Methods for treating chronic hand eczema in patients with moderate to severe chronic hand eczema.

Abstract

A method for treating moderate to severe chronic hand eczema in a human patient, comprising administering an acidified aqueous topical composition containing 20 mg / g delgocitinib or a pharmaceutically acceptable salt on a free base basis to the skin of the human patient requiring treatment twice daily.

Description

Technical Field

[0001] The present invention relates to a method for treating chronic hand eczema in a human patient, comprising administering to the skin of the human patient an acidified aqueous topical formulation comprising delgocitinib.

[0002] Background Chronic hand eczema (CHE) is a severe inflammatory skin disorder that can occur anywhere on the hands or wrists. It is clinically characterized by erythema, infiltration, hyperkeratosis, edema, and small vesicles. Secondary signs include scaling, fissures, and erosions, and the condition may be exacerbated by bacterial infections. Important symptoms include itching and pain, and the disease is often characterized by chronic recurrence and poor prognosis.

[0003] CHE refers to hand eczema that persists for more than 3 months or recurs more than twice within 12 months.

[0004] There is general agreement that hand eczema is usually multifactorial and that there is no simple relationship between the clinical pattern and the etiological diagnosis (J Eur Acad Dermatol Venereol. 2015;29(12):2417-2422).

[0005] Several different classifications have been proposed (Diepgen et al., J Dtsch Dermatol Ges. 2015;13(1): e1-22, Cronin E et al., Contact Dermatitis. 1985;13(3):153-161, Johansen et al. Contact Dermatitis. 2011;65(1):13-21), and it has been found that the most common subtypes of CHE are irritant contact dermatitis, atopic hand eczema, and keratotic eczema (Apfelbacher et al. Acta Derm Venereol. 2014;94(2):163-167).

[0006] Other subtypes include allergic contact dermatitis, urticaria / protein contact dermatitis, and recurrent vesicular hand eczema (dyshidrotic eczema).

[0007] Reported prevalence and incidence rates of hand eczema vary considerably depending on the data collection methodology. A review of available data from 1964–2007 indicates that the point prevalence of hand eczema in the general population is approximately 4%, the 1-year prevalence is about 10%, and the lifetime prevalence is nearly 15%. Approximately 7–10% of patients with hand eczema report symptoms "almost constantly," which signifies a chronic state of the disease. Based on data from seven studies, the incidence rate of hand eczema is 5.5 cases / 1000 person-years, with a higher median incidence rate in women (Diepgen et al., J Dtsch Dermatol Ges. 2015;13(1): e1-22). Several risk factors have been identified, including pre-existing AD, female gender, wet work, and contact allergies (Thyssen et al., Contact Dermatitis. 2010;62(2):75-87, Mortz el al., Br J Dermatol. 2014;171(2):313-323).

[0008] The prevalence of hand eczema varies across age groups (6), with the mean / median first onset occurring in the early to mid-20s (Anveden et al., Contact Dermatitis. 2006;54(5):272-277, Hald et al., Br J Dermatol. 2008;158(4):773-777, Lind et al., Occup Environ Med. 2007;64(3):191-195). However, approximately one-third of men and women report experiencing their first case of hand eczema by the age of 20 (Meding B et al., J Invest Dermatol. 2004;122(4):873-877).

[0009] Although the underlying molecular mechanisms of CHE are not fully understood, a large panel of cytokine-mediated signaling cascades has been identified as part of the pathophysiology, including cytokine responses via the Th2 pathway (IL-4, IL-13), Th22 pathway (IL-22), Th17 pathway (IL-17), Th1 pathway (interferon-γ), and the JAK / STAT pathway. Since the JAK protein is required for most cytokine signaling, inhibiting JAK reduces cytokine signaling, thereby breaking the vicious cycle that leads to the development of CHE (Pedersen et al., J Invest Dermatol. 2007;127(11):2585-2595, Brunner et al., J Allergy Clin Immunol. 2017;139(4S): S65-S76, Gittler et al., Journal of Allergy and Clinical Immunology. 2013;131(2):300-313).

[0010] CHE is generally difficult to treat and involves alternating periods of redness and remission.

[0011] Treatment for CHE (Cardiopulmonary Eczema) involves various disease management strategies, including allergen removal, general skin care, and a stepwise approach to anti-inflammatory therapy. General skin care with emollients is widely used and recommended by physicians, but evidence of its effectiveness is limited. Allergen and irritant removal is effective and may be a necessary prerequisite for the success of longer-term therapy, but removal is likely difficult to achieve in many situations. Although there is no documented treatment efficacy, TCS (Tracheal Cellulose Stimulant) remains the mainstay of topical anti-inflammatory therapy for hand eczema. However, long-term use of TCS is limited due to side effects such as skin atrophy and potential inhibition of skin barrier repair.

[0012] While mild cases of CHE can be managed to some extent by removing triggers and general skincare, managing moderate to severe cases of CHE is more complex. Alitretinoin is the only approved product specifically indicated for the treatment of CHE, but it is only indicated for severe CHE and is approved in only a few countries worldwide. Due to various safety limitations, alitretinoin treatment is only indicated for use in adults with severe CHE that does not respond to treatment with potent TCS.

[0013] Given the lack of approved therapies for treating CHE, other treatment options are limited to those approved for other skin conditions with inflammatory pathophysiology. These applicable treatments are limited to short-term use and are not suitable for chronic disorders characterized by relapse, often leading to long-term treatment exposure, due to a lack of clinical documentation for use in CHE.

[0014] Currently available treatment options are limited by a lack of documented efficacy or restrictions on long-term use due to safety concerns. Therefore, there is a significant unmet medical need for a new topical treatment for moderate to severe CHE that offers high efficacy combined with a favorable safety profile for long-term use. A new and better treatment would likely potentially improve the daily lives of patients with moderate to severe CHE. Delgocitinib may address this unmet medical need associated with this serious condition.

[0015] Delgocitinib is disclosed in International Publication No. 2011013785, and its general formula is [ka] It has the properties of and is appropriately prepared by one of the methods disclosed in International Publication No. 2018117152.

[0016] Delgocitinib is a pan-JAK inhibitor that blocks various cytokine-mediated signaling pathways, broadly suppressing the activation of immune and inflammatory cells such as T cells, B cells, mast cells, and monocytes that are activated by these cytokines.

[0017] The efficacy and safety of delgocitinib in mild to severe CHE have been demonstrated in a Phase 2a trial with delgocitinib 30 mg / g and a Phase 2b dose-range trial with delgocitinib (1, 3, 8, and 20 mg / g) (Worm et al., British Journal of Dermatology (2022), 187, pp. 42-51 and British Journal of Dermatology (May 2020, 185, (5), 1103-1110).

[0018] The need for new long-term treatment options in patients with moderate to severe CHE is clearly not being met.

[0019] In this study, an acidified aqueous composition containing delgocitinib was found to have a significant effect in patients with moderate to severe chronic hand eczema (CHE).

[0020] Summary of the Invention The present invention relates to a method for treating moderate to severe chronic hand eczema in a human patient requiring treatment for chronic hand eczema, comprising administering an acidified aqueous topical composition containing 20 mg / g delgocitinib or a pharmaceutically acceptable salt thereof on a free base basis to the skin of the human patient twice daily, wherein the patient has a disease severity classified as moderate to severe (i.e., an IGA-CHE score of 3 or 4) upon screening and baseline by IGA-CHE.

[0021] In another aspect, the present invention relates to the acidified aqueous topical composition for use in a method for treating moderate to severe chronic hand eczema.

[0022] Detailed description of the invention

Brief Description of the Drawings

[0023] [Figure 1] It is a diagram showing IGA-CHE TS responders from 0 to 16 weeks, where a) IGA-CHE TS by visit, and b) TS defined as an IGA-CHE score of 0 (disappeared) or 1 (almost disappeared) with a ≥2-step improvement from baseline. [Figure 2A] It is a diagram showing HECSI75 as the responder percentage from 0 weeks to 16 weeks. [Figure 2B] It is a diagram showing HECSI90 and DLQI≥4 as the responder percentage from 0 weeks to 16 weeks. [Figure 2C] It is a diagram showing HECSI75, HECSI90 and DLQI≥4 as the responder percentage at 16 weeks. [Figure 3] It is a diagram showing the change (in the entire analysis population, WOCF) in the HESD pain score (weekly average) from baseline up to 16 weeks in DELTA 1 and DELTA 2. The HESD pain score is reported daily by the study participants and ranges from 0 ("asymptomatic") to 10 ("severe symptoms"). [Figure 4A] It is a diagram showing the percentage of patients who achieved a ≥4-point decrease in HESD pain from baseline up to 16 weeks among study participants with a corresponding baseline HESD pain score (weekly average) of ≥4 points in DELTA 1 and DELTA 2 (in the entire analysis population, NRI). The HESD pain score is reported daily by the study participants and ranges from 0 ("asymptomatic") to 10 ("severe symptoms"). [Figure 4B] It is a diagram showing the percentage of patients who achieved a ≥4-point decrease in HESD itching from baseline up to 16 weeks among study participants with a corresponding baseline HESD itching score (weekly average) of ≥4 points in DELTA 1 and DELTA 2 (in the entire analysis population, NRI). The HESD itching score is reported daily by the study participants and ranges from 0 ("asymptomatic") to 10 ("severe symptoms"). [Figure 5]This figure shows the change in HESD pruritus score (weekly mean) from baseline up to 16 weeks in DELTA 1 and DELTA 2 (WOCF). HESD pruritus scores were reported daily by study participants and ranged from 0 ("asymptomatic") to 10 ("severely symptomatic"). [Figure 6] This figure shows an overview of adverse events (safety analysis population) in DELTA 1 and DELTA 2, including AEs whose start date is after the date of initial study treatment application, or AEs whose severity worsened after initial study treatment application. Classification is according to MedDRA version 24.0. a. Report exacerbation or worsening of CHE that exceeds normal variation or occurs in areas not normally affected by CHE. [Figure 7] This figure shows the outcomes after adverse events in DELTA 1 and DELTA 2, and the measures taken with the study drug (safety analysis population). [Figure 8] This figure shows the relative (%) individual and average effects (compared to positive controls) of ointment and cream application to human skin explants (NativeSkin) 24 hours after treatment, with different colors representing different donors for each treatment. [Figure 9] This figure shows an open-flow micro-perfusion probe inserted into the dermis. [Figure 10] This figure shows the change in EQ-5D from baseline to treatment response at 16 weeks in all patients, as assessed by the HECSI score, IGA-CHE score, and HESD pruritus and pain score. [Figure 11] This figure shows the change in DLGQI from baseline due to treatment response in all patients at 16 weeks, as assessed by the HECSI score, IGA-CHE score, and HESD pruritus and pain score. [Figure 12]This figure shows the percentage of patients who achieved a ≥4-point improvement in HESD pruritus and a ≥4-point improvement in HESD pain over time—pooled data from DELTA 1 and DELTA 2. *Statistically significant relative to vehicle after adjusting for multiplicity **Statistically significant relative to vehicle without adjusting for multiplicity Based on the number of patients whose baseline value was ≥4 (on a scale of 0-10).

[0024] Abbreviation AE = Adverse event; CHE=chronic hand eczema; cDLQI = Quality of Life Index for Childhood Skin Diseases; HECSI=Hand Eczema Severity Index; HECSI-75 = At ​​least 75% improvement in HECSI score from baseline HECSI-90 = at least 90% improvement in HECSI score from baseline; HESD=Hand Eczema Symptom Diary (C) . IE = Intermediate event; IGA-CHE = Overall assessment of chronic hand eczema by researchers (C) ; IGA-CHE TS = IGA-CHE treatment success, i.e., an IGA-CHE score of 0 (clear) or 1 (nearly clear) with a ≥2-step improvement from baseline; TS = Treatment successful. DLQI = Quality of Life Index for Skin Diseases; EQ-5D-5L=EuroQol 5-dimensional health questionnaire 5 levels; HEIS=Hand Eczema Impact Scale; PDAL = Recent daily activity restrictions WPAI:CHE = Work productivity and activity impairment: Chronic hand eczema. cDLQI = Quality of Life Index for Childhood Skin Diseases; AS = Area Score; SS = Severity Score; CI, confidence interval; LS, least squares; SE, standard error; WOCF, worst-case scenario: observation carried over; NRI, Non-Responder Complementary; E, number of events; N: Number of patients in the population being analyzed; n, number of observed patients; PYO: Patient Years of Observation; R: Ratio calculated as (E / PYO) × 100.

[0025] When used herein in relation to a value or quantity, "about" means + / - 10% of that value or quantity.

[0026] Measurement of effectiveness IGA-CHE The IGA-CHE scale rates the overall severity of the disease in the patient, using a 5-point scale ranging from 0 (clear) to 4 (severe) (Table 1). The assessment is based on the disease state at the time of assessment and is independent of the state at previous visits. New lesions occurring in areas that have not been treated beforehand are included in the assessment.

[0027] [Table 1]

[0028] Hand Eczema Severity Index (HECSI) HECSI is a tool used in clinical trials to rate the severity of six clinical signs (erythema, infiltrative / papulogenesis, vesicles, fissures, scaling, and edema) and the extent of lesions in each of five hand regions (fingertips, fingers [excluding fingertips], palm, back of hand, and wrist) using a standardized scale (Held et al., Br J Dermatol. 2005;152(2):302-307).

[0029] For each hand area (total for both hands, e.g., all ten fingers), the researcher rates the mean severity of each of the six clinical signs of hand eczema using a 4-point severity scale ranging from 0 (none / absent) to 3 (severe) (Table 2). The researcher also rates the extent of the lesions by assessing the percentage of hand area occupied by these lesions and converting it into a score (area score) based on a 5-point scale (Table 2). For each hand area, the area score is calculated by summing the severity scores of the six clinical signs of hand eczema and multiplying it by the area score (Table 3). The HECSI score is equal to the sum of the area scores and ranges from 0 (lowest possible score) to 360 (highest possible score).

[0030] The assessment is based on the disease state at the time of assessment and is independent of the state at the time of the previous visit. New CHE lesions that develop in areas that have not been treated beforehand are included in the assessment.

[0031] [Table 2]

[0032] [Table 3]

[0033] Patient-reported outcomes (effectiveness) PRO HESD is considered an effectiveness evaluation.

[0034] Hand Eczema Symptom Diary (HESD) HESD is a 6-item PRO tool designed to assess the severity of CHE signs and symptoms. Participants use an 11-point numerical rating scale with anchors of 0 = "none (symptoms)" and 10 = "severe (symptoms)" to assess the worst severity of six individual signs and symptoms of CHE (itching, pain, cracking, redness, dryness, and peeling) over the past 24 hours. The HESD score is derived as the mean of the 6 items.

[0035] Safety evaluation Patient-reported outcomes (health-related quality of life and work productivity) Patient's General Impression of Severity (PGI-S) Questionnaire The PGI-S is a one-item questionnaire designed to assess a subject's overall perception of pruritus, pain, or chronic hand eczema signs and symptoms over the past week using a four-point response scale ("none," "mild," "moderate," or "severe") (Table 4).

[0036] [Table 4]

[0037] Patient's General Impression of Change (PGI-C) Questionnaire The PGI-C is a one-item questionnaire designed to assess a subject's perception of change (38). Subjects must select one response from five options ("much better," "somewhat better," "no change," "somewhat worse," or "much worse") that best describes the overall change in their itching, pain, or chronic hand eczema signs and symptoms since initiating IMP treatment (Table 5).

[0038] [Table 5]

[0039] Hand Eczema Impact Scale (HEIS) The HEIS consists of nine items that address the subject's perception of the impact of hand eczema on their daily activities, embarrassment, frustration, sleep, work, and physical function over the past seven days. Each item is scored on a 5-point scale (0 = "not at all", 1 = "somewhat", 2 = "fairly", 3 = "quite a bit", 4 = "very much"). The HEIS score is the average of the nine items. The highest possible score is 4, and a higher score indicates a greater impact. Six domain scores can be calculated for the HEIS: PDAL (average of 3 items), embarrassment about the appearance of hands (average of 2 items), frustration with CHE (1 item), sleep (1 item), work (1 item), and physical function (1 item).

[0040] Patient-led global assessment of disease severity (PaGA) The subjects underwent an overall assessment of the severity of their hand eczema. The assessment was conducted using a 5-point scale (0 = "clear," 1 = "almost clear," 2 = "mild," 3 = "moderate," 4 = "severe") and was based on the severity of the subjects' hand eczema at the time of assessment (Table 6).

