A method of treating vitiligo using upadacitinib

Abstract

This disclosure relates to a method for treating vitiligo using the selective JAK1 inhibitor upadacitinib.

Description

[Technical Field]

[0001] This disclosure relates to a method for treating vitiligo using the JAK1 selective inhibitor upadacitinib. [Background technology]

[0002] Upadacitinib is a JAK1 selective inhibitor approved for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic spondyloarthritis, ulcerative colitis in adults, and atopic dermatitis.

[0003] Vitiligo is a chronic autoimmune disorder affecting 0.5% to 2.0% of the population. It is characterized by depigmentation of the skin caused by the deletion of melanocytes (Bergqvist et al., Dermatology 2020, 236:571-92; Ezzedine et al., Pigment Cell Melanoma Res 2012, 25:E1-13). Vitiligo is classified into two main forms (non-segmental or segmental) based on the distribution of lesions (Taieb et al., Pigment Cell Res 2007, 20:27-35). Studies have shown that vitiligo places a significant burden on the quality of life of patients. Patients with vitiligo bear direct costs associated with medical treatment, as well as indirect costs in the form of psychosocial impacts, loss of work productivity, and loss of social and occupational opportunities. Therefore, there is a substantial unmet need for effective and cost-effective treatments.

[0004] Treating vitiligo remains one of the most challenging dermatological issues. Currently, there is no available cure. Treatment options are limited and generally restricted to topical corticosteroids, UVB irradiation, and surgical management (Bergqvist et al., 2020). For reasons including patient convenience and compliance, it is desirable to provide an effective oral treatment for vitiligo, especially in long-term treatment. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Bergqvist et al., Dermatology 2020, 236: pp. 571-5792. [Non-Patent Document 2] Ezzedine et al., Pigment Cell Melanoma Res 2012, 25:E1~13 [Non-Patent Document 3] Taieb et al., Pigment Cell Res 2007, 20:27-35 [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] (Summary of Disclosure) This disclosure provides a method for treating vitiligo using the selective JAK1 inhibitor upadacitinib. The treatment method generally involves administering upadacitinib to a patient who requires a therapeutically effective dose of it. [Means for solving the problem]

[0007] One embodiment provides a method for treating a human adult patient having vitiligo, comprising orally administering 15 mg of upadacitinib to the patient once daily.

[0008] In some embodiments, the patient has non-segmental vitiligo (NSV).

[0009] In some embodiments, the NSV is stable.

[0010] In some embodiments, the NSV is active.

[0011] In some embodiments, the patient has a facial vitiligo area scoring index (F-VASI) of 0.5 or higher before the start of treatment.

[0012] In some embodiments, the patient has a total vitiligo area scoring index (T-VASI) of 5 or greater prior to the start of treatment.

[0013] In some embodiments, the patient has not received any immunomodulatory biologic therapy prior to the start of treatment.

[0014] In some embodiments, the patient has not received any topical JAK inhibitor within 12 weeks prior to the start of treatment.

[0015] In some embodiments, the patient has leukotrichia in 33% or less of the affected area.

[0016] In some embodiments, the patient achieves F-VASI75 at week 24 after the start of treatment.

[0017] In some embodiments, the patient achieves one or more of T-VASI50, T-VASI75, T-VASI90, F-VASI50 or F-VASI90 at week 36 after the start of treatment.

[0018] In some embodiments, the patient achieves T-VASI50 at week 48 after the first dose of daily administration.

[0019] In some embodiments, the patient achieves F-VASI75 at week 48 after the first dose of daily administration.

[0020] In some embodiments, the patient achieves T-VASI50 at week 52 after the first dose of daily administration.

[0021] In some embodiments, the patient achieves F-VASI75 at week 52 after the first dose of daily administration.

[0022] In some embodiments, the patient achieves improvement in the overall impression of change (PaGIC-V) for total body vitiligo at week 36 after the start of treatment.

[0023] In some embodiments, patients achieve a Vitiligo Sampling Scale (VNS) score of “Not Significantly Significant (4)” or “Not Significantly Significant (5)” at 36 weeks after the start of treatment.

[0024] In some embodiments, patients achieve improvement from baseline in the vitiligo extent score (VES) at 36 weeks after the start of treatment.

[0025] In some embodiments, patients achieve improvement from baseline in VitiQoL at 36 weeks after the start of treatment.

[0026] In some embodiments, patients achieve a total dermatological quality of life index (DLQI) score of "0" or "1" at 36 weeks after the start of treatment.

[0027] In some embodiments, patients achieve improvement from baseline in their Hospital Anxiety and Depression Scale (HADS) score at 36 weeks after the start of treatment.

[0028] In some embodiments, patients achieve an improvement in the time to the onset of pigment re-deposition compared to patients not treated with upadacitinib.

[0029] In some embodiments, the patient achieves a "much better (1)" or "somewhat better (2)" physician-generalized impression change (PhGIC-V) score for vitiligo at 36 weeks after the start of treatment. In some embodiments, the patient achieves a "much better (1)" or "somewhat better (2)" patient-generalized impression saturation (PaGIC-V) score for vitiligo at 36 weeks after the start of treatment. In some embodiments, the patient achieves a "no depigmentation (0)" or "limited depigmentation (1)" facial-physician-generalized vitiligo assessment (F-PhGVA) score at 36 weeks after the start of treatment. In some embodiments, the patient achieves a "no depigmentation (0)" or "limited depigmentation (1)" whole-body-physician-generalized vitiligo assessment (T-PhGVA) score at 36 weeks after the start of treatment. In some embodiments, the patient achieves a facial-total vitiligo evaluation (F-PaGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks after the start of treatment. In some embodiments, the patient achieves a whole-body-total vitiligo evaluation (T-PaGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks after the start of treatment.

[0030] In some embodiments, patients achieve improvement in itching or burning sensation within 36 weeks of starting treatment.

[0031] In some embodiments, the method halts the progression of vitiligo within 36 weeks of the start of treatment.

[0032] In some embodiments, the method leads to a reduction from baseline in one or more biomarkers of vitiligo within 36 weeks of the start of treatment. In some embodiments, the biomarkers are inflammatory chemotactic proteins or T cell activation markers. In some embodiments, the biomarkers are CXCL9, CXCL10, IL12B, TNFSF9, or a combination thereof.

[0033] In some embodiments, patients are treated in combination with exposure to ultraviolet light.

[0034] In another embodiment, a method for treating vitiligo in a pediatric human patient, This includes administering a therapeutically effective dose of upadacitinib to pediatric patients. If a pediatric patient weighs between approximately 10 kg and less than approximately 20 kg, (i) Upadacitinib is administered twice daily at doses of 3 mg each (3 mg BID), or (ii) Upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID), If a pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, (i) Upadacitinib is administered twice daily at doses of 4 mg each (4 mg BID), or (ii) Upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID), If a pediatric patient weighs approximately 30 kg or more, (i) Upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID), (ii) Upadacitinib is administered twice daily at doses of 8 mg each (8 mg BID), or (ii) A method is provided in which upadacitinib is administered once daily at a dose of 15 mg (15 mg QD).

[0035] In some embodiments, upadacitinib is administered to pediatric patients as a stable oral liquid at doses of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, or 8 mg twice daily.

[0036] In some embodiments, the stable oral pharmaceutical solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

[0037] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

[0038] In some embodiments, pediatric patients are administered a dose of 15 mg of upadacitinib once daily as a sustained-release tablet.

[0039] In some embodiments, pediatric patients have non-segmental vitiligo (NSV).

[0040] In some embodiments, the NSV is stable.

[0041] In some embodiments, the NSV is active.

[0042] In some embodiments, pediatric patients have a facial vitiligo area scoring index (F-VASI) of 0.5 or higher before the start of treatment.

[0043] In some embodiments, pediatric patients have a total vitiligo area scoring index (T-VASI) of 5 or higher before the initiation of treatment.

[0044] In some embodiments, pediatric patients have not received any immunomodulatory biological therapy prior to the initiation of treatment.

[0045] In some embodiments, pediatric patients have not received any topical JAK inhibitors within 12 weeks of the start of treatment.

[0046] In some embodiments, pediatric patients have alopecia covering 33% or less of the affected area.

[0047] In some embodiments, pediatric patients achieve F-VASI75 at 24 weeks after the start of treatment.

[0048] In some embodiments, pediatric patients achieve one or more of the following scores at 36 weeks after the start of treatment: T-VASI50, T-VASI75, T-VASI90, F-VASI50, or F-VASI90.

[0049] In some embodiments, patients achieve T-VASI50 at 48 weeks after the first daily dose.

[0050] In some embodiments, pediatric patients achieve F-VASI75 at 48 weeks after the first daily dose.

[0051] In some embodiments, pediatric patients achieve T-VASI50 at 52 weeks after the first daily dose.

[0052] In some embodiments, pediatric patients achieve F-VASI75 at 52 weeks after the first daily dose.

[0053] In some embodiments, pediatric patients achieve improvement in the Generalized Image Criteria (PaGIC-V) for generalized vitiligo at 36 weeks after the start of treatment.

[0054] In some embodiments, pediatric patients achieve a Vitiligo Sampling Scale (VNS) score of “Not Significantly Significant (4)” or “Not Significantly Significant (5)” at 36 weeks after the start of treatment.

[0055] In some embodiments, pediatric patients achieve improvement from baseline in the vitiligo extent score (VES) at 36 weeks after the start of treatment.

[0056] In some embodiments, pediatric patients achieve improvement from baseline in VitiQoL at 36 weeks after the start of treatment.

[0057] In some embodiments, pediatric patients achieve a total dermatological quality of life index (DLQI) score of "0" or "1" at 36 weeks after the start of treatment.

[0058] In some embodiments, pediatric patients achieve improvement from baseline in their Hospital Anxiety and Depression Scale (HADS) scores at 36 weeks after the start of treatment.

[0059] In some embodiments, pediatric patients achieve an improvement in the time to the onset of pigment redeposition compared to pediatric patients not treated with upadacitinib.

[0060] In some embodiments, pediatric patients achieve improvement in itching or burning sensation within 36 weeks of starting treatment.

[0061] In some embodiments, pediatric patients achieve a "much better (1)" or "somewhat better (2)" physician-generalized impression change (PhGIC-V) score for vitiligo at 36 weeks after the start of treatment. In some embodiments, pediatric patients achieve a "much better (1)" or "somewhat better (2)" patient-generalized impression change (PaGIC-V) score for vitiligo at 36 weeks after the start of treatment. In some embodiments, pediatric patients achieve a "no depigmentation (0)" or "limited depigmentation (1)" facial-physician-generalized vitiligo assessment (F-PhGVA) score at 36 weeks after the start of treatment. In some embodiments, pediatric patients achieve a "no depigmentation (0)" or "limited depigmentation (1)" whole-body-physician-generalized vitiligo assessment (T-PhGVA) score at 36 weeks after the start of treatment. In some embodiments, pediatric patients achieve a facial-total vitiligo evaluation (F-PaGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks after the start of treatment. In some embodiments, pediatric patients achieve a whole-body-total vitiligo evaluation (T-PaGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks after the start of treatment.

