document.

[0221] In some embodiments where the disease is atopic dermatitis (e.g., moderate to severe atopic dermatitis), a satisfactory clinical response during the transition period can be one or more of the following: A decrease in the Eczema Area and Severity Index (EASI) score relative to baseline (e.g., a decrease of 50% (EASI50) or more, a decrease of 75% (EASI75) or more, a decrease of 90% (EASI90) or more, or a decrease of 100% (EASI100) or more). The Investigator Global Assessment (IGA-AD) score for AD decreased relative to baseline (e.g., the subject achieved a clearance (0) or near clearance (1) score and the IGA-AD score improved by at least 2 points). Achieve IGA-AD of 0; The empirical investigator global assessment (vIGA-AD) score for AD decreased relative to baseline (e.g., the subject achieved a score of clearance (0) or near clearance (1) and the vIGA-AD score improved by at least 2 points). Achieve vIGA-AD of 0; Peak pruritus numerical rating scale (NRS) decreased relative to baseline; The numerical rating scale for most severe pruritus (NRS) decreased relative to baseline; The affected body surface area (BSA) decreased relative to baseline; The Dermatology Quality of Life Index score decreased relative to baseline; The patient-oriented eczema scale score decreased relative to baseline; Patient's overall impression - severity decreased relative to baseline; The patient's overall impression-change score is 1 or 2; The NRS score for sleep disturbance decreased relative to baseline; A decrease in the NRS score for skin pain relative to baseline; or Changes in skin biomarkers relative to baseline, such as a decrease in TARC (thymus activation-regulated chemokine, also known as CCL17) or C6A6.

[0222] In some embodiments where the disease is atopic dermatitis (e.g., moderate to severe atopic dermatitis), a satisfactory clinical response during the transition period can be a primary, secondary, or tertiary endpoint in the atopic dermatitis clinical trials disclosed in Examples 8 and 13 herein.

[0223] In some embodiments where the disease is hidradenitis suppurativa (HS), a satisfactory clinical response during the transition period may be one or more of the following: The number of abscesses and nodules (AN count) decreased relative to baseline. The International Hidradenitis Severity Score (IHS4) decreased relative to baseline; The clinical response score (HiSCR) for hidradenitis suppurativa decreased relative to baseline; The quality of life (HiSQoL) score for hidradenitis suppurativa decreased relative to baseline. The physician's overall assessment of disease severity (HS-PGA) decreased relative to baseline; The Dermatology Quality of Life Index (DLQI) score decreased relative to baseline; The patient's overall NRS score for skin pain decreased relative to baseline; The amount of C-reactive protein decreased relative to baseline. Dosing regimen D (fourth aspect of the invention)

[0224] A fourth aspect of the invention provides an optimized dosing regimen for subjects whose weight is between a lower limit and a threshold weight, wherein the lower limit weight is between 50 kg and 75 kg.

[0225] Therefore, osrester is provided for use in a method for treating a disease or disorder that improves by inhibiting PDE4 in a subject. This method includes administering osrester to the subject, wherein: (Di) Administer the initial dose of orlistat to the subject once daily for the initial period, then; (Dii) Administer a maintenance dose of orexate to the subject twice daily; in: (a) The initial dose of orinelast and the maintenance dose of orinelast are both 20 mg orinelast; (b) The initial time period is two to eight weeks; (c) The subject’s weight is between the lower limit and the threshold weight, wherein the threshold weight is at least 90 kg and the lower limit weight is between 50 kg and 75 kg.

[0226] A method is also provided for treating a disease or disorder in a subject whose weight is improved by inhibiting PDE4, the subject being at a lower limit weight to less than a threshold weight, the method comprising administering orlistat to the 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 50 kg to 75 kg.

[0227] It also provides the use of orestrate in the manufacture of a medicament for treating a disease or disorder that improves in a subject by inhibiting PDE4, the subject having a lower limit weight to less than a threshold weight, the method comprising administering orestrate to the 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 50 kg to 75 kg.

[0228] In some embodiments, the initial time period in (Di) is two to six weeks. In some embodiments, the initial time period in (Di) is two to four weeks. In some embodiments, the initial time period in (Di) is two weeks to as long as four weeks. In some embodiments, the initial time period in (Di) is three weeks. In some embodiments, the initial time period in (Di) is four weeks. Preferably, the initial time period in (Di) is two weeks.

[0229] In some embodiments of the fourth aspect, the threshold weight is 90 kg. In some embodiments of the fourth aspect, the threshold weight is 90 kg. In some embodiments of the fourth aspect, the threshold weight is 95 kg. In a preferred embodiment of the fourth aspect, the threshold weight is 100 kg.

[0230] In some embodiments 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 some embodiments of the fourth aspect, the lower limit weight is 50 kg. In some embodiments of the fourth aspect, the lower limit weight is 60 kg. In some embodiments of the fourth aspect, the lower limit weight is 70 kg. In some embodiments of the fourth aspect, the lower limit weight is 75 kg.

[0231] Therefore, the subject's weight may be from 50 kg to less than 100 kg. In some embodiments, the subject's weight is from 60 kg to less than 100 kg. The subject's weight is from 70 kg to less than 100 kg.

[0232] In one embodiment of the fourth aspect, osrester is provided for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject, the method comprising administering the osrester to the subject, wherein: (Di) The subject was given an initial dose of 20 mg of orlistat once daily for two weeks, and then; (Dii) The subject was given a maintenance dose of 20 mg of orestrate twice daily; The subjects weighed between 75 kg and less than 100 kg.

[0233] In one embodiment of the fourth aspect, osrester is provided for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject, the method comprising administering the osrester to the subject, wherein: (Di) The subject was given an initial dose of 20 mg of orlistat once daily for two weeks, and then; (Dii) The subject was given a maintenance dose of 20 mg of orestrate twice daily; The subjects weighed between 60 kg and less than 100 kg.

[0234] In another embodiment of the fourth aspect, osrester is provided for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject, the method comprising administering osrester to the subject, wherein: (Di) The subject was given an initial dose of 20 mg of orlistat once daily for two weeks, and then; (Dii) The subject was given a maintenance dose of 20 mg of orestrate twice daily; The subjects weighed between 50 kg and less than 100 kg. Dosing regimen E (fifth aspect of the invention)

[0235] As illustrated in the examples in this article, population pharmacokinetic (PK) models based on pooled osrelastide clinical trial data have determined that treatment with 20 mg osrelastide twice daily in subjects with a lower body weight (e.g., less than 50 kg, such as adolescent patients) resulted in higher systemic exposure to osrelastide compared to heavier subjects. As stated above, analysis of the phase 2b psoriasis data showed that increasing systemic exposure beyond what was initially necessary for efficacy may not improve efficacy and could even decrease it. Therefore, specific dosing regimens may be required for lighter-weight subjects.

[0236] In a fifth aspect of the invention, osrester is provided for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject, the subject having a weight less than a lower limit of body weight, the method comprising administering osrester to the subject, wherein: (Ei) The subject was given an initial dose of 10 mg of orestradiol once daily for the initial period, and then; (Eii) The subject was given a maintenance dose of 10 mg of orestradiol twice daily; The initial time period is two to eight weeks, and the lower limit weight is 50 kg to 75 kg.

[0237] A method is also provided for treating a disease or disorder that improves in a subject by inhibiting PDE4, the subject having a weight below a lower limit weight, the method comprising administering orlistat to the subject according to the dosing regimens (Ei) and (Eii) described above, wherein the lower limit weight is 50 kg to 75 kg.

[0238] Also provided is the use of orestradiol in the manufacture of a medicament for treating a disease or disorder that improves in a subject by inhibiting PDE4, the subject having a weight below a lower limit of body weight, the method comprising administering orestradiol to the subject according to the dosing regimens (Ei) and (Eii) described above, wherein the lower limit of body weight is 50 kg to 75 kg.

[0239] In some embodiments, the initial time period in (Ei) is two to six weeks. In some embodiments, the initial time period in (Ei) is two to four weeks. In some embodiments, the initial time period in (Ei) is two weeks to up to four weeks. In some embodiments, the initial time period in (Ei) is three weeks. In some embodiments, the initial time period in (Ei) is four weeks. Preferably, the initial time period in (Ei) is two weeks.

[0240] In some embodiments of the fifth aspect of the invention, osrester is provided for use in a method of treating a disease or disorder improved by inhibiting PDE4 in a subject, the subject having a weight less than a lower limit of body weight, the method comprising administering osrester to the subject, wherein: (Ei) Subjects were given an initial dose of 10 mg of orestradiol once daily for two weeks, and then; (Eii) The subject was given a maintenance dose of 10 mg of orestradiol twice daily; The lower limit of this weight ranges from 50 kg to 75 kg.

[0241] In some embodiments of the fifth aspect of the invention, the lower limit weight is selected from 50 kg, 55 kg, 60 kg, 65 kg, 70 kg, and 75 kg. In some embodiments of the fifth aspect, the lower limit weight is 50 kg. In some embodiments of the fifth aspect, the lower limit weight is 60 kg. In some embodiments of the fifth aspect, the lower limit weight is 70 kg. In some embodiments of the fifth aspect, the lower limit weight is 75 kg. Alternative initial dose titration

[0242] Variations of any of the dosing regimens A, B, C, D, or E described herein, wherein the initial oxiracetam dose, dosing frequency, and / or initial or preliminary time period differ from the once-daily dosing described in dosing regimens A, B, C, D, or E. Therefore, variations of dosing regimens A, B, C, D, or E are also provided, wherein in (Ai), (Bi), (Ci), (Di), or (Ei), an initial orelastide dose (e.g., 10 mg or 20 mg) is administered to the subject once or twice daily for an initial or preliminary period (e.g., two weeks) prior to the administration of the transitional or maintenance orelastide dose twice daily. Variations of dosing regimens A, B, C, D, or E are also provided, wherein in (Ai), (Bi), (Ci), (Di), or (Ei), an initial orelastide dose of 10 mg is administered to the subject once or twice daily for an initial or preliminary period of one or two weeks prior to the administration of the transitional or maintenance orelastide dose twice daily. Variations in dosing regimens A, B, C, D, or E are also provided, wherein in (Ai), (Bi), (Ci), (Di), or (Ei), an initial dose of 10 mg of orelastide is administered to the subject twice daily for an initial or preliminary period of one or two weeks prior to the administration of the transitional or maintenance orelastide dose twice daily. Variations in dosing regimens A, B, C, D, or E are also provided, wherein in (Ai), (Bi), (Ci), (Di), or (Ei), an initial dose of 20 mg of orelastide is administered to the subject once or twice daily for an initial or preliminary period of one or two weeks prior to the administration of the transitional or maintenance orelastide dose twice daily. Variations in dosing regimens A, B, C, D, or E are also provided, wherein in (Ai), (Bi), (Ci), (Di), or (Ei), an initial dose of 20 mg of orelastide is administered to the subject twice daily for an initial or preliminary period of one or two weeks prior to the administration of the transitional or maintenance orelastide dose twice daily.

[0243] In some embodiments of alternative initial dose titration, in any of the dosing regimens A, B, C, D, or E described herein, steps (Ai), (Bi), (Ci), (Di), or (Ei) are replaced by any of variants 1, 2, or 3 shown in the table below, for the first 14 days of treatment: After completing the initial 14 days of treatment, the subject is then treated with a transitional dose of orexusol starting from day 15 of treatment as described in any of dosing regimens A or B, or with a maintenance dose of orexusol as described in any of dosing regimens C, D, or E.

[0244] In some embodiments of alternative initial dose titration, 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 titration shown in Table 5 of Example 3, respectively. After completing the initial 14 days of treatment, the subject is then treated with a transitional orelastide dose starting from day 15 of treatment as described in any of dosing regimens A or B, or with a maintenance orelastide dose as described in any of dosing regimens C, D, or E. Pharmaceutical Composition

[0245] Oresta may be included in a pharmaceutical composition. Therefore, the present invention also covers a pharmaceutical composition comprising oresta for use in any of the dosing regimens described herein.

[0246] Pharmaceutical compositions containing orexate may optionally also contain one or more viscosity modifiers, carriers (e.g., mannitol, lactose, microcrystalline cellulose, or trehalose), emulsifiers, surfactants, humectants, oils, waxes, polymers, preservatives, pH adjusters (e.g., suitable acids or bases, such as organic acids or organic amine bases), buffers, stabilizers, electrolytes, antioxidants (e.g., butylated hydroxyanisole or butylated hydroxytoluene), crystallization inhibitors (e.g., cellulose derivatives, such as hydroxypropyl methylcellulose or polyvinylpyrrolidone), colorants, flavorings, and taste masking agents. Such excipients are well known, for example, as listed in Handbook of Pharmaceutical Excipients, 10th edition, by Sheskey et al.

[0247] In some embodiments, orexusite is present in the pharmaceutical composition in an amount of about 0.01% to 50% by weight of the composition. Therefore, orexusite may be present in the solid composition in amounts 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 based on the weight of the composition. Pharmaceutical compositions for oral administration

[0248] In some embodiments, the pharmaceutical composition containing osrester is suitable for oral administration. Suitably, the pharmaceutical composition is a solid pharmaceutical composition, preferably a solid pharmaceutical composition suitable for oral administration. The pharmaceutical composition containing osrester may be in the form of discrete units, such as capsules, pouches, tablets, lozenges, or granules, each containing a predetermined amount of osrester. The discrete units may be compositions in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids (such as ethanol or glycerin), 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 suspensions include synthetic or natural gums, such as astragalus gum, alginate, gum arabic, dextran, sodium carboxymethyl cellulose, gelatin, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carbomer, and polyvinylpyrrolidone. The formulation may also be administered in the form of pellets, saccharides, or pastes.

[0249] The powder can be prepared using well-known methods, such as by grinding, blending, microprecipitation, lyophilization, or spray drying, or spray freeze-drying of a solution containing orestradiol.

[0250] The amount of orexusone in each oral dosage form (e.g., tablet, capsule, capsule, or lozenge) can be from about 1 mg to about 40 mg. The amount of orexusone can be, for example, 5 mg to 40 mg, 10 mg to 40 mg, 15 mg to 35 mg, 20 mg 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 orexusone in each oral dosage form (e.g., tablet, capsule, capsule, or lozenge) is 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg.

[0251] In some embodiments, particles containing orestrate can be prepared by precipitation, lyophilization, or spray drying or spray freeze-drying of a solution containing orestrate and a suitable carrier to provide powder particles containing orestrate and a carrier as composite particles. Suitable carriers include inert carriers such as starch, sugars (e.g., mannitol, lactose, microcrystalline cellulose, or trehalose).

[0252] In some embodiments, orexin is present in the composition as a micronized powder, such as a micronized crystalline powder (e.g., micronized crystal form E of orexin). Therefore, the particle size distribution of orexin 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 orexin in the composition has D(90) ≤ 10 µm. In some embodiments, the particle size distribution of orexin in the composition has a D(50) of about 1 µm to about 6 µm.

[0253] As described herein, powders containing orestradiol can be dissolved or suspended in a suitable solvent (preferably water) prior to application (e.g., application of a spray or gel). Alternatively, powders or granules containing orestradiol can be sprinkled onto food or liquids prior to application.

[0254] Tablets can be prepared by compression or molding of a composition, optionally with one or more excipients. Compressed tablets can be prepared by compressing a formulation in a free-flowing form (such as powder or granules) in a suitable tablet press, optionally mixed with: binders such as lactose, glucose, starch, gelatin, gum arabic, astragalus gum, sodium alginate, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, waxes, etc.; lubricants such as sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc.; disintegrants such as starch, methyl cellulose, agar, bentonite, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, etc.; or dispersants such as polysorbate 80.

[0255] Molded tablets can be prepared by molding. Suitable techniques for molding tablets are well known in the art. For example, in a suitable machine, a mixture of powdered active ingredient and suitable carrier can be wetted with an inert liquid diluent. In some embodiments, molded tablets can be prepared by dispersing a water-soluble excipient with powdered orexate in a suitable solvent, such as water, alcohol, or organic solvent (e.g., acetone, hydrocarbons). Alternatively, molded tablets can be prepared using thermoplastic polymers (e.g., polyethylene oxide or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymers) without the use of an inert liquid diluent.

[0256] Table 2 shows representative examples of oral pharmaceutical compositions containing orlistat. Table 2 Sustained-release composition

[0257] In some embodiments, orexustralis is included in a sustained-release composition formulation, such as a sustained-release composition for oral administration. Therefore, orexustralis can be included in a sustained-release tablet composition for oral administration. Using a sustained-release composition allows for controlled release of the therapeutic agent, thus controlling the absorption of orexustralis from the gastrointestinal tract. The applicant has previously described (in PCT application published as WO2020 / 148271) that by formulating orexustralis in a sustained-release tablet formulation, beneficial effects regarding improved tolerability to gastrointestinal adverse events and maintenance of systemic exposure can be achieved, wherein in vitro release is rapid compared to conventional delayed or extended-release oral release profiles, but not as rapid as immediate-release tablets (where major tolerability issues are observed).

[0258] It should be understood that the dissolution rate of a sustained-release composition will be determined by several factors, such as the nature of the excipients and the composition itself, the particle size of the components used in the composition, particularly the particle size of orexazol, and whether coating or encapsulation is used to regulate the release of orexazol from the composition. (WO 2020 / 0148271) Figure 1 The dissolution target region in the figure indicates a suitable dissolution profile for sustained-release compositions containing orestradiol, which was suitably determined in vitro using European Pharmacopoeia 2.9.3 Method II (paddle method) with 900 ml of 0.5% sodium dodecyl sulfate in 0.1 N HCl solution, a paddle speed of 75 rpm, and a dissolution temperature of 37 ± 0.5°C. This determination is referred to herein as the "standard dissolution determination".

[0259] In some embodiments, orestradiol is formulated as a sustained-release formulation as described in WO 2020 / 0148271 (which is incorporated herein by reference).

[0260] Other sustained-release compositions containing orexate are also considered. For example, orexate can be dispersed, dissolved, or conjugated (e.g., compounded) with a polymer matrix. The polymer matrix can be hydrophobic or hydrophilic, but is preferably hydrophilic. In some embodiments, the composition comprises orexate and a polymer matrix, wherein the polymer is one or more polymers selected from: hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene oxide, polyethylene glycol; polyethylene oxide and polypropylene oxide block copolymers (such as poloxamer), cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinylpyrrolidone (PVP), copolymers of PVP and vinyl acetate, poly(ethylene-vinyl acetate), polyvinyl alcohol, sugar alcohols (such as xylitol or sorbitol), and biodegradable polymers (such as poly(lactide-co-glycolic acid)).

[0261] Oreste can also be dissolved, dispersed, or conjugated with 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; carob gum; gum arabic; guizitan gum, agar, or cyclodextrin.

[0262] In some embodiments, the polymer matrix is ​​present in the composition in an amount of 10% to 40% by weight of the composition, for example, 15% to 30% by weight of the composition. Sustained-release compositions containing orestradiol may further contain one or more fillers, binders, or flow aids. Such additional excipients are well known to those skilled in the art.

[0263] In some embodiments, orexeter is dissolved or dispersed in a polymer matrix by melt extrusion. Alternatively, orexeter can be dispersed or dissolved in a polymer matrix by blending excipients and then wet or dry granulating and / or compressing the composition into a suitable dosage form (e.g., tablets). Orexeter can also be dispersed or dissolved in a gel matrix, such as a hydrogel system comprising a gel-forming polymer.

[0264] Sustained-release compositions containing ozenaste can also be prepared as nanoparticle compositions. For example, nanoparticles may contain ozenaste and biodegradable polymers such as poly(lactide-co-glycolic acid) or ozenaste conjugated with a suitable polymer carrier.

[0265] In some embodiments, the composition containing osrester is a solid dispersion in which osrester exists in an amorphous form within a 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 using known methods, such as hot melt extrusion.