[0041] [Table 6]

[0042] Quality of Life Index for Skin Diseases (DLQI) The DLQI is a validated questionnaire with specific content for individuals with skin conditions. It consists of 10 items that deal with the subject's perception of the impact of their skin condition on different aspects of their quality of life over the past week, including skin-related symptoms and feelings, daily activities, leisure, work or school, relationships, and treatment (39). Each item is scored on a 4-point Likert scale (0 = "not relevant at all"; 1 = "somewhat relevant"; 2 = "quite relevant"; 3 = "very relevant"). The DLQI score is the sum of the 10 items (scores ranging from 0 to 30); a higher score indicates a lower quality of life.

[0043] The cDLQI is a validated questionnaire with specific content for individuals with skin conditions. It consists of 10 items that deal with the subject's perception of the impact of their skin condition on different aspects of their quality of life over the past week, including skin-related symptoms and emotions, social relationships, leisure, school or holidays, negative comments, sleep, and treatment (35). Each item is scored on a 4-point Likert scale (0 = "not at all / not relevant"; 1 = "somewhat relevant"; 2 = "quite relevant"; 3 = "very relevant"). The total score is the sum of the 10 items (0-30); a higher score indicates a lower quality of life.

[0044] EuroQol 5-dimensional health questionnaire 5 levels (EQ-5D-5L) EQ-5D-5L is a standardized health status scale developed by the EuroQol group to provide a simple and general health scale for clinical and economic assessment (EuroQol—a new facility for the measurement of health-related quality of life. Health Policy. 1990;16(3):199-208).

[0045] The EQ-5D-5L is a self-administered questionnaire used to assess your "current" health status and is divided into two sections.

[0046] The first section includes five dimensions (mobility, self-care, daily activities, pain / discomfort, and anxiety / depression). Each dimension is assessed by the subject using a five-point scale ("no problem", "minor problem", "moderate problem", "serious problem", and "impossible / extreme problem"). The EQ-5D-5L index score is derived from the five dimensions and converted from the 5L system to the 3L system using the EQ-5D-5L crosswalk value set. The index score ranges from -0.594 to 1.0 (based on a UK country-specific value set), with higher scores indicating better health.

[0047] The second section consists of a vertical visual analog scale fixed at 0 ("worst health imaginable") and 100 ("best health imaginable"). Work productivity and activity impairment: chronic hand eczema (WPAI:CHE)

[0048] The impact of CHE on the target work capacity and ability to perform normal activities is assessed using WPAI:CHE, a tool that measures impairment in both paid and unpaid work (Reilly et al., Pharmacoeconomics. 1993;4(5):353-365). WPAI:CHE consists of six items and allows for the calculation of scores for four domains, each reflecting the percentage of impairment due to CHE over the past seven days. Higher scores indicate greater impairment and lower productivity. Absenteeism: The percentage of time currently absent due to CHE (Certified Absence from Work) among currently employed individuals. • Presenteeism: The percentage of people currently employed who have actually worked in the past 7 days who have experienced work-related disabilities as measured by CHE (Critical Efficiency Assessment). • Work productivity loss: The percentage of overall work impairment due to CHE among currently employed people. • Activity impairment: Percentage of activity impairment due to CHE in all responders.

[0049] The endpoints to be investigated are shown in Tables 7 and 8 below.

[0050] [Table 7-1] [Table 7-2]

[0051] [Table 8-1] [Table 8-2]

[0052] [Table 9]

[0053] [Table 10]

[0054] As described above, the present invention relates to a method for treating moderate to severe chronic hand eczema in a human patient, comprising administering an acidified aqueous topical composition containing 20 mg / g delgocitinib or a pharmaceutically acceptable salt thereof on a free base basis to the skin of the human patient requiring treatment twice daily, wherein the patient has a disease severity classified as moderate to severe (i.e., an IGA-CHE score of 3 or 4) upon screening and baseline by IGA-CHE.

[0055] In further embodiments, the present invention relates to the use of an acidified aqueous topical composition comprising 20 mg / g delgocitinib or a pharmaceutically acceptable salt thereof on a free base basis for the treatment of moderate to severe chronic hand eczema in human patients, comprising administration twice daily to the skin of the human patient requiring treatment, wherein the patient has a disease severity classified as moderate to severe upon screening by IGA-CHE and at baseline (i.e., an IGA-CHE score of 3 or 4).

[0056] In further embodiments, the present invention relates to the use of delgocitinib for preparing an acidified aqueous topical composition comprising 20 mg / g delgocitinib or a pharmaceutically acceptable salt thereof on a free base basis for treating moderate to severe chronic hand eczema in human patients, comprising administering the delgocitinib twice daily to the skin of the human patient requiring treatment, wherein the patient has a disease severity classified as moderate to severe upon screening by IGA-CHE and at baseline (i.e., an IGA-CHE score of 3 or 4).

[0057] In further embodiments, the present invention relates to a method, use, or use described above in which a patient has a baseline HESD pruritus score (weekly mean) of ≥4 points.

[0058] In further embodiments, the present invention relates to a method, use, or use described above, in which the patient is a young person aged 12 to 17 years or an adult aged 18 years or older, and the patient has hand eczema that has lasted for more than 3 months or has recurred more than twice within the past 12 months.

[0059] In further embodiments, the present invention relates to methods, uses, or the above uses in which a patient has a documented recent history of an inadequate response to treatment with topical corticosteroids (TCS), or otherwise it is documented that TCS is not medically recommended for the patient (e.g., due to significant side effects or safety risks).

[0060] In further embodiments, the present invention relates to a method, use, or use described above for a patient to achieve an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 16 weeks.

[0061] In further embodiments, the present invention relates to a method, use, or use described above for a patient to achieve an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 12 weeks.

[0062] In further embodiments, the present invention relates to a method, use, or use described above for a patient to achieve an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 8 weeks.

[0063] In further embodiments, the present invention relates to a method, use, or use described above for a patient to achieve an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 4 weeks.

[0064] In further embodiments, the present invention relates to a method, use, or use described above for a patient to achieve an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline in two weeks.

[0065] In further embodiments, the present invention relates to a method, use, or use described above for a patient to achieve an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline in one week.

[0066] In further embodiments, the present invention relates to a method, use, or use described above for a patient to achieve at least a 90% improvement in HECSI score from baseline at 16 weeks, or 8 weeks, or 4 weeks, 2 weeks, or 1 week.

[0067] In further embodiments, the present invention relates to a method, use, or use described above for a patient to achieve at least a 75% improvement in HECSI score from baseline at 16 weeks, or 8 weeks, or 4 weeks, or 2 weeks, or 1 week.

[0068] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD score (weekly mean) of ≥4 points and achieving a reduction of ≥4 points in the HESD score (weekly mean) from baseline over 16 weeks.

[0069] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD score (weekly mean) of ≥4 points and achieving a reduction of ≥4 points in the HESD score (weekly mean) from baseline over 12 weeks.

[0070] In a further embodiment, the present invention relates to a method, use, or use described above for a patient who has a baseline HESD score (weekly mean) of ≥4 points at baseline and achieves a reduction of ≥4 points in the HESD score (weekly mean) from baseline over 8 weeks.

[0071] In a further embodiment, the present invention relates to a method, use, or use described above for a patient who has a baseline HESD score (weekly mean) of ≥4 points at baseline and achieves a reduction of ≥4 points in the HESD score (weekly mean) from baseline over 4 weeks.

[0072] In a further embodiment, the present invention relates to a method, use, or use described above for a patient who has a baseline HESD score (weekly mean) of ≥4 points at baseline and achieves a reduction of ≥4 points in the HESD score (weekly mean) from baseline over two weeks.

[0073] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD score (weekly mean) of ≥4 points at baseline and achieving a reduction of ≥4 points in the HESD score (weekly mean) from baseline in one week.

[0074] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD score (weekly mean) of ≥3 points and achieving a reduction of ≥3 points in the HESD score (weekly mean) from baseline over 16 weeks.

[0075] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD score (weekly mean) of ≥3 points and achieving a reduction of ≥3 points in the HESD score (weekly mean) from baseline over 12 weeks.

[0076] In a further embodiment, the present invention relates to a method, use, or use described above for a patient who has a baseline HESD score (weekly mean) of ≥3 points at baseline and achieves a reduction of ≥3 points in the HESD score (weekly mean) from baseline over 8 weeks.

[0077] In a further embodiment, the present invention relates to a method, use, or use described above for a patient who has a baseline HESD score (weekly mean) of ≥3 points at baseline and achieves a reduction of ≥3 points in the HESD score (weekly mean) from baseline over four weeks.

[0078] In a further embodiment, the present invention relates to a method, use, or use described above for a patient who has a baseline HESD score (weekly mean) of ≥3 points at baseline and achieves a reduction of ≥3 points in the HESD score (weekly mean) from baseline in two weeks.

[0079] In further embodiments, the present invention relates to a method, use, or use described above for a patient who has a baseline HESD score (weekly mean) of ≥3 points at baseline and achieves a reduction of ≥3 points in the HESD score (weekly mean) from baseline in one week.

[0080] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having an HEDS pruritus score of ≥4 points (weekly mean) and achieving a reduction of ≥4 points in the HEDS pruritus score (weekly mean) from baseline over 16 weeks.

[0081] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pruritus score (weekly mean) of ≥4 points and achieving a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline over 12 weeks.

[0082] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pruritus score (weekly mean) of ≥4 points and achieving a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline over 8 weeks.

[0083] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pruritus score (weekly mean) of ≥4 points and achieving a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline over 4 weeks.

[0084] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pruritus score (weekly mean) of ≥4 points, and for a patient achieving a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline over two weeks.

[0085] In further embodiments, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pruritus score (weekly mean) of ≥4 points, and for a patient achieving a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline in one week.

[0086] In further embodiments, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pruritus score (weekly mean) of ≥3 points and achieving a reduction of ≥3 points in the HESD pruritus score (weekly mean) from baseline over 16 weeks.

[0087] In further embodiments, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pruritus score (weekly mean) of ≥3 points and achieving a reduction of ≥3 points in the HESD pruritus score (weekly mean) from baseline over 12 weeks.

[0088] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pruritus score (weekly mean) of ≥3 points and achieving a reduction of ≥3 points in the HESD pruritus score (weekly mean) from baseline over 8 weeks.

[0089] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pruritus score (weekly mean) of ≥3 points and achieving a reduction of ≥3 points in the HESD pruritus score (weekly mean) from baseline over 4 weeks.

[0090] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pruritus score (weekly mean) of ≥3 points and achieving a reduction of ≥3 points in the HESD pruritus score (weekly mean) from baseline over two weeks.

[0091] In further embodiments, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pruritus score (weekly mean) of ≥3 points and achieving a reduction of ≥3 points in the HESD pruritus score (weekly mean) from baseline in one week.

[0092] In further embodiments, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pruritus score (weekly mean) of ≥3 points and achieving a reduction of ≥3 points from baseline in the HESD pruritus score (weekly mean) within 36 hours on day 6, day 5, day 4, day 3, day 2, or day 1, or within 24 hours.

[0093] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pain score (weekly mean) of ≥4 points and achieving a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline over 16 weeks.

[0094] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pain score (weekly mean) of ≥4 points and achieving a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline over 12 weeks.

[0095] In further embodiments, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pain score (weekly mean) of ≥4 points and achieving a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline over 8 weeks.

[0096] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pain score (weekly mean) of ≥4 points and achieving a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline over 4 weeks.

[0097] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pain score (weekly mean) of ≥4 points and achieving a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline over two weeks.

[0098] In further embodiments, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pain score (weekly mean) of ≥4 points and achieving a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline in one week.

[0099] In further embodiments, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pain score (weekly mean) of ≥3 points and achieving a reduction of ≥3 points in the HESD pain score (weekly mean) from baseline over 16 weeks.

[0100] In further embodiments, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pain score (weekly mean) of ≥3 points and achieving a reduction of ≥3 points in the HESD pain score (weekly mean) from baseline over 12 weeks.

[0101] In further embodiments, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pain score (weekly mean) of ≥3 points and achieving a reduction of ≥3 points in the HESD pain score (weekly mean) from baseline over 8 weeks.

[0102] In further embodiments, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pain score (weekly mean) of ≥3 points and achieving a reduction of ≥3 points in the HESD pain score (weekly mean) from baseline over 4 weeks.

[0103] In a further embodiment, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pain score (weekly mean) of ≥3 points and achieving a reduction of ≥3 points in the HESD pain score (weekly mean) from baseline over two weeks.

[0104] In further embodiments, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pain score (weekly mean) of ≥3 points and achieving a reduction of ≥3 points in the HESD pain score (weekly mean) from baseline in one week.

[0105] In further embodiments, the present invention relates to a method, use, or use described above for a patient having a baseline HESD pain score (weekly mean) of ≥3 points and achieving a reduction of ≥3 points from baseline in the HESD pain score (weekly mean) within 36 hours on day 6, day 5, day 4, day 3, day 2, or day 1, or within 24 hours.

[0106] In further embodiments, the present invention relates to a method, use, or use described above for a patient to achieve a reduction of ≥4 points in their DLQI score from baseline over 16 weeks.

[0107] In further embodiments, the present invention relates to a method, use, or use described above for a patient to achieve a reduction of ≥4 points in their DLQI score from baseline over 12 weeks.

[0108] In further embodiments, the present invention relates to a method, use, or use described above for a patient to achieve a reduction of ≥4 points in their DLQI score from baseline over 8 weeks.

[0109] In further embodiments, the present invention relates to a method, use, or use described above for a patient to achieve a reduction of ≥4 points in their DLQI score from baseline over 4 weeks.

[0110] In further embodiments, the present invention relates to a method, use, or use described above for a patient to achieve a reduction of ≥4 points in their DLQI score from baseline over two weeks.

[0111] In further embodiments, the present invention relates to a method, use, or use described above for a patient to achieve a reduction of ≥4 points in their DLQI score from baseline in one week.

[0112] In further embodiments, the present invention relates to a method, use, or use described above in which no accumulation of delgocitinib in the body is observed.

[0113] In further embodiments, the present invention relates to a method, use, or use described above in which the treatment is continued until the patient achieves complete or near-complete disappearance of the skin.

[0114] In further embodiments, the present invention relates to a method, use, or use described above, wherein if signs and symptoms of (redness) recur, treatment of the affected area twice daily is resumed as necessary.

[0115] In further embodiments, the present invention relates to a method, use, or use of delgocitinib in which it is dissolved in the aqueous phase of a topical formulation.

[0116] In further embodiments, the present invention relates to a method, use, or use of an aqueous topical formulation having a pH of less than about 4.6.

[0117] In further embodiments, the present invention relates to a method, use, or use thereof of an aqueous topical formulation having a pH of about 3.8 to about 4.6.

[0118] In further embodiments, the present invention relates to a method, use, or use of an aqueous topical formulation having a pH of about 4.3 or less.

[0119] In further embodiments, the present invention relates to a method, use, or use of an aqueous topical formulation having a pH of about 4.2 or less.

[0120] In further embodiments, the present invention relates to a method, use, or use thereof in which the aqueous cream comprises a lipid base.

[0121] In further embodiments, the present invention relates to a method, use, or use thereof, in which the lipid base is liquid paraffin.

[0122] In some embodiments, the acidified aqueous topical composition or aqueous cream is an oil-in-water emulsion, such as that described in International Publication No. 2020 / 229622.

[0123] In some embodiments, the acidified topical composition or aqueous cream used in the present invention contains a large amount of water and is acidified to a pH of 3.8 to 4.6, more preferably about 4.2, using a pharmaceutically acceptable acid such as hydrochloric acid.

[0124] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises one or more bases selected from medium-chain triglycerides, safflower oil, castor oil, liquid paraffin, or mixtures thereof. In some embodiments, the base is liquid paraffin.

[0125] The base is typically present in amounts of approximately 50 mg / g to 500 mg / g, 200 mg / g to 400 mg / g, 75 mg / g to 125 mg / g, or 100 mg / g. The base is appropriately liquid paraffin.

[0126] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises a surfactant, an emulsifier, or a stabilizer, the surfactant, emulsifier, or stabilizer being selected from one or more fatty alcohols such as cetyl alcohol, stearyl alcohol, cetostearyl alcohol, sorbitan esters, sucrose esters, macrogol cetostearyl ethers, or mixtures thereof.

[0127] Typically, surfactants, emulsifiers, or stabilizers are present in amounts of 40–150 mg / g, 60–120 mg / g, or approximately 80–100 mg / g.