[0062] In some embodiments, the method halts the progression of vitiligo within 36 weeks of the start of treatment.

[0063] In some embodiments, the method leads to a reduction from baseline in one or more biomarkers of vitiligo within 36 weeks of the start of treatment. In some embodiments, the biomarkers are inflammatory chemotactic proteins or T cell activation markers. In some embodiments, the biomarkers are CXCL9, CXCL10, IL12B, TNFSF9, or a combination thereof.

[0064] In some embodiments, pediatric patients are treated in combination with exposure to ultraviolet light. [Brief explanation of the drawing]

[0065] [Figure 1] Example 1 provides a schematic illustration of a clinical trial according to a non-limiting embodiment of the present disclosure. [Figure 2] This is a graphic representation of efficacy by the primary endpoint in the subjects of the clinical trial in Example 1 (percentage change from baseline (MMRM) in F-VASI at week 24). [Figure 3] This is a graphic representation of efficacy based on secondary endpoints in the subjects of the clinical trial in Example 1 (percentage achieving F-VASI75 at week 24 (NRI)). [Figure 4] This is a graphic representation of efficacy based on secondary endpoints in the subjects of the clinical trial in Example 1 (percentage change from baseline (NRI) in T-VASI at week 24). [Figure 5A] This is a graphic depiction of efficacy based on secondary endpoints at weeks 24 and 52 in the subjects of the clinical trial in Example 1 (percentage change from baseline in T-VASI50). [Figure 5B] This is a graphic depiction of efficacy based on secondary endpoints at weeks 24 and 52 in the subjects of the clinical trial in Example 1 (percentage change from baseline in F-VASI75). [Figure 6A] This is a graphic depiction of the model-predicted and observed exposure-response efficacy analysis for the CFB F-VASI and CFB T-VASI evaluation items at week 24 according to Example 2. [Figure 6B] This is a graphic depiction of the model-predicted and observed exposure-response efficacy analysis for evaluation items F-VASI75 and T-VASI50 at week 24 according to Example 2. [Figure 7A] This is a graphic representation of the model-predicted efficacy response rates for the F-VASI75 endpoint at week 24 with various doses of upadacitinib according to Example 2. [Figure 7B] This is a graphic representation of the model-predicted efficacy response rates for the T-VASI50 endpoint at week 24 with various doses of upadacitinib according to Example 2. [Figure 8A] This is a graphic representation of the exploratory exposure-response analysis for the efficacy evaluation item CFB F-VASI at week 52 according to Example 2. [Figure 8B] This is a graphic representation of the exploratory exposure-response analysis for the efficacy evaluation item CFB T-VASI at week 52 according to Example 2. [Figure 9] Figure 9A is a graphic representation of the model-predicted response rate for the F-VASI75 endpoint with a 15 mg dose of upadacitinib according to Example 2. Figure 9B is a graphic representation of the model-predicted response rate for the T-VASI50 endpoint with a 15 mg dose of upadacitinib according to Example 2. [Figure 10] Figure 10A is a graphical representation of the percentage change in facial vitiligo area using cherry 3D imaging for various doses of upadacitinib and placebo according to Example 3. Figure 10B is a graphical representation of the percentage change in F-VASI for various doses of upadacitinib and placebo according to Example 3. [Figure 11] Example 4 provides a schematic illustration of a clinical trial according to a non-limiting embodiment of the present disclosure. [Figure 12] This is a graphical representation of the percentage change from baseline in F-VASI over 52 weeks, according to Example 7. [Figure 13] This is a graphical representation of the percentage change from baseline in T-VASI over 52 weeks, according to Example 7. [Figure 14] Figure 14A is a graphic representation of the response rate for achieving F-VASI 50 at week 52 according to Example 7. Figure 14B is a graphic representation of the response rate for achieving F-VASI 75 at week 52 according to Example 7. Figure 14C is a graphic representation of the response rate for achieving T-VASI 50 at week 52 according to Example 7. [Figure 15]Figure 15A is a graphic representation of the response rate for achieving F-VASI75 at week 24 according to Example 7. Figure 15B is a graphic representation of the response rate for achieving F-VASI75 at week 36 according to Example 7. Figure 15C is a graphic representation of the response rate for achieving F-VASI75 at week 52 according to Example 7 (non-responder complementation, while incorporating multiple complementation; NRI-MI). Figure 15D is a graphic representation of the response rate for achieving F-VASI75 at week 52 according to Example 7 (AO). [Figure 16] Example 16A is a graphic representation of the response rate for achieving T-VASI50 at week 24 according to Example 7. Figure 16B is a graphic representation of the response rate for achieving T-VASI50 at week 36 according to Example 7. Figure 16C is a graphic representation of the response rate for achieving T-VASI50 at week 52 according to Example 7 (NRI-MI). Figure 16D is a graphic representation of the response rate for achieving T-VASI50 at week 52 according to Example 7 (based on actual measurements; AO). [Modes for carrying out the invention]

[0066] I. Definition The section headings used in this section and throughout the disclosure are not intended to be limiting.

[0067] When a range of numbers is given, each number within that range is assumed with a similar degree of certainty. For example, in the range 6–9, the numbers 7 and 8 are assumed in addition to 6 and 9, and in the range 6.0–7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are assumed. Using the same method, all ratios given include all sub-ratios that fall within the broader ratio.

[0068] The singular forms "a," "an," and "the" refer to multiple objects unless the context clearly indicates otherwise.

[0069] The term "approximately" generally refers to a range of numbers that a person skilled in the art could consider to be equal to (i.e., having the same function or result as) the values ​​listed. In many cases, the term "approximately" may include numbers rounded to the nearest significant figure.

[0070] Unless otherwise required by context, the terms “comprise,” “comprises,” and “comprising” are used on the basis and with clear understanding that they should be interpreted comprehensively and not exclusively, and that the applicant intends each of these terms to be interpreted in this way in the interpretation of this Patent, including the claims below.

[0071] The term "AUC" refers to the area under the curve. AUC is the definite integral of a curve that describes the change in plasma drug concentration as a function of time.

[0072] "C max The term "T" refers to a dosage form or pharmaceutical composition, for example, a single dose of the dosage forms and compositions of this disclosure, or a T produced by oral ingestion of the number of doses indicated. max This refers to the plasma concentration of the indicated drug in the specified area, and is expressed herein as ng / mL. Unless otherwise specified, C max This refers to the overall maximum observed concentration.

[0073] As used herein, terms such as “treating,” “treatment,” and “therapy” include means of treatment for a disease or disorder that produce a clinically desirable or beneficial effect, including, but not limited to, significant clinical improvement over time in depigmentation.

[0074] As used herein, the term “pediatric patient” refers to a human patient under the age of 18. The terms “patient” and “subject” are used interchangeably herein.

[0075] "Pharmacologically acceptable salts" refer to salts obtained by reaction with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or organic acids, such as sulfonic acid, carboxylic acid, organophosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, monomalic acid, monooxalic acid, tartaric acid, such as monotartaric acid (e.g., (+) or (-)-tartaric acid, or mixtures thereof), amino acids (e.g., (+) or (-)-amino acids, or mixtures thereof), which retain their biological efficacy and the properties of the free base. These salts can be prepared by methods known to those skilled in the art. Examples of pharmaceutically acceptable salts of upadacitinib can be found in WO2017 / 066775, which is incorporated herein by reference in its entirety.

[0076] As used herein, the term “active vitiligo” refers to vitiligo that shows new lesions or progression (enlargement) of existing lesions within the last six months; and / or the presentation of clinical subtypes of progressive vitiligo (confetti-like depigmentation, trichrome pattern, Koebner phenomenon).

[0077] As used herein, the term “stable vitiligo” refers to vitiligo that is free from new lesions and / or from the spread of pre-existing lesions.

[0078] The Vitiligo Area Scoring Index (VASI) is a qualitative tool similar to the Psoriasis Area and Severity Index (PASI). VASI is used to assess the severity and / or therapeutic efficacy of vitiligo. It is the current absolute standard for semi-objectively evaluating vitiligo, representing a composite estimate of the total area of ​​vitiligo lesions and the degree of depigmentation within these lesions. VASI is determined by estimating the percentage of affected body surface area and multiplying this by the percentage of depigmentation within the body surface area. For the body surface area percentage, the hand is equal to 1%, and the thumb is equal to 0.1%. VASI can be referred to as whole-body (T-VASI) or facial (F-VASI). F-VASI includes the facial contribution, with a possible range of 0-3. For the purpose of evaluating F-VASI, the facial area includes the forehead, original hairline, temples, around the eyes (including eyelids), nose, cheeks (mid and lateral), and around the mouth (including the chin). "Face" excludes the lips, ears, and scalp.

[0079] The Vitiligo Sampling Scale (VNS) is a single-item, validated questionnaire used in clinical trials to assess the significance of vitiligo lesions after treatment. The item is scored on a 5-point scale: 1 = more significant; 2 = equally significant; 3 = slightly less significant; 4 = considerably less significant; and 5 = no longer significant. A score of 4 or 5 indicates treatment success.

[0080] The Vitiligo Quality of Life (VitiQoL) is a valid questionnaire used in clinical trials to assess the stigma-related impact of vitiligo. VitiQoL uses subject-elicited social, affective, and behavioral items extracted from participants who rate the impact of vitiligo on their condition over the past month. Fifteen items are scored on a 7-point scale ranging from 0 ("never") to 6 ("always"). The item scores (0-6) are summed to obtain a total score ranging from 0 to 90, with higher scores indicating greater quality of life (QoL) impairment. Additional items do not contribute to the total impact score and ask patients to rank the current severity of their condition on a 7-point scale ranging from 0 ("no skin involvement") to 6 ("most severe case"). VitiQoL is administered on a tablet during facility visits, following the PRO assessment schedule outlined in the Protocol Research Activity Chart.

[0081] The Dermatological Quality of Life Index (DLQI) is a 10-item questionnaire developed and effective for use in measuring QoL in patients with skin conditions.3 It has been used in clinical practice and several clinical trials to evaluate the symptoms of vitiligo and the impact of treatment on QoL.4 It consists of 10 questions that assess the impact of skin disease on various aspects of a subject's QoL over the previous week. The DLQI measures several areas, including symptoms and sensations, daily activities, leisure, work or school, relationships, and treatment burden. Each item is scored on a 4-point scale: 0 = not at all / not relevant; 1 = slightly; 2 = a lot; and 3 = very much. Item scores (0-3) are added to obtain an overall score ranging from 0 to 30, with higher scores indicating greater QoL impairment. In general inflammatory skin conditions, a change of at least 4 points in the DLQI score is considered the minimum clinically significant difference.