[0266] Sustained release of osrester can also be achieved by using a coating on a core composition containing osrester (e.g., a tablet core), or wherein osrester is present in a coating applied to a suitable substrate (e.g., an inert core, such as a sugar or polymer core) to provide an osrester-containing layer on the core. Suitable coatings that can provide sustained release of osrester include, for example, modified cellulose, polymethacrylate, polyvinylpyrrolidone, polyvinyl acetate phthalate, zein, and / or shellac or natural gums, such as carrageenan. For example, the coating may contain a water-soluble polymer, such as low-viscosity hydroxypropyl methylcellulose, hydroxypropyl cellulose, or a PVA polymer.

[0267] Coatings applied to a core composition containing osrester are also considered, such as those described herein, which contain osrester and a polymer matrix. The coating can be any coating described herein and is used to further modulate the release of osrester from the composition. In some embodiments, the composition comprises an osrester-containing core, wherein the core is coated with an osrester-containing coating. In this embodiment, osrester is released from both the coating and the core.

[0268] Sustained-release compositions containing osrester can also be formulated as lipid-based compositions, such as liposomes, emulsions or microemulsions, self-emulsifying drug delivery systems, nanoemulsions, lipid-drug conjugates, solid-lipid nanoparticles, or solid lipid microparticles. Therefore, the composition can 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 can be, for example, monoglycerides, diglycerides, or triglycerides (e.g., medium-chain triglycerides), lipid emulsifiers such as phosphatidylcholine, 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC), 1,2-distearate-sn-glycerol-3-phosphocholine (DSPC), hydrogenated soybean phosphatidylcholine (HSPC), 1-myristoyl-2-stearoyl-sn-glycerol-3-phosphocholine (MSPC), 1-hexadecenyl-2-oleoyl-sn-glycerol- 3-Phosphocholine (HOPC), 1,2-dipalmitoyl-sn-glycerol-3-phosphatidylglycerol (DPPG), 1,2-distearyl-sn-glycerol-3-phosphatidylglycerol (DSPG), 1,2-dimyristoyl-sn-glycerol-3-phosphatidylglycerol (DMPG), 1,2-distearyl-sn-glycerol-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000), 1,2-dimyristoyl-sn 1,2-Dioleoyl-sn-glycero-3-phosphate ethanolamine (DMPE), DOPE, unsaturated polyethylene glycol-modified glycerides (e.g., oleoyl polyethylene glycol glyceride or linoleoyl polyethylene glycol glyceride), sorbitol esters (e.g., sorbitol monooleate, sorbitol monostearate, sorbitol monolaurate, or sorbitol monopalmitate), polyoxyethylene sorbitol esters (e.g., polysorbate 20, polysorbate 40, etc.). Sorbitol 60 and polysorbate 80), polyoxyethylene castor oil derivatives (e.g., polyoxyethylene 35 castor oil or polyoxyethylene 40 hydrogenated castor oil), polyoxyethylene-polyoxypropylene block copolymers (e.g., poloxamer 188 or poloxamer 407), saturated polyethylene glycol-modified glycerides (e.g., lauroyl polyethylene glycol glyceride or stearoyl polyethylene glycol glyceride), polyethylene glycol-modified caprylic / capric glyceride (e.g., octylhexanoyl polyethylene glycol glyceride), or vitamin E derivatives (e.g., D-tocopherol polyethylene glycol succinate). Lipid formulations may further comprise one or more surfactants and / or co-solvents.Lipid-based drug delivery systems are described in the examples of emulsifiers in Rahim MA et al., Recent Advancements in Stimuli Responsive Drug Delivery Platforms for Active and Passive Cancer Targeting. Cancers (Basel). 7 Feb 2021;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.

[0269] An osmotic release drug delivery system was also considered, comprising a composition containing orlistat and an osmotic agent surrounded by a semi-permeable membrane capsule with a small orifice. In use, water is drawn through the semi-permeable membrane by the osmotic agent, and the osmotic agent becomes hydrated and swollen, forcing the drug out through the orifice in the capsule.

[0270] In some embodiments, the sustained-release formulation releases less than 40% of osrexate after 12 minutes. In some embodiments, the sustained-release formulation releases less than 20% of osrexate after 12 minutes. In some embodiments, the sustained-release composition releases less than 40% of osrexate after 30 minutes. In some embodiments, the sustained-release composition releases less than 35% of osrexate after 30 minutes. In some embodiments, the sustained-release composition releases about 20% to about 40% of osrexate after 30 minutes. In some embodiments, the sustained-release composition releases about 25% to about 35% of osrexate after 30 minutes. In some embodiments, the sustained-release composition releases about 25% to about 50% of osrexate after 30 minutes. In some embodiments, the sustained-release composition releases about 25% to about 45% of osrexate after 30 minutes. In some embodiments, the sustained-release composition releases about 24% to about 36% of osrexate after 30 minutes. In some embodiments, the sustained-release composition releases about 11% to about 65% of osrexate after 45 minutes. In some embodiments, the sustained-release composition releases about 25% to about 60% of osrexate after 45 minutes. In some embodiments, the sustained-release composition releases about 35% to about 55% of osrexate after 45 minutes. In some embodiments, the sustained-release composition releases about 30% to about 45% of osrexate after 45 minutes. In some embodiments, the sustained-release composition releases about 30% to about 46% of osrexate after 45 minutes. In some embodiments, the sustained-release composition releases about 40% to about 65% of osrexate after 60 minutes. In some embodiments, the sustained-release composition releases about 40% to about 55% of osrexate after 60 minutes. In some embodiments, the sustained-release composition releases more than about 60% of osrexate after 60 minutes. In some embodiments, the sustained-release composition releases more than about 40% of osrexate after 60 minutes. In some embodiments, the sustained-release composition releases more than about 60% of osrexate after 60 minutes. In some embodiments, the sustained-release composition releases about 35% to about 65% of osrexate after 60 minutes. In some embodiments, the sustained-release composition releases about 35% to about 50% of osrester after 60 minutes. In some embodiments, the sustained-release composition releases about 40% to about 50% of osrester after 60 minutes. In some embodiments, the sustained-release composition releases about 35% to about 53% of osrester after 60 minutes. In some embodiments, the sustained-release composition releases about 50% to about 75% of osrester after 90 minutes. In some embodiments, the sustained-release composition releases about 50% to about 60% of osrester after 90 minutes. In some embodiments, the sustained-release composition releases about 44% to about 66% of osrester after 90 minutes. In some embodiments, the sustained-release composition releases about 60% to about 80% of osrester after 120 minutes. In some embodiments, the sustained-release composition releases about 65% to about 80% of osrester after 120 minutes.In some embodiments, the sustained-release composition releases about 60% to about 70% of osrester after 120 minutes. In some embodiments, the sustained-release composition releases about 52% to about 78% of osrester after 120 minutes. In some embodiments, the sustained-release composition releases more than about 70% of osrester after 180 minutes. In some embodiments, the sustained-release composition releases more than about 80% of osrester after 180 minutes. In some embodiments, the sustained-release composition releases about 66% to about 100% of osrester after 180 minutes. In some embodiments, the sustained-release composition releases about 70% to about 100% of osrester after 180 minutes. In some embodiments, the sustained-release composition releases about 80% to about 100% of osrester after 180 minutes. In some embodiments, the sustained-release composition releases about 85% to about 100% of osrester after 180 minutes. In some embodiments, the sustained-release composition releases about 90% to about 100% of osrester after 180 minutes. In some embodiments, the sustained-release composition releases about 95% to about 100% of orestrate after 180 minutes.

[0271] In some embodiments, the sustained-release composition releases about 11% to about 65% of osrester after 45 minutes and more than 80% of osrester after 180 minutes. In some embodiments, the sustained-release composition releases about 25% to about 65% of osrester after 45 minutes and at least 75% of osrester after 180 minutes. In some embodiments, the sustained-release composition releases about 30% to about 50% of osrester after 45 minutes and at least 75% of osrester after 180 minutes. In some embodiments, the sustained-release composition releases about 30% to about 55% of osrester after 45 minutes and at least 80% of osrester after 180 minutes.

[0272] In some embodiments, the sustained-release composition releases about 30% to about 46% of osrester after 45 minutes and at least 80% of osrester after 180 minutes. In some embodiments, the sustained-release composition releases about 30% to about 50% of osrester after 45 minutes and about 80% to about 100% of osrester after 180 minutes. In some embodiments, the sustained-release composition releases about 30% to about 55% of osrester after 45 minutes, about 44% to about 66% after 90 minutes, and at least 80% of osrester after 180 minutes.

[0273] In some embodiments, the sustained-release composition releases about 50% of osrester between about 60 and 100 minutes. In some embodiments, the sustained-release composition releases about 80% of osrester between about 120 and 180 minutes. In some embodiments, the sustained-release composition releases less than 40% of osrester after 30 minutes; releases 50% of osrester between 60 and 100 minutes; and releases 80% of osrester between 115 and 180 minutes. In some embodiments, the sustained-release composition releases about 30% to about 46% of osrester after 45 minutes; releases about 52% to about 78% of osrester after 120 minutes; and releases at least about 80% of osrester after 180 minutes.

[0274] In any of the embodiments in the above four paragraphs, the sustained-release composition releases, for example, less than 40% of oresite after 30 minutes, for example, less than about 30% after 30 minutes. In any of the embodiments in the above four paragraphs, the sustained-release composition releases, for example, less than 20% of oresite after 12 minutes.

[0275] In each of the above paragraphs and elsewhere, the release of orestate refers to the in vitro release measured using the “standard dissolution assay” as defined herein.

[0276] In the above paragraphs, "orlistat release from the composition" refers to the percentage by weight of orlistat initially present in the sustained-release composition released into the dissolution medium at a specified time point, as measured using a standard dissolution assay. The amount of orlistat present in the dissolution medium can be determined by reversed-phase isocratic HPLC using a C18 column with UV detection at 272 nm. Suitablely, the percentage release of orlistat is an average obtained by measuring the release profiles of more than one sample of the sustained-release composition, thereby reducing the influence of batch-to-batch or intra-batch variability. The average release percentage can be obtained by measuring the release of, for example, 6, 12, or 24 samples of the sustained-release composition.

[0277] The sustained-release composition may be any of the sustained-release compositions described herein that provide the release profile described herein.

[0278] In some embodiments, the composition containing orestrol has the same properties as Figure 11 The in vitro release curves shown are similar to those measured using standard dissolution assays. The term "similar" release curves refers to those considered similar from a regulatory perspective, such as those described in the FDA's dissolution testing for immediate-release solid oral dosage forms. Industry guidance (August 1997) is available online: https: / / www.fda.gov / downloads / drugs / guidances / ucm070237.pdf Alternatively, the EMA 2010 Guidelines for Bioequivalence Studies are available online. https: / / www.ema.europa.eu / en / documents / scientific-guideline / guideline-investigation-bioequivalence-rev1_ en.pdf .

[0279] Therefore, in some embodiments, with Figure 11 Compared to the release curves in the original formulation, the compositions containing orlistat have in vitro release curves with a similarity factor f2 of 50 to 100, wherein: Where R is Figure 11 One of the reference compositions containing orestradiol, T is a similar composition, n is the number of time points, and R is... t and T t These are the average percentages of drug released from products (R) and (T) at time t, respectively, 1 ≤ t ≤ n, and the logarithm is log. 10 .

[0280] Appropriately, according to the FDA guidance mentioned above, the following conditions apply to the f2 value: (1) The dissolution rate of the two products was measured under the same conditions; (2) For two products, consider at least three time points (excluding time zero). (3) For both products, the time point for measuring dissolution is the same; (4) Both products are used in at least 12 separate dose units; (5) For any product, no more than one average percentage value shall exceed 85%; (6) The coefficient of variation (CV) of any product should be less than 20% at the first (non-zero) time point and less than 10% at subsequent time points.

[0281] In some embodiments, with Figure 11 Compared to the release curves of other compositions, the compositions containing orlistat exhibited in vitro release curves with a difference factor f1 ranging from 0 to 15.

[0282] The difference factor is the sum of the absolute values ​​of the differences between the (T) product and the (R) product relative to the average percentage of drug released from the (R) product.

[0283] In some embodiments, the composition containing osrester has an in vitro release profile corresponding to the release profile shown in Table C of Example 1, wherein the % of osrester 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 example, at 45 minutes, the 30 mg tablet releases 39% of osrester. Therefore, in this embodiment, the composition containing osrester releases ±20% of this value at 45 minutes, i.e., 31.2% to 46.8% of osrester is released at 45 minutes. The same ±20% value applies to the other time points shown in Table C.

[0284] In some embodiments, the sustained-release composition comprises osrelastide and a pharmaceutically acceptable hydrophilic matrix forming agent (e.g., HPMC). In some embodiments, the sustained-release composition comprises osrelastide; a pharmaceutically acceptable hydrophilic matrix forming agent (e.g., HPMC); and a filler (e.g., lactose monohydrate). In some embodiments, the sustained-release composition comprises osrelastide; and 15% w / w to 30% w / w of a pharmaceutically acceptable hydrophilic matrix forming agent (e.g., HPMC). In some embodiments, the sustained-release composition comprises the osrelastide compound; and 15% w / w to 25% w / w of HPMC.

[0285] In some embodiments, the sustained-release composition comprises orestrate; and 15% w / w to 20% w / w HPMC.

[0286] In some embodiments, the sustained-release composition includes a core comprising... (i) Oreste; (ii) One or more pharmaceutically acceptable hydrophilic matrix-forming agents; (iii) Optionally, one or more pharmaceutically acceptable excipients selected from the group consisting of fillers, flow aids, and lubricants; and (iv) Optionally, a pharmaceutically acceptable coating system on the core.

[0287] In some embodiments, the hydrophilic matrix forming agent in the sustained-release composition comprises hydroxypropyl methylcellulose or hydroxypropyl cellulose or a mixture thereof.

[0288] In some embodiments, one or more pharmaceutically acceptable excipients present in the sustained-release composition comprise a filler selected from lactose monohydrate and microcrystalline cellulose, and mixtures thereof. In some embodiments, the filler is present at a concentration of about 30% to about 78% w / w lactose monohydrate and 0% to about 40% w / w 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. The reference herein to “% w / w based on core weight” means % by weight of the core component prior to application of the coating system.

[0289] In some embodiments, the sustained-release composition comprises a coating on the core. For example, a PVA-based coating system.

[0290] In some embodiments, the sustained-release composition includes a core comprising... (i) Oreste; (ii) A hydrophilic matrix forming agent, wherein the hydrophilic matrix forming agent is present at a concentration of about 15% w / w to about 25% w / w hydroxypropyl methylcellulose based on the weight of the core; (iii) Based on the core, approximately 30% w / w to approximately 78% w / w lactose monohydrate; and (iv) Optionally, one or more pharmaceutically acceptable excipients selected from the group consisting of gliding agents and lubricants; Optionally, the composition further comprises a pharmaceutically acceptable coating system on the core.

[0291] In some embodiments, the sustained-release composition comprises a core, which, based on the weight of the core, comprises orestradiol, about 0.5% w / w colloidal silica, about 1.0% w / w magnesium stearate; and optionally a PVA-based coating system on the core.

[0292] In some embodiments, the sustained-release composition comprises a core, which, based on the weight of the core, comprises orestradiol, about 17.5% w / w HPMC, about 71.0% w / w lactose monohydrate, about 0.5% w / w colloidal silica, and about 1.0% w / w magnesium stearate; and optionally a PVA-based coating system on the core.

[0293] In some embodiments, osrester is present in the sustained-release composition at an amount of about 1% w / w to about 40% w / w. In some embodiments, osrester is present in the sustained-release composition at an amount of about 1% w / w to about 30% w / w. In some embodiments, osrester is present in the sustained-release composition at an amount of about 1% w / w to about 20% w / w. In some embodiments, osrester is present in the sustained-release composition at an amount of about 2% w / w to about 15% w / w. In some embodiments, osrester is present in the sustained-release composition at an amount of about 2% w / w to about 5% w / w. In some embodiments, osrester is present in the sustained-release composition at an amount of about 8% w / w to about 12% w / w.

[0294] In some embodiments, orestradiol is present in the sustained-release composition in amounts of about 5 mg to about 60 mg; about 10 mg to about 50 mg (e.g., about 10 mg, or about 30 mg).

[0295] In some embodiments, osrelast is uniformly distributed in the pharmaceutical composition. In some embodiments, the osrelast in the pharmaceutical composition is micronized. In some embodiments, the osrelast in the pharmaceutical composition is crystalline. In some embodiments, the osrelast present in the pharmaceutical composition is both crystalline and micronized.

[0296] In some embodiments, the pharmaceutical composition comprises polymorph E of osrester. In some embodiments, polymorph E of osrester is micronized. In some embodiments, polymorph E of osrester is both crystalline and micronized.

[0297] 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 from about 10% w / w to about 30% w / w HPMC. In some embodiments, the hydrophilic matrix forming agent is present in an amount from about 15% w / w to about 25% w / w HPMC. In some embodiments, the hydrophilic matrix forming agent is present in an amount from 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 HMPC.

[0298] In some embodiments, the hydrophilic matrix forming agent in the sustained-release composition comprises hydroxypropyl methylcellulose (HPMC). In some embodiments, the hydrophilic matrix forming agent in the sustained-release composition is composed of HPMC. In some embodiments, HPMC has a viscosity of 30 to 150 mPa·s. In some embodiments, HPMC has a viscosity of 35 to 130 mPa·s. In some embodiments, HPMC has a viscosity of 40 to 60 mPa·s. In some embodiments, HPMC has a viscosity of 80 to 120 mPa·s. The viscosity of HPMC mentioned herein refers to the viscosity of a 2% (w / w) solution of HPMC in water at 20°C, according to the United States Pharmacopeia (USP XXIII).

[0299] In some embodiments, the hydrophilic matrix forming agent in the sustained-release composition comprises HPMC with a methoxy substitution degree of about 5% to about 35%. In some embodiments, HPMC has a methoxy substitution degree of about 15% to about 30%. In some embodiments, HPMC has a methoxy substitution degree of about 19% to about 24%. In some embodiments, HPMC has a methoxy substitution degree of about 25% to about 35%. In some embodiments, HPMC has a methoxy substitution degree of about 28% to about 30%. In some embodiments, HPMC has a methoxy substitution degree of about 22% to about 24%.

[0300] In some embodiments, the hydrophilic matrix forming agent in the sustained-release composition comprises HPMC with a hydroxypropyl substitution degree of about 4% to about 15%. In some embodiments, the hydrophilic matrix forming agent in the sustained-release composition comprises HPMC with a hydroxypropyl substitution degree of about 4% to about 12%. In some embodiments, the hydrophilic matrix forming agent in the sustained-release composition comprises HPMC with a hydroxypropyl substitution degree of about 7% to about 12%. In some embodiments, the hydrophilic matrix forming agent in the sustained-release composition comprises HPMC with a hydroxypropyl substitution degree of about 7.5% to about 9.5%.

[0301] In some embodiments, the hydrophilic matrix forming agent in the sustained-release composition comprises HPMC with a methoxy degree of substitution of about 19% to about 24% and a hydroxypropyl degree of substitution of about 4% to about 12%.

[0302] In some embodiments, the hydrophilic matrix forming agent in the sustained-release composition comprises HPMC with a methoxy degree of substitution of about 19% to about 24% and a hydroxypropyl degree of substitution of about 7% to about 12%.

[0303] In some embodiments, the hydrophilic matrix forming agent in the sustained-release composition comprises HPMC with a methoxy degree of substitution of about 28% to about 30% and a hydroxypropyl degree of substitution of about 7% to about 12%.