[0128] Typically, the surfactant, emulsifier, or stabilizer may be selected from fatty alcohols such as cetostearyl alcohol and is present in amounts of about 30 mg / g to about 120 mg / g, for example, about 50 mg / g to about 90 mg / g, or about 70 to 75 mg / g. Typically, the surfactant, emulsifier, or stabilizer may be selected from cetostearyl alcohol and is present in amounts of about 70 to 75 mg / g, or about 72 mg / g.

[0129] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises a surfactant, an emulsifier, or a stabilizer, the surfactant, emulsifier, or stabilizer being selected from sorbitan esters, sucrose esters, macrogol fatty alcohol ethers, or mixtures thereof. For example, the surfactant or emulsifier is macrogol cetostearyl ether.

[0130] Typically, surfactants, emulsifiers, or stabilizers selected from sorbitan esters, sucrose esters, macrogol cetostearyl ethers, or mixtures thereof are present in amounts of about 10 mg / g to about 30 mg / g, about 14 mg / g to about 22 mg / g, or about 20 to 22 mg / g. Typically, the surfactant, emulsifier, or stabilizer is macrogol cetostearyl or other fatty alcohol ethers in amounts of about 20 to 22 mg / g or about 18 mg / g.

[0131] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention includes a buffer or pH adjuster. A pharmaceutically acceptable buffer or pH adjuster may be one or more of phosphoric acid or citrate, sodium acetate, sodium carbonate, sodium citrate dihydrate, hydrochloric acid, or mixtures thereof. For example, the buffer or pH adjuster may be one or more of citric acid monohydrate and sodium citrate dihydrate. Typically, a buffer selected from phosphoric acid, citric acid, or acetate buffers is used.

[0132] Buffering agents or pH adjusters may be present in various amounts, ranging from approximately 0.5 mg / g to approximately 4 mg / g, or from approximately 0.7 mg / g to approximately 2 mg / g, or approximately 1 g / g.

[0133] Typically, the buffer is a citrate buffer containing citrate monohydrate and sodium citrate dihydrate, where sodium citrate dihydrate is present in amounts of approximately 0.5 mg / g to approximately 4 mg / g, approximately 0.7 mg / g to approximately 2 mg / g, or approximately 1 g / g, and sodium citrate dihydrate is present in amounts of 0 mg / g to approximately 1 mg / g, 0 mg / g to approximately 0.5 mg / g, or is absent.

[0134] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention contains a pharmaceutically acceptable preservative, such as a preservative selected from benzyl alcohol, sodium dehydroacetate, sorbic acid / salt, or a mixture thereof. In one embodiment, the preservative is benzyl alcohol.

[0135] Preservatives may be present in various amounts, ranging from approximately 5 mg / g to 20 mg / g, from approximately 7 mg / g to 13 mg / g, or in an amount of approximately 10 mg / g.

[0136] Typically, the preservative is benzyl alcohol, present in amounts of approximately 5 mg / g to 20 mg / g, 7 mg / g to 13 mg / g, or 10 mg / g.

[0137] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention contains a pharmaceutically acceptable antioxidant, such as an antioxidant selected from sodium sulfite, disodium edetate, trisodium edetate, butylhydroxyanisole, or a mixture thereof. In one embodiment, the antioxidant is butylhydroxyanisole.

[0138] The antioxidant may be present in various amounts ranging from approximately 0.05 mg / g to approximately 0.3 mg / g, approximately 0.1 mg / g to approximately 0.25 mg / g, or in an amount of approximately 0.2 mg / g. Typically, the antioxidant is butylhydroxyanisole, and is present in amounts ranging from approximately 0.05 mg / g to approximately 0.3 mg / g, approximately 0.1 mg / g to approximately 0.25 mg / g, or in an amount of approximately 0.2 mg / g.

[0139] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises a pharmaceutically acceptable chelating agent such as EDTA, disodium edetate, EGTA, or ethylenediamine. In one embodiment, the chelating agent is disodium edetate.

[0140] Typically, chelating agents are present in various amounts ranging from approximately 0.05 mg / g to approximately 1.5 mg / g, approximately 0.5 mg / g to approximately 1 mg / g, or in an amount of approximately 0.6 mg / g. Typically, the chelating agent is EDTA, present in amounts ranging from approximately 0.05 mg / g to approximately 1.5 mg / g, approximately 0.5 mg / g to approximately 1 mg / g, or in an amount of approximately 0.6 mg / g.

[0141] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention contains a pharmaceutically acceptable acidifying agent, which may be one or more strong acids such as hydrochloric acid or citric acid.

[0142] In one embodiment, the acidifying agent is hydrochloric acid.

[0143] The acidifying agent may be present in amounts of 1 mg / g to approximately 25 mg / g, approximately 10 mg / g to approximately 20 mg / g, or approximately 17.7 mg / g. Typically, the acidifying agent is hydrochloric acid present in amounts of 1 mg / g to approximately 25 mg / g, approximately 10 mg / g to approximately 20 mg / g, or approximately 17.7 mg / g.

[0144] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention may contain purified water in various amounts ranging from about 500 mg / g to about 900 mg / g, for example, 760 mg / g.

[0145] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 50 to 500 mg / g of an oily base and 40 to 150 mg / g of a surfactant, emulsifier, or stabilizer.

[0146] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 50 to 500 mg / g of liquid paraffin, 30 to 120 mg / g of cetostearyl alcohol or another fatty alcohol, and 10 to 30 mg / g of macrogol cetostearyl ether or other fatty alcohol ether.

[0147] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 200 to 400 mg / g of an oily base and 60 to 120 mg / g of a surfactant, emulsifier, or stabilizer.

[0148] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 200-400 mg / g of liquid paraffin, 50-90 mg / g of cetostearyl alcohol or another fatty alcohol, and 14-22 mg / g of macrogol cetostearyl ether or other fatty alcohol ether.

[0149] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 75 to 125 mg / g of an oily base and 80 to 100 mg / g of a surfactant, emulsifier, or stabilizer.

[0150] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 75 to 125 mg / g of liquid paraffin, 70 to 75 mg / g of cetostearyl alcohol or another fatty alcohol, and 14 to 22 mg / g of macrogol cetostearyl ether or other fatty alcohol ether.

[0151] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 50 to 500 mg / g of an oily base, 40 to 150 mg / g of a surfactant, emulsifier or stabilizer, and 0.5 to 4 mg / g of a buffer (total of acid and base).

[0152] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 50 to 500 mg / g of liquid paraffin, 30 to 120 mg / g of cetostearyl alcohol or another fatty alcohol and 10 to 30 mg / g of macrogol cetostearyl ether or other fatty alcohol ether and 0.5 to 4 mg / g of a buffer (total of base and acid).

[0153] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 200 to 400 mg / g of an oily base, 60 to 120 mg / g of a surfactant, emulsifier or stabilizer, and 0.7 to 2 mg / g of citrate buffer (total of base and acid) or another suitable buffering agent.

[0154] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 200-400 mg / g of liquid paraffin, 50-90 mg / g of cetostearyl alcohol or another fatty alcohol, 14-22 mg / g of macrogol cetostearyl ether or other fatty alcohol ether, and 0.7-2 mg / g of citrate buffer (total of base and acid) or another suitable buffer.

[0155] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 75 to 125 mg / g of an oily base, 80 to 100 mg / g of a surfactant, emulsifier or stabilizer, and about 1 mg / g of a buffer (total of base and acid).

[0156] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 75 to 125 mg / g of liquid paraffin, 70 to 75 mg / g of cetostearyl alcohol or another fatty alcohol and 14 to 22 mg / g of macrogol cetostearyl ether or other fatty alcohol ether and about 1 mg / g of citrate buffer (total of base and acid) or another suitable buffer.

[0157] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 50 to 500 mg / g of liquid paraffin, 30 to 120 mg / g of cetostearyl alcohol or another fatty alcohol and 10 to 30 mg / g of macrogol cetostearyl ether or other fatty alcohol ether, 0.5 to 4 mg / g of buffer (total of base and acid) and 1 to 25 mg / g of acidifying agent.

[0158] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 200 to 400 mg / g of an oily base, 60 to 120 mg / g of a surfactant, emulsifier or stabilizer, 0.7 to 2 mg / g of a buffer (total of base and acid) or another suitable buffer and 1 to 25 mg / g of an acidifying agent.

[0159] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 200-400 mg / g of liquid paraffin, 50-90 mg / g of cetostearyl alcohol or another fatty alcohol, 14-22 mg / g of macrogol cetostearyl ether or other fatty alcohol ether, 0.7-2 mg / g of citrate buffer (total of base and acid) or another suitable buffer, and 10-20 mg / g of hydrochloric acid or another pharmaceutically acceptable acidifying agent.

[0160] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 75 to 125 mg / g of an oily base, 80 to 100 mg / g of a surfactant, emulsifier or stabilizer, and about 1 mg / g of a buffer (total of base and acid), and 10 to 20 mg / g of an acidifying agent.

[0161] In some embodiments, the acidified aqueous topical composition or aqueous cream used in the present invention comprises 75 to 125 mg / g of liquid paraffin, 70 to 75 mg / g of cetostearyl alcohol or another fatty alcohol and 14 to 22 mg / g of macrogol cetostearyl ether or other fatty alcohol ether and about 1 mg / g of citrate buffer (total of base and acid) or another suitable buffer and 10 to 20 mg / g of hydrochloric acid or another pharmaceutically acceptable acidifying agent.

[0162] According to any of the embodiments described above, an acidified aqueous topical composition or aqueous cream comprising various amounts of an oily base, a surfactant, an emulsifier or stabilizer, a buffer, a pH adjuster and / or an acidifying agent also comprises a preservative, an antioxidant and / or an acidifying agent.

[0163] The acidified aqueous topical composition or aqueous cream used in the present invention may be prepared by separately preparing an aqueous phase and an oil phase, then adding the oil phase to the aqueous phase and mixing them.

[0164] Water phase: A mixture of purified water, pH adjuster, buffer, acidifier, preservative, and chelating agent was used.

[0165] Delgocitinib was added and dissolved in the aqueous phase.

[0166] The pH was adjusted.

[0167] The aqueous phase was heated.

[0168] Oil phase: Liquid paraffin, surfactant, emulsifier, stabilizer, and antioxidant were mixed together.

[0169] The oil phase was heated.

[0170] The oil phase was added to the aqueous phase and mixed.

[0171] The mixture was homogenized and cooled. The acidified aqueous topical composition or aqueous cream was then filled into the container closure.

[0172] Exemplary pharmaceutical formulations used in the present invention: Ingredient amounts (mg / g): Delgocitinib 20; paraffin solution 100; cetostearyl alcohol 72; macrogol cetostearyl ether 18; benzyl alcohol 10; citric acid monohydrate 1.0; butylhydroxyanisole 0.2; disodium edetate 0.6; 3M hydrochloric acid 17.7; and purified water 760.

[0173] The acidified aqueous topical composition or aqueous cream used in the present invention may be prepared as follows:

[0174] Water phase: A mixture of purified water, pH adjuster, buffer, acidifier, preservative, and chelating agent was used.

[0175] The drug substance was added and dissolved in an aqueous phase at a temperature of approximately 15-25°C.

[0176] The pH was adjusted to 4.0-4.4.

[0177] The aqueous phase was heated to approximately 65-75°C.

[0178] Oil phase: Liquid paraffin, surfactant, emulsifier, stabilizer, and antioxidant were mixed together.

[0179] The oil phase was heated to approximately 65-75°C.

[0180] The oil phase was added to the aqueous phase and mixed.

[0181] The mixture was homogenized for approximately 20 minutes, followed by cooling to approximately 30°C. The cream was then filled into container closures.

[0182] Further Embodiments 1. A method for treating moderate to severe chronic hand eczema in a human patient requiring treatment for chronic hand eczema, comprising administering an acidified aqueous topical composition containing 20 mg / g delgocitinib or a pharmaceutically acceptable salt thereof on a free base basis to the skin of the human patient twice daily, wherein the patient has a disease severity classified as moderate to severe upon screening by IGA-CHE and at baseline.

[0183] 2. The method according to Embodiment 1, wherein the patient has a baseline HESD pruritus score of ≥4 points (weekly mean).

[0184] 3. The method according to Embodiment 1 or 2, wherein the patient is a young adult aged 12 to 17 years or an adult aged 18 years or older, and the patient has hand eczema that has persisted for more than 3 months or has recurred more than twice within the past 12 months.

[0185] 4. The method according to any one of Embodiments 1 to 3, wherein the patient has a documented recent history of an inadequate response to treatment with topical corticosteroids (TCS), or otherwise it is documented that TCS is not medically recommended for the patient (e.g., due to significant side effects or safety risks).

[0186] 5. The method according to any one of Embodiments 1 to 4, wherein delgocitinib is dissolved in the aqueous phase of an acidified aqueous topical formulation.

[0187] 6. The method according to Embodiment 5, wherein the acidified aqueous topical formulation has a pH of less than about 4.6 or less than about 4.4.

[0188] 7. The method according to Embodiment 6, wherein the acidified aqueous topical formulation has a pH of approximately 3.8 to approximately 4.6.

[0189] 8. The method according to Embodiment 7, wherein the aqueous topical formulation has a pH of approximately 4.3 or less.

[0190] 9. The method according to Embodiment 8, wherein the aqueous topical formulation has a pH of approximately 4.2 or less.

[0191] 10. The method according to any one of Embodiments 5 to 9, wherein the aqueous cream contains a lipid base.

[0192] 11. The method according to Embodiment 10, wherein the lipid base is liquid paraffin.

[0193] 12. A method according to any one of Embodiments 1 to 11, wherein a patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 16 weeks.

[0194] 13. The method according to Embodiment 12, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 8 weeks.

[0195] 14. The method according to Embodiment 12, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 4 weeks.

[0196] 15. The method according to Embodiment 12, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 2 weeks.

[0197] 16. The method according to Embodiment 12, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline in one week.

[0198] 17. The method according to Embodiment 12, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline on day 5 or 6.

[0199] 18. The method according to Embodiment 12, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline on day 4.

[0200] 19. The method according to Embodiment 12, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline on day 3.

[0201] 20. The method according to Embodiment 12, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline within 2 days or 36 hours.

[0202] 21. The method according to Embodiment 12, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline within 1 day or 24 hours.

[0203] 22. A method according to any one of Embodiments 1 to 21, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline at 16 weeks.

[0204] 23. The method according to Embodiment 22, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline at 8 weeks.

[0205] 24. The method according to Embodiment 22, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline at 4 weeks.

[0206] 25. The method according to Embodiment 22, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline within two weeks.

[0207] 25. The method according to Embodiment 22, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline in one week.

[0208] 26. The method according to Embodiment 22, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline on day 6.

[0209] 27. The method according to Embodiment 22, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline on day 5.

[0210] 28. The method according to Embodiment 22, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline on day 4.

[0211] 29. The method according to Embodiment 22, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline on day 3.

[0212] 30. The method according to Embodiment 22, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline within two days or 36 hours.

[0213] 31. The method according to Embodiment 22, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline within 1 day or 24 hours.

[0214] 32. A method according to any one of Embodiments 1 to 31, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline at 16 weeks.

[0215] 33. The method according to embodiment 32, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline at 8 weeks.

[0216] 34. The method according to Embodiment 32, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline at 4 weeks.

[0217] 35. The method according to Embodiment 32, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline within two weeks.

[0218] 36. The method according to embodiment 32, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline in one week.

[0219] 37. The method according to Embodiment 32, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline on day 6.

[0220] 38. The method according to Embodiment 32, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline on day 5.

[0221] 39. The method according to Embodiment 32, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline on day 4.

[0222] 40. The method according to Embodiment 32, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline on day 3.

[0223] 41. The method according to Embodiment 32, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline within two days or 36 hours.

[0224] 42. The method according to Embodiment 32, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline within 1 day or 24 hours.

[0225] 43. The method according to any one of Embodiments 1 to 42, wherein the patient has a baseline HESD score (weekly mean) of ≥4 points and achieves a reduction of ≥4 points in the HESD score (weekly mean) from baseline at 16 weeks.

[0226] 44. The method according to Embodiment 43, wherein the patient has a baseline HESD score (weekly mean) of ≥4 points and achieves a reduction of ≥4 points in the HESD score (weekly mean) from baseline at 12 weeks.

[0227] 45. The method according to Embodiment 43, wherein the patient has a baseline HESD score (weekly mean) of ≥4 points at baseline and achieves a reduction of ≥4 points in the HESD score (weekly mean) from baseline at 8 weeks.