[0082] The Hospital Anxiety and Depression Scale (HADS) is a 14-item questionnaire, with 7 items related to anxiety (HADS-A) and 7 items related to depression (HADS-D). Each item is scored from 0 to 3, each subscale is scored from 0 to 21, and the overall scale score is scored from 0 to 42 (emotional distress), with higher scores indicating greater distress. In each area, a score of 7 or less is considered normal, 8 to 10 is borderline, and 11 or more indicates clinical anxiety or depression. The HADS is administered on a tablet upon facility visit, according to the PRO assessment schedule outlined in the Protocol Research Activity Chart.

[0083] The Patient Global Impression Change (PaGIC-V) scale for vitiligo is a study in which subjects rate the overall change in their vitiligo symptoms by comparing the current severity of their symptoms with the severity of their symptoms since the start of research treatment. The response ranges from 1 = "much better" to 5 = "much worse".

[0084] The Generalized Vitiligo Assessment (T-PaGVA) and the Generalized Vitiligo Assessment (F-PaGVA) are two region-specific severity generalized assessments that measure a subject's perception of their current vitiligo status. Both are single-item questionnaires with a 5-point classification of response options. The T-PaGVA measures a subject's perception of vitiligo across the entire body. The F-PaGVA measures a subject's perception of vitiligo on the face. Each scale is structured to ask about the severity of the disease based on the extent of the area covered by depigmented skin. The response options range from 1 = no depigmentation to 5 = very extensive depigmentation.

[0085] The Vitiligo Extent Score (VES) is a clinical scoring tool that measures the overall involvement (extent) of vitiligo on the body. The VES tool involves 19 separate areas of the body and reflects six levels of involvement (grades 0-6: 0%, 1%, 5%, 10%, 25%, 50%, and 75% involvement in each area, based on the clinical presentation).

[0086] The whole-body - physician-generalized vitiligo assessment (T-PhGVA) and the face - physician-generalized vitiligo assessment (F-PhGVA) are tools for quantifying the severity of vitiligo. They use a 5-point scale: 0 = no depigmentation; 1 = limited depigmentation; 2 = moderate depigmentation; 3 = extensive depigmentation; and 4 = very extensive depigmentation. The T-PhGVA includes contributions from all areas of the body, while the F-PhGVA includes contributions from the face.

[0087] The Physiologist's General Impression Change (PhGIC-V) scale for vitiligo is a study in which the principal investigator rates the overall change in a patient's vitiligo symptoms by comparing the current severity of vitiligo symptoms with the severity of vitiligo symptoms since the patient started the research treatment. The response ranges from 1 = "much better" to 5 = "much worse".

[0088] The Individual Component Vitiligo Assessment (ICVA) is a paper-based worksheet completed by the principal investigator and is used to collect information on the examination of vitiligo involvement in individual components of the genitals and face, using two assessments: PhGVA and how uncomfortable the vitiligo lesions are to the subject. The level of discomfort is based on a four-point scale: 1 = not uncomfortable at all; 2 = slightly uncomfortable; 3 = moderately uncomfortable; and 4 = very uncomfortable, based on questions asking subjects how uncomfortable the vitiligo on the genitals and individual areas on the face are to them. There is also an "N / A" (not applicable) response option for areas not affected by vitiligo. Individual components of the face include the forehead / temples, around the eyes, nose, mid-cheeks (medial to the outer corner of the eye), lateral cheeks (lateral to the outer corner of the eye), around the mouth, lips, ears, and scalp.

[0089] II. JAK1 Inhibition Upadacitinib (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide) or a pharmaceutically acceptable salt thereof or in solid form is an oral Janus kinase (JAK) inhibitor that exhibits specific selectivity for the JAK1 receptor. Upadacitinib has the structure shown below:

[0090] [ka]

[0091] The dose titers of upadacitinib as described in this application are based on the weight of anhydrous free base upadacitinib present in the active ingredient delivered to the patient. For example, a dose of "15 mg of upadacitinib" or "UPA 15MG" refers to 15 mg of neutral free base upadacitinib present in the active ingredient, and does not include any conformers (e.g., solvents or water molecules of the solvate or hydrate (including hemihydrate)) or counteranions of pharmaceutically acceptable salts that may also be present in the active ingredient. Therefore, for example, a dose of "15 mg of upadacitinib" includes a dose of 15.4 mg of crystalline free base hemihydrate (containing 1 / 2 a water conformer molecule per free base upadacitinib molecule) to deliver 15 mg of anhydrous free base upadacitinib to the patient.

[0092] 3. Treatment of Vitiligo Provided herein is a method for treating vitiligo using the selective JAK1 inhibitor upadacitinib. Vitiligo is a common chronic autoimmune disorder that causes skin patches to lose pigmentation and become milky white when melanocytes are attacked and destroyed. The global prevalence of vitiligo is approximately 0.5% to 2%. Early depigmentation typically occurs on the face and limbs. In 2011, international agreement classified vitiligo into segmental and non-segmental vitiligo (NSV; Ezzedine et al., Pigment Cell Melanoma Res. 2012, 25(3):E1~13). The majority of patients (>90%) present with the non-segmental variant, in which white patches sometimes appear symmetrically on both sides of the body, for example, both hands or both knees, and cover a large area, sometimes with rapid loss of pigment. Hair (scalp hair, eyebrows, eyelashes, beard and body hair) and mucous membranes may also become white. NSV can occur at any age. Segmental vitiligo (SV), which differs from NSV in appearance and causal relationship, is less common. SV tends to affect areas of skin associated with the spinal cord and dorsal roots, is most often unilateral and more stable / static during its course, and does not improve with topical treatment or UV light. The segmental subtype of vitiligo often begins at a young age, progresses for 6–12 months, and then typically stops.

[0093] Damage or death of melanocytes is considered the direct cause of vitiligo. Melanocytes produce melanin pigment, which colors the skin and provides protection from UV irradiation. Several theories explain the pathogenesis of vitiligo, but the exact etiology remains unknown. The autoimmune theory posits that interferon (IFN)-γ is a key cytokine expressed in lesional skin, and that replenishment of melanocyte-specific autoreactive CD8+ T cells to the skin is required via the chemokines CXCL9 / 10 and CXCR3 (Rodrigues et al., J Am Acad Dermatol. 2017, 77(1):1-13; Harris et al., J Invest Dermatol. 2012, 132(7):1869-76). Cytotoxic CD8+ T cells are both essential and sufficient for the destruction of melanocytes in the skin of vitiligo patients, and thus play an effector arm in promoting autoimmunity in vitiligo.

[0094] Overall, the impact of vitiligo on quality of life appears to depend on the distribution of the lesions (e.g., face, genital area) and the extent of the disease, highlighting the unmet need for effective systemic treatment. There are few treatment options for vitiligo, and those that are available have limited efficacy. Therefore, given the limited response to currently available topical and systemic treatments, there are insufficient options for patients with vitiligo, especially those with severe manifestations of the disease. Considering the lack of treatment options and other emotional, psychological, and disease-related costs, it is desirable for the industry to provide patients with safe, well-tolerated, and effective treatments for vitiligo.

[0095] A. Adult patients Therefore, in one embodiment, a method for treating vitiligo in adult human patients is provided, comprising orally administering 15 mg of upadacitinib once daily to an adult human patient.

[0096] In some embodiments, adult patients are in the age range of approximately 18 to 65 years.

[0097] In some embodiments, adult patients have non-segmental vitiligo (NSV).

[0098] In some embodiments, the NSV is stable.

[0099] In some embodiments, the NSV is active.

[0100] In some embodiments, adult patients have a facial vitiligo area scoring index (F-VASI) of 0.5 or higher before the start of treatment.

[0101] In some embodiments, adult patients have a total vitiligo area scoring index (T-VASI) of 5 or higher before the initiation of treatment.

[0102] In some embodiments, adult patients have not received any immunomodulatory biological therapy prior to the initiation of treatment.

[0103] In some embodiments, adult patients had not received any topical JAK inhibitors within 12 weeks of starting treatment.

[0104] In some embodiments, adult patients have alopecia covering 33% or less of the affected area.

[0105] In some embodiments, adult patients achieve F-VASI75 at 24 weeks.

[0106] In some embodiments, adult patients achieve one or more of the following scores at 36 weeks: T-VASI50, T-VASI75, T-VASI90, F-VASI50, and F-VASI90.

[0107] In some embodiments, patients achieve T-VASI50 at 48 weeks after the first daily dose.

[0108] In some embodiments, patients achieve F-VASI75 at 48 weeks after the first daily dose.

[0109] In some embodiments, patients achieve T-VASI50 at 52 weeks after the first daily dose.

[0110] In some embodiments, patients achieve F-VASI75 at 52 weeks after the first daily dose.

[0111] In some embodiments, adult patients achieve improvement in the overall impression change (PaGIC-V) for vitiligo at 36 weeks.

[0112] In some embodiments, adult patients achieve a Vitiligo Sampling Scale (VNS) score of “Not very prominent (4)” or “Not prominent anymore (5)” at 36 weeks.

[0113] In some embodiments, adult patients achieve improvement from baseline in the vitiligo extent score (VES) at 36 weeks.

[0114] In some embodiments, adult patients achieve improvement from baseline in VitiQoL at 36 weeks.

[0115] In some embodiments, adult patients achieve a total dermatological quality of life index (DLQI) score of "0" or "1" at week 36.

[0116] In some embodiments, adult patients achieve improvement from baseline in their Hospital Anxiety and Depression Scale (HADS) scores at week 36.

[0117] In some embodiments, adult patients achieve an improvement in the time to the onset of pigment redeposition compared to patients not treated with upadacitinib.

[0118] In some embodiments, adult patients achieve improvement in itching or burning within 36 weeks of starting treatment.

[0119] In some embodiments, adult patients achieve a Physician Global Impression Change (PhGIC-V) score of "much better (1)" or "somewhat better (2)" for vitiligo at 36 weeks. In some embodiments, adult patients achieve a Patient Global Impression Change (PaGIC-V) score of "much better (1)" or "somewhat better (2)" for vitiligo at 36 weeks. In some embodiments, adult patients achieve a Facial-Physician Global Vitiligo Assessment (F-PhGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks. In some embodiments, adult patients achieve a Generalized-Physician Global Vitiligo Assessment (T-PhGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks. In some embodiments, adult patients achieve a Facial-Patient Global Vitiligo Assessment (F-PaGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks. In some embodiments, adult patients achieve a total body-to-patient vitiligo assessment (T-PaGVA) score of “no depigmentation (0)” or “limited depigmentation (1)” at 36 weeks.

[0120] In some embodiments, the method halts the progression of vitiligo within 36 weeks of the start of treatment.

[0121] In some embodiments, the method leads to a reduction from baseline in one or more biomarkers of vitiligo within 36 weeks of the start of treatment. In some embodiments, the biomarkers are inflammatory chemotactic proteins or T cell activation markers. In some embodiments, the biomarkers are CXCL9, CXCL10, IL12B, TNFSF9, or a combination thereof.