[0304] In some embodiments, the hydrophilic matrix forming agent in the sustained-release composition comprises HPMC with a methoxy degree of substitution of about 22% to about 24% and a hydroxypropyl degree of substitution of about 7.5% to about 9.5%.

[0305] Suitablely, in any of the above six paragraphs, HPMC has a viscosity of 80 to 120 mPa·s. The viscosity of HPMC mentioned herein refers to the viscosity of a 2% (w / w) solution of HPMC in water at 20°C, according to the United States Pharmacopeia (USP XXIII).

[0306] In some embodiments, hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2910, hydroxypropyl methylcellulose 2208, Methocel K100, or a mixture thereof.

[0307] Suitablely, the hydrophilic matrix forming agent is present at a concentration of about 10% w / w to about 30% w / w hydroxypropyl methylcellulose, based on the weight of the core. Therefore, the hydrophilic matrix forming agent may be present at a concentration of about 15% w / w to about 25% w / w hydroxypropyl methylcellulose, based on the weight of the core. For example, the hydrophilic matrix forming agent is present at a concentration of 17.5% w / w hydroxypropyl methylcellulose, based on the weight of the core. The hydroxypropyl methylcellulose can be any grade of hydroxypropyl methylcellulose disclosed herein (e.g., hydroxypropyl methylcellulose 2910, hydroxypropyl methylcellulose 2208, Methocel K100, or mixtures thereof).

[0308] In some embodiments, the sustained-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, aqueous or anhydrous lactose, microcrystalline cellulose, mannitol, isomaltitol, 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 comprise about 30% w / w to about 78% w / w of lactose monohydrate and about 0% to about 40% w / w of microcrystalline cellulose. For example, the filler may be about 71% w / w of lactose monohydrate.

[0309] In some embodiments, the sustained-release composition (e.g., a sustained-release tablet composition) comprises one or more flow aids. As used herein, the term "flow aid" includes colloidal silica, talc, etc. For example, the flow aid may be colloidal silica. Flow aids may be present at various concentrations from about 0.1% w / w to about 2% w / w (e.g., about 0.2% w / w to about 1% w / w, such as about 0.5% w / w).

[0310] In some embodiments, the sustained-release composition (e.g., a sustained-release tablet composition) further comprises one or more lubricants. As used herein, the term "lubricant" includes magnesium stearate, sodium stearoyl fumarate, talc, etc. 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 (e.g., about 0.5% w / w to about 1.5% w / w, such as about 1.0% w / w).

[0311] The %w / w of a component constituting a sustained-release composition (e.g., a sustained-release tablet composition, such as those containing orexamin, a hydrophilic matrix forming agent, a filler, a flow aid, and / or a lubricant) refers to the %w / w before optional coating is added to the composition (e.g., to a core containing orexamin and other excipients). Therefore, as those skilled in the art will recognize, in those embodiments where a sustained-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, will be lower than the %w / w based on the uncoated composition due to the additional weight of the coating.

[0312] In some embodiments, the sustained-release composition comprises a membrane coating on the core. Suitable coatings may be PVA-based coating systems. 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 ethyl cellulose-based functional barrier membrane 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% by weight of the core composition (e.g., 4% by weight of the core).

[0313] In some embodiments, the composition containing orestrol 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: Table A The core is coated with a water-soluble membrane, which provides approximately 3% to 5% weight gain to the core. Table B

[0314] Suitably, the film coating on the core of Tables A and B is a PVA-based coating. Preferably, the film coating comprises polyvinyl alcohol (European Pharmacopoeia 1961), polyethylene glycol (European Pharmacopoeia 1444), titanium dioxide (European Pharmacopoeia 0150), talc (European Pharmacopoeia 0438), and optionally a colorant. For example, the film coating may be Opadry® II.

[0315] Suitably, the lactose monohydrate in the compositions described herein (including those in Tables A and B) conforms to European Pharmacopoeia (Ph. Eur.) 0187. Suitably, the anhydrous colloidal silica in the compositions described herein (including those in Tables A and B) conforms to European Pharmacopoeia 0434. Suitably, the magnesium stearate in the compositions described herein (including those in Tables A and B) conforms to European Pharmacopoeia 0229. Suitably, the hydroxymethyl cellulose (HPMC, hydroxypropyl methylcellulose) in the compositions described herein (including those in Tables A and B) conforms to European Pharmacopoeia 0348.

[0316] Suitably, the HPMC in Tables A and B comprises HPMC with a methoxy substitution degree of about 22% to about 24% and a hydroxypropyl substitution degree of about 7.5% to about 9.5%. Suitably, the HPMC has a viscosity of 80 to 120 mPa·s. The viscosity of HPMC mentioned herein refers to the viscosity of a 2% (w / w) solution of HPMC in water at 20°C, according to the United States Pharmacopeia (USP XXIII). For example, HPMC is Methocel™ K100 or a mixture thereof.

[0317] Sustained-release compositions comprising a hydrophilic matrix such as HPMC as described herein can be prepared using well-known methods, including the compositions in Tables A and B. For example, this can be achieved by blending and screening osmectite and excipients, followed by direct pressing, or by roll pressing followed by pressing. A water-soluble coating is then applied to the core using, for example, a spray gun.

[0318] In a preferred embodiment, the sustained-release composition containing osrester described herein is a sustained-release tablet containing osrester. In some embodiments, the sustained-release composition containing osrester is the sustained-release tablet containing osrester described in the examples herein.

[0319] In some embodiments, the particle size distribution of orlistat present in the pharmaceutical composition (e.g., 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 in Tables A and B, the particle size distribution of orlistat may be D(90) ≤ 10 µm and D(50) < 1 to 6 µm.

[0320] In some embodiments, the pharmaceutical composition comprising osrelastol is formulated as a unit dosage form, such as a tablet or capsule. The amount of osrelastol in each unit dosage form (e.g., a tablet) may be from about 1 mg to about 40 mg, from about 5 mg to about 35 mg, from 5 mg to 30 mg, from 10 mg to 30 mg, or from 10 mg to 20 mg. In some embodiments, the amount of osrelastol in each unit dosage form (e.g., a tablet) may be from about 10 mg to about 30 mg. In some embodiments, the amount of osrelastol in each unit dosage form (e.g., a 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 osrelastol in each unit dosage form (e.g., a tablet) is 10 mg. In some embodiments, the amount of osrelastol in each unit dosage form (e.g., a tablet) is 20 mg. In some embodiments, the amount of osrelastol in each unit dosage form (e.g., a tablet) is 30 mg. In some embodiments, the amount of orestradiol in each unit dosage form (e.g., tablet) is 40 mg.

[0321] In some embodiments, orestrate is included in the particulate blend composition. The particulate blend composition may comprise: - Oreste; 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 aids, and lubricants; and - Hard capsule shell material.

[0322] The hydrophilic matrix forming agent can be hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), or a mixture thereof. The hydrophilic matrix forming agent can be present in various concentrations and combinations of HPMC from about 10% w / w to about 20% w / w.

[0323] The filler / binder may be selected from lactose monohydrate, hydrated lactose, or microcrystalline cellulose, and mixtures thereof. The filler / binder may be present at 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 aid may be colloidal silica, which may be present at various concentrations of about 0.1% w / w to about 2% w / w.

[0324] The lubricant may be magnesium stearate, which may be present at various concentrations from about 0.1% w / w to about 2% w / w.

[0325] In some embodiments, orestrate is present in the particulate blend composition in an amount of about 1% w / w to about 40% w / w (e.g., 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).

[0326] The blend composition can be dispensed into hard capsules. The capsule shell material of the hard capsule can be made from several materials (such as gelatin (pig, cow, fish, etc.)), and hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol, starch, and pullulan can be used.

[0327] In some embodiments, the particulate blend composition is formulated as a unit dosage form (e.g., a capsule composition). The amount of osrester in each unit dosage form may be from about 1 mg to about 40 mg, or from about 5 mg to about 30 mg. The amount of the compound may be, for example, from 10 mg to 30 mg. In some embodiments, the amount of the compound in a unit dosage form comprising the particulate blend composition may be from about 10 mg to about 30 mg. In some embodiments, the amount of osrester 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.

[0328] Particulate blend compositions can be prepared, for example, by blending and screening of active pharmaceutical ingredients and excipients, followed by granulation, such as rolling and encapsulation. Diseases and Disabilities

[0329] Oresta, administered according to the dosing regimen described herein, may be used to treat or prevent diseases or disorders that improve by inhibiting PDE4.

[0330] In some embodiments, the diseases or disorders treated with orlistat according to the dosing regimen are selected from: inflammatory diseases, autoimmune diseases, central nervous system diseases, cerebrovascular diseases, diabetes, obesity, metabolic syndrome, wounds, and proliferative diseases.

[0331] Inhibition of PDE4 is expected to be beneficial in a wide range of diseases with inflammatory components. Therefore, in a preferred embodiment, the disease or disorder treated with orlistat is an inflammatory disease.

[0332] In some embodiments, the disease or disorder treated with orlistat according to the dosing regimen is an inflammatory disease, such as inflammatory airway disease (e.g., asthma or COPD), allergic rhinitis, acute lung injury, acute respiratory distress syndrome, allergic disease, 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 discoid lupus erythematosus), depression, amnesia, cognitive impairment, dementia, Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, diabetes (e.g., insulin resistance syndrome), acute 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), epidermal inflammation, acne, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritus, eczema, neutrophilic dermatitis (e.g., pyoderma gangrenosa, prurigo nodosa), alopecia, skin atrophy, steroid-induced skin atrophy, skin aging, photoaging of the skin, vitiligo, lichen planus, organ diseases associated with ischemic reflux (e.g., caused by heart failure, shock, and cerebrovascular disease), uveitis, and Behçet's disease (e.g., oral ulcers associated with Behçet's disease).

[0333] In some embodiments, the diseases or disorders treated with ospermia according to the dosing regimen are selected from: dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, including irritant contact dermatitis and allergic contact dermatitis, hand dermatitis, psoriasis, psoriasis vulgaris, plaque psoriasis, inverse psoriasis, nail psoriasis, psoriatic arthritis, spondyloarthritis, epidermal inflammation, alopecia, alopecia areata, rosacea, skin atrophy, steroid-induced skin atrophy, photoaging of the skin, SAPHO syndrome (synovitis, acne, pustular dermatitis). Osteophytes and osteitis), acne vulgaris, hidradenitis suppurativa (HS), urticaria, pruritus, eczema and neutrophilic dermatitis (e.g., pyoderma gangrenosa (PG), pustular PG, atypical / bullous PG, phytotoxic PG, pathological PG, necrotizing fasciitis-like PG, peristomal PG and postoperative PG), Sweet syndrome (SS, also known as acute febrile neutrophilic dermatitis, including bullous SS, pustular SS, giant cellulitis-like SS, necrotizing fasciitis-like SS, drug-induced SS and subcutaneous SS). S), Sneddon-Wilkinson's disease (also known as subkeratotic pustular dermatitis), Behçet's disease, neutrophilic panniculitis, neutrophilic eccrine sweat gland inflammation, persistent erythema raisedis, neutrophilic urticaria, IgA neutrophilic dermatitis, aseptic pustulosis of the folds, Halleau continuous acrodermatitis, acute generalized exanthematous pustulosis, infantile acropustulosis, aseptic abscess, PASH syndrome (pyoderma gangrenosa, acne, and HS), PAPA syndrome (gangrenous pustulosis). Pyoderma, acne and septic arthritis), PASS syndrome (PG, acne conglobata, HS, seropositive spondyloarthritis), PAPASH syndrome (PG, septic arthritis, acne, HS), PsAPASH (psoriatic arthritis, PG, acne, HS), histiocytic neutrophilic dermatitis, dorsolateral neutrophilic dermatitis, intestinal bypass syndrome (intestinal-associated dermatitis-arthritis syndrome), palisade neutrophilic granulomatous dermatitis and VEXAS syndrome. psoriasis

[0334] In some embodiments, the disease or disorder treated with osrelastide according to the dosing regimen is psoriasis. In some embodiments, psoriasis is plaque psoriasis or var. plaque psoriasis. Psoriasis can be mild, moderate, or severe. The severity of psoriasis in a subject can be assessed using known methods, such as: • Static Physician Overall Assessment (sPGA) uses a 5-point scale to determine the severity of psoriasis at a single time point, categorized as clear (0), almost clear (1), mild (2), moderate (3), or severe (4). • Body surface area (BSA) is an estimate of the extent of psoriasis disease or skin involvement and is expressed as a percentage of the total body surface area. Mild psoriasis is considered to be <3%, moderate is 3%-10%, and severe is >10% of the body affected by lesions. The Psoriasis Area and Severity Index (PASI) scores range from 0 to 72, with higher scores reflecting greater disease severity (Fredriksson et al., Dermatologica. [Dermatology] 1978; 157(4):238-244). Erythema, induration / thickness, and scale were scored on a scale of 0 (none) to 4 (extremely severe) across four anatomical regions of the body: head, trunk, upper extremities, and lower extremities. The extent of involvement in each of the four anatomical regions was scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement). The total qualitative score (the sum of the scores for erythema, thickness, and scale) was multiplied by the extent of involvement in each anatomical region, and then multiplied by a constant. The scores for each anatomical region were combined to obtain the final PASI. • Investigator Global Assessment (IGA) for Psoriasis: The IGA is a measure used by physicians to determine the overall severity of a patient’s disease. This trial used a static version (Langley et al., J Dermatolog Treat. 2015 Feb;26(1):23-31) to measure at a single time point as shown in the assessment schedule. Investigators will rate the severity of patients’ psoriasis on a 5-point scale, ranging from 0 (clear) to 4 (severe). The examples provide details on sPGA, BSA, PASI, and IGA for psoriasis.

[0335] The severity of the disease is the baseline severity (i.e., the severity before treatment with orestradiol).

[0336] In some embodiments, psoriasis may be moderate or severe, wherein the subject has PASI ≥ 12, BSA ≥ 10%, and sPGA ≥ 3 prior to treatment with orlistat.

[0337] In some embodiments, the psoriasis is moderate psoriasis, for example, the subject's psoriasis IGA was 3 before treatment with orlistat.

[0338] In some embodiments, psoriasis is severe psoriasis, for example, the subject's psoriasis IGA was 4 before treatment with orlistat.

[0339] In some embodiments, treatment with ospermia ulcerative colitis index (PASI) with the dosing regimen results in a reduction in PASI score relative to baseline. In some embodiments, the PASI score is reduced by 50% (PASI50) or more at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, it is PASI50 or more at week 16 of treatment. In some embodiments, the PASI score is reduced by 75% (PASI75) or more at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, it is PASI75 or more at week 16 of treatment. In some embodiments, the PASI score is reduced by 90% (PASI90) or more at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, it is PASI90 or more at week 16 of treatment. In some embodiments, the PASI score is reduced by 100% (PASI100) at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, it is PASI100 at week 16 of treatment. Details of the PASI assessment are provided in Example 4 of this document.

[0340] In some embodiments, treatment with osrelastide according to the dosing regimen provides a clearance (0) or near-clearance (1) score and an improvement in Investigator Global Assessment (IGA) of at least 2 points. In some embodiments, treatment with osrelastide according to the dosing regimen provides a clearance (0) or near-clearance (1) score at weeks 4, 8, 12, 16, or 20 of treatment and an improvement in IGA of at least 2 points. In some embodiments, treatment with osrelastide according to the dosing regimen provides a clearance (0) score at weeks 4, 8, 12, 16, or 20 of treatment and an improvement in IGA of at least 2 points. 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.

[0341] In some embodiments, treatment with ospermia ulcerative colitis (OSL) according to the dosing regimen reduces the total SLS score relative to baseline. In some embodiments, treatment with ospermia ulcerative colitis (OSL) according to the dosing regimen reduces the total SLS score relative to baseline at weeks 4, 8, 12, 16, or 20 of treatment. For example, treatment may reduce the total SLS score by 1, 2, or 3 points. Details of the PSS are provided in Example 3.

[0342] In some embodiments, treatment with osrelastide according to the dosing regimen provides a static physician global assessment (sPGA) of 0 (cleared) or 1 (nearly cleared). In some embodiments, treatment with osrelastide 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.

[0343] In some embodiments, treatment with ospermia ulcerative collateral reduces the affected body surface area (BSA) relative to baseline according to the dosing regimen. In some embodiments, the dosing regimen reduces BSA by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% relative to baseline. In some embodiments, the dosing regimen reduces BSA by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% relative 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% relative to baseline at week 16 of treatment. Details of BSA are provided in Example 3.

[0344] In some embodiments, treatment with ospermia ulcerative colitis index (DLQI) according to the dosing regimen reduces the DLQI score relative to baseline. In some embodiments, the dosing regimen reduces the DLQI score by ≥ 4 points relative to baseline at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen reduces the DLQI score by ≥ 4 points relative to baseline at week 16 of treatment. In some 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.

[0345] In some embodiments, treatment with orlistat according to the dosing regimen provides a scalp-specific physician overall assessment (ScPGA) of 0 (cleared) or 1 (almost cleared). In some embodiments, treatment with orlistat according to the dosing regimen provides an ScPGA of 0 or 1 at weeks 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen provides an ScPGA of 0 or 1 at week 16 of treatment. Details of ScPGA are provided in Example 4.

[0346] In some embodiments, treatment with osrelastide according to the dosing regimen provides a scalp-specific investigator-wide assessment (ss-IGA) of 0 (cleared) or 1 (nearly cleared). In some embodiments, treatment with osrelastide 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.

[0347] In some embodiments, treatment with orlistat according to the dosing regimen provides a genital static physician overall assessment (sPGA-G) of 0 (clear) or 1 (minimum). In some embodiments, treatment with orlistat according to the dosing regimen provides an sPGA-G of 0 or 1 at weeks 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment. Details of the sPGA-G are provided in Example 4.

[0348] In some embodiments, treatment with osrelastide according to the dosing regimen provides a Physician Overall Assessment (PPPGA) of 0 (cleared) or 1 (nearly cleared). In some embodiments, treatment with osrelastide 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.

[0349] In some embodiments, treatment with orestradiol according to the dosing regimen preferably provides a Physician Overall Assessment of Nail Psoriasis (PGA-F) score of 0 or 1 at week 16 of treatment. Details of the PGA-F are provided in Example 3.

[0350] In some embodiments, treatment with orestradiol according to a dosing regimen reduces the NRS score on generalized pruritus relative to baseline. For example, the dosing regimen reduces the NRS score on generalized pruritus by ≥ 4 points relative to baseline. In some embodiments, the dosing regimen reduces the NRS score on generalized pruritus by ≥ 4 points relative to baseline at weeks 2, 8, 12, or 16 of treatment. Details of the NRS score on generalized pruritus are provided in Example 4.

[0351] In some embodiments, treatment with orestradiol according to a dosing regimen reduces the Numerical Rating Scale (NRS) score relative to baseline. For example, the dosing regimen reduces the NRS score by ≥ 4 points relative to baseline. In some embodiments, the dosing regimen reduces the NRS score by ≥ 4 points relative to baseline at weeks 2, 8, 12, or 16 of treatment. Details of the NRS score are provided in Example 4.

[0352] In some embodiments, treatment with orestradiol according to a dosing regimen reduces the Numerical Rating Scale (NRS) score for pruritus scalp relative to baseline. For example, the dosing regimen reduces the pruritus scalp NRS score by ≥ 4 points relative to baseline. In some embodiments, the dosing regimen reduces the pruritus scalp NRS score by ≥ 4 points relative to baseline at weeks 2, 8, 12, or 16 of treatment. Details of the pruritus scalp NRS are provided in Example 4.