[0228] 46. ​​The method according to Embodiment 43, wherein the patient has a baseline HESD score (weekly mean) of ≥4 points at baseline and achieves a reduction of ≥4 points in the HESD score (weekly mean) from baseline at 4 weeks.

[0229] 47. The method according to Embodiment 43, wherein the patient has a baseline HESD score (weekly mean) of ≥4 points at baseline and achieves a reduction of ≥4 points in the HESD score (weekly mean) from baseline at 2 weeks.

[0230] 48. The method according to Embodiment 43, wherein the patient has a baseline HESD score (weekly mean) of ≥4 points at baseline and achieves a reduction of ≥4 points in the HESD score (weekly mean) from baseline in one week.

[0231] 49. A method according to any one of Embodiments 1 to 48, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points and achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline at 16 weeks.

[0232] 50. The method according to Embodiment 49, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline at 8 weeks.

[0233] 51. The method according to Embodiment 49, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline at 4 weeks.

[0234] 52. The method according to Embodiment 49, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline in 2 weeks.

[0235] 53. The method according to Embodiment 49, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline in one week.

[0236] 54. The method according to Embodiment 49, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline on day 6.

[0237] 55. The method according to Embodiment 49, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline on day 5.

[0238] 56. The method according to Embodiment 49, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline on day 4.

[0239] 57. The method according to Embodiment 49, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline on day 3.

[0240] 58. The method according to Embodiment 49, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline within 2 days or 36 hours.

[0241] 59. The method according to Embodiment 49, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline within 1 day or 24 hours.

[0242] 60. A method according to any one of Embodiments 1 to 59, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points and achieves a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline at 16 weeks.

[0243] 61. The method according to embodiment 60, wherein the patient has a baseline HESD pain score (weekly average) of ≥ 4 points and achieves a decrease in the HESD pain score (weekly average) of ≥ 4 points from the baseline at 8 weeks.

[0244] 62. The method according to embodiment 60, wherein the patient has a baseline HESD pain score (weekly average) of ≥ 4 points and achieves a decrease in the HESD pain score (weekly average) of ≥ 4 points from the baseline at 4 weeks.

[0245] 63. The method according to embodiment 60, wherein the patient has a baseline HESD pain score (weekly average) of ≥ 4 points and achieves a decrease in the HESD pain score (weekly average) of ≥ 4 points from the baseline at 2 weeks.

[0246] 64. The method according to embodiment 60, wherein the patient has a baseline HESD pain score (weekly average) of ≥ 4 points and achieves a decrease in the HESD pain score (weekly average) of ≥ 4 points from the baseline at 1 week.

[0247] 65. The method according to embodiment 60, wherein the patient has a baseline HESD pain score (weekly average) of ≥ 4 points and the patient achieves a decrease in the HEDS pain score (weekly average) of ≥ 4 points from the baseline on the 6th day.

[0248] 66. The method according to embodiment 60, wherein the patient has a baseline HESD pain score (weekly average) of ≥ 4 points and the patient achieves a decrease in the HEDS pain score (weekly average) of ≥ 4 points from the baseline on the 5th day.

[0249] 67. The method according to embodiment 60, wherein the patient has a baseline HESD pain score (weekly average) of ≥ 4 points and the patient achieves a decrease in the HEDS pain score (weekly average) of ≥ 4 points from the baseline on the 4th day.

[0250] 68. The method according to embodiment 60, wherein the patient has a baseline HESD pain score (weekly average) of ≥ 4 points and the patient achieves a decrease in the HEDS pain score (weekly average) of ≥ 4 points from the baseline on the 3rd day. <00

[0251] 69. The method according to Embodiment 60, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, and the patient achieves a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline within 2 days or 36 hours.

[0252] 70. The method according to Embodiment 60, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, and the patient achieves a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline within 1 day or 24 hours.

[0253] 71. The method according to any one of Embodiments 1 to 70, wherein the patient achieves a reduction of ≥4 points in the DLQI score from baseline at 16 weeks.

[0254] 72. The method according to embodiment 71, wherein the patient achieves a reduction of ≥4 points in the DLQI score from baseline at 8 weeks.

[0255] 73. The method according to embodiment 71, wherein the patient achieves a reduction of ≥4 points in the DLQI score from baseline at 4 weeks.

[0256] 74. The method according to embodiment 71, wherein the patient achieves a reduction of ≥4 points in the DLQI score from baseline over two weeks.

[0257] 75. The method according to embodiment 71, wherein the patient achieves a reduction of ≥4 points in the DLQI score from baseline in one week.

[0258] 77. The method according to any one of Embodiments 1 to 75, wherein the treatment is continued until the patient achieves clear or nearly clear skin.

[0259] 78. The method according to Embodiment 77, wherein the administration is maintained for at least two weeks.

[0260] 79. The method according to Embodiment 77, wherein the administration is maintained for at least 4 weeks.

[0261] 80. The method according to Embodiment 77, wherein the administration is maintained for at least 8 weeks.

[0262] 81. The method according to Embodiment 77, wherein the administration is maintained for at least 12 weeks.

[0263] 82. A method for reducing pruritus in a human patient having moderate to severe chronic hand eczema, comprising administering an acidified aqueous topical composition containing 20 mg / g delgocitinib or a pharmaceutically acceptable salt thereof on a free base basis to the skin of the human patient requiring relief, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points.

[0264] 83. The method according to Embodiment 82, wherein the patient is a young adult aged 12 to 17 years or an adult aged 18 years or older, and the patient has hand eczema that has persisted for more than 3 months or has recurred more than twice within the past 12 months.

[0265] 84. The method according to Embodiment 82 or 83, wherein the patient has a documented recent history of an inadequate response to treatment with topical corticosteroids (TCS), or otherwise it is documented that TCS is not medically recommended for the patient (e.g., due to significant side effects or safety risks).

[0266] 85. The method according to any one of Embodiments 82 to 84, wherein delgocitinib is dissolved in the aqueous phase of an acidified aqueous topical formulation.

[0267] 86. The method according to Embodiment 85, wherein the acidified aqueous topical formulation has a pH of less than about 4.6 or less than about 4.4.

[0268] 87. The method according to Embodiment 86, wherein the acidified aqueous topical formulation has a pH of approximately 3.8 to approximately 4.6.

[0269] 88. The method according to Embodiment 87, wherein the aqueous topical formulation has a pH of approximately 4.3 or less.

[0270] 89. The method according to embodiment 88, wherein the aqueous topical formulation has a pH of about 4.2 or less.

[0271] 90. The method according to any one of embodiments 83 to 89, wherein the aqueous cream contains a lipid base.

[0272] 91. The method according to any one of embodiments 82 to 90, wherein the patient achieves a decrease in the HEDS pruritus score (weekly average) of ≧4 points from baseline at 8 weeks.

[0273] 92. The method according to embodiment 91, wherein the patient achieves a decrease in the HEDS pruritus score (weekly average) of ≧4 points from baseline at 4 weeks.

[0274] 93. The method according to embodiment 91, wherein the patient achieves a decrease in the HEDS pruritus score (weekly average) of ≧4 points from baseline at 2 weeks.

[0275] 94. The method according to embodiment 91, wherein the patient achieves a decrease in the HEDS pruritus score (weekly average) of ≧4 points from baseline at 1 week.

[0276] 95. The method according to embodiment 91, wherein the patient achieves a decrease in the HEDS pruritus score (weekly average) of ≧4 points from baseline on the 6th day.

[0277] 96. The method according to embodiment 91, wherein the patient achieves a decrease in the HEDS pruritus score (weekly average) of ≧4 points from baseline on the 5th day.

[0278] 97. The method according to embodiment 91, wherein the patient achieves a decrease in the HEDS pruritus score (weekly average) of ≧4 points from baseline on the 4th day.

[0279] 98. The method according to embodiment 91, wherein the patient achieves a decrease in the HEDS pruritus score (weekly average) of ≧4 points from baseline on the 3rd day.

[0280] 99. The method according to Embodiment 91, wherein the patient achieves a reduction of ≥4 points in the HEDS pruritus score (weekly mean) from baseline within 2 days or 36 hours.

[0281] 100. The method according to Embodiment 91, wherein the patient achieves a reduction of ≥4 points in the HEDS pruritus score (weekly mean) from baseline within 1 day or 24 hours.

[0282] 101. The method according to Embodiment 82, wherein the patient achieves immediate relief of itching.

[0283] 102. A method according to any one of Embodiments 82 to 101, wherein a patient achieves a statistically significant reduction in the HEDS pruritus score from baseline within 1 day or 24 hours compared to a patient administered a placebo.

[0284] 103. A method according to any one of Embodiments 82 to 101, wherein a patient achieves a 1-point reduction in the HEDS pruritus score from baseline on day 1 or within 24 hours.

[0285] 104. A method according to any one of Embodiments 82 to 101, wherein a patient achieves a statistically significant reduction in the HEDS pruritus score from baseline within 2 days or 36 hours compared to a patient administered a placebo.

[0286] 105. A method according to any one of embodiments 82 to 101, wherein the patient achieves a 2-point reduction in the HEDS pruritus score from baseline within 2 days or 36 hours.

[0287] 106. A method according to any one of embodiments 82 to 101, wherein a patient achieves a 3-point reduction in the HEDS pruritus score from baseline at 8 weeks.

[0288] 107. A method according to any one of embodiments 82 to 101, wherein a patient achieves a 3-point reduction in the HEDS pruritus score from baseline at 4 weeks.

[0289] 108. A method according to any one of embodiments 82 to 101, wherein a patient achieves a 3-point reduction in the HEDS pruritus score from baseline over two weeks.

[0290] 109. A method according to any one of embodiments 82 to 101, wherein a patient achieves a 3-point reduction in the HEDS pruritus score from baseline in one week.

[0291] 110. A method according to any one of embodiments 82 to 101, wherein a patient achieves a 4-point reduction in the HEDS pruritus score from baseline at 8 weeks.

[0292] 111. A method according to any one of embodiments 82 to 101, wherein a patient achieves a 4-point reduction in the HEDS pruritus score from baseline at 4 weeks.

[0293] 113. A method according to any one of embodiments 82 to 112, wherein a patient achieves a significant improvement in their IGA CHE score from baseline compared to a placebo.

[0294] 114. A method according to any one of embodiments 82 to 113, wherein a patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 8 weeks.

[0295] 115. The method according to Embodiment 114, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 4 weeks.

[0296] 116. The method according to Embodiment 114, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 2 weeks.

[0297] 117. The method according to Embodiment 114, wherein a patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline in one week.

[0298] 118. The method according to Embodiment 114, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline on day 5 or 6.

[0299] 119. The method according to Embodiment 114, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline on day 4.

[0300] 120. The method according to Embodiment 114, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline on day 3.

[0301] 121. The method according to Embodiment 114, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline within 1 day or 24 hours.

[0302] 122. The method according to Embodiment 114, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline within 2 days or 36 hours.

[0303] 123. A method according to any one of embodiments 82 to 122, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline at 16 weeks.

[0304] 124. The method according to Embodiment 123, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline at 8 weeks.

[0305] 125. The method according to Embodiment 123, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline at 4 weeks.

[0306] 126. The method according to Embodiment 123, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline within two weeks.

[0307] 127. The method according to Embodiment 123, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline in one week.

[0308] 128. The method according to Embodiment 123, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline on day 6.

[0309] 129. The method according to Embodiment 123, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline on day 5.

[0310] 130. The method according to Embodiment 123, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline on day 4.

[0311] 131. The method according to Embodiment 123, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline on day 3.

[0312] 132. The method according to Embodiment 123, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline within two days or 36 hours.

[0313] 133. The method according to Embodiment 123, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline within 1 day or 24 hours.

[0314] 134. A method according to any one of embodiments 82 to 122, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline at 16 weeks.

[0315] 135. The method according to Embodiment 134, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline at 8 weeks.

[0316] 136. The method according to Embodiment 134, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline at 4 weeks.

[0317] 137. The method according to Embodiment 134, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline within two weeks.

[0318] 138. The method according to Embodiment 134, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline in one week.

[0319] 139. The method according to Embodiment 134, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline on day 6.

[0320] 140. The method according to Embodiment 134, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline on day 5.

[0321] 141. The method according to Embodiment 134, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline on day 4.

[0322] 143. The method according to Embodiment 134, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline on day 3.

[0323] 144. The method according to Embodiment 134, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline within two days or 36 hours.

[0324] 145. The method according to Embodiment 134, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline within 1 day or 24 hours.

[0325] 146. The method according to any one of embodiments 82 to 145, wherein the treatment is continued until the patient achieves clear or nearly clear skin.

[0326] 147. The method according to any one of embodiments 82 to 146, wherein the administration is maintained for at least two weeks.

[0327] 148. The method according to Embodiment 147, wherein the administration is maintained for at least 4 weeks.

[0328] 149. The method according to Embodiment 147, wherein the administration is maintained for at least 8 weeks.

[0329] 150. The method according to Embodiment 147, wherein the administration is maintained for at least 12 weeks.

[0330] 151. The method according to any one of embodiments 82 to 150, wherein the patient is not administered any other therapeutic agent used to treat chronic hand eczema.

[0331] 152. A method according to any one of Embodiments 82 to 150, wherein administering the acidified aqueous formulation does not cause burns at the administration site.

[0332] 153. A method for reducing pain in a human patient having moderate to severe chronic hand eczema, comprising administering an acidified aqueous topical composition containing 20 mg / g delgocitinib or a pharmaceutically acceptable salt thereof on a free base basis to the skin of the human patient in need of relief, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points.

[0333] 154. The method according to Embodiment 153, wherein the patient is a young adult aged 12 to 17 years or an adult aged 18 years or older, and the patient has hand eczema that has persisted for more than 3 months or has recurred more than twice within the past 12 months.

[0334] 155. The method according to Embodiment 153 or 154, wherein the patient has a documented recent history of an inadequate response to treatment with topical corticosteroids (TCS), or otherwise it is documented that TCS is not medically recommended for the patient (e.g., due to significant side effects or safety risks).

[0335] 156. The method according to any one of Embodiments 153 to 155, wherein delgocitinib is dissolved in the aqueous phase of an acidified aqueous topical formulation.

[0336] 157. The method according to Embodiment 156, wherein the acidified aqueous topical formulation has a pH of less than about 4.6 or less than about 4.4.

[0337] 158. The method according to Embodiment 157, wherein the acidified aqueous topical formulation has a pH of approximately 3.8 to approximately 4.6.

[0338] 159. The method according to Embodiment 158, wherein the aqueous topical formulation has a pH of approximately 4.3 or less.

[0339] 160. The method according to Embodiment 159, wherein the aqueous topical formulation has a pH of approximately 4.2 or less.

[0340] 161. The method according to any one of Embodiments 156 to 160, wherein the aqueous topical formulation comprises a lipid base.

[0341] 162. A method according to any one of embodiments 153 to 161, wherein a patient achieves a reduction of ≥4 points in the HEDS pain score (weekly mean) from baseline over 8 weeks.

[0342] 163. The method according to Embodiment 162, wherein the patient achieves a reduction of ≥4 points in the HEDS pain score (weekly mean) from baseline over 4 weeks.

[0343] 164. The method according to Embodiment 163, wherein the patient achieves a reduction of ≥4 points in the HEDS pain score (weekly mean) from baseline over two weeks.

[0344] 165. The method according to Embodiment 164, wherein a patient achieves a weekly reduction of ≥4 points in the HEDS pain score (weekly mean) from baseline.

[0345] 166. The method according to embodiment 165, wherein the patient achieves a reduction of ≥4 points in the HEDS pain score (weekly mean) from baseline on day 6.

[0346] 167. The method according to Embodiment 166, wherein the patient achieves a reduction of ≥4 points in the HEDS pain score (weekly mean) from baseline on day 5.

[0347] 168. The method according to Embodiment 167, wherein the patient achieves a reduction of ≥4 points in the HEDS pain score (weekly mean) from baseline on day 4.

[0348] 169. The method according to Embodiment 168, wherein the patient achieves a reduction of ≥4 points in the HEDS pain score (weekly mean) from baseline on day 3.

[0349] 170. The method according to Embodiment 169, wherein the patient achieves a reduction of ≥4 points in the HEDS pain score (weekly mean) from baseline within 2 days or 36 hours.

[0350] 171. The method according to Embodiment 170, wherein the patient achieves a reduction of ≥4 points in the HEDS pain score (weekly mean) from baseline within 1 day or 24 hours.

[0351] 172. The method according to Embodiment 153, wherein the patient achieves immediate pain relief.