[0122] In some embodiments, adult patients are treated in combination with exposure to ultraviolet light.

[0123] The disclosed methods generally involve administering upadacitinib orally to an adult patient daily for a set period of time. In some embodiments, administration continues for the duration of treatment at the same dose and frequency. The duration of treatment may vary. For example, the treatment duration may be at least one month, e.g., three months, four months, six months, nine months, one year, two years, five years, ten years, twenty years, or fifty years or more. In some embodiments, the treatment duration is 24 weeks. In some embodiments, the treatment duration is 36 weeks. In some embodiments, the treatment duration is 52 weeks. In some embodiments, the treatment duration is at least 24 weeks or at least 36 weeks. In some embodiments, the treatment duration is 48 weeks.

[0124] B. Pediatric patients In some embodiments, the patients exhibiting vitiligo are pediatric human patients (i.e., under approximately 18 years of age). In some embodiments, the dose administered to pediatric patients may differ from that administered to adult human patients.

[0125] Therefore, in another embodiment, a method for treating vitiligo in pediatric human patients is provided. This method generally involves administering upadacitinib to pediatric patients as a stable oral pharmaceutical formulation or sustained-release tablets, with the dosage based on body weight. The amount of upadacitinib administered, the oral dosage form, and the frequency of administration (e.g., once or twice daily) vary based on the patient's weight.

[0126] In some embodiments, the pediatric patient is under 18 years of age. In some embodiments, the pediatric patient is under 12 years of age. In some embodiments, the pediatric patient is under 6 years of age. In some embodiments, the pediatric patient is in the age range of about 2 to under 6 years of age, about 6 to under 12 years of age, or about 12 to under 18 years of age. In some embodiments, the pediatric patient is in the age range of about 2 to under 18 years of age, for example, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, or about 18 years of age.

[0127] In some embodiments, the pediatric patient has a weight of at least about 10 kg. In some embodiments, the pediatric patient has a weight of about 10 kg to less than about 30 kg, for example, about 20 to less than 20 kg or about 20 to less than 30 kg. In some embodiments, the pediatric patient has a weight of 30 kg or more.

[0128] In some embodiments, the pediatric patient has a body weight in the range of about 10 to less than about 20 kg, and the method involves administering 3 mg of upadacitinib twice daily (3 mg BID) as an oral solution.

[0129] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL, for example, about 0.8, 0.9, or about 1.0 to about 1.1 or about 1.2 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 1.0 mg / mL.

[0130] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, with a 3 mg dose provided as a BID of approximately 3 mL of approximately 1 mg / mL solution.

[0131] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, for example, about 0.3, 0.4, or about 0.5 to about 0.6 or about 0.7 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 0.5 mg / mL.

[0132] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, with a 3 mg dose provided as a BID of approximately 6 mL of approximately 0.5 mg / mL solution.

[0133] In some embodiments, the pediatric patient has a body weight in the range of about 10 to less than about 20 kg, and the method involves administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.

[0134] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL, for example, about 0.8, 0.9, or about 1.0 to about 1.1 or about 1.2 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 1.0 mg / mL.

[0135] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, with a 6 mg dose provided as a BID of approximately 6 mL of approximately 1 mg / mL solution.

[0136] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, for example, about 0.3, 0.4, or about 0.5 to about 0.6 or about 0.7 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 0.5 mg / mL.

[0137] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, with a 6 mg dose provided as a BID of approximately 12 mL of approximately 0.5 mg / mL solution.

[0138] In some embodiments, the pediatric patient has a body weight in the range of about 20 to less than about 30 kg, and the method includes administering 4 mg of upadacitinib twice daily (4 mg BID) as an oral solution. In some embodiments, the pediatric patient has a body weight in the range of about 20 to less than about 30 kg, and the method includes administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.

[0139] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL, for example, about 0.8, 0.9, or about 1.0 to about 1.1 or about 1.2 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 1.0 mg / mL.

[0140] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, with an 8 mg dose provided as a BID of approximately 8 mL of approximately 1 mg / mL solution.

[0141] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, for example, about 0.3, 0.4, or about 0.5 to about 0.6 or about 0.7 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 0.5 mg / mL.

[0142] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, with an 8 mg dose provided as a BID of approximately 16 mL of approximately 0.5 mg / mL solution.

[0143] In some embodiments, the pediatric patient has a body weight of approximately 30 kg or more, and the method involves administering 6 mg of upadacitinib twice daily (6 mg BID) as an oral solution.

[0144] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL, for example, about 0.8, 0.9, or about 1.0 to about 1.1 or about 1.2 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 1.0 mg / mL.

[0145] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, with a 6 mg dose provided as a BID of approximately 6 mL of approximately 1 mg / mL solution.

[0146] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, for example, about 0.3, 0.4, or about 0.5 to about 0.6 or about 0.7 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 0.5 mg / mL.

[0147] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, with a 6 mg dose provided as a BID of approximately 12 mL of approximately 0.5 mg / mL solution.

[0148] In some embodiments, the pediatric patient has a body weight of approximately 30 kg or more, and the method involves administering 15 mg of upadacitinib once daily (15 mg QD) as a sustained-release tablet.

[0149] In some embodiments, the pediatric patient has a body weight of approximately 30 kg or more, and the method includes the step of administering 8 mg of upadacitinib twice daily (8 mg BID) as an oral solution.

[0150] In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL, for example, about 0.8, 0.9, or about 1.0 to about 1.1 or about 1.2 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 1.0 mg / mL.

[0151] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 1 mg / mL, with an 8 mg dose provided as a BID of approximately 8 mL of approximately 1 mg / mL solution.

[0152] In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, for example, about 0.3, 0.4, or about 0.5 to about 0.6 or about 0.7 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 0.5 mg / mL.

[0153] In some embodiments, the oral solution contains upadacitinib at a concentration of approximately 0.5 mg / mL, with an 8 mg dose provided as a BID of approximately 16 mL of approximately 0.5 mg / mL solution.

[0154] In some embodiments, the pediatric patient has a body weight of approximately 30 kg or more, and the method involves administering 15 mg of upadacitinib once daily (15 mg QD) as a sustained-release tablet.

[0155] The maximum concentration achieved with the aforementioned administration (C max ) may vary depending, for example, the dose, the patient's weight, and the individual patient's metabolism of upadacitinib.

[0156] In some embodiments, when the immediate-release oral solution described herein is administered via BID to children, the mean C1 of upadacitinib max This is achieved in the range of approximately 20 to 160 ng / mL.

[0157] In some embodiments, when administered to pediatric subjects at doses of 3 or 4 mg twice daily (3 or 4 mg BID), the mean C1 of upadacitinib max This is achieved in the range of approximately 25 to 50 ng / mL, for example, approximately 25 to 35, 25 to 33, 25 to 31, 25 to 29, or 25 to 27 ng / mL.

[0158] In some embodiments, when administered to pediatric subjects at doses of 6 or 8 mg twice daily (6 or 8 mg BID), the mean C1 of upadacitinib maxis achieved in the range of about 40 to about 100 ng / mL, such as about 40 to about 95, about 40 to about 90, about 40 to about 85, about 40 to about 80, about 40 to about 75, about 40 to about 70, about 40 to about 65, about 40 to about 60, about 40 to about 55, about 40 to about 50 or about 40 to about 45 ng / mL.

[0159] In some embodiments, when the sustained release 15 mg tablets described herein are administered once daily (15 mg QD) to pediatric subjects, the mean C of upadacitinib max is achieved in the range of about 45 to about 50 ng / mL, such as about 45 to about 49, about 45 to about 48, about 45 to about 47, about 45 to about 46 or about 45 to about 45 ng / mL.

[0160] The mean 24-hour exposure (AUC 0~24 ) achieved with the aforementioned administration may vary depending on, for example, the dose, the patient's weight, the fed-to-fasted state, and the metabolism of upadacitinib by the individual patient.

[0161] In some embodiments, when the immediate release oral solution described herein is administered BID to pediatric subjects, the mean AUC of upadacitinib 0~24 is achieved in the range of about 200 to about 700 ng·h / mL.

[0162] In some embodiments, when administered twice daily (3 or 4 mg BID) to pediatric subjects at doses of 3 or 4 mg each, the mean AUC of upadacitinib 0~24 is achieved in a range from about, such as about 220 to about 270 ng·h / mL, such as about 220 to about 265, about 220 to about 260, about 220 to about 255, about 220 to about 250, about 220 to about 245, about 220 to about 240, about 220 to about 235, about 220 to about 230 or about 220 to about 225 ng·h / mL.

[0163] In some embodiments, when administered twice daily (6 or 8 mg BID) to pediatric subjects at doses of 6 or 8 mg each, the mean AUC of upadacitinib 0~24This ranges from approximately 340 to 590 ng·h / mL, for example, approximately 340 to 580, 340 to 570, 340 to 560, 340 to 550, 340 to 540, 340 to 530, 340 to 520, 340 to 510, 340 to 500, 340 to 490, 340 to 480, and 340 to 470. This is achieved at approximately 340-460, 340-450, 340-440, 340-430, 340-420, 340-410, 340-400, 340-390, 340-380, 340-370, 340-360, 340-350, or 340-345 ng·h / mL. In some embodiments, when upadacitinib is administered to pediatric subjects at doses of 6 or 8 mg twice daily (6 or 8 mg BID), the mean AUC is approximately 340-460, 340-450, 340-440, 340-430, 340-420, 340-410, 340-400, 340-390, 340-380, 340-370, 340-360, 340-350, or 340-345 ng·h / mL. 0~24 This is achieved in the range of approximately 570 to 590 ng·h / mL, for example, approximately 570 to 590, approximately 570 to 588, approximately 570 to 586, approximately 570 to 584, approximately 570 to 582, or approximately 570 to 580 ng·h / mL.

[0164] In some embodiments, the 15 mg sustained-release tablets described herein, when administered once daily (15 mg QD) to children, have a mean AUC of upadacitinib. 0~24 This is achieved in the range of approximately 45 to 50 ng·h / mL, for example, approximately 45 to 49, approximately 46 to 48, or approximately 47 to 48 ng·h / mL.

[0165] In some embodiments, pediatric patients have non-segmental vitiligo (NSV).

[0166] In some embodiments, the NSV is stable.

[0167] In some embodiments, the NSV is active.

[0168] In some embodiments, pediatric patients have a facial vitiligo area scoring index (F-VASI) of 0.5 or higher before the start of treatment.

[0169] In some embodiments, pediatric patients have a total vitiligo area scoring index (T-VASI) of 5 or higher before the initiation of treatment.

[0170] In some embodiments, pediatric patients have not received any immunomodulatory biological therapy prior to the initiation of treatment.

[0171] In some embodiments, pediatric patients had not received any topical JAK inhibitors within 12 weeks prior to the initiation of treatment.