[0353] In some embodiments, treatment with ozenafil according to the dosing regimen achieves a EuroQol 5D-5L quality of life level (EQ-5D-5L). TM The score increased relative to the baseline. Appropriately, EQ-5D-5LTM The score increases by at least 50%, for example, at least 75% or at least 90%. In some embodiments, the dosing regimen makes EQ-5D-5L effective at weeks 2, 8, 12, or 16 of treatment. TM The score must increase by at least 50%, at least 75%, or at least 90% relative to the baseline. EQ-5D-5L TM Details are provided in Example 4.

[0354] In some embodiments, treatment with osrelastide according to the dosing regimen increases the WHO-5 score relative to baseline. Suitably, the WHO-5 score increases by at least 50%, for example at least 75%, or for example at least 90%. In some embodiments, the dosing regimen increases the WHO-5 score by at least 50%, at least 75%, or at least 90% relative to baseline at weeks 2, 8, 12, or 16 of treatment.

[0355] In some embodiments, treatment with osrelastide according to the dosing regimen results in a reduction in the subject's weight relative to baseline. In some embodiments, the dosing regimen results in a reduction of the subject's weight by 5%, 10%, or 15% relative to baseline. In some embodiments, the dosing regimen results in a reduction of the subject's weight by 5%, 10%, or 15% relative to baseline at week 16 of treatment. In some embodiments, the dosing regimen results in a reduction of the subject's weight by ≥ 5% relative to baseline, wherein the subject's baseline BMI is ≥ 30. In some embodiments, the dosing regimen results in a reduction of the subject's weight by ≥ 5% relative to baseline at week 16 of treatment, wherein the subject's baseline BMI is ≥ 30.

[0356] In some embodiments, treatment with orestradiol according to the dosing regimen reduces or eliminates one or more symptoms of psoriasis, such as erythema, induration (plaque elevation), scaling, psoriasis-related pain or itching (itching), and the size (area) of the lesions.

[0357] In some embodiments, the subject with psoriasis has comorbidities, such as obesity, metabolic syndrome, diabetes, inflammatory bowel disease, spondyloarthritis, or any combination thereof. In a particular embodiment, the subject with psoriasis is obese.

[0358] In some embodiments, treatment with osrelastide, according to a dosing regimen, is used to reduce inflammation caused by or associated with psoriasis. In some embodiments, osrelastide is used to reduce inflammation caused by or associated with psoriasis, wherein treatment with osrelastide reduces one or more psoriasis-related inflammatory biomarkers in the subject, such as any psoriasis-related inflammatory biomarkers described in the examples. Therefore, the dosing regimen may reduce C-reactive protein relative to 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% of baseline.

[0359] In some embodiments, treatment with olestradiol according to the dosing regimen satisfies any of the primary, secondary, or tertiary endpoints described in the psoriasis clinical trials disclosed in Examples 3, 4, and 5 of this document. Atopic dermatitis

[0360] In some embodiments, the disease or disorder treated with ospermia according to the dosing 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 recognized methods, such as the Eczema Area and Severity Index (EASI) score. The EASI assessment integrates the intensity of the body surface and affected skin into a comprehensive score. The final EASI score is the sum of the scores of the four regions, ranging from 0 to 72. 0 indicates clear or no eczema, 0.1 to 1.0 indicates almost clear, 1.1 to 7 indicates mild disease, 7.1 to 21 indicates moderate disease, 21.1 to 50 indicates severe disease, and greater than 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 [British Journal of Dermatology] 2015;172(5):1353–1357).

[0361] In some embodiments, atopic dermatitis is moderate to severe atopic dermatitis. Therefore, a subject may have moderate to severe atopic dermatitis with a baseline EASI score ≥ 16. Suitably, a subject with moderate to severe atopic dermatitis has a baseline BSA of ≥ 10% of the affected body surface area (BSA). Suitably, a subject with moderate to severe atopic dermatitis has a baseline IGD-AD of ≥ 3. Suitably, a subject with moderate to severe atopic dermatitis has a baseline peak pruritus NRS of ≥ 4. Suitably, a subject with moderate to severe atopic dermatitis has a baseline weekly mean peak pruritus NRS of ≥ 4.

[0362] In some embodiments, atopic dermatitis is moderate atopic dermatitis. Therefore, a subject may have moderate atopic dermatitis with a baseline EASI score ≥ 16 to ≤ 21. Suitably, a subject with moderate atopic dermatitis has a baseline BSA of ≥ 10% to ≤ 28%. Suitably, a subject with severe atopic dermatitis has a baseline peak pruritus NRS of ≥ 4 to ≤ 7. Suitably, a subject with moderate to severe atopic dermatitis has a baseline weekly mean peak pruritus NRS of ≥ 4 to ≤ 7.

[0363] In some embodiments, atopic dermatitis is severe atopic dermatitis. Therefore, a subject may have severe atopic dermatitis with a baseline EASI score > 21. Suitably, a subject with severe atopic dermatitis has a baseline BSA > 28%. Suitably, a subject with severe atopic dermatitis has a baseline peak pruritus NRS > 7. Suitably, a subject with moderate to severe atopic dermatitis has a baseline weekly mean peak pruritus NRS > 7. In some embodiments, treatment with osrelastide according to the dosing regimen reduces or eliminates one or more symptoms of atopic dermatitis, such as erythema, edema, papules, scratch marks, pruritus, lichenification size (lesion area), or one or more of these.

[0364] In some embodiments, osrelastide is used to reduce inflammation caused by or associated with atopic dermatitis, according to a dosing regimen. In some embodiments, osrelastide is used to reduce inflammation caused by or associated with atopic dermatitis, wherein treatment with osrelastide reduces one or more inflammatory biomarkers associated with atopic dermatitis in the subject. For example, osrelastide can reduce C-reactive protein. In some embodiments, the dosing regimen reduces TARC (thymus activation-regulated chemokine, also known as CCL17) relative to baseline. In some embodiments, the dosing regimen reduces C6A6 relative 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% of baseline. In some embodiments, the dosing regimen increases anti-inflammatory biomarkers in the skin relative to baseline. In some embodiments, the dosing regimen increases anti-inflammatory biomarkers in the blood (e.g., plasma or serum) relative to baseline. In some embodiments, the dosing regimen reduces 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% relative to baseline. In some embodiments, the dosing regimen results in changes in biomarkers at weeks 1, 2, 4, 8, 12, 16, or 20. Skin biomarkers can be collected using tape peeling and analyzed using well-known proteomics methods.

[0365] In some embodiments, treatment with ozenafil according to the dosing regimen reduces the Eczema Area and Severity Index (EASI) score relative to baseline. In some embodiments, the EASI score decreases by 50% (EASI50) at weeks 2, 4, 8, 12, 16, or 20 of treatment. Preferably, the EASI score is 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, the EASI score is 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, the EASI score is 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, the EASI score is at week 16 of treatment. Details of the PASI assessment are provided in Example 8 of this document.

[0366] In some embodiments, treatment with ospermia according to the dosing regimen resulted in a decrease in the Investigator Global Assessment (IGA-AD) score for atopic dermatitis relative to baseline. In some embodiments, treatment with ospermia according to the dosing regimen provided an IGA-AD score of clearance (0) or near clearance (1) and an improvement of at least 2 points relative to baseline. In some embodiments, treatment with ospermia according to the dosing regimen provided an IGA-AD score of clearance (0) or near clearance (1) and an improvement of at least 2 points at weeks 2, 4, 8, 12, 16, or 20 of treatment. In some embodiments, treatment with ospermia according to the dosing regimen provided an IGA-AD score of clearance (0) or near clearance (1) at weeks 2, 4, 8, 12, 16, or 20 of treatment. In some embodiments, treatment with ospermia according to the dosing regimen provided an IGA-AD score of clearance (0) at weeks 2, 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen provided an IGA-AD score of 0 or 1 at week 16 of treatment. Details of the IGA-AD are provided in Example 8.

[0367] In some embodiments, treatment with ospermia according to the dosing regimen reduces the peak pruritus numerical rating scale (PPNRS) score relative to baseline in subjects with atopic dermatitis. In some embodiments, treatment with ospermia according to the dosing regimen reduces the PPNRS score by ≥ 4 points relative to baseline. In some embodiments, treatment with ospermia according to the dosing regimen reduces the PPNRS score by ≥ 4 points relative to baseline at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment. Suitably, treatment with ospermia according to the dosing regimen reduces the PPNRS score by ≥ 4 points relative to baseline at week 1 of treatment. Preferably, treatment with ospermia according to the dosing regimen reduces the PPNRS score by ≥ 4 points relative to baseline at week 2 of treatment. In some embodiments, as described herein, treatment with ospermia according to the dosing regimen reduces the PPNRS score by ≥ 4 points relative to baseline and reduces the score relative to baseline by one or more of the following: EASI, IGA-AD, BSA, DLQI, POEM, PGIS, PGIC, sleep disturbance NRS, and skin pain NRS. In some embodiments, treatment with ospermia serotonin at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment, according to the dosing regimen, results in a PPNRS score reduction of ≥ 4 points relative to baseline and an EASI score reduction of 50% or more (EASI50). In some embodiments, treatment with ospermia serotonin at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment, according to the dosing regimen, results in a PPNRS score reduction of ≥ 4 points relative to baseline and an EASI score reduction of 75% or more (EASI75). In some embodiments, treatment with ospermia serotonin at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment, according to the dosing regimen, results in a PPNRS score reduction of ≥ 4 points relative to baseline and an EASI score reduction of 90% or more (EASI90). In some embodiments, treatment with ospermia serotonin at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment, according to the dosing regimen, results in a PPNRS score reduction of ≥ 4 points relative to baseline and an EASI score reduction of 100% (EASI100). In some embodiments, treatment with ospermia serotonin at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment resulted in a reduction of ≥ 4 points in the PPNRS score relative to baseline and the subject achieved clearance (0) or near-clearance (1) of the IGA-AD score, according to the dosing regimen. In some embodiments, treatment with ospermia serotonin at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment resulted in a reduction of ≥ 4 points in the PPNRS score relative to baseline and the subject achieved clearance (0) of the IGA-AD score, according to the dosing regimen. In any of the above embodiments, treatment with ospermia serotonin may reduce the PPNRS score relative to baseline, for example, by 4, 5, 6, 7, or 8 points. For example, treatment with ospermia serotonin may reduce the PPNRS score to 4 or lower, for example, ≤ 3, ≤ 2, or ≤ 1.For example, treatment with orestradiol can reduce PPNRS to 3, 2, 1 or 0.

[0368] In any of the embodiments described above, the baseline PPNRS may be ≥ 4. In some embodiments, the subject had a PPNRS of at least 4, 5, 6, 7, or 8 at baseline. In some embodiments, the subject may have a PPNRS of 4, 5, 6, 7, or 8 at baseline. Analysis of clinical data from stage 2b atopic dermatitis suggests that subjects with more severe baseline PPNRS may respond particularly well to ospermia treatment and show a rapid decrease in PPNRS scores (see Example 9). Therefore, in any of the embodiments described above, the subject may have a PPNRS of ≥ 7 at baseline.

[0369] Details of the peak pruritus NRS are provided in Examples 8 and 9, where subjects recorded their peak pruritus NRS for the previous day (i.e., the previous 24 hours). Alternatively, the peak pruritus NRS is the weekly average peak pruritus NRS. "Weekly average peak pruritus NRS" refers to the PPNRS score, where subjects recorded their peak pruritus score for the previous day each day of the week, and then the weekly average of each subject's PPNRS score was calculated.

[0370] In some embodiments, treatment with ospermia serotonin according to a dosing regimen reduces the affected body surface area (BSA) relative to baseline. In some embodiments, the dosing regimen reduces BSA by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% of baseline. In some embodiments, the dosing regimen reduces BSA by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% of 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% of baseline at week 16 of treatment. Details of BSA are provided in Example 8.

[0371] In some embodiments, treatment with osrelastide according to a dosing regimen reduces the Dermatology Quality of Life Index (DLQI) relative to baseline. In some embodiments, the dosing regimen reduces the DLQI score by ≥ 4 points relative to baseline at weeks 8, 16, or 20 of treatment. Preferably, the dosing regimen reduces the DLQI score by ≥ 4 points relative to baseline at week 16 of treatment. In some 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.

[0372] In some embodiments, treatment with ospermia ulcerative colitis scale (POEM) according to the dosing regimen reduces the POEM score relative to baseline. In some embodiments, the dosing regimen reduces the POEM score by ≥ 4 points relative to baseline at weeks 2, 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen reduces the POEM score by ≥ 4 points relative to baseline at week 16 of treatment. In some 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 POEM are provided in Example 8.

[0373] In some embodiments, treatment with orlistat according to the dosing regimen reduces the patient's global impression-severity (PGIS) score relative to baseline. In some 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 PGIS are provided in Example 8.

[0374] In some embodiments, treatment with orestradiol, depending on the dosing regimen, reduces the patient's Overall Impression-Change (PGIC) score relative to baseline by 1 or 2. In some 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.

[0375] In some embodiments, treatment with ospermia ulcerative colitis (OLS) according to a dosing regimen reduces the sleep disturbance NRS score relative to baseline. In some embodiments, the dosing regimen reduces the sleep disturbance NRS score by ≥ 4 points relative to baseline at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen reduces the sleep disturbance NRS score by ≥ 4 points relative to baseline at week 16 of treatment. In some embodiments, the dosing regimen provides a sleep disturbance 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 disturbance NRS score of 0 or 1 at week 16 of treatment. Details of the sleep disturbance NRS score are provided in Example 8.

[0376] In some embodiments, treatment with ospermia ulcerative colitis (OLS) according to a dosing regimen reduces the skin pain NRS score relative to baseline. In some embodiments, the dosing regimen reduces the skin pain NRS score by ≥ 4 points relative to baseline at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment. Preferably, the dosing regimen reduces the skin pain NRS score by ≥ 4 points relative to baseline at week 16 of treatment. In some 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.

[0377] In any clinical scoring or efficacy measurement of atopic dermatitis described above or in this document, the reference to an “IGA-AD” score is equivalent to the “vIGA-AD” score described in Example 13. Therefore, a 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” are equivalent and interchangeable in this document. Similarly, a reference to a “peak pruritus NRS” score is equivalent to and interchangeable with a “most severe pruritus NRS”, which is described in Example 13.

[0378] In some embodiments, treatment with orestradiol according to the dosing regimen satisfies any of the primary, secondary, or tertiary endpoints described in the atopic dermatitis clinical trials disclosed in Examples 8 and 13 herein. suppurative hidradenitis

[0379] In some embodiments, the disease or disorder treated with orestradiol according to the dosing regimen is hidradenitis suppurativa (HS).

[0380] Subjects may have mild, moderate, or severe HS. In some embodiments, subjects have mild HS. In some embodiments, subjects have moderate HS. In some embodiments, subjects have severe HS.

[0381] The severity of HS can be assessed using known scoring methods. For example, severity (also known as disease state or progression) can be defined using the Internationalized Hidradenitis Severity Scoring System (IHS4), a validated international clinical measurement scale (Zouboulis et al., Br J Dermatol [British Journal of Dermatology]. 2017;177(5):1401-1409). The score is based on the count of inflammatory lesions. The resulting IHS4 score is obtained by adding the number of nodules (multiplied by 1) to the number of abscesses (multiplied by 2) to the number of drainage tubes (multiplied by 4). A total score of 4 or lower indicates mild, 4-10 indicates moderate, and 11 or higher indicates severe disease. In some embodiments, subjects with HS have comorbidities selected from obesity, metabolic syndrome, inflammatory bowel disease, spondyloarthritis, or any combination thereof.

[0382] In some embodiments, the subject has not previously been treated with antibodies or other biological therapies targeting HS. In some embodiments, the subject has not previously been treated with a TNF-α inhibitor (e.g., adalimumab).

[0383] In other embodiments, the subject has previously been treated with antibodies or other biological therapies targeting HS. In some embodiments, the subject has previously been treated with anti-inflammatory antibodies. In some embodiments, the subject has previously been treated with a TNF-α inhibitor (e.g., adalimumab). The subject may be unresponsive or refractory to prior antibody therapy for HS, for example, where the subject is unresponsive or refractory to treatment with a TNF-α inhibitor (e.g., adalimumab). This article mentions "biological therapies for HS" including anti-TNF-α biologics (e.g., adalimumab, certolizumab, infliximab, etanercept, or golimumab); anti-IL-17 biologics (e.g., bimekizumab, brodalumab, CJM112, ixekizumab, or secukinumab); and anti-IL-12 / 23 biologics (e.g., ustekinumab); anti- IL-23 biologics (e.g., guselkumab, risankizumab, or tildrakizumab); anti-IL-1 biologics (e.g., anakinin, bermkimab, or canakinumab); anti-CD (e.g., iscalimab); or anti-IL-36 biologics (e.g., spesolimab or isidolimab); anti-CXCR1 / CXCR2 biologics (e.g., LY 3041658); or complement C5a inhibitors; or any combination thereof. In some embodiments, the biologic therapy for HS is an anti-TNF-α biologic (e.g., adalimumab or infliximab). In some embodiments, the biologic therapy for HS is adalimumab.

[0384] In some embodiments, ospermia is used to treat symptoms of HS according to a dosing regimen. For example, the compound can be used to eliminate inflammatory nodules, abscesses, comedones, and / or sinus tracts, or to reduce their number, severity, and / or spread. In some embodiments, the compounds of the present invention are used to eliminate or reduce abscesses, nodules, and / or draining fistulas caused by or associated with HS. In some embodiments, the compounds of the present invention are used to eliminate or reduce abscesses and / or nodules caused by or associated with HS.

[0385] In some embodiments, treatment with osrelastide, according to a dosing regimen, reduces inflammation caused by or associated with HS. In some embodiments, osrelastide is used to reduce inflammation caused by or associated with HS, wherein the compound reduces one or more inflammatory biomarkers associated with HS in the subject. For example, relative to baseline levels prior to treatment with osrelastide, osrelastide may reduce one or more of the following: C-reactive protein (e.g., high-sensitivity C-reactive protein (hs-CRP)); erythrocyte sedimentation rate; white blood cell count; or platelet count.

[0386] In some embodiments, treatment with ospermiazide, depending on the dosing regimen, reduces the total number of abscesses and nodules (AN count) prior to ospermiazide treatment. For example, the AN count decreases by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% relative to baseline. In some embodiments, the AN count decreases by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% relative 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% relative to baseline at week 16 of treatment.

[0387] In some embodiments, treatment with orestradiol according to the dosing regimen eliminates or reduces pruritus caused by or associated with HS.

[0388] In some embodiments, orelastide treatment according to a dosing regimen is used to eliminate or reduce swelling caused by or associated with HS. For example, orelastide can reduce swelling in HS lesions.

[0389] In some embodiments, orestradiol treatment according to the dosing regimen is used to eliminate or reduce scar formation caused by or associated with HS.

[0390] In some embodiments, oristil treatment, according to a dosing regimen, is used to reduce the size of HS-related lesions. For example, the compound can be used to reduce or eliminate HS-related lesions.

[0391] In some embodiments, orestrate treatment according to the dosing regimen is used to relieve pain caused by or associated with HS.

[0392] Pain can be assessed using the 0-10 Numerical Rating Scale (NRS) based on the patient’s overall assessment of skin pain (0 = no pain, 10 = most severe imaginable pain) (Newton et al., J Patient Rep Outcomes. 2019;3(1):42). Appropriately, a reduction in NRS of at least 30% compared to baseline is required. Other well-known pain scoring systems can be used to assess pain relief associated with HS. For example, pain relief can also be assessed using the Visual Analogue Scale for Pain (VAS Pain), which also assesses pain on a visual scale from 0 (no pain) to 10 (most severe imaginable pain).

[0393] Pain can also be assessed using the McGill Pain Questionnaire. The McGill Pain Questionnaire can be used to evaluate the sensation, intensity, and changes over time of experienced pain. It can monitor pain over time or determine the effectiveness of interventions (Melzack, Pain, September 1975, Vol. 1, No. 3, pp. 277-299).