[0352] 173. A method according to any one of Embodiments 153 to 172, wherein a patient achieves a statistically significant reduction in the HEDS pain score from baseline within 1 day or 24 hours compared to a patient administered a placebo.

[0353] 174. A method according to any one of Embodiments 153 to 172, wherein a patient achieves a 1-point reduction in the HEDS pain score from baseline on day 1 or within 24 hours.

[0354] 175. A method according to any one of Embodiments 153 to 172, wherein a patient achieves a statistically significant reduction in the HEDS pain score from baseline within 2 days or 36 hours compared to a patient administered a placebo.

[0355] 176. A method according to any one of embodiments 153 to 172, wherein the patient achieves a 2-point reduction in the HEDS pain score from baseline within 2 days or 36 hours.

[0356] 177. A method according to any one of embodiments 153 to 172, wherein a patient achieves a 3-point reduction in the HEDS pain score from baseline at 8 weeks.

[0357] 178. A method according to any one of embodiments 153 to 172, wherein a patient achieves a 3-point reduction in the HEDS pain score from baseline at 4 weeks.

[0358] 179. A method according to any one of embodiments 153 to 172, wherein a patient achieves a 3-point reduction in the HEDS pain score from baseline over two weeks.

[0359] 180. A method according to any one of Embodiments 153 to 172, wherein a patient achieves a 3-point reduction in the HEDS pain score from baseline in one week.

[0360] 181. A method according to any one of embodiments 153 to 172, wherein a patient achieves a 4-point reduction in the HEDS pain score from baseline at 8 weeks.

[0361] 182. A method according to any one of Embodiments 153 to 172, wherein a patient achieves a 4-point reduction in the HEDS pain score from baseline at 4 weeks.

[0362] 183. A method according to any one of embodiments 153 to 182, wherein a patient achieves a significant improvement in their IGA CHE score from baseline compared to a placebo.

[0363] 184. A method according to any one of embodiments 153 to 182, wherein a patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 8 weeks.

[0364] 185. The method according to Embodiment 184, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 4 weeks.

[0365] 186. The method according to Embodiment 184, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 2 weeks.

[0366] 187. The method according to Embodiment 184, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline in one week.

[0367] 188. The method according to Embodiment 184, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline on day 5 or 6.

[0368] 189. The method according to Embodiment 184, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline on day 4.

[0369] 190. The method according to Embodiment 184, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline on day 3.

[0370] 191. The method according to Embodiment 184, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline within 1 day or 24 hours.

[0371] 192. The method according to Embodiment 184, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline within 2 days or 36 hours.

[0372] 193. A method according to any one of embodiments 153 to 192, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline at 16 weeks.

[0373] 194. The method according to Embodiment 193, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline at 8 weeks.

[0374] 195. The method according to Embodiment 193, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline at 4 weeks.

[0375] 196. The method according to Embodiment 193, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline within two weeks.

[0376] 197. The method according to Embodiment 193, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline in one week.

[0377] 198. The method according to Embodiment 193, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline on day 6.

[0378] 199. The method according to Embodiment 193, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline on day 5.

[0379] 200. The method according to Embodiment 193, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline on day 4.

[0380] 201. The method according to Embodiment 193, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline on day 3.

[0381] 202. The method according to Embodiment 193, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline within two days or 36 hours.

[0382] 203. The method according to Embodiment 193, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline within 1 day or 24 hours.

[0383] 204. A method according to any one of embodiments 153 to 203, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline at 16 weeks.

[0384] 205. The method according to embodiment 204, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline at 8 weeks.

[0385] 206. The method according to embodiment 204, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline at 4 weeks.

[0386] 207. The method according to embodiment 204, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline within two weeks.

[0387] 208. The method according to embodiment 204, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline in one week.

[0388] 209. The method according to Embodiment 204, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline on day 6.

[0389] 210. The method according to Embodiment 204, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline on day 5.

[0390] 211. The method according to Embodiment 204, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline on day 4.

[0391] 213. The method according to Embodiment 204, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline on day 3.

[0392] 214. The method according to Embodiment 204, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline within two days or 36 hours.

[0393] 215. The method according to Embodiment 204, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline within 1 day or 24 hours.

[0394] 216. The method according to any one of embodiments 153 to 215, wherein the treatment is continued until the patient achieves clear or nearly clear skin.

[0395] 217. The method according to any one of embodiments 82 to 146, wherein the administration is maintained for at least two weeks.

[0396] 218. The method according to Embodiment 217, wherein the administration is maintained for at least 4 weeks.

[0397] 219. The method according to Embodiment 217, wherein the administration is maintained for at least 8 weeks.

[0398] 220. The method according to Embodiment 217, wherein the administration is maintained for at least 12 weeks.

[0399] 221. The method according to any one of embodiments 153 to 220, wherein the patient is not administered any other therapeutic agent used to treat chronic hand eczema.

[0400] 222. The method according to any one of Embodiments 153 to 220, wherein administering the acidified aqueous formulation does not cause burns at the administration site.

[0401] 223. A method for treating moderate to severe chronic hand eczema in a human patient, comprising administering to the skin of the human patient requiring treatment an acidified aqueous topical composition comprising 20 mg / g delgocitinib or a pharmaceutically acceptable salt thereof on a free base basis twice daily, wherein the administration is maintained for at least 12 weeks, the patient achieving an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2-step improvement from baseline at 12 weeks, the patient having a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieving a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline at 12 weeks.

[0402] 224. The method according to Embodiment 223, wherein the patient is an adult aged 18 years or older and has hand eczema that has persisted for more than 3 months or has recurred more than twice within the past 12 months.

[0403] 225. A method for treating moderate to severe chronic hand eczema in a human patient, comprising administering to the skin of the human patient requiring treatment an acidified aqueous topical composition comprising 20 mg / g delgocitinib or a pharmaceutically acceptable salt thereof on a free base basis twice daily, wherein the administration is maintained for at least 8 weeks, the patient achieving an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2-step improvement from baseline at 8 weeks, the patient having a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieving a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline at 8 weeks.

[0404] 226. The method according to Embodiment 224, wherein the patient is an adult aged 18 years or older and has hand eczema that has persisted for more than 3 months or has recurred more than twice within the past 12 months.

[0405] 227. A method for treating moderate to severe chronic hand eczema in a human patient, comprising administering to the skin of the human patient requiring treatment a topical acidified aqueous composition comprising 20 mg / g delgocitinib or a pharmaceutically acceptable salt thereof on a free base basis twice daily, wherein the administration is maintained for at least 6 weeks, the patient achieving an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2-step improvement from baseline at 6 weeks, the patient having a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieving a reduction of ≥4 points in the HEDS pruritus score (weekly mean) from baseline at 6 weeks.

[0406] 228. The method according to Embodiment 224, wherein the patient is an adult aged 18 years or older and has hand eczema that has persisted for more than 3 months or has recurred more than twice within the past 12 months.

[0407] 229. A method for treating moderate chronic hand eczema in a human patient, comprising administering a topical formulation containing 20 mg / g delgocitinib or a pharmaceutically acceptable salt thereof on a free base basis to the skin of the human patient requiring treatment twice daily.

[0408] 230. A method for treating severe chronic hand eczema in a human patient, comprising administering a topical formulation containing 20 mg / g delgocitinib or a pharmaceutically acceptable salt thereof on a free base basis to the skin of the human patient in need of treatment twice daily.

[0409] 231. The method according to Embodiment 229 or 230, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points.

[0410] 232. The method according to any one of embodiments 229 to 231, wherein the patient has an IGA-CHE score of 3 or 4.

[0411] 233. The method according to any one of Embodiments 229 to 232, wherein the patient has a documented recent history of an inadequate response to treatment with topical corticosteroids (TCS), or otherwise it is documented that TCS is not medically recommended for the patient (e.g., due to significant side effects or safety risks).

[0412] 234. The method according to Embodiment 233, wherein the patient has a documented recent history of an inadequate response to treatment with topical corticosteroids (TCS).

[0413] 235. The method according to Embodiment 233, wherein it has been documented that topical corticosteroids (TCS) are not medically recommended for patients.

[0414] 236. The method according to any one of embodiments 229 to 235, wherein the patient is an adult aged 18 years or older.

[0415] 237. The method according to any one of embodiments 229 to 235, wherein the patient is an adolescent aged 12 to 17 years.

[0416] 238. The method according to any one of embodiments 229 to 237, wherein the topical formulation is administered for at least two weeks.

[0417] 239. The method according to Embodiment 238, wherein the topical formulation is administered for at least 4 weeks.

[0418] 240. The method according to Embodiment 239, wherein the topical formulation is administered for at least 8 weeks.

[0419] 241. The method according to Embodiment 240, wherein the topical formulation is administered for at least 12 weeks.

[0420] 242. The method according to Embodiment 241, wherein the topical preparation is administered for at least 16 weeks.

[0421] 243. A method according to any one of embodiments 229 to 242, wherein a patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 8 weeks.

[0422] 244. A method according to any one of embodiments 229 to 242, wherein a patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 6 weeks.

[0423] 245. A method according to any one of embodiments 229 to 242, wherein a patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 4 weeks.

[0424] 246. A method according to any one of embodiments 229 to 242, wherein a patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 2 weeks.

[0425] 247. The method according to any one of embodiments 229 to 242, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, the patient achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline at 8 weeks, and the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2 steps improvement from baseline at 8 weeks.

[0426] 248. The method according to any one of embodiments 229 to 242, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, the patient achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline at 6 weeks, and the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2-step improvement from baseline at 6 weeks.

[0427] 249. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, the patient achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline at 4 weeks, and the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2-step improvement from baseline at 4 weeks.

[0428] 250. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, the patient achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline at 2 weeks, and the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2-step improvement from baseline at 2 weeks.

[0429] 251. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, the patient achieves a decrease of ≥4 points in the HESD pruritus score (weekly mean) from baseline in one week, and the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2 steps improvement from baseline in one week.

[0430] 252. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, the patient achieves a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline at 8 weeks, and the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2 steps improvement from baseline at 8 weeks.

[0431] 253. The method according to any one of embodiments 229 to 242, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, the patient achieves a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline at 6 weeks, and the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2 steps improvement from baseline at 6 weeks.

[0432] 254. The method according to any one of embodiments 229 to 242, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, the patient achieves a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline at 4 weeks, and the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2 steps improvement from baseline at 4 weeks.

[0433] 255. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, the patient achieves a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline at 2 weeks, and the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2 steps improvement from baseline at 2 weeks.

[0434] 256. The method according to any one of embodiments 229 to 242, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, the patient achieves a decrease of ≥4 points in the HESD pain score (weekly mean) from baseline in one week, and the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline in one week.

[0435] 257. A method according to any one of embodiments 229 to 242, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 8 weeks, and finally, a 90% improvement in the HECSI score from baseline at 8 weeks.

[0436] 258. A method according to any one of embodiments 229 to 242, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 6 weeks, and finally, a 90% improvement in the HECSI score from baseline at 6 weeks.

[0437] 259. A method according to any one of Embodiments 229 to 242, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 4 weeks, and finally, a 90% improvement in the HECSI score from baseline at 4 weeks.

[0438] 260. A method according to any one of embodiments 229 to 242, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 2 weeks, and finally, a 90% improvement in the HECSI score from baseline at 2 weeks.

[0439] 261. A method according to any one of embodiments 229 to 242, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline in one week, and finally, a 90% improvement in the HECSI score from baseline in one week.

[0440] 262. A method according to any one of embodiments 229 to 242, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 8 weeks, and finally, a 75% improvement in the HECSI score from baseline at 8 weeks.

[0441] 263. A method according to any one of embodiments 229 to 242, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 6 weeks, and finally, a 90% improvement in the HECSI score from baseline at 6 weeks.

[0442] 264. A method according to any one of embodiments 229 to 242, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 4 weeks, and finally, a 75% improvement in the HECSI score from baseline at 4 weeks.

[0443] 265. A method according to any one of embodiments 229 to 242, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 2 weeks, and finally, a 75% improvement in the HECSI score from baseline at 2 weeks.

[0444] 266. A method according to any one of embodiments 229 to 242, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline in one week, and finally, a 75% improvement in the HECSI score from baseline in one week.

[0445] 267. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pruritus score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an ≥2-step improvement from baseline, and finally, a 75% improvement in the HECSI score from baseline at 8 weeks.

[0446] 268. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pruritus score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an ≥2-step improvement from baseline, and finally, a 75% improvement in the HECSI score from baseline at 6 weeks.

[0447] 269. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pruritus score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2-step improvement from baseline, and finally, a 75% improvement in the HECSI score from baseline at 4 weeks.

[0448] 270. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pruritus score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an ≥2-step improvement from baseline, and finally, a 75% improvement in the HECSI score from baseline at 2 weeks.

[0449] 271. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pruritus score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an ≥2-step improvement from baseline, and finally, a 75% improvement in the HECSI score from baseline in one week.

[0450] 272. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pruritus score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2-step improvement from baseline at 8 weeks, and finally, a 90% improvement in the HECSI score from baseline at 8 weeks.

[0451] 273. The method according to any one of embodiments 229 to 242, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pruritus score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2-step improvement from baseline at 8 weeks, and finally, a 90% improvement in the HECSI score from baseline at 6 weeks.

[0452] 274. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pruritus score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2-step improvement from baseline at 8 weeks, and finally, a 90% improvement in the HECSI score from baseline at 4 weeks.

[0453] 275. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pruritus score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2-step improvement from baseline at 8 weeks, and finally, a 90% improvement in the HECSI score from baseline at 2 weeks.

[0454] 276. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pruritus score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2-step improvement from baseline at 8 weeks, and finally, a 90% improvement in the HECSI score from baseline at 1 week.

[0455] 277. The method according to any one of embodiments 229 to 242, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pain score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an ≥2-step improvement from baseline, and finally, a 75% improvement in the HECSI score from baseline at 8 weeks.

[0456] 278. The method according to any one of embodiments 229 to 242, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pain score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an ≥2-step improvement from baseline, and finally, a 75% improvement in the HECSI score from baseline at 6 weeks.

[0457] 279. The method according to any one of embodiments 229 to 242, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pain score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an ≥2-step improvement from baseline, and finally, a 75% improvement in the HECSI score from baseline at 4 weeks.

[0458] 280. The method according to any one of embodiments 229 to 242, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pain score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an ≥2-step improvement from baseline, and finally, a 75% improvement in the HECSI score from baseline at 2 weeks.

[0459] 281. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pain score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an ≥2-step improvement from baseline, and finally, a 75% improvement in the HECSI score from baseline in one week.

[0460] 282. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pain score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2 steps improvement from baseline at 8 weeks, and finally, a 90% improvement in the HECSI score from baseline at 8 weeks.

[0461] 283. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pain score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2 grade improvement from baseline at 8 weeks, and finally, a 90% improvement in the HECSI score from baseline at 6 weeks.

[0462] 284. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pain score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2 grade improvement from baseline at 8 weeks, and finally, a 90% improvement in the HECSI score from baseline at 4 weeks.

[0463] 285. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pain score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2 grade improvement from baseline at 8 weeks, and finally, a 90% improvement in the HECSI score from baseline at 2 weeks.

[0464] 286. The method according to any one of Embodiments 229 to 242, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points, and the patient achieves a decrease of ≥4 points in the HESD pain score (weekly mean) from baseline, an IGA-CHE score of 0 (clear) or 1 (nearly clear) with ≥2 steps improvement from baseline at 8 weeks, and finally a 90% improvement in the HECSI score from baseline at 1 week.

[0465] 287. The method according to any one of Embodiments 229 to 286, wherein the patient is an adolescent aged 12 to 17 years or an adult aged 18 years or older, and the patient has hand eczema that has persisted for more than 3 months or has recurred more than twice in the past 12 months.

[0466] 288. The method according to any one of Embodiments 229 to 286, wherein the patient has a documented recent history of an inadequate response to treatment with topical corticosteroids (TCS), or otherwise it is documented that TCS is not medically recommended for the patient (e.g., due to significant side effects or safety risks).

[0467] 289. The method according to any one of Embodiments 229 to 286, wherein the topical preparation is an aqueous cream.

[0468] 290. The method according to Embodiment 289, wherein delgocitinib is dissolved in the aqueous phase of an aqueous cream.

[0469] 291. The method according to Embodiment 290, wherein the aqueous cream is acidified and has a pH of less than about 4.6.

[0470] 292. The method according to Embodiment 291, wherein the aqueous cream has a pH of about 3.8 to about 4.6.