[0172] In some embodiments, pediatric patients have alopecia covering 33% or less of the affected area.

[0173] In some embodiments, pediatric patients achieve F-VASI75 at 24 weeks after the start of treatment.

[0174] In some embodiments, pediatric patients achieve one or more T-VASI50, T-VASI75, T-VASI90, F-VASI50, or F-VASI90 at 36 weeks after the start of treatment.

[0175] In some embodiments, pediatric patients achieve F-VASI75 at 36 weeks after the start of treatment.

[0176] In some embodiments, pediatric patients achieve T-VASI50 at 36 weeks after the start of treatment.

[0177] In some embodiments, pediatric patients achieve one or more of the following scores at 48 weeks after the start of treatment: T-VASI50, T-VASI75, T-VASI90, F-VASI50, or F-VASI90.

[0178] In some embodiments, pediatric patients achieve F-VASI75 at 48 weeks after the start of treatment.

[0179] In some embodiments, pediatric patients achieve T-VASI50 at 48 weeks after the start of treatment.

[0180] In some embodiments, pediatric patients achieve one or more of the following scores at 52 weeks after the start of treatment: T-VASI50, T-VASI75, T-VASI90, F-VASI50, or F-VASI90.

[0181] In some embodiments, pediatric patients achieve F-VASI75 at 52 weeks after the start of treatment.

[0182] In some embodiments, pediatric patients achieve T-VASI50 at 52 weeks after the start of treatment.

[0183] In some embodiments, pediatric patients achieve improvement in the Generalized Image Criteria (PaGIC-V) for generalized vitiligo at 36 weeks after the start of treatment.

[0184] In some embodiments, pediatric patients achieve a Vitiligo Sampling Scale (VNS) score of “Not Significantly Significant (4)” or “Not Significantly Significant (5)” at 36 weeks after the start of treatment.

[0185] In some embodiments, pediatric patients achieve improvement from baseline in the vitiligo extent score (VES) at 36 weeks after the start of treatment.

[0186] In some embodiments, pediatric patients achieve improvement from baseline in VitiQoL at 36 weeks after the start of treatment.

[0187] In some embodiments, pediatric patients achieve a total dermatological quality of life index (DLQI) score of "0" or "1" at 36 weeks.

[0188] In some embodiments, pediatric patients achieve improvement from baseline in their Hospital Anxiety and Depression Scale (HADS) scores at 36 weeks after the start of treatment.

[0189] In some embodiments, pediatric patients achieve an improvement in the time to the onset of pigment redeposition compared to patients not treated with upadacitinib.

[0190] In some embodiments, pediatric patients achieve improvement in itching or burning sensation within 36 weeks of starting treatment.

[0191] In some embodiments, pediatric patients achieve a physician-generalized impression change (PhGIC-V) score of "much better (1)" or "somewhat better (2)" for vitiligo at 36 weeks after the start of treatment. In some embodiments, pediatric patients achieve a patient-generalized impression change (PaGIC-V) score of "much better (1)" or "somewhat better (2)" for vitiligo at 36 weeks after the start of treatment. In some embodiments, pediatric patients achieve a facial-physician-generalized vitiligo evaluation (F-PhGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks after the start of treatment. In some embodiments, pediatric patients achieve a whole-body-physician-generalized vitiligo evaluation (T-PhGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks after the start of treatment. In some embodiments, pediatric patients achieve a facial-total vitiligo evaluation (F-PaGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks after the start of treatment. In some embodiments, pediatric patients achieve a whole-body-total vitiligo evaluation (T-PaGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks after the start of treatment.

[0192] In some embodiments, the method halts the progression of vitiligo within 36 weeks of the start of treatment.

[0193] In some embodiments, the method leads to a reduction from baseline in one or more biomarkers of vitiligo within 36 weeks of the start of treatment. In some embodiments, the biomarkers are inflammatory chemotactic proteins or T cell activation markers. In some embodiments, the biomarkers are CXCL9, CXCL10, IL12B, TNFSF9, or a combination thereof.

[0194] In some embodiments, pediatric patients are treated in combination with exposure to ultraviolet light.

[0195] The disclosed methods generally involve orally administering upadacitinib to a pediatric patient daily for a set period of time. In some embodiments, administration continues for the duration of treatment at the same dose and frequency. The duration of treatment may vary. For example, the treatment duration may be at least one month, e.g., three months, four months, six months, nine months, one year, two years, five years, ten years, twenty years, or fifty years or more. In some embodiments, the treatment duration is 24 weeks. In some embodiments, the treatment duration is at least 24 weeks or at least 36 weeks. In some embodiments, the treatment duration is 36 weeks. In some embodiments, the treatment duration is 48 weeks. In some embodiments, the treatment duration is 52 weeks.

[0196] III. Pharmaceutical Compositions and Routes of Administration Upadacitinib may be administered to human patients by itself or in pharmaceutical compositions mixed with biocompatible carriers or excipients in doses that treat or alleviate the diseases or conditions described herein. Mixtures of these compounds may also be administered to patients as simple mixtures or in suitable formulated pharmaceutical compositions.

[0197] The pharmaceutical compositions of this disclosure may be manufactured by methods known to the extent of the present invention, for example, by conventional mixing, dissolution, granulation, sugar coating, grinding, emulsification, encapsulation, encapsulation, or freeze-drying processes.

[0198] Pharmaceutical compositions for use in accordance with this disclosure can therefore be formulated by conventional methods using one or more physiologically acceptable carriers, which include excipients and adjuvants that facilitate the processing of the active compound into a preparation that can be used as a pharmaceutical. The appropriate formulation depends on the chosen route of administration.

[0199] In some embodiments, the pharmaceutical composition is in the form of tablets. In some embodiments, the tablets are in the form of controlled-release formulations, such as sustained-release tablets (also referred to herein as controlled-release or sustained-release formulations). Examples of solid dosage forms containing upadacitinib can be found in International Patent Application Publication WO2017 / 066775, which is incorporated herein by reference in its entirety.

[0200] In some embodiments, the composition is a stable liquid pharmaceutical composition. In some embodiments, the stable liquid pharmaceutical composition is a stable oral liquid preparation. In some embodiments, the stable liquid pharmaceutical composition is a stable oral suspension. A preferred and stable liquid pharmaceutical composition comprises upadacitinib or a pharmaceutically acceptable salt thereof or a solid form, together with excipients, such as a buffer, preservative, sweetener, flavoring agent, pH adjuster, and solvent. In some embodiments, the stable liquid pharmaceutical composition is a stable oral pharmaceutical liquid preparation comprising upadacitinib, a buffer and / or pH adjuster, a preservative, a sweetener, and water. In some embodiments, the stable liquid pharmaceutical composition is a stable oral suspension preparation comprising upadacitinib, a buffer and / or pH adjuster, a preservative, a sweetener, and water.

[0201] The concentration of upadacitinib in a stable liquid pharmaceutical composition may vary. Due to its bitterness, upadacitinib is difficult to mask for palatability at higher concentrations (see, for example, Example 5) and is generally present at concentrations of about 1 mg / mL or less. In some embodiments, the stable pharmaceutical composition is an oral solution containing upadacitinib at concentrations ranging from about 0.3 mg / mL to about 1.2 mg / mL, for example, in the range of about 0.3 to about 0.7 mg / mL or about 0.8 to about 1.2 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 1 mg / mL, for example, about 0.8, 0.9 or about 1.0 to about 1.1 or about 1.2 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 1.0 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL, for example, about 0.3, 0.4, or about 0.5 to about 0.6 or about 0.7 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains upadacitinib at a concentration of 0.5 mg / mL.

[0202] In some embodiments, the oral solution includes a pH adjuster. Suitable pH adjusters include acids, such as mineral acids or organic acids. Mineral acids include, but are not limited to, hydrochloric acid, sulfuric acid, and phosphoric acid. As used herein, the term “organic acid” refers to organic (i.e., carbon-based) compounds characterized by their acidic nature. Typically, organic acids are relatively weak acids (i.e., they do not completely dissociate in the presence of water), such as carboxylic acids (-CO2H). In some embodiments, the pH adjuster is an organic acid. Suitable organic acids include benzoic acid, toluic acid, salicylic acid, benzenesulfonic acid, p-toluenesulfonic acid, 2-(4-isobutylphenyl)propanoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, adipic acid, ascorbic acid (L), aspartic acid (L), alpha-methylbutyric acid, camphor acid (+), camphor-10-sulfonic acid (+), cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, and fumaric acid. This includes, but is not limited to, furic acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, isovaleric acid, lactobionic acid, lauric acid, levulinic acid, malic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, oleic acid, palmitic acid, pamoic acid, phenylacetic acid, pyroglutamic acid, pyruvic acid, sebacic acid, stearic acid, tartaric acid, and undecylenic acid. In some embodiments, the pH adjuster is selected from the group consisting of citric acid, phosphoric acid, tartaric acid, succinic acid, formic acid, acetic acid, and combinations thereof. In some embodiments, the pH adjuster is citric acid.

[0203] In some embodiments, the stable liquid pharmaceutical composition includes a buffer. Preferred buffers include, but are not limited to, citrates, phosphates, tarlates, succinates, glycinates, glycerophosphates, formates, and acetates. In some embodiments, the buffer is selected from the group consisting of citrates, phosphates, tarlates, succinates, formates, acetates, and combinations thereof. In some embodiments, the buffer is selected from the group consisting of citrates and phosphates. In some embodiments, the buffer is sodium citrate.

[0204] The amounts of pH adjusters and / or buffers may vary. Generally, their concentrations are adjusted to obtain a stable liquid pharmaceutical composition within the desired pH range. In some embodiments, the stable liquid pharmaceutical composition has a pH in the range of about 2 to about 5 or about 3 to about 4 or about 2 to about 3 or about 4 to about 5 or about 2.0 to about 2.5 or about 2.5 to about 3.0 or about 3.0 to about 3.5 or about 3.5 to about 4.0 or about 4.0 to about 4.5 or about 4.5 to about 5.0 or about 3.0 to about 3.1 or about 3.0 to about 3.2 or about 3.0 to about 3.3 or about 3.1 to about 3.2 or about 3.1 to about 3.3 or about 3.1 to about 3.4 or about 3.1 to about 3.5 or about 3.2 to about 3.3 or about 3.2 to about 3.4 or about 3.2 to about 3.5 or about 3.3 to about 3.4 or about 3.3 to about 3.5. In some embodiments, the stable liquid pharmaceutical composition has a pH of about 3.0 or about 3.1 or about 3.2.

[0205] In some embodiments, the stable liquid pharmaceutical composition includes a preservative. Suitable preservatives include, but are not limited to, benzoic acid, sodium benzoate, benzyl alcohol, ascorbic acid, potassium sorbate, 4-hydroxybenzoic acid, 4-hydroxybenzoate, methylparaben, propylparaben, sodium metabisulfite, and combinations thereof. In some embodiments, the preservative is selected from the group consisting of sodium benzoate, benzoic acid, propylparaben, sodium metabisulfite, potassium sorbate, hydroxyparabenzoic acid, hydroxyparabisulfate, and combinations thereof.