[0394] In some embodiments, HS-related pain is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% relative to baseline pain levels prior to treatment with ospermia ulmosiderin, using a suitable pain scoring method (e.g., one of the scoring methods described herein). In some embodiments, HS-related pain is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% relative to baseline at weeks 2, 4, 8, 12, 16, or 20 of treatment. In some embodiments, HS-related pain is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% relative to baseline at week 16 of treatment.

[0395] In some embodiments, the total HisQoL score of patients treated with the compound decreases during the treatment period. In some embodiments, the subject's HisQoL decreases by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% relative to baseline levels prior to treatment with ospermia ulcerative collateral. Suitably, the patient's HisQoL decreases by at least 50%, such as at least 75% or such as at least 90%. In some embodiments, the patient's HisQoL decreases by at least 50%, such as at least 75% or such as at least 90%, at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment.

[0396] HiSQOL is based on the work of the international collaboration on the core outcome set for hidradenitis suppurativa (HISTORIC). Developed and validated systematically, HiSQOL is a 17-item questionnaire that includes HS-specific items such as drainage and odor, in addition to more general skin-specific items. HiSQOL is an HS-specific questionnaire designed to evaluate HRQOL in clinical trials (Thorlacius et al., Skin Appendage Disorder. 2019, 5(4):221-229; Kirby et al., Br...). J Dermatol [British Journal of Dermatology]. Aug 2020;183(2):340-348). Its review period was 7 days and consisted of 17 items divided into three domains: four symptom problems, five psychosocial problems, and eight activity adaptation problems. For each item, a score between 0 and 4 was given, with higher scores indicating a greater adverse effect on HRQOL. In some embodiments, subjects' HRQOL decreased by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% relative to baseline levels before treatment with ospermia ulcerative colitis (HS). In some embodiments, at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment, subjects' HRQOL decreased by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% relative to baseline.

[0397] In some embodiments, the clinical response rate (HiSCR) of 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% relative to baseline levels prior to treatment with osrelastol. In some embodiments, the patient's HiSCR decreases by at least 50% relative to baseline, such as at least 75% or such as at least 90%. In some embodiments, at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment, the patient's HiSCR decreases by at least 50% relative to baseline, such as at least 75% or such as at least 90%.

[0398] HiSCR is a treatment target based on the correlation between changes in lesion counts and PROM (pain and HRQoL). Clinical response to hidradenitis suppurativa (HiSCR; a ≥ 50% reduction in abscess and inflammatory nodule counts relative to baseline, without an increase in abscess or draining fistula counts) was defined as follows: (Kimball et al., Ann Intern Med [Annals of Internal Medicine]. 18 Dec 2012; 157(12): 846-55; Kimball et al., J Eur Acad Dermatol Venereol [Journal of the European Society of Dermatology and Venereology]. 20 Jun 2016; 30(6): 989-94). This was subsequently modified for further differentiation: HiSCR75; a ≥ 75% reduction in abscess and inflammatory nodule counts relative to baseline, without an increase in abscess or draining fistula counts) and HiSCR-90; a ≥ 90% reduction in abscess and inflammatory nodule counts relative to baseline, without an increase in abscess or draining fistula counts.

[0399] In some embodiments, the physician's overall assessment of disease severity (HS-PGA) of patients treated with orlistat decreases during the treatment period. Suitably, the patient's HS-PGA score decreases to 0 or 1 during or after treatment. 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 of treatment.

[0400] HS-PGA ranges from clearance to severe (Kimball et al., Ann Intern Med [Annals of Internal Medicine]. 2012 Dec 18;157(12):846-55). It was used in clinical trials to measure clinical improvement in inflammatory nodules, abscesses, and draining fistulas. The six phases were: Clearance: No inflammatory or non-inflammatory nodules. Mildest: Only non-inflammatory nodules are present. 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 2-5 abscesses or draining fistulas and fewer than 10 inflammatory nodules. Severe: 2-5 abscesses or draining fistulas and 10 or more inflammatory nodules. Extremely severe: More than 5 abscesses or drainage.

[0401] In some embodiments, the dosing regimen reduces the severity of HS in the subject. For example, the dosing regimen may reduce the severity by one or more (e.g., 1, 2, or 3) HS-PGA levels. Thus, the dosing regimen may reduce the severity of HS from very severe to severe, moderate, or mild HS. In some embodiments, the dosing regimen reduces the severity of HS from very severe to severe, moderate, or mild HS at week 16 of treatment.

[0402] In some embodiments, the compound reduces the amount of C-reactive protein (e.g., high-sensitivity C-reactive protein (hs-CRP)) in patients treated with the compound. Suitably, 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% relative to baseline levels prior to treatment with the compound. For example, the amount of C-reactive protein (e.g., hs-CRP) is reduced by at least 50%, such as at least 75% or such as at least 90%. In some embodiments, the dosing regimen reduces C-reactive protein by at least 50%, such as at least 75% or such as at least 90%, at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment.

[0403] In some embodiments, the dermatological quality of life index (DLQI) of subjects 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% relative to baseline levels prior to treatment with the compound for HS. In some embodiments, the subject's DLQI decreases by at least 50%, such as at least 75% or such as at least 90%. In some embodiments, the dosing regimen reduces the DLQI by at least 50%, such as at least 75% or such as at least 90% at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment.

[0404] The DLQI is a 10-question questionnaire that asks patients about their perceptions of the impact of a skin condition on different aspects of their health-related quality of life over the past week. Each question is scored on a four-point scale (0-3), ranging from 0 to 30 (0 = no impact on quality of life, 30 = the greatest impact on quality of life). The validated scale was first introduced by Finlay and Khan, Clin. Exp. Dermatol. [Clinical Experimental Dermatology], 19 (1994), pp. 210-216.

[0405] In some embodiments, the percentage of impairment on the Working Performance Inventory (WPAI) of patients treated with the compound decreases during the treatment period. Suitably, the patient's impairment score decreases by at least 50%, such as at least 75% or such as at least 90%. In some embodiments, the patient's impairment score decreases by at least 50%, such as at least 75% or such as at least 90%, at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment.

[0406] WAPI is a questionnaire describing work impairments caused by specific diseases. Outcomes are expressed as a percentage of impairment, with higher numbers indicating greater impairment and lower efficiency (Reilly et al., Pharmacoeconomics. November 1993;4(5):353-65).

[0407] In some embodiments, the anxiety and depression (HADS) scores of subjects treated with the dosing regimen decrease relative to baseline. Suitably, the patient's HADS score decreases by at least 50%, such as at least 75% or such as at least 90%. In some embodiments, the dosing regimen reduces the HADS score by at least 50%, such as at least 75% or such as at least 90%, at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment.

[0408] The HADS is a questionnaire consisting of seven anxiety questions and seven depression questions. Each question is associated with four answers and is scored from 0 to 3. For each case, 0-7 corresponds to a normal case; 8-10 corresponds to a borderline abnormal case; and 11-21 corresponds to an abnormal case (Zigmond and Snaith, Acta Psychiatrica Scandinavica [Scandinavian Journal of Psychiatry] (1983), 67(6): 361-370).

[0409] In some embodiments, the European Quality of Life-5 Dimensions (EQ-5D) score of the subject treated with the dosing regimen increases relative to baseline during treatment. Suitably, the patient's EQ-5D score increases by at least 50%, such as at least 75% or such as at least 90%. In some embodiments, at weeks 2, 4, 8, 12, 16, or 20 of treatment, preferably at week 16 of treatment, the dosing regimen results in an EQ-5D score increasing by at least 50%, such as at least 75% or such as at least 90%, relative to baseline.

[0410] The EQ-5D is a standardized tool for measuring general health status across five dimensions: mobility, self-care, daily activities, pain / discomfort, and anxiety / depression. Each dimension receives a value from 1 to 5, leaving 55 (55) different health statuses. This score is combined with an overall patient health rating of 0-100, where 0 is the worst conceivable health and 100 is the best conceivable health. This scale was further developed by Herdman et al., Qual Life Research. 2011 Dec; 20(10):1727-36, based on the original EQ-5D.

[0411] In some embodiments, patients treated with the dosing regimen showed improved responses to the Multidimensional Fatigue Scale 20 (MFI-20) relative to baseline. The MFI-20 was developed by Smets et al., J Psychosom Res [Journal of Psychosomatic Research] 1995; 39: 315–25. It consists of 20 items describing five fatigue subscales: general fatigue (GF), physical fatigue (PF), decreased motivation (RM), reduced activity (RA), and mental fatigue (MF). For each item, the respondent must specify the degree to which a particular statement is relevant to him / her on a five-point scale, ranging from yes (fact) to no (not true).

[0412] In some embodiments, orelastide treatment according to a dosing regimen is used to prevent or reduce HS attacks in a subject. In some embodiments, orelastide is used to reduce the severity of HS attacks in a subject. In some embodiments, orelastide treatment according to a dosing regimen is used to reduce the frequency of HS attacks in a subject. In some embodiments, orelastide treatment according to a dosing regimen is used to reduce both the frequency and severity of HS attacks in a subject. colitis

[0413] In some embodiments, the disease or disorder treated with orlistat according to the dosing regimen is colitis, such as ulcerative colitis. Itching associated with atopic dermatitis (sixth aspect of the invention)

[0414] As illustrated in this example, analysis of phase 2b clinical trial data from a study of subjects with moderate to severe atopic dermatitis treated with oral ospermia revealed a surprisingly strong and rapid effect of ospermia on pruritus. At week 2 of ospermia treatment, all active groups in the study showed a significant reduction in peak pruritus NRS (PPNRS) of ≥4 points relative to baseline (MI, p < 0.05 compared to placebo). In subjects with baseline PPNRS > 7, all active groups in the clinical trial demonstrated statistically significant improvement in PPNRS relative to baseline at week 16, with a reduction of ≥ 4 points (observed, p < 0.05 or p < 0.1 compared to placebo).

[0415] Itching is a particularly prominent symptom in subjects with atopic dermatitis. Interestingly, the efficacy of known treatments for atopic dermatitis in treating pruritus is not always correlated with the efficacy in treating atopic dermatitis (Rodriguez-Le Roy Y et al., Efficacy of topical and systemic treatments for atopic dermatitis onpruritus: A systematic literature review and meta-analysis. Front Med (Lausanne). Dec 22, 2022;9:1079323. doi: 10.3389 / fmed.2022.1079323. PMID:36619624; PMCID: PMC9814490). Therefore, new treatments for pruritus associated with atopic dermatitis are needed.

[0416] Therefore, a sixth aspect of the invention provides orestrate for use in a method of treating pruritus associated with atopic dermatitis in a subject, the method comprising administering a therapeutically effective amount of orestrate to the subject.

[0417] A method for treating pruritus associated with atopic dermatitis in a subject is also provided, the method comprising administering a therapeutically effective amount of orestradiol to the subject.

[0418] The use of orestradiol in the manufacture of a medicine for treating pruritus associated with atopic dermatitis in subjects is also provided, wherein the treatment comprises administering a therapeutically effective amount of orestradiol to the subject.

[0419] In some embodiments of the sixth aspect of the 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 baseline at at least 10% of body surface area (BSA), an IGA-AD grade of at least 3, and an Eczema Area and Severity Index (EASI) score of ≥16. In some embodiments, the subject has a baseline EASI score >21.

[0420] In some embodiments of the sixth aspect of the invention, the subject has a PPNRS of at least 4 at baseline. For example, the subject may have a PPNRS of at least 4, 5, 6, 7, or 8 at baseline. In some embodiments, the subject may have a PPNRS of 4, 5, 6, 7, or 8 at baseline. In some embodiments, the subject has a baseline PPNRS > 7. In some embodiments, the subject has severe pruritus at baseline, for example, a baseline PPNRS > 7.

[0421] Details of the PPNRS are provided in Example 8. As described, the severity of pruritus (itching) can be assessed using a level 11-point NRS. Subjects may be asked to rate their “most severe pruritus caused by AD in the past 24 hours” on the NRS, anchored by the terms “no pruritus” (0) and “most severe pruritus possible” (10). In some embodiments, the PPNRS is the average PPNRS at the measurement time point of the previous day. In some embodiments, the PPNRS is the weekly average of the daily PPNRS scores determined in this manner.

[0422] Typically, treatment with osrelastide reduces a subject's PPNRS. For example, treatment can reduce the PPNRS by at least 4 points relative to baseline, such as at least 5 or 6 points relative to baseline. In some embodiments, treatment with osrelastide reduces the PPNRS by 4, 5, or 6 points relative to baseline. In some embodiments, treatment with osrelastide can reduce the absolute PPNRS to 4 or lower, such as ≤ 3, ≤ 2, or ≤ 1. For example, treatment with osrelastide can reduce the absolute PPNRS to 3, 2, 1, or 0.

[0423] Treatment with ospermia ulcerative colitis (PPNRS) can reduce PPNRS during weeks 1, 2, 4, 8, 12, 16, or 20 of treatment, for example, during weeks 1, 2, 8, or 16 of treatment. As shown in Example 9, treatment with ospermia ulcerative colitis results in a rapid reduction in PPNRS. Therefore, in some embodiments of the sixth aspect of the invention, treatment with ospermia ulcerative colitis reduces PPNRS during week 2 of treatment. In some embodiments, treatment with ospermia ulcerative colitis reduces PPNRS during week 1 of treatment.

[0424] In some embodiments of the sixth aspect of the invention, treatment with osiristar reduces the PPNRS score by ≥ 4 points relative to baseline at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment. Suitably, treatment with osiristar reduces the PPNRS score by ≥ 4 points relative to baseline at week 2 or week 16 of treatment. In some embodiments, osiristar reduces the PPNRS score by ≥ 4 points relative to baseline at week 1 of treatment. Preferably, osiristar reduces the PPNRS score by ≥ 4 points relative to baseline at week 2 of treatment.

[0425] In some embodiments of the sixth aspect of the invention, treatment with ospermia also results in an improvement in one or more additional efficacy measures of atopic dermatitis treatment. For example, treatment may also reduce one or more additional atopic dermatitis measures described herein relative to baseline. In some embodiments, as described herein, treatment with ospermia may reduce one or more of the following relative to baseline: EASI, IGA-AD, BSA, DLQI, POEM, PGIS, PGIC, sleep disturbance NRS, and skin pain NRS. In some embodiments, as described herein, treatment with ospermia reduces PPNRS relative to baseline (e.g., a reduction of ≥ 4 points in PPNRS at week 2 or week 16 of treatment), and also reduces one or more of EASI and IGA-D relative to baseline. In some embodiments, treatment reduces PPNRS relative to baseline (e.g., a reduction of ≥ 4 points in PPNRS at week 2 or week 16 of treatment), and also provides 0 or 1 IGA-AD at week 16 of treatment. As described herein, treatment with ospermia may cause changes in one or more biomarkers in the skin, such as a reduction in TARC relative to baseline. In some embodiments, treatment with orlistat at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment (e.g., week 16 of treatment) reduces TARC by at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

[0426] In some embodiments of the sixth aspect of the invention, treatment with ospermia ulmosiderin at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment (e.g., week 16 of treatment) results in a reduction of ≥ 4 points in the PPNRS score relative to baseline and a reduction of 50% (EASI50) or more in the EASI score. In some embodiments, treatment with ospermia ulmosiderin at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment (e.g., week 16 of treatment) results in a reduction of ≥ 4 points in the PPNRS score relative to baseline and a reduction of 75% (EASI75) or more in the EASI score. In some embodiments, treatment with ospermia ulmosiderin at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment (e.g., week 16 of treatment) results in a reduction of ≥ 4 points in the PPNRS score relative to baseline and a reduction of 90% (EASI90) or more in the EASI score. In some embodiments, treatment with ospermia ulcerative colitis (OSP) at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment (e.g., week 16 of treatment) resulted in a reduction of ≥ 4 points in the PPNRS score relative to baseline and a 100% reduction in the EASI score (EASI100). In some embodiments, treatment with ospermia ulcerative colitis (OSP) at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment (e.g., week 16 of treatment) resulted in a reduction of ≥ 4 points in the PPNRS score relative to baseline, and the subject achieved a clearance (0) or near-clearance (1) IGA-AD score. In some embodiments, treatment with ospermia ulcerative colitis (OSP) at weeks 1, 2, 4, 8, 12, 16, or 20 of treatment (e.g., week 16 of treatment) resulted in a reduction of ≥ 4 points in the PPNRS score relative to baseline, and the subject achieved a clearance (0) IGA-AD score. In any of the above embodiments, treatment with ospermia ulcerative colitis (OSP) may result in a reduction of 4, 5, 6, 7, or 8 points in the PPNRS score relative to baseline.

[0427] In any embodiment of the sixth aspect of the invention, the baseline PPNRS may be ≥ 4. In some embodiments, the subject has a PPNRS of at least 4, 5, 6, 7, or 8 at baseline. In some embodiments, the subject may have a PPNRS of 4, 5, 6, 7, or 8 at baseline.

[0428] Analysis of clinical data from stage 2b atopic dermatitis suggests that subjects with more severe baseline PPNRS may respond particularly well to ospermia ulcerative colitis treatment and show a rapid decrease in PPNRS scores (see Example 9). Therefore, in any embodiment of the sixth aspect of the invention, baseline PPNRS may be ≥ 7.

[0429] In some embodiments of the sixth aspect of the invention, according to the first to fifth aspects of the invention, a subject is treated with orlistat according to any dosing regimen described herein and its variations.

[0430] In some embodiments of the sixth aspect of the invention, the treatment of the subject is as described herein with respect to other aspects of the invention, for example, involving any of orexusone, pharmaceutical compositions, and combination therapies.

[0431] In a sixth aspect of the invention, the reference to an “IGA-AD” score is equivalent to the “vIGA-AD” score described in Example 13. Therefore, a 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” are equivalent and interchangeable herein. Similarly, a reference to a “peak pruritus NRS” score is equivalent to and interchangeable with “most severe pruritus NRS,” which is described in Example 13. Combination therapy

[0432] Oresta, or formulations or compositions containing this compound, may be used alone to provide a therapeutic effect. Oresta, or formulations or compositions containing this compound, may also be used in combination with other therapies.

[0433] In some embodiments, additional therapies are selected from antiandrogens, hormones, antibiotics (e.g., dapsone, doxycycline, clindamycin, rifampin, or carbapenems (e.g., ertapenem)), retinoids, vitamin D analogs, anti-inflammatory agents (including steroids (e.g., budesonide, prednisolone)), nonsteroidal anti-inflammatory agents, colchicine, mycophenolate mofetil, thioguanine, hydroxyurea, sulfasalazine, azathioprine, or fumarate, PDE4 inhibitors other than orexine, analgesics, immunosuppressants (e.g., tacrolimus, pimecrolimus, sirolimus, or cyclosporine), methotrexate, anthralin / dithroxyphene, metformin, nutritional supplements (e.g., zinc gluconate), TNF-α inhibitors (e.g., adalimumab, etanercept, infliximab, or pecelizumab), and IL-1 inhibitors (e.g., anaspirin), anti-IL-17 agents (including IL-17A, I...). L-17F and IL17AF drugs (e.g., secukinumab, bimegitizumab, brodatumab, or ixekizumab) and anti-IL-23 drugs (e.g., radizumab, tetragergizumab, or gusecurumab), anti-IL-12 / 23 drugs (e.g., ustekinumab), anti-IL-12 drugs, anti-IL-23 drugs (e.g., gusecurumab), Janus kinase (JAK) inhibitors (e.g., baricitinib, abuxitinib, tofacitinib, povoxitinib (also known as INCB054707), or utpatinib), anti-IL-4 / 13 drugs (e.g., dupilumab), tyrosine kinase 2 (TYK2) inhibitors (e.g., deuterocecixinib), TYK2 / JAK1 inhibitors (e.g., PF-06700841), complement C5a inhibitors (e.g., avacopan), leukotriene A4 hydrolase inhibitors (e.g., LYS) 006), leukotriene A4 hydrolase inhibitors (e.g., LYS 006), IRAK4 degraders (e.g., KT-474), IRAK4 inhibitors (e.g., PF-06650833), phototherapy (e.g., ultraviolet B [UVB], psoralen, and ultraviolet A [PUVA] radiation), and surgery or any combination thereof.