[0471] 293. The method according to Embodiment 292, wherein the aqueous topical formulation has a pH of approximately 4.3 or less.

[0472] 294. The method according to Embodiment 293, wherein the aqueous topical formulation has a pH of approximately 4.2 or less.

[0473] 295. The method according to any one of Embodiments 291 to 294, wherein the aqueous cream contains a lipid base.

[0474] 296. The method according to Embodiment 295, wherein the lipid base is liquid paraffin.

[0475] 297. The method according to any one of Embodiments 1 to 296, wherein the acidified aqueous topical composition or aqueous cream comprises a surfactant, an emulsifier, or a stabilizer.

[0476] 298. The method according to claim 297, wherein the surfactant, emulsifier, or stabilizer is selected from one or more of cetostearyl alcohol and macrogol cetostearyl ether.

[0477] 299. The method according to Embodiment 298, wherein the surfactant, emulsifier, or stabilizer is selected from at least about 30 mg / g to about 80 mg / g of cetostearyl alcohol.

[0478] 300. The method according to Embodiment 298 or 299, wherein the surfactant, emulsifier, or stabilizer is selected from at least about 12 mg / g to about 22 mg / g of macrogol cetostearyl ether.

[0479] 301. The method according to Embodiment 296, wherein the aqueous cream or acidified aqueous topical composition comprises liquid paraffin present in an amount of about 60 mg / g to about 140 mg / g, cetostearyl alcohol in an amount of about 60 mg / g to about 90 mg / g, and macrogol cetostearyl ether present in an amount of about 14 mg / g to about 22 mg / g.

[0480] 302. The method according to Embodiment 301, wherein the aqueous cream or acidified aqueous topical composition comprises about 100 mg / g of liquid paraffin, about 72 mg / g of cetostearyl alcohol, and about 18 mg / g of macrogol cetostearyl ether.

[0481] 303. The method according to any one of Embodiments 296 to 302, wherein the aqueous cream or acidified aqueous topical composition comprises a buffer or a pH adjuster.

[0482] 304. The method according to Embodiment 303, wherein the buffer is a phosphoric acid, citric acid, or acetate buffer.

[0483] 305. The method according to Embodiment 304, wherein the aqueous cream or acidified aqueous topical composition contains citric acid monohydrate in an amount of about 0.5 mg / g to about 4 mg / g.

[0484] 306. The method according to Embodiment 305, wherein the aqueous cream or acidified aqueous topical composition contains sodium citrate dihydrate in an amount of 0 mg / g to about 1 mg / g.

[0485] 307. The method according to any one of Embodiments 296 to 306, wherein the aqueous cream or acidified aqueous topical composition contains benzyl alcohol in an amount of about 7 mg / g to about 13 mg / g.

[0486] 308. The method according to Embodiment 307, comprising an amount of benzyl alcohol of approximately 9 mg / g to approximately 11 mg / g.

[0487] 309. The method according to any one of Embodiments 296 to 308, wherein the aqueous cream or acidified aqueous topical composition contains butylhydroxyanisole in an amount of about 0.05 mg / g to about 0.3 mg / g.

[0488] 310. The method according to Embodiment 309, wherein the aqueous cream or acidified aqueous topical composition contains disodium edetate in an amount of about 0.05 mg / g to about 1.5 mg / g.

[0489] 311. The method according to any one of Embodiments 296 to 308, wherein the aqueous cream or acidified aqueous topical composition contains hydrochloric acid in an amount of 0.1 mg / g to about 25 mg / g.

[0490] 312. The method according to Embodiment 311, wherein the aqueous cream or acidified aqueous topical composition contains 10 mg / g to about 20 mg / g of hydrochloric acid.

[0491] 313. The method according to any one of Embodiments 296 to 308, comprising purified water in which an aqueous cream or acidified aqueous topical composition is present in an amount of about 500 mg / g to about 900 mg / g.

[0492] 314. The method according to any one of Embodiments 296 to 313, wherein the aqueous cream or acidified aqueous topical composition comprises delgocitinib 20 mg / g, liquid paraffin, cetostearyl alcohol, macrogol cetostearyl ether, benzyl alcohol, citric acid, butylhydroxyanisole, disodium edetate, hydrochloric acid, and purified water.

[0493] 315. The method according to Embodiment 314, wherein the aqueous cream or acidified aqueous topical composition comprises delgocitinib 20 mg / g, liquid paraffin 100 mg / g, cetostearyl alcohol 72 mg / g, macrogol cetostearyl ether 18 mg / g, benzyl alcohol 10 mg / g, citric acid monohydrate 1 mg / g, butylhydroxyanisole 0.2 mg / g, disodium edetate 0.6 mg / g, 3M hydrochloric acid 17.7 mg / g, and purified water 760 mg / g.

[0494] 316. The method according to any one of Embodiments 296 to 315, wherein the skin penetration of the aqueous cream or acidified aqueous topical composition is substantially the same as or improved compared to 30 mg of ointment containing 30 mg / g delgocitinib, 820 mg / g white soft paraffin, 50 mg / g hard paraffin and 100 mg / g squalene when measured in an open flow microperfusion test in pigs.

[0495] 317. If the signs and symptoms of (redness) recur, treatment of the affected area twice daily is resumed as necessary, according to any one of Embodiments 1 to 316.

[0496] 318. The method according to any one of Embodiments 1 to 317, wherein administration to the skin of a human patient is administered to the hands and wrists of a human patient.

[0497] 319. An acidified aqueous topical composition comprising 20 mg / g delgocitinib or a pharmaceutically acceptable salt thereof on a free base basis, as described in any one of Embodiments 1 to 318, for use in the method described in any one of Embodiments 1 to 318.

[0498] 320. Use of delgocitinib for preparing an acidified aqueous topical composition comprising 20 mg / g delgocitinib or a pharmaceutically acceptable salt thereof on a free base basis, according to any one of Embodiments 1 to 318, for use in the method according to any one of claims 1 to 318.

[0499] Example 1 Two Phase 3 clinical trials (Delta 1) in Delta 1 and Delta 2, involving adults with moderate to severe chronic hand eczema, to confirm the efficacy and evaluate the safety of delgocitinib cream 20 mg / g twice daily compared to a cream vehicle over a 16-week treatment period.

[0500] The primary target endpoint was IGA-CHE TS at 16 weeks.

[0501] The primary target secondary endpoints were HECSI-75 at 16 weeks, HECSI-75 at 8 weeks, HECSI-90 at 16 weeks, IGA-CHE TS at 8 weeks, IGA-CHE TS at 4 weeks, and the percentage change in HECSI score from baseline up to 16 weeks.

[0502] Other endpoints are disclosed in Tables 7 and 8 above.

[0503] For DELTA 1, 487 patients from six countries (Canada [n=97], France [n=81], Germany [n=135], Italy [n=45], Poland [n=105], and the United Kingdom [n=24]) were randomized to receive either delgocitinib cream (n=325; 66.7%) or cream vehicle (n=162; 33.3%). For DELTA 2, 473 patients from seven countries (Belgium [n=22], Canada [n=97], Denmark [n=22], Germany [n=147], the Netherlands [n=24], Poland [n=96], and Spain [n=65]) were randomized, with 314 patients (66.4%) receiving delgocitinib cream and 159 patients (33.6%) receiving cream vehicle. Overall, 487 patients (DELTA 1) and 472 patients (DELTA 2) were included in the overall analysis population and the safety analysis population, respectively. Overall, 459 patients (94.3%) and 420 patients (88.8%) completed DELTA 1 and DELTA 2, respectively. Overall, 6.2% (DELTA 1) and 7.0% (DELTA 2) of patients treated with delgocitinib cream, and 13.0% (DELTA 1) and 23.3% (DELTA 2) of patients in the cream vehicle group discontinued the study treatment. For both studies, baseline demographics and patient characteristics were similar between patients treated with delgocitinib cream and those treated with the cream vehicle (Table 11). Overall, 99.4% (DELTA 1) and 98.5% (DELTA 1) of patients had a recent history of inadequate response to TCS treatment (Table 12).

[0504] Baseline demographics and characteristics: [Table 11-1] [Table 11-2]

[0505] [Table 12-1] [Table 12-2]

[0506] Investigational drug (IMP) The active and placebo IMPs are listed in the table below: [Table 13]

[0507] Delgocitinib cream 20 mg / g is Delgocitinib 20 mg / g; liquid paraffin 100 mg / g; cetostearyl alcohol 72 mg / g; macrogol cetostearyl ether 18 mg / g; benzyl alcohol 10 mg / g; citric acid monohydrate 1 mg / g; butylhydroxyanisole 0.2 mg / g; disodium edetate 0.6 mg / g; 3M hydrochloric acid 17.7 mg / g; and purified water 760 mg / g Includes.

[0508] The cream vehicle contains the same amount of excipients.

[0509] IMP administration IMP (delgocitinib cream 20 mg / g or cream vehicle) was applied topically twice a day, approximately 12 hours apart, for 16 weeks.

[0510] Inclusion criteria: Applicants must meet all of the following criteria to be eligible for the exam:

[0511] 1. A dated, signed informed consent has been obtained prior to all protocol-related procedures.

[0512] 2. Must be 18 years of age or older at the time of screening.

[0513] 3. A diagnosis of CHE is defined as hand eczema that has persisted for more than 3 months or has recurred at least twice in the past 12 months.

[0514] 4. Disease severity classified as moderate to severe at baseline based on IGA-CHE screening (i.e., an IGA-CHE score of 3 or 4).

[0515] 5. A baseline HESD pruritus score of ≥4 (weekly mean). The baseline weekly mean is calculated from daily assessments of pruritus severity over the 7 days immediately preceding the baseline visit (7 days prior to 1 day prior). A minimum of 4 pruritus scores are required to calculate the baseline mean score over the 7 days.

[0516] 6. Patients who have a documented recent history of an inadequate response to TCS treatment (at any time within one year prior to the screening visit), or for whom TCS is otherwise documented not to be medically recommended (e.g., due to significant side effects or safety risks). An inadequate response is defined as a history of failure to achieve and maintain a low disease activity state (equivalent to an IGA-CHE score of ≤2) despite treatment with a daily regimen of TCS of Class III-IV (strong to very strong) in Europe and Class IV-I (moderate to very / extremely strong) in Canada, applied for at least 28 days or the shortest period recommended by the product prescribing information. • Significant side effects or safety risks that outweigh the potential benefits of the procedure include intolerance to the procedure, hypersensitivity reactions, and significant skin atrophy, as assessed by the physician.

[0517] 7. Subjects who adhere to standard non-medicated skincare practices, including avoidance of known related irritants and allergens.

[0518] 8. Women of childbearing age must use an acceptable method of contraception throughout the entire trial, up to the final application of IMP.

[0519] Exclusion criteria: Candidates are ineligible for the exam if they meet any of the following criteria:

[0520] 1. Concurrent skin conditions of the hands, such as tinea manuum.

[0521] 2. Active Alzheimer's disease (AD) requiring medical treatment in areas other than the hands and feet.

[0522] 3. Active psoriasis in any part of the body.

[0523] 4. Keratinized hand eczema combined with a history of psoriasis on any part of the body.

[0524] 5. Clinically significant infection of the hand (e.g., impetigo of the hand).

[0525] 6. Systemic treatment with immunosuppressants (e.g., methotrexate, cyclosporine, azathioprine), immunomodulators, retinoids (e.g., alitretinoin), or corticosteroids within 28 days prior to baseline (steroid eye drops and inhaled or intranasal steroids equivalent to up to 1 mg prednisolone for allergic conjunctivitis, asthma, or rhinitis are acceptable).

[0526] 7. Use of tanning beds, phototherapy (e.g., UVB, UVA1, PUVA), or bleaching baths on the hands within 28 days prior to baseline.

[0527] 8. Previous or current treatment (systemic or topical) with JAK inhibitors (including delgocitinib / LEO 124249).

[0528] 9. Topical skin treatment of the hands with immunomodulatory substances (e.g., PDE-4 inhibitors, pimecrolimus, tacrolimus) or TCS within 14 days prior to baseline.

[0529] 10. Use of systemic antibiotics or topical antibiotics applied to the hands within 14 days prior to baseline.

[0530] 11. Other transdermal or topical therapies applied to the hands within 7 days prior to baseline (excluding the use of the subject's own emollients).

[0531] 12. Skin application treatments in areas other than the hands within 7 days prior to baseline that may interfere with clinical trial evaluation or raise safety concerns.

[0532] 13. Treatment with any commercially available biological therapy or investigational biological agent (including immunoglobulins, anti-IgE, and dupilumab): • Any cell removal agent, including but not limited to rituximab: within 6 months prior to baseline, or until lymphocyte count returns to normal, whichever is longer. • Other biologics: Whichever is longer: 3 months prior to baseline or within 5 half-lives.

[0533] 14. Treatment with any unmarketed drug substance (i.e., a drug that has been registered but not yet available for clinical use) within the past 28 days prior to baseline or within 5 half-lives, whichever is longer.

[0534] 15. A clinically significant infection within 28 days prior to baseline that, in the opinion of the investigator, could impair the safety of subjects in the study, interfere with the assessment of IMP, or reduce the ability of subjects to participate in the study.

[0535] A clinically significant infection is defined as follows: ·Systemic infection. • Severe skin infections requiring parenteral (intravenous or intramuscular) antibiotics, antivirals, or antifungals.

[0536] 16. Subjects taking antiretroviral drugs, as determined by a known history of any primary immunodeficiency disorder, including a positive HIV virus test result on screening, or by the subject's oral report.

[0537] 17. Major surgery within 8 weeks prior to screening, or planned inpatient surgery or hospitalization during the trial period.

[0538] 18. Cancer history: Subjects with basal cell carcinoma, focal squamous cell carcinoma of the skin, or carcinoma in situ of the cervix are eligible, provided they are in remission and curative treatment was completed at least 12 months prior to screening. Subjects with other malignant tumors are eligible provided they are in remission and curative treatment was completed at least five years prior to screening.

[0539] 19. Unstable and potentially has any of the following issues: • This affects the safety of the subjects throughout the entire test. • It hinders the subject's ability to complete the test.

[0540] Examples include, but are not limited to, cardiovascular disorders, gastrointestinal disorders, liver disorders, kidney disorders, neurological disorders, musculoskeletal disorders, infectious disorders, endocrine disorders, metabolic disorders, hematological disorders, immune disorders, and mental disorders, as well as severe physical disabilities.

[0541] 20. Any possible abnormal findings: • Participants are exposed to risk by taking the test. • It affects the ability of the person to complete the test.

[0542] Abnormal findings must be clinically significant and observed during the screening period. Examples include abnormal findings in physical examination, vital signs, ECG, hematology, clinical chemistry, or urinalysis.

[0543] 21. Serological testing for hepatitis B surface antigen or hepatitis C virus antibody that is positive in screening.

[0544] 22. Screening shows ALT or AST level ≥ 2.0 × ULN.

[0545] 23. Known or suspected hypersensitivity to any (one or more) components of IMP.

[0546] 24. Current participation in any other interventional clinical trials.

[0547] 25. Previous randomization in this clinical trial.

[0548] 26. Current or recent chronic alcohol or drug abuse, or any other condition associated with low compliance as determined by the investigator.

[0549] 27. An employee of the testing facility, or any other person directly involved in the planning or conducting of the test, or a close relative of such person.

[0550] 28. Individuals who are legally confined to an institution.

[0551] Pregnant or breastfeeding women.

[0552] Exam Overview Screening period (4 weeks prior to week 0) The screening period ranged from a minimum of one week to a maximum of four weeks (i.e., screening visits took place between four weeks and one week prior to treatment). For subjects using the exclusion criteria, the length of the screening period depended on the required washout period. In light of the 28-day washout for some of these treatments, the screening period could be extended up to a maximum of 31 days. Only subjects deemed able to discontinue the prohibited treatment during the screening period without experiencing an unbearable exacerbation of CHE symptoms were included in the trial.

[0553] During the screening visit, we confirmed the eligibility of the individuals to participate in the study.

[0554] The subjects' (one or more) CHE subtypes were classified according to standard clinical practice in Canada and Europe.

[0555] Treatment period (weeks 0-16) At baseline (Day 1), eligibility for participation in the study was confirmed. Eligible participants were randomized in a 2:1 ratio to either delgocitinib cream 20 mg / g or cream vehicle.

[0556] IMP (delgocitinib cream 20 mg / g or cream vehicle) was applied twice daily for 16 weeks. After all baseline assessments were completed, the first application of IMP was performed at the laboratory on day 1. All subsequent IMP applications were performed at home, depending on the participant.