[0206] In some embodiments, the stable liquid pharmaceutical composition contains a sweetener. The sweetener may be a natural or artificial form, or a combination of natural and artificial sweeteners. Examples of natural sweeteners include fructose, sucrose, glucose, maltose, mannose, galactose, lactose, stevia, and honey. Examples of artificial sweeteners include sucralose, isomaltulose, maltodextrin, saccharin, aspartame, acesulfame K, and neotame. In some embodiments, the sweetener contains one or more sugar alcohols. The sugar alcohols are polyols derived from monosaccharides or disaccharides having a partially or fully hydrogenated form. Sugar alcohols include, for example, erythritol, arabitol, ribitol, isomalt, maltitol, dulcitol, iditol, mannitol, xylitol, lactitol, sorbitol, and combinations thereof (e.g., hydrolyzed hydrogenated starch), which have about 4 to about 20 carbon atoms. In some embodiments, the sweetener is selected from the group consisting of sucralose, acesulfame potassium, sodium saccharin, neotame, sucrose, maltitol, xylitol, and combinations thereof.

[0207] In some embodiments, a stable oral medicinal liquid formulation comprises one or more flavoring agents. Any flavoring or aromatic substance capable of altering the taste, fragrance, or both of the liquid formulation may be used. The flavoring agents may be natural or synthetic. Suitable flavoring agents include, but are not limited to, flavoring packages that impart flavors such as cherry, orange, lemon, lime, bubblegum, grape, strawberry, and mango.

[0208] In some embodiments, the stable oral pharmaceutical solution includes a taste modifier. Suitable taste modifiers include, but are not limited to, salts such as sodium chloride and monoammonium glycyrrhizinate to enhance sweetness.

[0209] In some embodiments, the stable pharmaceutical composition is an oral solution comprising upadacitinib, citric acid, sodium citrate, sodium benzoate, a sweetener, and water.

[0210] In some embodiments, the stable pharmaceutical composition contains citric acid in an amount ranging from about 0.1 to about 1 mg / mL.

[0211] In some embodiments, the stable pharmaceutical composition contains sodium citrate in an amount ranging from about 0.01 to about 1 mg / mL.

[0212] In some embodiments, the stable pharmaceutical composition contains sodium benzoate in an amount ranging from about 0.01 to about 0.1 mg / mL.

[0213] In some embodiments, the stable pharmaceutical composition contains a sweetener in an amount ranging from about 1 to about 50 mg / mL.

[0214] In certain embodiments, the oral solution has the formulation shown in Table 1.

[0215] [Table 1] [Examples]

[0216] [Example 1] A multicenter, randomized, double-blind, placebo-controlled dose-determining study to assess the safety and efficacy of upadacitinib in subjects with non-segmental vitiligo. This study was a 52-week phase 2 multiple-dose placebo-controlled, double-blind clinical trial in adult patients with non-segmental vitiligo. The study consisted of two periods. The first period was a 24-week study, followed by a blinded 28-week extension, which was blinded but not placebo-controlled. A summary of the study is shown in Figure 1.

[0217] The primary objective of this study was to assess the safety and efficacy of upadacitinib for the treatment of adult subjects with non-segmental vitiligo (NSV). The primary endpoint was the percentage change from baseline in the facial vitiligo area scoring index (F-VASI) at 24 weeks.

[0218] Inclusion / exclusion criteria Eligible subjects were adult women and men aged ≥18–65 years at the time of screening, with a clinically confirmed diagnosis of NSV and no segmental or focal vitiligo. Subjects had stable or active NSV. Approximately 130 adult males or females were enrolled. Enrolled subjects met all of the following criteria at screening and baseline: • Facial vitiligo area scoring index (F-VASI) ≥ 0.5 and total vitiligo area scoring index (T-VASI) ≥ 5. Subjects with other skin conditions that may interfere with the assessment of vitiligo, subjects with uncontrolled thyroid disease, and subjects with more than 33% vitiligo on the face or more than 33% vitiligo on the body (including the face) were not eligible for enrollment in this study. • Suitable candidates must not have previously been treated with any topical or systemic JAK inhibitors or long-lasting skin bleaching agents. • Participants must not have received any systemic vitiligo therapy (e.g., methotrexate, mycophenolate mofetil, corticosteroids), additional vitiligo therapy (antioxidants / vitamins / herbal medicines / traditional Chinese medicines), and / or topical vitiligo therapy, including permanent or temporary tattoos, within at least 30 days prior to the initial administration of the investigational drug (Note: Camouflage and makeup may be used). • Suitable subjects must not have received any phototherapy (or other form of laser therapy), including excimer therapy, within at least 12 weeks prior to the first administration of the investigational drug. • Subjects previously exposed to immunomodulatory biological therapies must discontinue the biological therapy before the first dose of the investigational drug, regardless of any instructions. Recommended drug-free periods for biological therapies include at least 4 weeks for etanercept; at least 8 weeks for adalimumab, infliximab, certolizumab, golimumab, abatacept, tocilizumab, and ixekizumab; at least 16 weeks for secukinumab; and at least 12 weeks for ustekinumab. For biological therapies not specified, the therapy must have been discontinued for at least 5 times the mean final elimination half-life of the drug, or 3 months prior to baseline, whichever is longer. • Laboratory values ​​meeting the following criteria were required during the screening period prior to the initial administration of the investigational drug: • Serum aspartate transaminase (AST) ≤ 2 × upper limit of normal (ULN) • Serum alanine transaminase (ALT) ≤ 2 × ULN • Estimated glomerular filtration rate ≥ 30 mL / min / 1.73 m² using the simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula. 2 ·Total WBC count ≧2,500 / μL • Absolute neutrophil count (ANC) ≥ 1,200 / μL ·Platelet count ≧100,000 / μL • Absolute lymphocyte count (ALC) ≥ 750 / μL • Hemoglobin ≥ 9 g / dL • Patients do not need to have the following current or past medical history: • Two or more episodes of herpes zoster or one or more episodes of disseminated herpes zoster • One or more episodes of disseminated herpes simplex (including herpetic eczema / Kaposi's varicelliform eruption) Human immunodeficiency virus (HIV) infection is defined as a positive result on an anti-HIV antibody (HIV Ab) test. • Active tuberculosis (TB), or meeting the TB exclusion parameters. • Positive result for beta-D-glucan (screening for Pneumocystis jirovecii infection), or two consecutive inconclusive results for beta-D-glucan during the screening period (only applicable to subjects in Japan) • Active infection(s) requiring treatment with intravenous anti-infective drugs within 30 days prior to baseline visit, or oral / intramuscular (IM) anti-infective dye within 14 days. • Chronic recurrent infections and / or active viral infections • Confirmed COVID-19 • Hepatitis B virus (HBV): In subjects who are positive for hepatitis B nuclear antibody (HBc Ab) (and, where required by local requirements, in subjects who are positive for hepatitis B surface antibody [HBs Ab]), a positive hepatitis B surface antigen test (+) or a detectable HBV DNA PCR qualitative test. • Hepatitis C virus (HCV): Detectable HCV RNA in any subject in whom anti-HCV Ab is detected. • Recent (within the past 6 months) cerebrovascular accident, myocardial infarction, coronary artery stenting, and aortic coronary artery bypass surgery • History of organ transplantation requiring continuous immunosuppression • History of GI perforation (other than due to appendicitis or mechanical injury), diverticulitis, or a significantly increased risk of GI perforation as determined by the principal investigator. Conditions that may inhibit drug absorption, including but not limited to short bowel syndrome or gastric bypass surgery; patients with a history of gastric banding / segmentation are not excluded. • A history of malignant disease, excluding properly treated NMSC or localized carcinoma in situ of the cervix. • Uncontrolled thyroid disorder Other skin conditions that may interfere with the assessment of vitiligo • More than 33% of the face is covered in gray hair or more than 33% of the body (including the face) • Systemic use of known potent CYP3A inhibitors (including over-the-counter or prescription drugs, vitamins, and / or herbal supplements) was not permitted from screening to the end of investigational drug administration, and the use of potent CYP3A inducers was not permitted from 30 days prior to investigational drug administration until the end of investigational drug administration. Furthermore, herbal therapies and other traditional medicines with unknown effects on CYP3A were not permitted from screening to the end of investigational drug administration.

[0219] Duration of investigational drug and treatment The study consisted of a 35-day screening period, a 24-week double-blind treatment period (Period 1), a 28-week blinded extended treatment period (Period 2), and a 30-day follow-up period. At baseline, participants meeting the selection criteria were randomized to one of five treatment groups in a 2:2:2:1:1 ratio as follows: Group 1: Upadacitinib 22 mg once daily (QD) (N=40) (Period 1) → Upadacitinib 22 mg QD (Period 2) Group 2: Upadacitinib 11mg QD (N=40) (Period 1) → Upadacitinib 11mg QD (Period 2) Group 3: Upadacitinib 6mg QD (N=40) (Period 1) → Upadacitinib 6mg QD (Period 2) • Group 4: Placebo (N=20) (Period 1) → Upadacitinib 22mg bQD (Period 2) • Group 5: Placebo (N=20) (Period 1) → Upadacitonib 11mg QD (Period 2) Upadacitinib was administered orally once daily (QD).

[0220] Stratification Patients were randomized and stratified as follows: • Age (50 years old or younger; over 50 years old) • Baseline disease severity (T-VASI <15 or greater than 15 / equal to 15) • Status of active vitiligo (present / absent)

[0221] Research objectives and evaluation items Efficacy evaluation items The following efficacy parameters were used. Primary evaluation criteria: • Percentage change from baseline to placebo in F-VASI at 24 weeks with upadacitinib treatment in an intention-to-treat (ITT) population consisting of all randomized subjects. Secondary evaluation criteria: • Percentage of subjects who achieved F-VASI75, defined as at least 75% improvement from baseline in F-VASI at week 24. • Percentage of subjects who achieved F-VASI50, defined as at least a 50% improvement from baseline in F-VASI at week 24. • Percentage of subjects who achieved T-VASI50, defined as at least a 50% improvement from baseline in the T-VASI at week 24. • Percentage change from baseline in T-VASI at week 24 • Change from baseline in the total instrumental score of the Vitiligo Quality of Life (VitiQoL) measurement at 24 weeks. Additional evaluation items • Achievement of F-VASI90 • Achievement of T-VASI90 • Achievement of T-VASI75 • Mean and percentage change from baseline in the Vitiligo Extent Score (VES) • Achieving a Vitiligo Sampling Scale (VNS) score of "Not very noticeable (4)" or "No longer noticeable (5)" • Overall Dermatological Quality of Life Index (DLQI) score of "0" or "1" • Change from baseline in Hospital Anxiety and Depression Scale (HADS) score • The percentage of people who selected each of the 16 response categories in the VitiQoL questionnaire. • Achieving a "much better (1)" or "slightly better (2)" rating on the Physiologist General Impression Index (PhGIC-V) for vitiligo. • Achieving a "significantly better (1)" or "slightly better (2)" overall patient impression change (PaGIC-V) for vitiligo. • Faces with "no depigmentation (0)" or "limited depigmentation (1)" - Achievement of Generalized Vitiligo Assessment (F-PhGVA) • Achievement of Generalized Vitiligo Assessment (T-PhGVA) with "no depigmentation (0)" or "limited depigmentation (1)" • Faces with "no depigmentation (0)" or "limited depigmentation (1)" - Achievement of Generalized Vitiligo Assessment (F-PaGVA) • Achievement of a total vitiligo assessment (T-PaGVA) of the patient with "no depigmentation (0)" or "limited depigmentation (1)".