[0434] In some embodiments, an additional treatment is a topical steroid, such as a topical steroid selected from: amcinonide, clobetasol (e.g., clobetasol propionate or clobetasol butyrate), betamethasone (e.g., betamethasone dipropionate or betamethasone valerate), desonide, deshydroxymethasone, diflubenzuron, diflucolone (e.g., diflucolone valerate), fluocinolone acetonide, fluocinolone acetonide, fluticasone propionate, fluticasone propionate, halcinonide, halometasol propionate, halometasol, hydrocortisone (e.g., hydrocortisone, hydrocortisone butyrate, hydrocortisone acetate or hydrocortisone valerate), mometasone (e.g., mometasone furoate), methylprednisolone (e.g., methylprednisolone ethylpropionate), and triamcinolone (e.g., triamcinolone acetonide), or a combination of two or more thereof.

[0435] Such combination therapy can be achieved by administering the individual components of the therapy simultaneously, sequentially, or separately. These combination products utilize the orestradiol dosing regimen of the present invention, along with other pharmaceutically active agents within their approved dosage range.

[0436] In this document, the term "combination" is understood to mean simultaneous, separate, or sequential application. In one aspect of the invention, "combination" means simultaneous application. In another aspect of the invention, "combination" means separate application. In yet another aspect of the invention, "combination" means sequential application. In the case of sequential or separate application, delaying the application of the second component should not result in the loss of the beneficial effects of the combination. Example

[0437] The following numbered embodiments further illustrate the present invention. A1. A method for treating a disease or disorder in a subject that improves by inhibiting PDE4, the method comprising administering orlistat to the subject, in: (Ai) The initial dose of orexate was administered to the subject once daily for the initial period, and then; (Aii) Administer the transitional dose of orlistat to the subject twice daily during the transition period, then; (Aiii) Administer a maintenance dose of orexusone twice daily to the subject; in: (a) The initial orinexetine dose and the transition orinexetine dose are independently selected from 10 mg to 30 mg of orinexetine, provided that the transition orinexetine dose is greater than or equal to the initial orinexetine dose; (b) The initial time period is two to eight weeks; (c) The transition period is one to eight weeks; and (d) When the subject’s weight is greater than or equal to the threshold weight, the maintenance dose of orexus is greater than the transition dose of orexus, wherein the threshold weight is at least 90 kg. A2. The method according to Example A1, wherein the initial olivate dose and the transition olivate dose are the same; Optionally, both the initial orinester dose and the transition orinester dose are 20 mg orinester. A3. The method according to Example A1 or Example A2, wherein when the subject's weight is less than the threshold weight, the maintenance oxiracetam dose is the same as the transition oxiracetam dose. A4. The method according to any one of Examples A1 to A3, wherein when the subject's weight is greater than or equal to the threshold weight, the maintenance orelastide dose is up to 40 mg orelastide, provided that the maintenance orelastide dose is greater than the transition orelastide dose. A5. The method according to any one of Examples A1 to A4, wherein when the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexate is 30 mg orexate. A6. The method according to any one of embodiments A1 to A5, wherein the initial time period is two to six weeks; Optionally, the initial time period may be two weeks, four weeks, or six weeks. A7. The method according to any one of embodiments A1 to A5, wherein the initial time period is two weeks. A8. The method according to any one of embodiments A1 to A7, wherein the transition period is one to six weeks; Optionally, the transition period may be two weeks, four weeks, or six weeks; Alternatively, the transition period may be two weeks. A9. The method according to any one of embodiments A1 to A7, wherein the total duration of the initial time period and the transition time period is four to eight weeks; Optionally, the total duration of the initial time period and the transition period is eight weeks. A10. The method according to any one of embodiments A1 to A12, wherein: (i) When the subject's weight is below the lower limit, the initial orelastine dose in (Ai), the transition orelastine dose in (Aii), and the maintenance orelastine dose in (Aiii) are all 10 mg orelastine; or (ii) When the subject's weight is within the range of the lower limit weight to less than the threshold weight, the initial orelastide dose in (Ai), the transition orelastide dose in (Aii), and the maintenance orelastide dose in (Aiii) are all 20 mg orelastide; The lower limit of this weight ranges from 50 kg to 75 kg. A11. The method according to any one of Examples A1 to A12, wherein when the subject's weight is less than the lower limit weight, the initial oxiracetam dose, the transition oxiracetam dose, and the maintenance oxiracetam dose are all 10 mg oxiracetam; The lower limit of this weight is 50 kg to 75 kg; Optionally, when the subject's weight is less than 60 kg, the initial orinester dose, the transition orinester dose, and the maintenance orinester dose are all 10 mg orinester. A12. The method according to Example A1, wherein when the subject's weight is within the range of lower limit weight to less than the threshold weight, the initial oxiracetam dose, the transition oxiracetam dose, and the maintenance oxiracetam dose are all 20 mg oxiracetam; The lower limit of this weight is 50 kg to 75 kg; Optionally, when the subject's weight is in the range of 60 kg to less than the threshold weight, the initial orinester dose, the transition orinester dose, and the maintenance orinester dose are all 20 mg orinester. A13. The method according to embodiment A1, wherein: (Ai) The initial dose of olivrazine was 20 mg olivrazine, administered to the subject once daily for two weeks; (Aii) The transitional dose of olivrazine was 20 mg olivrazine administered to the subject twice daily for two weeks; and (Aiii) If the subject's weight is below the threshold weight, the maintenance dose of orexate is 20 mg orexate twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexate is 30 mg orexate, administered to the subject twice daily. A14. The method according to embodiment A1, wherein: (Ai) The initial dose of olivrazine was 20 mg olivrazine, administered to the subject once daily for two weeks; (Aii) The transitional dose of olivrazide was 20 mg olivrazide administered to the subject twice daily for four weeks; and (Aiii) If the subject's weight is below the threshold weight, the maintenance dose of orexate is 20 mg orexate twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexate is 30 mg orexate, administered to the subject twice daily. A15. The method according to embodiment A1, wherein: (Ai) The initial dose of olivrazine was 20 mg olivrazine, administered to the subject once daily for two weeks; (Aii) The transitional dose of orexusone was 20 mg orexusone administered to the subject twice daily for six weeks; (Aiii) If the subject's weight is below the threshold weight, the maintenance dose of orexate is 20 mg orexate twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexate is 30 mg orexate, administered to the subject twice daily. A16. The method according to embodiment A1, wherein (Ai) If the subject's weight is below the lower limit, the initial dose of osrelastide is 10 mg osrelastide administered once daily for two to four weeks, or If the subject's weight is between the lower limit and the threshold, the initial dose of orexusone is 20 mg orexusone, administered to the subject once daily for two to four weeks. (Aii) If the subject's weight is below the lower limit, the transitional dose of orexusone is 10 mg orexusone twice daily for one to eight weeks; or If the subject's weight is between the lower limit and below the threshold, the transitional olivate dose is 20 mg olivate administered twice daily for one to eight weeks; and (Aiii) If the subject's weight is below the lower limit, the maintenance dose of olivraz is 10 mg olivraz, administered to the subject twice daily; or If the subject's weight is between the lower limit and below the threshold, the maintenance dose of orexamin is 20 mg orexamin administered twice daily; or If the subject's weight is greater than or equal to the threshold weight, the maintenance dose of orexusone is 30 mg orexusone, administered to the subject twice daily. The lower limit of this weight ranges from 50 kg to 75 kg. A17. The method according to Example A16, wherein the lower limit weight is selected from 50 kg, 55 kg, 60 kg, 65 kg, 70 kg and 75 kg; The lower limit of the weight is 50 kg; The lower limit of the weight is 60 kg. A18. The method according to any one of embodiments A1 to A17, wherein the threshold body weight is 90 kg. A19. The method according to any one of embodiments A1 to A17, wherein the threshold body weight is 95 kg. A20. The method according to any one of embodiments A1 to A17, wherein the threshold weight is 100 kg. A21. The method according to any one of embodiments A1 to A17, wherein the threshold body weight is 105 kg. A22. The method according to any one of Examples A1 to A21, wherein the initial dose of orlistat is administered to the subject at night. A22. The method according to any one of Examples A1 to A21, wherein the initial dose of orestradiol is administered to the subject in the morning. A23. The method according to any one of Examples A1 to A22, wherein the maintenance dose of orestradiol is administered to the subject twice daily for at least one week, such as for at least one month, at least six months or at least one year. A24. A method for treating a disease or disorder in a subject whose weight is greater than or equal to a threshold weight by inhibiting PDE4, the method comprising administering orlistat to the subject. in: (Bi) The initial dose of orlistat was administered to the subject once daily for the initial period, and then; (Bii) Administer the transitional dose of orlistat to the subject twice daily during the transition period, then; (Biii) The subject was given a maintenance dose of orinelast twice daily, wherein the maintenance dose of orinelast was greater than the transition dose of orinelast. in: (a) The initial orinexetine dose and the transition orinexetine dose are independently selected from 10 mg to 30 mg of orinexetine, provided that the transition orinexetine dose is greater than or equal to the initial orinexetine dose; (b) The initial timeframe is one to eight weeks; (c) The transition period lasts for eight weeks; and (d) The threshold weight is at least 90 kg. A25. The method according to Example A24, wherein the initial oxiracetam dose and the transition oxiracetam dose are the same; Optionally, both the initial orinester dose and the transition orinester dose are 20 mg orinester. A26. The method according to Example A24 or Example A25, wherein the maintenance dose of orexine is up to 40 mg of orexine, provided that the maintenance dose of orexine is greater than the transition dose of orexine. A27. The method according to any one of Examples A24 to A26, wherein the maintenance dose of orestradiol is 30 mg. A28. The method according to any one of embodiments A24 to A27, wherein the initial time period is from 1 day to 8 weeks; Optional, wherein the initial time period is: (i) 2 days to 8 weeks (ii) One to eight weeks; (iii) One to six weeks; (iv) Two to four weeks; (v) One week; (vi) Two weeks; (vii) all around; or (viii) Six weeks. A29. The method according to any one of embodiments A24 to A28, wherein the initial time period is two weeks. A30. The method according to any one of embodiments A24 to A29, wherein the transition period is one to eight weeks; Optionally, the transition period may be one to six weeks; Optionally, the transition period may be one to two weeks; Optionally, the transition period may be two to four weeks; Optionally, the transition period may be two, four, or six weeks. A31. The method according to any one of embodiments A24 to A30, wherein the total duration of the initial time period and the transition time period is four to eight weeks; Optionally, the total duration of the initial period and the transition period is eight weeks. A32. The method according to embodiment A24, wherein: (Bi) The initial dose of orinester was 20 mg orinester, administered to the subject once daily for two weeks; (Bii) The transitional dose of osrelastide was 20 mg osrelastide administered twice daily to the subject for one to eight weeks; and (Biii) The maintenance dose of orestradiol was 30 mg orestradiol, administered to the subject twice daily. A33. The method according to embodiment A24, wherein: (Bi) The initial dose of olivrazine was 20 mg olivrazine, administered to the subject once daily for one week; (Bii) The transitional dose of orexusone was 20 mg orexusone administered to the subject twice daily for two weeks; (Biii) The maintenance dose of orestradiol was 30 mg orestradiol, administered to the subject twice daily. A34. The method according to embodiment A24, wherein: (Bi) The initial dose of orinester was 20 mg orinester, administered to the subject once daily for two weeks; (Bii) The transitional dose of orexusone was 20 mg orexusone administered to the subject twice daily for two weeks; (Biii) The maintenance dose of orestradiol was 30 mg orestradiol, administered to the subject twice daily. A35. The method according to embodiment A24, wherein: (Bi) The initial dose of orinester was 20 mg orinester, administered to the subject once daily for two weeks; (Bii) The transitional dose of orexusone was 20 mg orexusone, administered to the subject twice daily for four weeks; (Biii) The maintenance dose of orestradiol was 30 mg orestradiol, administered to the subject twice daily. A36. The method according to embodiment A24, wherein: (Bi) The initial dose of orinester was 20 mg orinester, administered to the subject once daily for two weeks; (Bii) The transitional dose of orexusone was 20 mg orexusone administered to the subject twice daily for six weeks; (Biii) The maintenance dose of orestradiol was 30 mg orestradiol, administered to the subject twice daily. A37. The method according to any one of Examples A24 to A36, wherein the threshold body weight is 90 kg. A38. The method according to any one of Examples A24 to A36, wherein the threshold body weight is 95 kg. A39. The method according to any one of Examples A24 to A36, wherein the threshold body weight is 100 kg. A40. The method according to any one of Examples A24 to A36, wherein the threshold body weight is 105 kg. A41. The method according to any one of Examples A24 to A40, wherein the initial dose of orestradiol is administered to the subject at night. A42. The method according to any one of Examples A24 to A40, wherein the initial dose of orestradiol is administered to the subject in the morning. A43. The method according to any one of Examples A24 to A42, wherein the maintenance dose of orestradiol is administered to the subject twice daily for at least one week, for example for at least one month, at least six months or at least one year. A44. A method for treating a disease or disorder in a subject whose weight is greater than or equal to a threshold weight by inhibiting PDE4, the method comprising administering orlistat to the subject. in: (Ci) The initial dose of orlistat was administered to the subject once daily for the initial period, and then; (Cii) The subject was given a maintenance dose of orinelast twice daily, wherein the maintenance dose of orinelast was greater than the initial dose of orinelast. in: (a) The initial dose of orexaminase is 10 mg to 20 mg orexaminase; (b) This initial period lasted eight weeks; and (c) The threshold weight is at least 90 kg (e.g., where the threshold weight is 100 kg). A45. A method for treating a disease or disorder in a subject whose weight is less than a lower limit of body weight, which is improved by inhibiting PDE4, the method comprising administering orlistat to the subject, wherein: (Ei) The subject was given an initial dose of 10 mg of orestradiol once daily for the initial period, and then; (Eii) The subject was given a maintenance dose of 10 mg of orestradiol twice daily; in: The initial timeframe is two to eight weeks, and The lower limit of this weight is 50 kg to 75 kg; The lower limit of weight is 50 kg; Optionally, the lower limit of body weight is 60 kg. A46. A method for treating pruritus associated with atopic dermatitis in a subject, the method comprising administering to the subject a therapeutically effective amount of orestradiol. A47. The method according to Example A46, wherein the subject has a baseline PPNRS of ≥ 4. A48. The method according to Example A46, wherein the subject has a baseline PPNRS > 7. A49. The method according to any one of Examples A46 to A48, wherein the method reduces the baseline peak pruritus NRS (PPNRS) by ≥ 4 points. A50. The method according to any one of Examples A46 to A49, wherein after two weeks of treatment, the method reduces the baseline peak pruritus NRS (PPNRS) by ≥ 4 points. A51. The method according to any one of Examples A46 to A50, wherein the subject suffers from moderate to severe atopic dermatitis. A52. The method according to any one of Examples A1 to A51, wherein the orlistat is administered orally to the subject. A53. The method according to any one of Examples A1 to A51, wherein the orlistat is orally administered to the subject in the form of a sustained-release formulation containing the orlistat. A55. The method according to Example A53, wherein when measured in vitro using the standard dissolution assay described in the instructions, the sustained-release formulation releases an average amount of about 10% to about 70% of orexate after 45 minutes and more than about 70% after 180 minutes. A56. The method according to any one of Examples A1 to A55, wherein the orlistat is administered to the subject simultaneously, alone, or sequentially with a therapeutically effective amount of one or more other therapeutic agents. Example

[0438] The invention is further illustrated by the following examples. Example 1 Oral sustained-release tablet formulation

[0439] Prepare 10 mg and 30 mg oxiracetam and placebo oral extended-release tablets according to Table 3: Table 3 Note 1: Oreste uses the ground crystal form E with a D50 particle size distribution of 1 to 6 µm. Note 2: Hydroxypropyl methylcellulose is Methocel ™ K100 Premium LV DC2; viscosity at 20°C in water (2% concentration): 80-120 mPa·s; methoxyl content: 22%-24%; hydroxypropyl content: 7.5% to 9.5%. Note 3: Contains polyvinyl alcohol (European Pharmacopoeia 1961), polyethylene glycol (European Pharmacopoeia 1444), titanium dioxide (European Pharmacopoeia 0150), talc (European Pharmacopoeia 0438) and yellow iron oxide (NF).

[0440] Tablets are prepared by blending excipients and orlistat together and compressing them into tablets using a rotary press to provide a tablet core. The tablet core is then coated with a PVA-based coating (Opadry II).

[0441] The average dissolution profiles of 10 mg and 30 mg sustained-release tablets were measured using the standard dissolution assay described in the instructions for use, and the results are shown in Table C. The % values ​​represent the percentage of orexin in the dissolution medium at each time point. Table C: In vitro dissolution curves Dissolution curves are shown in Figure 11 middle. Characteristics of Oreste

[0442] The orexin used in the sustained-release tablet formulation is orexin E. The powder X-ray diffraction (XRPD) pattern of orexin E is shown in... Figure 9 XRPD was obtained using an X'pert PRO MPD diffractometer from PANalytical, configured with transmission geometry and equipped with a PIXcel detector. A continuous 2θ scan range of 3–45° was used, with a CuKα radiation source of λ = 1.5418 Å, generator power of 40 mA and 45 kV. A 2θ step size of 0.0070° / step and a step time of 148.92 s were used. The sample was gently flattened onto the wells in a 96-well plate for transmittance measurements. The 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 Oreste crystal form E are shown in Table C: Table C:

[0443] Crystal form E was also characterized using DSC with a TA instrument Q20 system. A few mg of sample was gently placed into an aluminum dish and weighed. A cap with pre-drilled pinholes was modified and pressed onto the dish. Modulated temperature profiles and conventional temperature profiles were used at different heating rates from 2°C to 10°C / min. Figure 10 The DSC traces (average of two measurements) of two batches of oreste are shown. Crystal form E exhibits endothermic melting with onset temperatures of 211.6°C and 211.7°C, and enthalpy changes of 83 J / g and 85 J / g, respectively. No glass transition was observed in the modulated DSC of both samples, indicating that crystal form E is crystalline and contains no detectable amorphous material. Example 2 Dosage basis

[0444] The extended-release formulation was investigated in a clinical trial (LP0058-1442) and administered to a total of 36 healthy volunteers: 18 in Part 1, 9 in Part 2, and 9 in Part 3. Twenty-seven (27) healthy volunteers received a single dose of 30 mg orexate, and nine subjects received multiple doses over 17 days, with up-titration up to a maximum of 60 mg BID. Part 1 of this study evaluated key pharmacokinetic parameters of the new extended-release formulation compared to the immediate-release reference capsule formulation. Orexate was rapidly absorbed from both formulations, with a median tmax of 3.00 hours post-dosage for the immediate-release capsules and 2.52 hours post-dosage for the extended-release tablets. Individual tmax ranged from approximately 1 to 6 hours post-dosage for the immediate-release capsules and from approximately 1 to 4 hours post-dosage for the extended-release tablets. After tmax, the plasma concentrations of orestradiol in both formulations decreased in an overall biphasic manner, with geometric mean terminal half-lives (t1 / 2) of 6.48 and 6.67 hours for the sustained-release tablets and immediate-release capsules, respectively. AUC 0-∞ The geometric mean was 507 ng·h / mL, and the systemic exposure of orestradiol after administration of the extended-release tablets was comparable to that of the immediate-release capsules (506 ng·h / mL). Statistical analysis comparing the key pharmacokinetic parameters of orestradiol in the two formulations showed no significant differences, and it was concluded that there was no difference in systemic exposure after administration of the extended-release formulation compared to the immediate-release formulation. Therefore, it is reasonable to assume that the safety profile of systemic effects can be inferred from studies investigating the immediate-release formulation, particularly study LP0058-1072, a phase 2a study involving 36 patients with moderate to severe psoriasis vulgaris.