[0557] During the 16-week treatment period, subjects returned to the study site for efficacy and safety evaluation. The final IMP application was performed at the subject's home before their scheduled visit at week 16. Efficacy and safety evaluations were conducted during the treatment period.

[0558] Prior to week 16, all eligible participants who would not permanently discontinue IMP were asked to participate in the LTE trial.

[0559] Follow-up period (16-18 weeks) For subjects not participating in the LTE trial, a follow-up visit (conducted by telephone, but may be a facility visit if necessary) will be conducted approximately two weeks after the final IMP application for safety evaluation. Please note that for subjects who permanently discontinue IMP, the two-week follow-up period begins at the time of the final IMP application.

[0560] Since safety data collection and safety surveillance will continue during the LTE trial, participants in the LTE trial are not required to complete a follow-up period.

[0561] Effectiveness at weeks 4, 8, and 16: For DELTA 1 and DELTA 2, the primary study endpoint (IGA-CHE score of 0 [clear] or 1 [nearly clear] with at least two-step improvement at 16 weeks) was achieved in 19.7% (n=64; DELTA 1) and 29.1% (n=91; DELTA 2) patients in the delgocitinib cream group, and in 9.9% (n=16; DELTA 1) and 6.9% (n=11; DELTA 2) patients in the corresponding cream vehicle group (Figure 1). The proportion of patients achieving IGH-CHE TS at 16 weeks was statistically significantly higher in the delgocitinib cream group compared to the vehicle cream group (P ≤ 0.006 for both studies). Throughout the entire 16-week treatment period for DELTA 1 and DELTA 2, the proportion of patients achieving IGA-CHE treatment success was higher with delgocitinib cream treatment compared with cream vehicle treatment. At weeks 4 (P ≤ 0.043) and 8 (P ≤ 0.001), a statistically significantly larger number of delgocitinib-treated patients achieved IGA-CHE treatment success compared to patients treated with cream vehicle (Figure 1).

[0562] At 16 weeks, the percentage of patients achieving a reduction of ≥4 points in HECSI-75 and HECSI-90 scores, as well as a ≥4 point reduction in DLQI score from baseline, was statistically significantly higher in the delgocitinib cream groups of DELTA 1 and DELTA 2 compared to the corresponding cream vehicle groups (P<0.001; Figures 2A-C).

[0563] In the DELTA 1 trial, the mean least squares (LS) change in HESD pain score from baseline up to 16 weeks was -3.4 in patients treated with delgocitinib cream and -1.8 in patients treated with cream vehicle (P<0.001; Figure 3). In the DELTA 2 study, the corresponding mean LS change was -3.3 in the delgocitinib cream group and -1.3 in the cream vehicle group (P<0.001). Among patients with a baseline HESD pain score of ≥4 points, the proportion of patients treated with delgocitinib cream who achieved a reduction of ≥4 points in HESD pain score from baseline up to 16 weeks was statistically significantly higher compared to patients treated with cream vehicle (DELTA 1: 27.5%; DELTA 2: 22.7%) (DELTA 1: 49.1%; DELTA 2: 48.6%; P<0.001; Figures 4A-B).

[0564] Similar decreases in HESD pruritus scores were observed in DELTA 1, with a mean change in LS from baseline up to 16 weeks being -3.6 in the delgocitinib cream group and -1.9 in the cream vehicle group (P<0.001; Figure 5). In the DELTA 2 study, the corresponding mean change in LS was -3.4 for patients treated with delgocitinib cream and -1.4 for patients treated with cream vehicle (P<0.001). Therefore, among study participants with a baseline HESD pruritus score of ≥4, the proportion of patients treated with delgocitinib cream who achieved a ≥4 point reduction in their HESD pruritus score from baseline by 16 weeks was statistically significantly higher compared to patients treated with cream vehicle (DELTA 1: 23.0%; DELTA 2: 19.9%) (DELTA 1: 47.1%; DELTA 2: 47.2%; delgocitinib cream vs. cream vehicle: P<0.001; Figure 4B).

[0565] In DELTA 1 and DELTA 2, patients treated with delgocitinib achieved a significantly greater mean reduction in pain and pruritus scores from baseline at weeks 1–4 compared to patients treated with cream vehicle (P ≤ 0.002; Figures 3 and 5). Similarly, among patients with a baseline HESD pain and pruritus score of ≥4, the proportion of patients treated with delgocitinib cream who achieved a reduction of ≥4 points in HESD pain and pruritus scores from baseline at weeks 2–4 was significantly higher than that of patients treated with cream vehicle (P ≤ 0.031; Figures 4A–B).

[0566] Among patients with a baseline HESD score of ≥4, the proportion of patients treated with delgocitinib cream who achieved a ≥4 point reduction in HESD score from baseline by 16 weeks was statistically significantly higher (DELTA 1: 47.2%; DELTA 2: 44.5%; P<0.001) compared to patients treated with the cream vehicle (DELTA 1: 24.4%; DELTA 2: 20.9%). The difference compared to the vehicle was 22.8% for Delta 1 and 23.6% for Delta 2.

[0567] Safety: In DELTA 1 and DELTA 2, similar percentages of patients treated with delgocitinib cream and cream vehicle reported adverse events (AEs) (delgocitinib cream: 45.2% [DELTA 1] and 45.7% [DELTA 2]; cream vehicle: 50.6% [DELTA 1] and 44.7% [DELTA 2]; Figure 6). Most AEs were mild to moderate and not considered related to the study treatment. In both trials, the most frequently reported AEs were COVID-19, nasopharyngitis, and headache. The proportion of patients reporting AEs leading to discontinuation of the study treatment was lower in the delgocitinib cream-treated group (DELTA 1: 0.6%; DELTA 2: 0.3%) compared to the corresponding cream vehicle group (DELTA 1: 3.7%; DELTA 2: 3.1%). Outcomes following AEs and the measures taken with the study drug were similar across all study groups in DELTA 1 and DELTA 2 (Figure 7). In both studies, a small number of serious AEs (≤1.9% of patients) were reported, all of which were assessed by both the researchers and sponsors as not being related to the study drug; none led to any safety concerns. No specific safety concerns emerged during treatment in DELTA 1 or DELTA 2. No AEs of particular interest (herpetic eczema, deep vein thrombosis, or pulmonary embolism) were reported in DELTA 1 or DELTA 2. No major adverse cardiac events were reported in the delgocitinib-treated arms of either study. There were no clinically relevant changes or differences between treatment groups in hematology, biochemistry, vital signs, physical examination, or ECG.

[0568] In DELTA 1 and DELTA 2, 41.9–47.2% of patients treated with delgocitinib cream and 36.9–41.2% of patients treated with cream vehicle did not experience stinging or burning at week 1, and the proportion of patients increased to 90.0–91.7% (delgocitinib cream) and 88.6–91.8% (cream vehicle) at week 16 (Table 13).

[0569] [Table 14-1] [Table 14-2]

[0570] From week 1 onward, a numerically higher proportion of patients treated with delgocitinib cream reported no or mild tolerability issues compared to patients in the cream vehicle group. Investigator assessments of topical tolerability indicated that delgocitinib cream was well-tolerated throughout both studies (Table 14). A small number of subjects underwent patch testing during the study (DELTA 1: n=2 [delgocitinib cream] and n=4 [cream vehicle]; DELTA 2: n=1 [delgocitinib cream] and n=4 [cream vehicle]).

[0571] [Table 15-1] [Table 15-2]

[0572] All adverse events (AEs), including those related to the study drug and those leading to study drug discontinuation, were numerically higher in the cream vehicle compared to delgocitinib from baseline to trial completion.

[0573] Overall, delgocitinib cream demonstrated greater improvement over the cream vehicle in both patient-reported and clinician-reported efficacy outcomes and showed good tolerability over 16 weeks.

[0574] Example 2 A Phase 3 randomized, double-blind, vehicle-controlled, parallel-group, multicenter clinical trial (DELTA 2) to confirm the efficacy and evaluate the safety of delgocitinib cream 20 mg / g twice daily compared to a cream vehicle over a 16-week treatment period in adults with moderate to severe chronic hand eczema.

[0575] subject A total of 473 subjects were randomized in a 2:1 ratio to receive either delgocitinib cream 20 mg / g (314) or cream vehicle (159).

[0576] The inclusion and exclusion criteria are the same as in Example 1.

[0577] The investigational drug (IMP) and the administration of IMP are the same as in Example 1.

[0578] The test design is the same as in Example 1.

[0579] Results: At 16 weeks, a significantly larger proportion of delgocitinib-treated patients achieved IGA-CHE TS (29.1% vs. 6.9%; p<0.001), HECSI-75 (49.5% vs. 18.2%; p<0.001), HECSI-90 (31.0% vs. 8.8%; p<0.001), and DLQI improvement of ≥4 points (72.2% vs. 45.8%; p<0.001) compared to the cream vehicle. There was no difference between delgocitinib and the cream vehicle in the proportion of patients reporting adverse events (AEs; 45.7% vs. 44.7%) or serious AEs (1.6% vs. 1.9%). The ratings for adverse events (AEs) that were likely, or possibly, related to the study drug were consistent between delgocitinib (31.29 per 100 observed patient-years [PYO]) and cream vehicle (30.87 per 100 PYO). The ratings for AEs leading to study drug discontinuation were numerically higher for cream vehicle (11.02 per 100 PYO) compared to delgocitinib (1.04 per 100 PYO).

[0580] Overall, delgocitinib cream demonstrated greater improvement over the cream vehicle in both patient-reported and clinician-reported efficacy outcomes and showed good tolerability over 16 weeks. These results were consistent with those previously reported in the similarly designed DELTA 1 study (Example 1).

[0581] Investigation of whole-body exposure: Plasma concentrations of delgocitinib were analyzed using liquid chromatography / mass spectrometry-based methods with a limit of quantification of 5 pg / ml, using blood samples collected 2–6 hours after application of the investigational drug at weeks 1, 4, and 16. The 50% inhibitory concentration (IC50) of delgocitinib in whole blood of healthy volunteers (n=4) was evaluated using an in vitro IL-4 release assay. In the Phase 1 trial, single oral doses of delgocitinib (1.5, 3, 6, and 12 mg) were tested in healthy volunteers (n=40). Data are reported as geometric means.

[0582] Results: The DELTA 2 analysis included samples from 313 subjects who received active treatment. Plasma concentrations of delgocitinib were 0.21, 0.20, and 0.12 ng / ml at weeks 1, 4, and 16, respectively. The IC50 for delgocitinib was 17.2 ng / ml. In the Phase 1 study, the lowest oral dose of delgocitinib tested (1.5 mg) was recognized as sub-therapeutic. The peak systemic exposure (Cmax) for orally administered 1.5 mg delgocitinib was 7.2 ng / ml, which means that the systemic exposure after topical application in the DELTA 2 study was less than 1 / 30th (7.2 ng / ml divided by 0.21 ng / ml).

[0583] Conclusion: Twice-daily application of delgocitinib cream resulted in minimal systemic exposure, i.e., less than 1 / 80th of the whole blood IC50 over 16 weeks (17.2 ng / ml divided by 0.21 ng / ml) and less than 1 / 30th of the oral 1.5 mg delgocitinib dose, with no overlap in plasma exposure between oral and topical administration. These data further support the favorable safety profile of topical delgocitinib cream and suggest that no systemic pharmacological effects are expected with a 20 mg / g dose in patients with moderate to severe CHE.

[0584] Example 3 DELTA 1 and DELTA 2 were similarly designed, multicenter, phase 3 trials that randomized (2:1) adult patients with moderate to severe eczema (CHE) to a double-blind treatment of delgocitinib cream 20 mg / g or cream vehicle twice daily for 16 weeks. In pooled analyses of both trials, the change in EQ-5D score from baseline up to week 16 was evaluated for all patients, and in post-hoc analyses, clinical response (defined as partial and severe hand eczema index (HECSI) -50, -75, and -90, investigator-assessed CHE treatment success [IGA-CHE TS; clear or nearly clear skin with ≥2-point improvement from baseline], and ≥4-point improvement in hand eczema symptom diary (HESD) pruritus and pain scores) was evaluated.

[0585] result: Across both trials, a total of 639 patients were randomized to delgocitinib cream 20 mg / g and 321 patients to cream vehicle. Most patients were Caucasian (90%), female (64%), and had moderate CHE disease severity at baseline (72%). The mean ± SD EQ-5D score at baseline was 0.65 ± 0.23 in the delgocitinib group and 0.64 ± 0.24 in the cream vehicle group. Treatment with delgocitinib resulted in a significantly greater improvement in EQ-5D from baseline at 16 weeks compared to cream vehicle (least squares mean change [SE] 0.17 ± 0.01 vs. 0.06 ± 0.01; difference [95% CI] 0.11 (0.08, 0.13), p < 0.001) (Figure 10). Improvements in EQ-5D were significantly greater with delgocitinib compared to cream vehicle across all five EQ-5D dimensions (mobility, self-care, routine activity, pain / discomfort, and anxiety / depression). When analyzed by clinical response, there were clinically meaningful EQ-5D changes (minimum significant difference >0.082) across different responder thresholds, suggesting that improvements in HRQoL may be related to clinical response. Furthermore, improvements in EQ-5D were consistently higher with delgocitinib compared to cream vehicle within each clinical responder group, all of which were statistically significant except for the IGA-CHE TS classification. This is in addition to the fact that significantly more patients treated with delgocitinib achieved clinical response across different clinical responder thresholds.

[0586] Conclusion: In patients with moderate to severe CHE (Chronic Epiphysical Disease) with substantial HRQoL impairment, treatment with delgocitinib cream 20 mg / g twice daily for 16 weeks resulted in statistically significantly greater improvements than the cream vehicle, not only in clinical outcomes but also in HRQoL as measured by the EQ-5D score. Among patients who achieved a clinical response across various responder thresholds, treatment with delgocitinib resulted in an even greater HRQoL benefit than the cream vehicle. This improvement in HRQoL was considered clinically significant.

[0587] Example 4 DELTA 1 and DELTA 2 were identically designed Phase 3 trials. In both trials, adult patients with moderate to severe eczema were randomized (2:1) to a double-blind treatment of delgocitinib cream 20 mg / g or cream vehicle twice daily for 16 weeks. Data were pooled from both trials, and the change in DLQI score from baseline up to 16 weeks was evaluated in all patients. This was assessed in a post-hoc analysis of patients who achieved a clinical response defined as an improvement of ≥4 points in the Hand Eczema Symptom Diary (HESD) pruritus and pain scores, along with an overall assessment of CHE treatment success by investigators (IGA-CHE TS; a score of 0 / 1 indicating ≥2-point improvement from baseline).

[0588] result: Across two trials, 639 patients were randomized to delgocitinib cream 20 mg / g and 321 patients to cream vehicle. The majority of patients were Caucasian (90%), female (64%), and had a mean duration of approximately 10 years of chronic heart disease (CHE). The mean ± SD DLQI score at baseline was 12.4 ± 6.1 in the delgocitinib group and 12.4 ± 6.7 in the cream vehicle group. Delgocitinib resulted in a significantly greater improvement (i.e., a decrease) in DLQI from baseline at 16 weeks compared to cream vehicle (least squares mean change [SE] -7.25 ± 0.22 vs. -3.46 ± 0.31; difference [95% CI] -3.79 (-4.55, -3.04), p < 0.001) (Figure 11). Improvement in DLQI at 16 weeks was significantly greater with delgocitinib compared to cream vehicle across all 10 DLQI items, particularly those relating to skin-related embarrassment or self-consciousness, as well as impacts on work, social and leisure activities, and other daily activities (p<0.001). When analyzed by clinical response, greater improvement in DLQI was observed with delgocitinib compared to cream vehicle across all clinical responder classifications, and these differences were statistically significant in all except HECSI-90 and IGA-CHE TS. This is in addition to the fact that patients treated with delgocitinib achieved a higher proportion of clinical responses evaluated across all responder thresholds (all p<0.001) than those treated with cream vehicle.

[0589] Conclusion: Applying delgocitinib cream 20 mg / g twice daily resulted in a significant improvement in HRQoL, as measured by DLQI, compared to a cream vehicle in patients with moderate to severe CHE. In patients with a clinical response, the HRQoL benefit was greater with delgocitinib than with a cream vehicle.

[0590] Example 5 A Phase 3 clinical trial (DELTA TEEN) evaluating the efficacy and safety of applying delgocitinib cream 20 mg / g twice daily compared to a cream vehicle over a 16-week treatment period in adolescents aged 12–17 years with moderate to severe chronic hand eczema.