[0222] result demographics The study enrolled a high percentage of subjects with extensive vitiligo (T-VASI > 10 BSA) and / or active vitiligo. Baseline demographics for the entire study population and each group (placebo, 6 mg, 11 mg, 22 mg doses) are shown in Table 2. Baseline disease characteristics (e.g., active vs. stable, years since diagnosis, disease severity) are shown in Table 3.

[0223] [Table 2]

[0224] [Table 3]

[0225] Breakdown of the target The breakdown of participants in Period 1 and Period 2 is shown in Tables 4 and 5 for each treatment group. Regarding Tables 4 and 5, the vast majority of randomized patients completed the study, and very few dropouts were observed.

[0226] [Table 4]

[0227] [Table 5]

[0228] Effect: Overall, upadacitinib 11 mg and 22 mg met the primary endpoint (% change from baseline in F-VASI at Week 24) and most of the secondary endpoints (% change from baseline in F-VASI75, F-VASI50, T-VASI). In general, consistency of upadacitinib response was observed across all pre-specified subgroups (active and stable, T-VASI ≤10 and >10). efficacy data are presented in Figures 2-5A / B and Tables 6-8. With respect to Table 6, upadacitinib 11 mg did not meet the secondary endpoint of T-VASI50 at Week 24. Notably, the proportion of subjects achieving F-VASI75 and T-VASI50 continued to increase over 52 weeks with all doses of upadacitinib (among subjects who had the opportunity to reach Week 52).

[0229] [Table 6]

[0230] With respect to Physician's Global Impression of Change (PhGIC) and Patient's Global Impression of Change (PaGIC), patients achieved greater efficacy with upadacitinib 11 and 22 mg compared to placebo (Table 7).

[0231] [Table 7]

[0232] [Table 8]

[0233] Preliminary 3D imaging data supports the higher efficacy of upadacitinib 11 and 22 mg compared to placebo (see Example 3). Specifically, in patients treated with upadacitinib 11 and 22 mg, 3D imaging assessment demonstrated a greater percentage change from baseline in the vitiligo extent score (VES).

[0234] biomarkers Decreases from baseline were observed in inflammatory chemotactic proteins (CXCL9 and CXCL10) and T-cell activation markers (IL12B and TNFSF9), indicating an effect on type 1 inflammation (data not shown). The maximum inhibitory reduction observed in type 1 inflammation biomarkers was achieved at the 11 mg dose. Biomarker reductions were observed as early as 2 weeks and maintained throughout 24 weeks, with similar effects observed across all upadacitinib doses, although a slightly lower effect was observed in the 6 mg treatment group. In CXCL10, levels decreased to those of healthy volunteers by 2 weeks in all dose groups. Overall, serum biomarker data support higher efficacy of UPA 11 mg and 22 mg compared to placebo. No clear difference was observed between active and stable subjects.

[0235] [Example 2:] Exposure-response analysis of efficacy at week 24 Drug exposure versus response analysis was performed using data from Example 1. Regression models were developed for the change from baseline in F-VASI at week 24, and for the changes from baseline in T-VASI, F-VASI75, and T-VASI50. Linear and nonlinear regression models were assessed for continuous endpoints (change from baseline in F-VASI and T-VASI). Linear, logarithmic, therapeutic effect, and Emax models were assessed for categorical endpoints (F-VASI75 and T-VASI50). Stratification factors from the Phase 2 study were included in all assessed models. The final model for each endpoint was selected based on the Akaike Information Criterion and visual prediction checks.

[0236] The preliminary exposure-response analysis for efficacy at week 24, based on data from period 1, showed clear exposure-response relationships for the change from baseline in F-VASI, T-VASI, F-VASI75, and T-VASI50, and upadacitinib mean plasma exposure (C avg As the values ​​in Figures 6A and 6B) increased, the response increased. These relationships were described using regression models for consecutive outcome measures (change from baseline in F-VASI and T-VASI) and logistic regression models for categorical outcome measures (F-VASI75 and T-VASI50). A logarithmic model was selected for the change from baseline in F-VASI, F-VASI75, and T-VASI50, and a linear model was selected for the change from baseline in T-VASI. The exposure-response relationships for the change from baseline in F-VASI and the changes from baseline in T-VASI and F-VASI75 were significant (P<0.05). The exposure-response relationship for T-VASI50 was not significant, which is likely due to the limited number of respondents for this outcome measure.

[0237] The simulation was conducted for 1000 trials, with 400 participants in each trial of placebo, 6 mg QD, 11 mg QD, 15 mg QD, 22 mg QD, and 30 mg QD regimens. The predicted response rates are shown in Figures 7A and 7B. Regarding Figures 7A / B, the simulation predicts that 22 mg QD upadacitinib will show 3–5% higher efficacy than the 11 mg dose in F- and T-VASI at week 24, and that 15 mg or 30 mg QD upadacitinib will show limited additional efficacy benefits compared to 11 mg or 22 mg QD upadacitinib, respectively.

[0238] Preliminary exposure-response analyses were performed for all subjects who completed 52 weeks, focusing on the change from baseline in F-VASI and T-VASI. Only limited data from 52 weeks were used. A logarithmic model best explained these exposure-response relationships at week 36, indicating that efficacy approached a plateau in plasma exposure associated with the 15 mg QD regimen (Figures 8A and 8B). The exposure-response relationships for the change from baseline in F-VASI and T-VASI at week 52 were shallower compared to week 24. Therefore, doses higher than 15 mg are not expected to produce a significant additional efficacy benefit at week 52.

[0239] Based on all available data (pharmacokinetic, CFB T-VASI, and CFB F-VASI), a longitudinal model was developed for all available visits throughout the 52-week period. The model-predicted efficacy was generally consistent with the data observed over the 52 weeks of treatment, showing an increase in therapeutic effect over the long term (Figures 9A and 9B). Regarding Figures 9A and 9B, the model-predicted magnitude of the effect of upadacitinib 15 mg at week 36 is estimated to be F-VASI 75: 23.2% (15.9%–30.4%) and T-VASI 50: 17.4% (10.9%–23.9%).

[0240] Upadacitinib 15 mg QD is approved for the treatment (maintenance therapy) of adults with RA, PsA, AD, AS, nr-axSpA, and UC, and for adolescents with AD. Furthermore, this dosing regimen has a robust and well-characterized safety profile across a variety of indications. The Phase 2b study in Example 1 assessed the doses of upadacitinib 6 mg QD, 11 mg QD, and 22 mg QD in a 24-week placebo-controlled manner. As detailed above herein, the dose-response and biomarker results from this Phase 2b study demonstrate the efficacy, safety, and pharmacodynamic response of 11 mg QD and higher doses in vitiligo.

[0241] As described above, the exposure-response analysis in the Phase 2b study demonstrated that efficacy in vitiligo approaches a plateau with plasma exposure associated with 15 mg QD. The proposed Phase 3 administration regimen of 15 mg QD (Example 4) was not studied in the Phase 2 study of Example 1, but is estimated to produce plasma exposure within the range assessed in the Phase 2b study of Example 1.

[0242] [Example 3] Clinical validation of 3D digital imaging In the clinical trial of Example 2, 3D imaging data was obtained and analyzed to assist in assessing therapeutic efficacy. Specifically, multiple 3D images of a subset of patients in the mentioned study were captured using a proprietary optical 3D scanner. The data acquisition procedure using the 3D platform and the determination of vitiligo area were as follows: 1. Scan the target object, acquire a 2D raw color image with real-time feedback, and generate a 3D grayscale low-resolution model. 2. Generate a full-resolution color model and upload it to the cloud. 3. The principal investigator opens the web application and manually selects thresholds for each area of ​​the face. 4. The area of ​​the detected white patches was measured and the results were reported.

[0243] To clinically validate the 3D digital imaging output in vitiligo patients in the study, two objectives were predefined: to determine the clinical validity of the 3D imaging platform in the vitiligo population by correlating facial 3D vitiligo measurements with two established clinical measures of vitiligo, F-VASI and FPhGVA, and with a patient-wide assessment of vitiligo on the face; and to evaluate whether vitiligo area measurements from the 3D imaging platform can be used to determine clinically meaningful changes after upadacitinib therapy, thereby supporting the validity of using facial vitiligo area measurements based on the 3D imaging platform to determine the efficacy of upadacitinib in vitiligo patients.

[0244] To achieve these objectives, 27 subjects were enrolled in a 3D imaging substudy across 6 clinical sites. Twenty-one subjects demonstrated high-quality 3D images available for analysis at week 24. Subjects enrolled in the 3D digital imaging substudy were randomized as per the main protocol. Demographics, including Fitzpatrick skin type, and baseline disease characteristics in the 3D imaging substudy are shown in Table 9. With respect to Table 9, the demographics generally matched the overall study subject population.

[0245]

Table 9

[0246] The quality and completeness of each scan were evaluated by visual inspection of the resulting 3D images by technicians and / or the principal investigators who set the baseline using Wood’s lamp visualization. The threshold was defined as the intensity value used to distinguish which 3D pixels within the image belonged to vitiligo areas or normal skin areas. The threshold determined by the principal investigator at baseline remained constant and was applied to all post-baseline 3D images during the treatment period to reflect changes in pigmentation. Each 3D image included 10 predetermined anatomical regions of the face: forehead, left eye, right eye, left cheek side / temple, left cheek middle, nose, right cheek middle, right cheek side / temple, upper lip, and chin. Results are presented as the sum (cm 2 ) of vitiligo area measurements across all anatomical regions of the face. Representative subjects from the study randomized to the upadacitinib 22 mg QD group at baseline and week 24 are shown in Table 10. With respect to Table 10, the results of 3D imaging of the entire face showed a percentage decrease (-27.20%) that was close to that observed with F-VASI (-24.62%) in terms of vitiligo area.