[0445] In this study, patients received osrelastide 30 mg BID immediate-release or placebo for 16 weeks. Efficacy in treating psoriasis was confirmed at each predefined endpoint. No significant safety issues were observed during the trial, and no adverse events previously not observed with PDE4 inhibitors were reported. However, high intolerance was observed in the osrelastide group. Throughout treatment, most patients treated with osrelastide experienced treatment-induced adverse events (Aes) related to GI function, primarily nausea and diarrhea. These intolerance issues led to half of the patients in the osrelastide group withdrawing from the trial. Hypothesizing that this high incidence of GI side effects was related to high local concentrations of osrelastide in the stomach, formulation efforts were focused on identifying a sustained-release formulation that would reduce the local concentration of the active compound in the stomach while maintaining similar systemic exposure to sustain efficacy. The study LP0058-1442 in healthy volunteers confirmed these characteristics by showing similar pharmacokinetic (PK) curves and improved safety profiles. Osrelastide extended-release tablets were safe and well-tolerated after multiple doses up to 60 mg BID. No clinically relevant findings were found in any subject's vital signs data, clinical laboratory assessments, 12-lead ECG parameters, or physical examinations, and no deaths or SAEs occurred at any stage of the trial. A total of 113 Ae were reported: 12 Ae in 3 subjects randomly assigned to placebo, and 101 Ae in 9 subjects after administration of up to 60 mg of orexamin BID extended-release tablets. Headache, nausea, dizziness, limb pain, and diarrhea were the most frequently reported Ae. Of the 14 headache adverse events reported in subjects receiving orexamin, 6 occurred at the 40 mg dose level. Dizziness was reported only after administration of 30 mg or higher of orexamin. Nausea was reported in 5 subjects receiving orexamin, with most events occurring at the 60 mg dose level. Only 2 participants experienced nausea at doses equal to or lower than 40 mg; these side effects resolved spontaneously after approximately 1 day despite maintenance of dosing and titration upregulation. Therefore, it is concluded that 40 mg BID is the maximum tolerated dose, with 30 mg BID being the target dose for further development. Oresta extended-release tablet formulation used in clinical trials

[0446] The following oxilastase extended-release tablet formulations were used in the clinical trials described in Examples 3, 4, 5, 8, and 13 of this article. Note 1: Oreste is used with milled crystal form E, where the D50 particle size distribution is < 1 to 6 µm and D(90) ≤ 10 µm. Note 2: European Pharmacopoeia 0187 Note 3: Hydroxypropyl methylcellulose: Methocel ™K100 Premium LV DC2; viscosity at 20°C in water (2% concentration): 80-120 mPa·s; methoxyl content: 22%-24%; hydroxypropyl content: 7.5% to 9.5%. Note 4: European Pharmacopoeia 0434 Note 5: European Pharmacopoeia 0229 Note 6: Contains polyvinyl alcohol (European Pharmacopoeia 1961), polyethylene glycol (European Pharmacopoeia 1444), titanium dioxide (European Pharmacopoeia 0150), talc (European Pharmacopoeia 0438) and yellow iron oxide (NF). Example 3 A randomized, double-blind, placebo-controlled, parallel-group, phase 2b dose-range study was conducted to evaluate the efficacy and safety of orestrate in adults with moderate to severe plaque psoriasis.

[0447] The following Phase 2b clinical trials were conducted: Main objectives: To evaluate the efficacy and safety of extended-release orexate tablets compared to placebo in adults with moderate to severe plaque psoriasis. Primary endpoint : • Percentage change in Psoriasis Activity and Severity Index (PASI) score at week 16 relative to baseline. Key secondary endpoints • At week 16, patients achieved a 75% reduction in PASI response (PASI75). • At week 16, patients achieved a clearance (0) or near clearance (1) score on the Investigator Global Assessment (IGA) with an improvement of at least 2 points. Other secondary endpoints • At weeks 4, 8, 12 and 20, patients achieved IGA clearance (0) or near clearance (1) scores and improved by at least 2 points. • Patients achieved a PASI75 response at weeks 4, 8, 12, and 20. • At weeks 4, 8, 12, 16 and 20, patients achieved a 50% reduction in PASI (PASI50) and a 90% reduction in PASI (PASI90) response. • Changes in PASI relative to baseline at weeks 4, 8, 12, and 20. • Changes in total Psoriasis Symptom Scale (PSS) scores relative to baseline at weeks 4, 8, 12, 16, and 20. • The variation of each individual item of PSS relative to baseline at weeks 4, 8, 12, 16, and 20. • Changes in affected body surface area (BSA) relative to baseline at weeks 4, 8, 12, 16, and 20. • Changes in Dermatology Quality of Life Index (DLQI) scores relative to baseline at weeks 16 and 20. • Patients experience a psoriasis rebound (defined as PASI ≥ 125% of baseline) or new-onset generalized pustular, erythrodermic, or more inflammatory psoriasis at week 20. Safety endpoint : • The incidence, severity, and severity of treatment-related adverse events (TEAEs) reported during the 16-week treatment period and 4-week follow-up period. • Physical examination of changes relative to baseline; vital sign measurements (body temperature, respiratory rate, heart rate, and systolic and diastolic blood pressure); and weight during the 16-week treatment period and the 4-week follow-up period. • Electrocardiograms (ECGs) during the 16-week treatment period and the 4-week follow-up period revealed changes relative to baseline. • Changes in safety laboratory values ​​(hematology, serum chemistry, and urinalysis) relative to baseline during the 16-week treatment period and 4-week follow-up period. • Hospital anxiety and depression scale at each visit except for the second week. • Except for the first and second weeks, the Columbia Suicide Severity Rating Scale (C-SSRS) was used at each visit. Exploratory endpoint: • Change in the overall assessment of the nails (PGA-F) by the physician at week 16 relative to baseline. • In the subgroup of patients with a baseline score of at least 2 (mild scalp psoriasis), the change in scalp-specific investigator global assessment (ss-IGA) relative to baseline at week 16. • In the subgroup of patients with a baseline score of at least 4 on the 11-point NRS, the change in the numerical rating scale (NRS) for pruritus scalp relative to baseline at week 16. • In patients with psoriatic arthritis (PsA) and a baseline joint pain score of at least 4, the change in the NRS of joint pain relative to baseline at week 16. • Changes in cardiovascular risk factors at week 16. The following parameters will be collected: weight, body mass index, waist and hip circumference, blood pressure, fasting blood glucose, triglycerides, cholesterol (total high-density lipoprotein / low-density lipoprotein fraction), and C-reactive protein. • Changes in skin biomarkers relative to baseline at week 16, collected by tape peeling and analyzed using proteomics methods. • Plasma levels of drugs and their metabolites at the scheduled visit. Research Design

[0448] A multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2b dose-range study is being conducted to evaluate the efficacy and safety of extended-release osrelastide compared to placebo in adult patients with moderate to severe plaque psoriasis. Efficacy and safety outcomes will be assessed to select the appropriate osrelastide dose for a subsequent phase 3 study.

[0449] Following a screening visit up to 28 days prior to baseline, 202 patients were randomized in a 1:1:1:1 ratio to receive one of three doses of orexusone (20 mg, 30 mg, or 40 mg) or placebo, twice daily (BID) for 16 weeks, with a 4-week follow-up. Administration was initiated at baseline with dose titration. The longest duration of study participation was approximately 24 weeks.

[0450] Patients were screened, at baseline (day 1), and at weeks 1, 2, 4, 8, 12, 16 (end of treatment visit) and week 20 (follow-up visit, 4 weeks after treatment completion or interruption). Visits at weeks 1 and 2 may be conducted by the investigator via telemedicine as appropriate.

[0451] PASI, BSA, IGA, and PSS were assessed at baseline and at each visit starting from week 4. Quality of life was assessed by administering the DLQI at baseline and at the weeks 16 and 20 visits. Additional efficacy parameters included SS-IGA, Physician’s Overall Assessment of Nail Psoriasis (PGA-F), and NRS for joint pain in patients diagnosed with PsA. 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 assessments of patient mood changes (Hospital Anxiety and Depression Scale) and investigator suicidal ideation assessment (C-SSRS). A set of cardiovascular risk factors were assessed at baseline and at week 16.

[0452] Blood samples were collected at baseline and prior to administration of the study drug at weeks 4, 8, and 16 to determine orlistat concentrations. Additionally, at baseline and week 16, non-invasive superficial skin samples were taken from the target lesions of all patients using tape peeling for proteomics analysis. Inclusion criteria

[0453] Patients are eligible for inclusion in this study only if all of the following criteria are met: 1. Able to sign informed consent forms, including complying with informed consent forms (ICF) and the requirements and limitations listed in this program. 2. Male and female patients aged ≥ 18 years at the time of signing the ICF. 3. Weight > 40 kg when signing the ICF. 4. A diagnosis of chronic stable plaque psoriasis must be made at least 2 months prior to the screening visit. If the patient is diagnosed with psoriatic arthritis, the arthritis should be stable. 5. At screening and baseline visits, moderate to severe plaque psoriasis is defined as PASI ≥ 12, BSA ≥ 10%, and IGA ≥ 3. 6. Candidates for systemic anti-psoriasis 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. Furthermore, sexually active WOCBPs must agree to use highly effective contraception until at least 4 weeks after the end of the study treatment. Exclusion criteria

[0454] Patients will be excluded from the study if any of the following criteria apply: 1. Treatment-resistant psoriasis is defined as the failure of ≥ 2 treatments in the past 5 years due to inadequate efficacy of any biological therapy (including, but not limited to, etanercept, adalimumab, infliximab, pecelizumab, gusecucurbita, secukinumab, rexazumab, ixekizumab, tetragezizumab, or ustekinumab) administered at adequate doses and durations according to label or local / national guidelines (not excluding patients who discontinued systemic therapy for reasons unrelated to lack of efficacy). 2. Unstable psoriasis or PsA with acute exacerbation within 4 weeks of the screening visit. 3. History of allergy or hypersensitivity to any component of the study treatment. 4. Systemic antibiotics are required to treat active infections (such as bacterial, viral, and fungal infections) within 4 weeks after the screening visit. 5. Malignant tumor or history of malignant tumor, except for basal cell carcinoma of the skin that has been treated (i.e. cured). 6. Based on the researcher's judgment, the current diagnosis is primarily guttate, erythrodermic, exfoliative, or pustular psoriasis, or drug-induced psoriasis, or other skin conditions that may confuse the assessment of psoriasis vulgaris (such as Alzheimer's disease, lupus). 7. Any recurrent medical condition associated with a serious GI disease, such as inflammatory bowel disease. 8. Any medical or psychiatric condition that the investigator believes would prevent the patient from adhering to the protocol, completing the study as directed, and / or placing the patient at an unacceptable risk of receiving the investigational therapy (e.g., current major depressive disorder, schizophrenia, suicidal behavior, or hospitalization for psychiatric disorders within the previous year with a baseline HADS depressive symptom score ≥ 15). 9. Any therapy or systemic treatment that does not meet the specified washout period. 10. Any previous treatment with orlistat or apremilast or any other systemic PDE4 inhibitor has failed. 11. Any condition that puts a patient at an unacceptable risk of participating in the study or that obscures the patient’s ability to interpret the study data, including laboratory or ECG abnormalities. 12. Severe liver injury based on medical history and laboratory abnormalities (e.g., low albumin and abnormal bilirubin). 13. Any abnormalities in clinical laboratory tests during 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. Patients with a history or evidence of hepatitis B virus (HBV) infection at the time of screening are excluded. Patients who are positive for hepatitis B surface antigen (HBsAg) are excluded. For patients who are positive for isolated hepatitis B core antibody (HbcAb), the hepatitis B surface antibody (HBsAb) result must also be positive to be considered for this study. 15. A history of hepatitis C virus (HCV) antibody testing or a positive test result at screening indicates ongoing infection. Patients with positive HCV antibody tests will undergo confirmatory HCV RNA testing. Patients with negative HCV RNA results will be eligible to participate in this study. 16. History of HIV positivity, or congenital or acquired immunodeficiency (e.g., common variant immunodeficiency). Patients who tested positive for HIV antibodies (HIV-1 or HIV-2) at screening were excluded from the study. 17. Suicidal ideation or behavior within the past 12 months, as indicated by a positive (yes) answer to question 4 or 5 on the C-SSRS completed at the screening visit or the C-SSRS completed at the baseline visit. 18. Pregnant or breastfeeding. 19. A history of alcohol or drug abuse within 6 months prior to baseline is considered by researchers to be a barrier to participation in the study. 20. Institutionalized by court order or local authorities. treat 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 on the evening of day 1. The dosing schedule used is shown in Table 4: Table 4 Abbreviation: BID, twice a day. Dosage titration Titrate the dose of orestradiol extended-release tablets over a period of up to 2 weeks, according to the schedule shown in Table 5: Table 5 efficacy assessment Psoriasis Area and Severity Index: The PASI is a measure of the severity of psoriasis, taking into account qualitative lesion features (erythema, induration, and scaling) and the percentage of skin surface area affected in defined anatomical regions. The PASI is a validated tool and the most widely used tool for measuring the severity of psoriasis. The PASI score ranges from 0 to 72, with higher scores reflecting greater disease severity (Fredriksson et al., Dermatologica. [Dermatology] 1978; 157(4):238-244). Erythema, induration / thickening, and scaling were scored on a scale of 0 (none) to 4 (extremely severe) in four anatomical regions of the body: head, trunk, upper extremities, and lower extremities. The extent of involvement in each of the four anatomical regions was scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement). The total qualitative score (the sum of scores for erythema, thickness, and fouling) is multiplied by the degree of involvement in each anatomical region, and then multiplied by a constant. The scores for each anatomical region are combined to obtain the final PASI. Overall investigator assessment: The IGA is a measure used by physicians to determine the overall severity of a patient's disease. This trial used a static version (Langley et al., J Dermatolog Treat. 2015 Feb;26(1):23-31) to measure at individual time points as shown in the assessment schedule. Investigators will rate the severity of patients' psoriasis using a 5-point scale, ranging from 0 (clear) to 4 (severe): Scalp-specific researcher overall assessment: The ss-IGA uses a 5-point scale to assess the degree of redness, thickness, and scale buildup of scalp lesions, with 0 points indicating no disease and 4 points indicating severe disease. Overall Assessment of Nail Psoriasis by Physicians: This study used the PGA-F to assess nail abnormalities and their severity in patients with nail psoriasis. This is a simple and reliable clinician rating scale, easy to use in clinical practice and research. The scale assesses the overall condition of the nails and is based on a 5-point scale, where 0 indicates clear nails and 4 indicates severe nails. Body surface area: BSA is an assessment that estimates the extent of disease or skin affected by psoriasis and is expressed as a percentage of the total body surface area. BSA will be determined by the investigator or designated personnel using the rule that the patient's palm = 1% BSA. Patient-reported outcomes Psoriasis Symptom Scale: The PSS is a 4-item patient-completed questionnaire (Rentz et al., J Patient RepOutcomes. 2017;1(1):4.). It is patient-relevant, its domains are reliable and effective, and it takes only a few minutes to complete. The PSS uses a 5-point severity scale from 0 = none to 4 = very severe to assess the severity of pain, itching, redness, and burning sensations over the past 24 hours. Numerical Rating Scale for Scalp Itching (NRS): Itching is assessed by having patients rate the most severe scalp itching in the past 24 hours on an 11-point NRS scale, where 0 corresponds to no itching and 10 corresponds to the most severe itch imaginable. Arthritis pain: Patients diagnosed with PsA at screening will be assessed for joint pain caused by arthritis in the past 24 hours using an 11-point NRS, where 0 corresponds to no pain and 10 corresponds to the most severe pain imaginable. The Dermatology Quality of Life Index (DLQI) is a 10-item patient-completed questionnaire designed to assess the impact of dermatology on a patient's overall quality of life (QoL) over the past week. The 10 questions cover the following topics: symptoms, embarrassment, shopping and home care, clothing, social and leisure activities, exercise, work or study, intimate relationships, and sex and treatment. Each question is scored from 0 to 3 ("absolutely none," "a little," "a lot," and "very much"), with a total score from 0 to 30. A high score indicates poor QoL. Results Summary

[0455] 202 patients were randomized and treated for 16 weeks. In the phase 2b dose-range study, all doses of orestradiol showed statistically significant therapeutic effects relative to placebo for the percentage change in PASI from baseline to week 16 (the primary endpoint).

[0456] The mean percentage change in PASI from baseline to week 16 for 20 mg twice daily (BID), 30 mg BID, 40 mg BID, and placebo were -52.6%, -61.2%, -63.7%, and -17.3%, respectively.

[0457] When missing data at week 16 was considered as non-response, the percentage of patients achieving PASI75, PASI90, and IGA 0 / 1 at week 16 was higher in the two lowest dose groups of orestradiol (20 mg and 30 mg) than in the 40 mg dose group.

[0458] Efficacy data analysis showed that in both the PASI-50 and PASI-75 groups, the 20 mg and 30 mg BID treatment groups exhibited similar efficacy during the first 8 weeks of treatment. Figure 1The data also showed that the 30 mg BID dose provided a higher and more sustained response in some patients after week 8.

[0459] Table 6 shows the most common adverse events that occurred during treatment with 20 mg and 30 mg BID (in ≥5% of subjects taking orestradiol). Table 6 Table 7 shows the most frequent adverse events during treatment that led to treatment interruption in the 20 mg and 30 mg BID orestradiol treatment groups. Table 7

[0460] Adverse events observed in clinical trials are considered mild or moderate. Figure 2 The total percentage of patients who discontinued treatment due to adverse events and the breakdown of discontinuations are shown in the placebo, 20 mg BID, 30 mg BID, and 40 mg BID treatment groups. Discontinuations due to adverse events were similar in patients treated with 20 mg and 30 mg olisterol BID (21% and 20%, respectively). Only in the 40 mg BID high-dose treatment group was the discontinuation rate higher than in the placebo group.

[0461] Most observed gastrointestinal adverse events were transient and occurred before week 8 of treatment. Figure 3 Most of these occur within the first 4 weeks of treatment. As mentioned above, Figure 1 Studies have shown that the 20 mg and 30 mg BID treatment groups exhibited similar efficacy in the first 8 weeks. Therefore, titrating the dose to the final maintenance dose during the initial treatmen...

Claims

1. Orelis for use in a method of improving a disease or disorder in a subject by inhibiting PDE4, the method comprising administering the orelis to the subject, wherein: (Ai) an initial orelis dose is administered to the subject once a day for an initial period of time, then; (Aii) a transition orelis dose is administered to the subject twice a day for a transition period of time, then; (Aiii) a maintenance orelis dose is administered to the subject twice a day; wherein: (a) the initial orelis dose and the transition orelis dose are independently selected from 10 mg to 30 mg of orelis, provided that the transition orelis dose is greater than or equal to the initial orelis dose; (b) the initial period of time is two weeks to eight weeks; (c) the transition period of time is one week to eight weeks; and (d) the maintenance orelis dose is greater than the transition orelis dose when the subject’s body weight is greater than or equal to a threshold body weight, wherein the threshold body weight is at least 90 kg.

2. The orelis for use of claim 1, wherein the initial orelis dose and the transition orelis dose are the same; optionally, wherein the initial orelis dose and the transition orelis dose are each 20 mg of orelis.