[0591] subject Approximately 92 subjects were randomized in a 3:1 ratio to receive either delgocitinib cream 20 mg / g or cream vehicle.

[0592] Inclusion Criteria Same as Example 2 except for the following inclusion criteria:

[0593] 1. A dated signed IC is obtained prior to all protocol-related procedures. The dated signed IC must be provided by the subject's parent / guardian and / or subject in the form of a dated signed IC / IA (where applicable under national laws or regulations).

[0594] 2. Ages 12-17 at screening and baseline.

[0595] 3. A baseline HESD pruritus score of ≥4 (weekly mean). The baseline weekly mean is calculated from daily assessments of pruritus severity over the 7 days immediately preceding the baseline visit (7 days prior to 1 day prior). A minimum of 4 pruritus scores are required to calculate the baseline mean score over the 7 days.

[0596] Exclusion criteria Same as Example 1 except for the following:

[0597] Individuals or parents / guardians who have current or recent chronic alcohol or drug abuse, or any other condition related to low compliance as determined by the investigator.

[0598] IMP Investigational drug (IMP) The active and placebo IMPs are listed in the table below:

[0599] [Table 16]

[0600] The excipients of delgocitinib cream 20 mg / g and the cream vehicle are the same as in Example 1.

[0601] IMP (delgocitinib cream 20 mg / g or cream vehicle) was applied topically twice a day, approximately 12 hours apart, for 16 weeks.

[0602] Exam Overview The trial is a phase 3 randomized, double-blind, vehicle-controlled, parallel-group, multicenter study. The trial is designed to evaluate the efficacy and safety of delgocitinib cream 20 mg / g applied twice daily for 16 weeks in adolescents aged 12–17 years with moderate to severe chronic hand eczema.

[0603] Screening period (4 weeks prior to week 0) The screening period is a minimum of one week and a maximum of four weeks (i.e., the screening visit should take place between four weeks and one week prior to treatment). For subjects using the treatments listed as exclusion criteria, the length of the screening period depends on the required washout period. In light of the 28-day washout and the permissible visit period (+3 days) for some of these treatments, the screening period has been extended to a maximum of 31 days. Only subjects deemed able to discontinue the prohibited treatment during the screening period without experiencing an unbearable exacerbation of CHE signs and symptoms will be included in the trial.

[0604] During the screening visit, eligibility for participation in the study was confirmed. (Study-specific measurements will be conducted as outlined in the study procedure schedule.)

[0605] The (one or more) CHE subtypes in question are classified according to standard clinical practice in Europe, Canada, and Australia.

[0606] Treatment period (0-16 weeks) At baseline (Day 1), eligibility for participation was confirmed. Eligible participants were randomized in a 3:1 ratio to either delgocitinib cream 20 mg / g or cream vehicle.

[0607] Participants / caregivers applied IMP (delgocitinib cream 20 mg / g or cream vehicle) twice daily for 16 weeks. After all baseline assessments were performed, the first application of IMP was performed at the study site on baseline (day 1). All subsequent IMP applications were performed at home by the participants / caregivers.

[0608] During the 16-week treatment period, participants returned to the study site for efficacy and safety evaluation.

[0609] Follow-up period (16-18 weeks) For safety assessment, subjects were followed up by telephone (or possibly a facility visit) approximately two weeks after the final IMP application. Note that for subjects who prematurely discontinued IMP treatment, the two-week follow-up period began at the time of the final IMP application.

[0610] endpoint The endpoints of the trial are disclosed in Tables 9 and 10 above.

[0611] Example 6 Two different formulations containing delgocitinib I) Human skin explant (NativeSkin) biomarker testing and II) In vivo Open Flow Microperfusion (OFM) in pigs to explore the PKPD profile of delgocitinib in different test systems. We tested it.

[0612] Tested formulations Ointment: 30 mg / g delgocitinib ointment disclosed in D1 (International Publication No. 2017 / 125523) Cream: A 20 mg / g delgocitinib cream formulation disclosed in the present patent application (International Publication No. 2020229622) at the time of filing.

[0613] Human skin explant biomarker testing Two formulations were tested using the NativeSkin model developed by Genoskin (France) (LEO Pharma A / S experiment number EXP-2017-6909). The JAK inhibition biomarker, the phosphorylated STAT3 / total STAT3 (pY-STAT3 / STAT3) ratio, was measured 24 hours after application of either the ointment (30 mg delgocitinib / g) or the cream (20 mg delgocitinib / g) compared to the control cream and the blank (three different donors for each treatment).

[0614] The results are shown in Figure 8.

[0615] The delgocitinib cream formulation significantly further inhibited the upregulation of the pY-STAT3 / STAT3 ratio compared to the ointment (Figure 3), and demonstrated that significantly more delgocitinib penetrated the skin from the 20 mg / g cream of the present invention compared to the 30 mg / g ointment described in International Publication No. 2017 / 125523.

[0616] Open flow micro-perfusion Two formulations were tested in vivo in landrace pigs at the Joanneum Research Institute (Austria) (LEO Pharma A / S report number REP-DJR-2018-01). Delgocitinib concentrations were measured in the dermis for up to 12 hours after application of either the ointment (30 mg delgocitinib / g) or the cream (20 mg delgocitinib / g) using OFM (Figure 9).

[0617] The unbound concentration of delgocitinib in the interstitial fluid was calculated from the perfusion fluid concentration, which compensated for the relative recovery rate in the setup, and from the protein binding measured in vitro. Two pigs with two test areas were treated for each formulation, and three probes were inserted into each test area (n=12 individual probes per treatment).

[0618] The concentration of delgocitinib in unbound interstitial fluid (dISF) was higher after application of the cream formulation compared to the ointment (Figure 3). The dISF concentration after cream application was significantly higher compared to the unbound potency, indicating that more delgocitinib penetrated the skin from the 20 mg / g cream compared to the 30 mg / g ointment, which was consistent with the inhibitory effect on biomarkers observed in human skin explant experiments.

[0619] Example 7 Itching and pain are two of the most common and troublesome symptoms of chronic hand eczema. Delgocitinib cream (a topical panjanus kinase inhibitor) was well-tolerated and demonstrated significant improvement in all primary and secondary efficacy endpoints in DELTA-1 and DELTA-2.

[0620] This analysis includes pooled data from DELTA-1 and -2 (delgocitinib cream 20 mg / g [n=639]; cream vehicle [n=321]; twice daily). The Hand Eczema Symptom eDiary (HESD) recorded patient-reported severity of pruritus and pain over the past 24 hours using an 11-point numerical rating scale (0 = no pruritus / pain ~ 10 = severe pruritus / pain). Changes in pruritus and pain from baseline were assessed daily during week (W) and weekly from W1 to W16.

[0621] For pruritus, the mean least squares (LS) reduction from baseline was 0.22–1.32 in the delgocitinib cream group and 0.21–0.68 in the cream vehicle group during days 1–7 (D). For pain, mean LS reductions from baseline were observed of 0.13–1.43 and 0.26–0.81, respectively. During weeks 1–16, delgocitinib-treated patients achieved a greater mean LS reduction from baseline in pruritus score (1.0–3.5; P<0.001) compared to patients treated with cream vehicle (0.4–1.7). Similar results were observed for mean pain LS reduction (delgocitinib cream: 0.9–3.3; cream vehicle: 0.4–1.5; P<0.001). Among patients with a baseline HESD pruritus / pain score of ≥4, the proportion of patients treated with delgocitinib cream who achieved a reduction of ≥4 points in their HESD pruritus / pain score from baseline at W2–16 was higher than that of patients treated with a cream vehicle (P ≤ 0.001).

[0622] In patients treated with delgocitinib, early onset of pruritus and pain relief was observed within Week 1, and this relief was significantly greater and sustained from Week 1 to Week 16 compared to patients treated with the cream vehicle.

[0623] Example 8 In the DELTA 2 Phase 3 trial, delgocitinib cream 20 mg / g (a topical panjanus kinase inhibitor) was well-tolerated and demonstrated significant improvement in all efficacy endpoints compared to the cream vehicle in adults with moderate to severe chronic hand eczema (CHE).

[0624] Pharmacokinetic blood sampling in DELTA 2 was performed at weeks 1, 4, and 16, 2–6 hours after delgocitinib application, using a liquid chromatography / mass spectrometry-based method (limit of quantification: 5 pg / ml). In the Phase 1 trial (NCT05050279), a single oral dose of delgocitinib was tested in healthy volunteers, with sampling performed up to 24 hours after administration.

[0625] In Delta 2, the geometric mean + / -SD peak plasma concentration (C) on day 8 is... max ) and the area under the concentration curve (AUC) for time 0-12 hours. 0-12 ) were 0.46 ng / ml + / - 0.28 and 3.7 ng, respectively. * The level was h / ml + / - 1.88. A steady state was reached by day 8. Whole-body exposure (AUC and C) between day 1 and day 8. max ) were similar and could be ignored.

[0626] In DELTA 2, minimal systemic exposure was recorded in 313 delgocitinib-treated patients, with a peak geometric mean plasma concentration of 0.21 ng / ml at 1 week (n=286). By week 16, cellular absorption was detectable in only some patients, and in the remaining subjects, detectable absorption decreased by 48% to a mean of 0.11 ng / ml. In the Phase 1 trial, the lowest oral delgocitinib dose tested (1.5 mg; n=8) was considered sub-therapeutic, showing a peak systemic exposure (geometric mean Cmax) of 7.2 ng / ml. In DELTA 2, adverse events (AEs) were reported by 45.7% (n=143 / 313; delgocitinib cream) and 44.7% (n=71 / 159; cream vehicle) patients, with COVID-19 being the most common (11.5% vs. 12.6%, respectively). In some cases, or perhaps possibly related to allergic reactions (AEs), the ratings were low and similar between delgocitinib cream and the cream vehicle. No deaths were reported. A small number of SAEs were reported, none of which were assessed as being related to the study drug.

[0627] The plasma protein binding rate of delgocitinib is 22-29%.

[0628] After repeated topical administration of delgocitinib cream, the mean half-life of delgocitinib was estimated to be 20.3 hours.

[0629] The DELTA 2 trial demonstrated minimal systemic exposure in relation to a favorable safety profile and supported the absence of meaningful systemic effects from twice-daily application of delgocitinib cream in patients with moderate to severe CHE.

Claims

1. A method for treating moderate to severe chronic hand eczema in a human patient requiring treatment for chronic hand eczema, comprising administering to the skin of the human patient an acidified aqueous topical composition containing 20 mg / g of delgocitinib or a pharmaceutically acceptable salt thereof on a free base basis twice daily, wherein the patient has a disease severity classified as moderate to severe (i.e., an IGA-CHE score of 3 or 4) upon screening and baseline by IGA-CHE.

2. The method according to claim 1, wherein the patient has a baseline HESD pruritus score of ≥ 4 points (weekly average).

3. The method according to claim 1 or 2, wherein the patient is a young person aged 12 to 17 years or an adult aged 18 years or older, and the patient has hand eczema that has persisted for more than 3 months or has recurred two or more times within the past 12 months.

4. The method according to any one of claims 1 to 3, wherein the patient has a documented recent history of an inadequate response to treatment with topical corticosteroids (TCS), or it is documented that TCS is not medically recommended for the patient (due to significant side effects or safety risks).

5. The method according to any one of claims 1 to 4, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 16 weeks.

6. The method according to claim 5, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 8 weeks.

7. The method according to claim 5, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at 4 weeks.

8. The method according to claim 5, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline at two weeks.

9. The method according to claim 5, wherein the patient achieves an IGA-CHE score of 0 (clear) or 1 (nearly clear) with an improvement of ≥2 levels from baseline in one week.

10. The method according to any one of claims 1 to 9, wherein the patient achieves at least a 90% improvement in the HECSI score from baseline at 16 weeks, or 8 weeks, or 4 weeks, 2 weeks, or 1 week.

11. The method according to any one of claims 1 to 9, wherein the patient achieves at least a 75% improvement in the HECSI score from baseline at 16 weeks, or 8 weeks, or 4 weeks, or 2 weeks, or 1 week.

12. The method according to any one of claims 1 to 11, wherein the patient has a baseline HESD score (weekly mean) of ≥4 points and achieves a reduction of ≥4 points in the HESD score (weekly mean) from baseline at 16 weeks.

13. The method according to claim 12, wherein the patient has a baseline HESD score (weekly mean) of ≥4 points and achieves a reduction of ≥4 points in the HESD score (weekly mean) from baseline at 12 weeks.

14. The method according to claim 13, wherein the patient has a baseline HESD score (weekly mean) of ≥ 4 points at baseline and achieves a reduction of ≥ 4 points in the HESD score (weekly mean) from baseline at 8 weeks.

15. The method according to claim 13, wherein the patient has a baseline HESD score (weekly mean) of ≥ 4 points at baseline and achieves a reduction of ≥ 4 points in the HESD score (weekly mean) from baseline at 4 weeks.

16. The method according to claim 13, wherein the patient has a baseline HESD score (weekly mean) of ≥ 4 points at baseline and achieves a decrease of ≥ 4 points in the HESD score (weekly mean) from baseline at 2 weeks.

17. The method according to claim 13, wherein the patient has a baseline HESD score (weekly mean) of ≥ 4 points at baseline and achieves a decrease of ≥ 4 points in the HESD score (weekly mean) from baseline in one week.

18. The method according to any one of claims 1 to 17, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points and achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline at 16 weeks.

19. The method according to claim 18, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥ 4 points, and the patient achieves a reduction of ≥ 4 points in the HESD pruritus score (weekly mean) from baseline at 8 weeks.

20. The method according to claim 18, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥ 4 points, and the patient achieves a reduction of ≥ 4 points in the HESD pruritus score (weekly mean) from baseline over 4 weeks.

21. The method according to claim 18, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥4 points, and the patient achieves a reduction of ≥4 points in the HESD pruritus score (weekly mean) from baseline over two weeks.

22. The method according to claim 18, wherein the patient has a baseline HESD pruritus score (weekly mean) of ≥ 4 points, and the patient achieves a reduction of ≥ 4 points in the HESD pruritus score (weekly mean) from baseline in one week.

23. The method according to any one of claims 1 to 22, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points and achieves a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline at 16 weeks.

24. The method according to any one of claims 1 to 22, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points and achieves a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline at 8 weeks.

25. The method according to claim 24, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points and achieves a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline in 4 weeks.

26. The method according to claim 24, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points and achieves a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline in two weeks.

27. The method according to claim 24, wherein the patient has a baseline HESD pain score (weekly mean) of ≥4 points and achieves a reduction of ≥4 points in the HESD pain score (weekly mean) from baseline in one week.

28. The method according to any one of claims 1 to 27, wherein the patient achieves a reduction of ≥4 points in the DLQI score from baseline at 16 weeks.

29. The method according to claim 28, wherein the patient achieves a reduction of ≥4 points in the DLQI score from baseline at 8 weeks.

30. The method according to claim 28, wherein the patient achieves a reduction of ≥4 points in the DLQI score from baseline over four weeks.

31. The method according to claim 28, wherein the patient achieves a reduction of ≥4 points in the DLQI score from baseline over two weeks.

32. The method according to claim 28, wherein the patient achieves a reduction of ≥4 points in the DLQI score from baseline in one week.

33. The method according to any one of claims 1 to 32, wherein no accumulation of delgocitinib in the body is observed.

34. The method according to any one of claims 1 to 33, wherein administration to the skin of a human patient is administration to the hands and wrists of a human patient.

35. The method according to any one of claims 1 to 34, wherein the treatment is continued until the patient achieves disappearance or near-disappearance of the skin.

36. The method according to claim 35, wherein if signs and symptoms of (redness) recur, treatment of the affected area twice a day is resumed as necessary.

37. The method according to any one of claims 1 to 36, wherein delgocitinib is dissolved in the aqueous phase of a topical formulation.

38. The method according to claim 36 or 37, wherein the aqueous topical formulation has a pH of less than about 4.6 or less than about 4.

4.

39. The method according to claim 38, wherein the aqueous topical formulation has a pH of about 3.8 to about 4.

6.

40. The method according to claim 39, wherein the aqueous topical formulation has a pH of about 4.3 or less.

41. The method according to claim 39, wherein the aqueous topical formulation has a pH of about 4.2 or less.

42. The method according to any one of claims 37 to 41, wherein the aqueous cream contains a lipid base.

43. The method according to claim 42, wherein the lipid base is liquid paraffin.

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