3. The orelis for use of claim 1 or claim 2, wherein the maintenance orelis dose is the same as the transition orelis dose when the subject’s body weight is less than the threshold body weight.

4. The orelis for use of any one of claims 1 to 3, wherein the maintenance orelis dose is up to 40 mg of orelis when the subject’s body weight is greater than or equal to the threshold body weight, provided that the maintenance orelis dose is greater than the transition orelis dose.

5. The orelis for use of any one of claims 1 to 4, wherein the maintenance orelis dose is 30 mg of orelis when the subject’s body weight is greater than or equal to the threshold body weight.

6. The orelis for use of any one of claims 1 to 5, wherein the initial period of time is two weeks to four weeks.

7. The orelis for use of any one of claims 1 to 5, wherein the initial period of time is two weeks.

8. The orelis for use of any one of claims 1 to 7, wherein the transition period of time is six weeks to eight weeks.

9. The orelis for use of any one of claims 1 to 7, wherein the transition period of time is one week to four weeks.

10. The orelis for use of any one of claims 1 to 7, wherein the transition period of time is two weeks.

11. The orelis for use of any one of claims 1 to 7, wherein the transition period of time is six weeks.

12. The orelis for use of any one of claims 1 to 7, wherein the total duration of the initial period of time and the transition period of time is four weeks to eight weeks; optionally, wherein the total duration of the initial period of time and the transition period of time is eight weeks.

13. The orelis for use of any one of claims 1 to 12, wherein: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ (i) when the subject’s body weight is less than a lower limit body weight, the initial orelvekin dose in (Ai), the transition orelvekin dose in (Aii), and the maintenance orelvekin dose in (Aiii) are each 10 mg orelvekin; or (ii) when the subject’s body weight is in a range from the lower limit body weight to less than the threshold body weight, the initial orelvekin dose in (Ai), the transition orelvekin dose in (Aii), and the maintenance orelvekin dose in (Aiii) are each 20 mg orelvekin; wherein the lower limit body weight is 50 kg to 75 kg; optionally wherein the lower limit body weight is 60 kg.

14. Orelvekin for use according to any one of claims 1 to 12, wherein when the subject’s body weight is less than a lower limit body weight, the initial orelvekin dose, the transition orelvekin dose, and the maintenance orelvekin dose are each 10 mg orelvekin; wherein the lower limit body weight is 50 kg to 75 kg; optionally wherein when the subject’s body weight is less than 60 kg, the initial orelvekin dose, the transition orelvekin dose, and the maintenance orelvekin dose are each 10 mg orelvekin.

15. Orelvekin for use according to any one of claims 1 to 12, wherein when the subject’s body weight is in a range from a lower limit body weight to less than the threshold body weight, the initial orelvekin dose, the transition orelvekin dose, and the maintenance orelvekin dose are each 20 mg orelvekin; wherein the lower limit body weight is 50 kg to 75 kg; optionally wherein when the subject’s body weight is in a range from 60 kg to less than the threshold body weight, the initial orelvekin dose, the transition orelvekin dose, and the maintenance orelvekin dose are each 20 mg orelvekin.

16. Orelvekin for use according to claim 1, wherein (Ai) the initial orelvekin dose is 20 mg orelvekin administered to the subject once per day for two weeks; (Aii) the transition orelvekin dose is 20 mg orelvekin administered to the subject twice per day for one to eight weeks; and (Aiii) if the subject’s body weight is less than the threshold body weight, the maintenance orelvekin dose is 20 mg orelvekin administered to the subject twice per day; or if the subject’s body weight is greater than or equal to the threshold body weight, the maintenance orelvekin dose is 30 mg orelvekin administered to the subject twice per day.

17. Orelvekin for use according to claim 16, wherein the transition orelvekin dose is administered to the subject twice per day for two to eight weeks; optionally wherein the transition orelvekin dose is administered to the subject twice per day for six to eight weeks.

18. Orelvekin for use according to claim 1, wherein: (Ai) the initial orelvekin dose is 20 mg orelvekin administered to the subject once per day for two weeks; (Aii) the transition orelvekin dose is 20 mg orelvekin administered to the subject twice per day for one to eight weeks; and (Aiii) if the subject’s body weight is less than the threshold body weight, the maintenance orelvekin dose is 20 mg orelvekin administered to the subject twice per day; or if the subject’s body weight is greater than or equal to the threshold body weight, the maintenance orelvekin dose is 30 mg orelvekin administered to the subject twice per day. (Aii) the transition orelvizumab dose is 20 mg orelvizumab administered to the subject twice a day for two weeks; and (Aiii) if the subject has a body weight less than the threshold body weight, the maintenance orelvizumab dose is 20 mg orelvizumab administered to the subject twice a day; or if the subject has a body weight greater than or equal to the threshold body weight, the maintenance orelvizumab dose is 30 mg orelvizumab administered to the subject twice a day.

19. Orelvizumab for use according to claim 1, wherein: (Ai) the initial orelvizumab dose is 20 mg orelvizumab administered to the subject once a day for two weeks; (Aii) the transition orelvizumab dose is 20 mg orelvizumab administered to the subject twice a day for six weeks; (Aiii) if the subject has a body weight less than the threshold body weight, the maintenance orelvizumab dose is 20 mg orelvizumab administered to the subject twice a day; or if the subject has a body weight greater than or equal to the threshold body weight, the maintenance orelvizumab dose is 30 mg orelvizumab administered to the subject twice a day.

20. Orelvizumab for use according to claim 1, wherein: (Ai) if the subject has a body weight less than a lower limit body weight, the initial orelvizumab dose is 10 mg orelvizumab administered to the subject once a day for two to four weeks, or if the subject has a body weight from the lower limit body weight to less than the threshold body weight, the initial orelvizumab dose is 20 mg orelvizumab administered to the subject once a day for two to four weeks; (Aii) if the subject has a body weight less than the lower limit body weight, the transition orelvizumab dose is 10 mg orelvizumab administered to the subject twice a day for one to eight weeks; or if the subject has a body weight from the lower limit body weight to less than the threshold body weight, the transition orelvizumab dose is 20 mg orelvizumab administered to the subject twice a day for one to eight weeks; and (Aiii) if the subject has a body weight less than the lower limit body weight, the maintenance orelvizumab dose is 10 mg orelvizumab administered to the subject twice a day; or if the subject has a body weight from the lower limit body weight to less than the threshold body weight, the maintenance orelvizumab dose is 20 mg orelvizumab administered to the subject twice a day; or if the subject has a body weight greater than or equal to the threshold body weight, the maintenance orelvizumab dose is 30 mg orelvizumab administered to the subject twice a day; wherein the lower limit body weight is 50 kg to 75 kg.

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

23. Orelvestat for use according to any one of claims 20 to 22, wherein the transition orelvestat dose is administered to the subject twice a day for two to eight weeks; optionally wherein the transition orelvestat dose is administered to the subject twice a day for six to eight weeks.

24. Orelvestat for use according to claim 1, wherein: (Ai) if the subject has a body weight less than 60 kg, the initial orelvestat dose is 10 mg orelvestat administered to the subject once a day for two weeks; or if the subject has a body weight of 60 kg to less than the threshold body weight, the initial orelvestat dose is 20 mg orelvestat administered to the subject once a day for two weeks; (Aii) if the subject has a body weight less than 60 kg, the transition orelvestat dose is 10 mg orelvestat administered to the subject twice a day for six weeks; or if the subject has a body weight of 60 kg to less than the threshold body weight, the transition orelvestat dose is 20 mg orelvestat administered to the subject twice a day for six weeks; and (Aiii) if the subject has a body weight less than 60 kg, the maintenance orelvestat dose is 10 mg orelvestat administered to the subject twice a day; or if the subject has a body weight of 60 kg to less than the threshold body weight, the maintenance orelvestat dose is 20 mg orelvestat administered to the subject twice a day; or if the subject has a body weight greater than or equal to the threshold body weight, the maintenance orelvestat dose is 30 mg orelvestat administered to the subject twice a day.

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

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

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

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

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

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

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

32. Orelvestat for use in a method of treating a disease or disorder ameliorated by inhibition of PDE4 in a subject having a body weight greater than or equal to a threshold body weight, the method comprising administering the orelvestat to the subject, wherein: (Bi) an initial orelvestat dose is administered to the subject once a day for a preliminary period of time, then; (Bii) a transition orelvestat dose is administered to the subject twice a day for a transition period of time, and then (Biii) a maintenance orelvestat dose is administered to the subject twice a day. (Bii) administering to the subject a transition orelvizumab dose twice per day over a transition period, then; (Biii) administering to the subject a maintenance orelvizumab dose twice per day, wherein the maintenance orelvizumab dose is greater than the transition orelvizumab dose; wherein: (a) the initial orelvizumab dose and the transition orelvizumab dose are independently selected from 10 mg to 30 mg orelvizumab, provided that the transition orelvizumab dose is greater than or equal to the initial orelvizumab dose; (b) the initial period is one week to eight weeks; (c) the transition period is up to eight weeks; and (d) the threshold body weight is at least 90 kg.

33. Orelvizumab for use according to claim 32, wherein the initial orelvizumab dose and the transition orelvizumab dose are the same; optionally, wherein the initial orelvizumab dose and the transition orelvizumab dose are each 20 mg orelvizumab.

34. Orelvizumab for use according to claim 32 or claim 33, wherein the maintenance orelvizumab dose is up to 40 mg orelvizumab, provided that the maintenance orelvizumab dose is greater than the transition orelvizumab dose.

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

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

37. Orelvizumab for use according to any one of claims 32 to 36, wherein the initial period is two weeks.

38. Orelvizumab for use according to any one of claims 32 to 37, wherein the transition period is six weeks to eight weeks.

39. Orelvizumab for use according to any one of claims 32 to 37, wherein the transition period is one week to four weeks.

40. Orelvizumab for use according to any one of claims 32 to 37, wherein the transition period is two weeks.

41. Orelvizumab for use according to any one of claims 32 to 37, wherein the transition period is six weeks.

42. Orelvizumab for use according to any one of claims 32 to 38, wherein the total duration of the initial period and the transition period is four weeks to eight weeks; optionally, wherein the total duration of the initial period and the transition period is eight weeks.

43. Orelvizumab for use according to claim 32, wherein: (Bi) the initial orelvizumab dose is 20 mg orelvizumab administered once per day to the subject for two weeks; (Bii) the transition orelvizumab dose is 20 mg orelvizumab administered twice per day to the subject for one week to eight weeks; and (Biii) the maintenance orelvizumab dose is 30 mg orelvizumab administered twice per day to the subject.

44. Orelvizumab for use according to claim 32, wherein: (Bi) the initial orelvizumab dose is 20 mg orelvizumab administered once per day to the subject for two weeks; (Bii) the transition orelvizumab dose is 20 mg orelvizumab administered twice per day to the subject for one week to eight weeks; and (Biii) the maintenance orelvizumab dose is 30 mg orelvizumab administered twice per day to the subject. (Bii) the transition orelse dose is 20 mg orelse administered to the subject twice a day for six weeks; and (Biii) the maintenance orelse dose is 30 mg orelse administered to the subject twice a day.

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

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

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

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

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

50. Orelse for use according to any one of claims 32 to 48, wherein the initial orelse dose is administered to the subject in the morning.

51. Orelse for use according to any one of claims 32 to 50, wherein the maintenance orelse dose is administered to the subject twice a day for at least 1 week, for example for at least one month, at least six months or at least one year.

52. Orelse for use in a method of treating a disease or disorder ameliorated by inhibition of PDE4 in a subject, the subject having a body weight greater than or equal to a threshold weight, the method comprising administering the orelse to the subject, wherein: (Ci) an initial orelse dose is administered to the subject once a day for an initial period of time, then; (Cii) a maintenance orelse dose is administered to the subject twice a day, wherein the maintenance orelse dose is greater than the initial orelse dose; wherein: (a) the initial orelse dose is 10 mg to 20 mg orelse; (b) the initial period of time is up to eight weeks; and (c) the threshold weight is at least 90 kg.

53. Orelse for use in a method of treating a disease or disorder ameliorated by inhibition of PDE4 in a subject, the method comprising administering the orelse to the subject, wherein: (Di) an initial orelse dose is administered to the subject once a day for an initial period of time, then; (Dii) a maintenance orelse dose is administered to the subject twice a day; wherein: (a) the initial orelse dose and the maintenance orelse dose are each 20 mg orelse; (b) the initial period of time is two weeks to eight weeks; (c) the subject has a body weight from a lower limit weight to less than a threshold weight; wherein the threshold weight is at least 90 kg, and the lower limit weight is 50 kg to 75 kg; optionally wherein the lower limit weight is 60 kg.

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

55. Oregovacine for use in a method of ameliorating a disease or disorder by inhibiting PDE4 in a subject whose body weight is less than a lower body weight, the method comprising administering the oregovacine to the subject, wherein: (Ei) administering to the subject an initial oregovacine dose of 10 mg once a day for an initial period of time, and then; (Eii) administering to the subject a maintenance oregovacine dose of 10 mg twice a day; wherein: the initial period of time is two weeks to eight weeks, and the lower body weight is 50 kg to 75 kg; optionally wherein the lower body weight is 60 kg.

56. Oregovacine for use according to any one of claims 1 to 55, wherein the disease or disorder is selected from the group consisting of: an inflammatory disease, an autoimmune disease, a central nervous system disease, a cerebrovascular disease, diabetes, obesity, metabolic syndrome, a wound and a proliferative disease.

57. Oregovacine for use according to any one of claims 1 to 55, wherein the disease or disorder is selected from the group consisting of: an inflammatory disease, such as an inflammatory airway disease (e.g. asthma or COPD), allergic rhinitis, acute lung injury, acute respiratory distress syndrome, an allergic disease, 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 discoid lupus erythematosus), depression, amnesia, cognitive dysfunction, dementia, Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, diabetes (e.g. insulin resistance syndrome), an acute or chronic wound disorder (e.g. wound healing), vulvodynia, cancer, an inflammatory or proliferative skin disorder (e.g. psoriasis (including plaque psoriasis and pustular psoriasis), epidermal inflammation, acne, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritis, eczema, neutrophilic dermatosis (e.g. pyoderma gangrenosum, nodular prurigo), hair loss, skin atrophy, steroid-induced skin atrophy, skin aging, skin photoaging, vitiligo, lichen planus, an organopathy associated with ischemic reflux (e.g. caused by heart failure, shock and cerebrovascular disease, etc.), uveitis, and Behcet's disease (e.g. oral ulceration associated with Behcet's disease).

58. Ocriplasatin for use according to any one of claims 1 to 55, wherein the disease or disorder is selected from dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis including irritant contact dermatitis and allergic contact dermatitis, hand dermatitis, psoriasis, psoriasis vulgaris, plaque psoriasis, inverse psoriasis, nail psoriasis, psoriatic arthritis, spondyloarthritis, epidermal inflammation, alopecia, alopecia areata, rosacea, skin atrophy, steroid-induced skin atrophy, skin photodamage, SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis), acne vulgaris, hidradenitis suppurativa (HS), urticaria, pruritus, eczema, and neutrophilic dermatosis (e.g. pyoderma gangrenosum (PG), pustular PG, atypical / bullous PG, vegetative PG, pathological PG, necrotizing fasciitis-like PG, peristomal PG, and post-surgical PG), Sweet syndrome (SS, also known as acute febrile neutrophilic dermatosis, including bullous SS, pustular SS, pyostomatitis vegetans-like SS, necrotizing fasciitis-like SS, drug-induced SS, and subcutaneous SS), Sneddon-Wilkinson disease (also known as subcorneal pustular dermatosis), Behcet’s disease, neutrophilic panniculitis, neutrophilic eccrine hidradenitis, persistent plantar erythroplasia, neutrophilic urticarial, IgA-associated neutrophilic dermatosis, sterile pustulosis palmoplantaris, Hallopeau’s acrodermatitis continua, acute generalized exanthematous pustulosis, infantile acrodermatitis pustulosa, sterile abscesses, PASH syndrome (pyoderma gangrenosum, acne, and HS), PAPA syndrome (pyoderma gangrenosum, acne, and pyogenic arthritis), PASS syndrome (PG, polyarthritic acne, HS, seropositive spondyloarthropathy), PAPASH syndrome (PG, pyogenic arthritis, acne, HS), PsAPASH (psoriatic arthritis, PG, acne, HS), histiocytoid neutrophilic dermatitis, dorsal hand neutrophilic dermatitis, intestinal bypass syndrome (enterically-associated dermatitis-arthritis syndrome), fencepost neutrophilic granulomatous dermatitis, or VEXAS syndrome.

59. Ocriplasatin for use according to any one of claims 1 to 55, wherein the disease or disorder is psoriasis; optionally wherein: (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.

60. Ocriplasatin 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 wherein the subject has a 75% reduction in PASI from baseline (PASI75) after 16 weeks of treatment.

61. Ocriplasatin 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 wherein: (i) the subject achieves a 90% reduction from baseline in PASI (PASI90) after 16 weeks of treatment; or (ii) the subject achieves a 100% reduction from baseline in PASI (PASI100) after 16 weeks of treatment; or (iii) the subject achieves an Investigator’s Global Assessment (IGA) of clear (0) or almost clear (1) after 16 weeks of treatment.

62. Ocriplasatin for use according to any one of claims 1 to 55, wherein the disease or disorder is atopic dermatitis; optionally, wherein the disease or disorder is moderate to severe atopic dermatitis.

63. Ocriplasatin for use according to any one of claims 1 to 55, wherein the disease or disorder is moderate to severe atopic dermatitis and wherein: (i) the subject achieves a 75% reduction from baseline in EASI (EASI75) after 16 weeks of treatment; or (ii) the subject achieves a 90% reduction from baseline in EASI (EASI90) after 16 weeks of treatment; or (iii) the subject achieves a 100% reduction from baseline in EASI (EASI100) after 16 weeks of treatment; or (iv) the subject achieves an Investigator’s Global Assessment of AD (IGA-AD) score of clear (0) or almost clear (1) and an improvement of at least 2 points in IGA-AD from baseline after 16 weeks of treatment; or (v) the subject achieves an Investigator’s Global Assessment of AD (IGA-AD) score of clear (0) after 16 weeks of treatment.

64. Ocriplasatin for use according to any one of claims 1 to 55, wherein the disease or disorder is moderate to severe atopic dermatitis, and wherein the treatment reduces the baseline Peak Pruritus Numerical Rating Scale (PPNRS) by > 4 points; preferably wherein the treatment reduces the baseline PPNRS by > 4 points after 2 weeks of treatment.

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

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

67. Ocriplasatin for use in a method of treating pruritus associated with atopic dermatitis in a subject, the method comprising administering to the subject a therapeutically effective amount of ocriplasatin.

68. Ocriplasatin for use according to claim 67, wherein the subject has a baseline Peak Pruritus Numerical Rating Scale (PPNRS) of > 4.

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

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

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

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

73. Otilonium bromide for use according to any one of claims 1 to 72, wherein the otilonium bromide is administered orally to the subject.

74. Otilonium bromide for use according to any one of claims 1 to 72, wherein the otilonium bromide is administered orally to the subject in the form of a sustained release formulation comprising the otilonium bromide, such as an oral sustained release tablet formulation.

75. Otilonium bromide for use according to claim 74, wherein the sustained release formulation releases an average amount of about 10% to about 70% of the otilonium bromide after 45 minutes and more than about 70% after 180 minutes when measured in vitro using the standard dissolution determination described in the instructions for use.

76. Otilonium bromide for use according to any one of claims 1 to 75, wherein the otilonium bromide is administered to the subject simultaneously, separately or sequentially with a therapeutically effective amount of one or more additional therapeutic agents.

Images