[0247]

Table 10

[0248] Because the number of sites involved in the 3D imaging sub-study was limited (N=6), the principal investigator was only able to recruit two patients with Fitzpatrick skin type V, and was unable to recruit patients with Fitzpatrick skin types I and VI. In the Example 2 study, approximately 30% of the subjects had Fitzpatrick skin types IV, V, or VI. Once data from more patients becomes available, we plan to analyze whether Fitzpatrick skin type has an influence on the 3D imaging results and their correlation with other clinical measurements.

[0249] Correlation was performed between 3D imaging measurements and F-VASI. At baseline, a high correlation (R=0.865, P<0.001) was observed between vitiligo area measured by 3D imaging and F-VASI. A moderate correlation (R=0.56, P=0.007) was observed between the percentage change from baseline in 3D imaging and the percentage change in F-VASI at week 24. The trend in percentage change from baseline was reflected in both measurements with treatment. A good correlation was observed between 3D imaging and F-VASI based on percentage change from baseline up to week 24, but some discrepancies were also noteworthy. Specifically, although only three placebo subjects were included in the 3D imaging sub-study, there was a significant difference in the assessment of the placebo subjects between 3D imaging and F-VASI measurements. Individual values ​​for the placebo subjects are presented in Table 11.

[0250] [Table 11]

[0251] 3D images emphasizing vitiligo area in the left eye were assessed and compared to F-VASI. The largest difference in percentage change measured between 3D imaging and F-VASI was: 3D: 43.80 vs. F-VASI: -57.14. This finding suggests that 3D imaging not only provides a visually verifiable image of vitiligo but also potentially reduces the placebo effect, resulting in better accuracy and objectivity than F-VASI. A similar relationship (R=0.53, P<0.001) was observed for the moderate correlation between vitiligo area and the 5-point category F-PhGVA based on 3D imaging. All time points from baseline to 24 weeks were included to ensure sufficient sample size to assess this category outcome. In summary, the correlation between 3D digital imaging and established clinical assessments F-VASI and F-PhGVA supports the clinical validity of 3D digital imaging technology for facial vitiligo assessment at baseline and post-treatment. The correlation between 3D imaging and the 5-point category F-PaGVA was weaker (R=0.29, P=0.004), similar to the weaker correlation between patient assessments and VASI scores.

[0252] The percentage change from baseline in facial vitiligo area at week 24, as measured by 3D imaging, is summarized in Table 12. At week 24, upadacitinib doses of 6 mg QD, 11 mg QD, and 22 mg QD resulted in percentage reductions of 15.2%, 34.96%, and 23% from baseline in facial vitiligo area, as measured by 3D imaging. Moderate to high correlations with F-VASI and dose-response results are consistent with the primary analysis of Phase 2, suggesting that 3D can measure clinically significant changes. The magnitude of the treatment effect (Cohen's d) measured by 3D imaging versus F-VASI is compared and summarized in Table 13. Although the number of subjects was relatively small, the results of 3D imaging showed a strong effect magnitude (>0.8) at the 11 mg QD and 22 mg QD doses, which was greater than that of F-VASI. Figure 10A shows the percentage change from baseline in vitiligo area as measured by 3D imaging in the treatment group at week 24, and Figure 10B shows the percentage change in F-VASI in the treatment group at week 24 (individual patients and mean values ​​(N=21)).

[0253] [Table 12]

[0254] [Table 13]

[0255] [Example 4] 36-week placebo-controlled, double-blind, phase 3 study This is a 36-week phase 3 single-dose placebo-controlled double-blind clinical trial in adult patients with non-segmental vitiligo. The trial comprises two studies. Study 1 is a 36-week study of 15 mg upadacitinib versus placebo. Study 2 is a 12-week study of 15 mg upadacitinib versus placebo, followed by 24 weeks of ultraviolet (UVB) phototherapy adjuvant treatment (placebo versus 15 mg upadacitinib). Each of Studies 1 and 2 is followed by a 104-week extension period. A summary of the studies is shown in Figure 11.

[0256] The selection of the 15mg QD dose is based on the following: The 11 mg QD and 22 mg QD regimens met most of the primary endpoints and important secondary endpoints at week 24, demonstrating higher efficacy of upadacitinib compared to placebo, with a nominal P-value < 0.05. Both the 11 mg and 22 mg QD regimens showed higher efficacy compared to placebo for the primary endpoint (percentage change from baseline in F-VASI), and for the percentage change from baseline in F-VASI50, F-VASI75, and T-VASI. Only the 22 mg QD regimen showed higher efficacy compared to placebo for T-VASI50. Biomarker data available from the Phase 2b study (Example 1) showed a reduction in circulating type 1 inflammatory biomarkers to levels seen in healthy subjects, suggesting that maximum inhibition is achieved at an 11 mg dose. The reduction in biomarkers was observed as early as 2 weeks and was maintained throughout 24 weeks. Similar effects were observed between the 11 mg and 22 mg dose levels, with a slightly smaller reduction observed in the 6 mg treatment group.

[0257] Inclusion / exclusion criteria In Study 1, Adults and young people aged 12 and over (males and females) • Less than 33% of the affected area has white hair. • No segmental or localized leukoplakia • No symptoms were present, and there was no exposure to any topical JAK inhibitors within 12 weeks of the baseline visit. In Study 2, Adults only • Must not show a lack of response to previous phototherapy, including narrowband UV-B (nbUVB) or equivalent laser therapy. • No contraindications should be indicated for nbUVB phototherapy. Photosensitivity, including but not limited to SLE and dermatomyositis. • Use of photosensitizing agents • Photoinducible epilepsy • Cataracts, aphakia Hereditary skin cancer syndrome, dysplastic nevus syndrome • History of treatment with arsenic or ionizing radiation

[0258] Evaluation items for efficacy Main: • Achieved F-VASI75 in week 36 Ranking as a secondary factor (Week 36) • Achievement of T-VASI50 • Achievement of F-VASI50 • Achievement of F-VASI90 • Patient-assessed overall change in perception of vitiligo (PaGIC-V) • Vitiligo Severity Scale (VNS) • Progression stopped at 12 weeks (only in phototherapy studies)

[0259] Additional evaluation items • Vitiligo Extent Score (VES) • Vitiligo Quality of Life (VitiQoL) ·Hospital Anxiety and Depression Scale (HADS) ·Dermatology Life Quality Index (DLQI) • Overall assessment of disease severity ·Progression stopped (depigmentation) • Time until pigment redeposition appears • Changes in itching or burning sensation • Skin tone matching

[0260] [Example 5] Upadacitinib immediate-release liquid formulation For pediatric use, an oral solution formulation was developed to improve tolerance (palatability and swallowability), stability, and manufacturability. Specifically, stable oral solutions of upadacitinib at 1 mg / mL and 0.5 mg / mL were prepared. Upadacitinib has good solubility at low pH (shown in Table 14). Therefore, low pH buffers, such as citrate, phosphate, tartrate, and formate, are suitable for preparing the oral solution formulation. Buffers with a higher pH range, such as succinate and acetate, are also suitable (see Example 6), but these result in oral suspensions. Citrate buffer was selected because it has a favorable pKa (approximately 3.1) close to the final pH of the oral solution formulation. Thus, the formulation was developed based on the solubility of upadacitinib in a liquid containing citrate and sodium citrate, which were added to completely dissolve the upadacitinib.

[0261] Upadacitinib has a strong bitter taste at concentrations above 0.1 mg / mL. A tolerable and palatable formulation has a bitterness intensity scale value of less than 1.0. Therefore, sweeteners, taste masking agents or modifiers, and flavoring agents can mitigate the bitterness of upadacitinib. Sweeteners, or combinations of sweeteners, such as acesulfame potassium, sodium saccharin, sucralose, neotame, sucrose, maltitol, and xylitol, are suitable for this oral solution. Taste modifiers, such as sodium chloride, citric acid, and monoammonium glycyrrhizinate, are also suitable for this oral solution. Flavoring agents, such as cherry, orange, bubblegum, strawberry, and mango, can improve the tolerability of the formulation.

[0262] Upadacitinib oral solution contains water and sweeteners, which can be potential causes of microbial growth. Upadacitinib oral solution is also a multi-dose formulation. Therefore, preservatives are added to the formulation to prevent microbial growth. Preservatives such as sodium benzoate and propylparaben are suitable, depending on the final pH of the oral solution. Other preservatives, such as sodium metabisulfite, benzoic acid, hydroxy-parabenzoate, potassium sorbate, and hydroxy-parabenzoic acid, may also be used, depending on the final pH of the oral solution or suspension.

[0263] Upadacitinib 1 mg / mL oral solution C contained citric acid, sodium citrate, sucralose, sodium benzoate, and water. The 1 mg / mL oral solution was clear and colorless to pale yellow.

[0264] The compositions of some 1 mg / mL and 0.5 mg / mL oral solutions are shown in Table 15.

[0265] [Table 14]

[0266] [Table 15]

[0267] [Example 6] Upadacitinib immediate-release or sustained-release liquid formulation (suspension) Immediate-release oral suspensions are prepared to correspond to higher dose potencies or higher pH levels. The buffers, preservatives, and sweeteners listed in Example 4 are applicable to this formulation. Generally, sustained-release liquid formulations are prepared to sustainably release upadacitinib with once-daily administration using release rate modifiers, such as ion exchange resins. The liquid dosage form contains an upadacitinib-ion exchange resin complex. The upadacitinib-ion exchange resin complex contains upadacitinib or a pharmaceutically acceptable salt thereof bound to an ion exchange resin. Suitable ion exchange resins include, but are not limited to, sulfonated copolymers containing styrene and divinylbenzene. In some such embodiments, the mobile or exchangeable cation is sodium. An exemplary cation ion exchange resin is AmberLite® IRP 69 (DuPont).

[0268] [Example 7] Analysis of efficacy over 52 weeks This example presents efficacy data from the clinical trial in Example 1 over 52 weeks. As described above in Example 1, at week 24, upadacitinib met the primary endpoint of percentage change from baseline in the facial vitiligo area scoring index (F-VASI) at 11 mg and 22 mg doses versus placebo in adults with non-segmental vitiligo (NSV). 166 patients (166; 89.7%) continued the 28-week blinded extension (period 2) described in Example 1. In Period 2, patients who received upadacitinib during Period 1 continued with their respective regimens (upadacitinib 22 mg, N=33; upadacitinib 11 mg, N=45; upadacitinib 6 mg, N=45); patients who received placebo in Period 1 were pre-assigned to receive either upadacitinib 11 mg (N=21) or upadacitinib 22 mg (N=22) in Period 2.

[0269] Data over 52 weeks are shown in Tables 16 and 17, and Figures 12 to 16D. Regarding Tables 16, 17, and Figures 12-16, the percentage reduction from baseline in F-VASI at week 52 of the study was numerically greater than the results observed at week 24 in all upadacitinib treatment groups. Furthermore, the response rates observed at week 52 in F-VASI75 and T-VASI50 were numerically greater than those observed at week 24 in all upadacitinib treatment groups.

[0270] [Table 16]

[0271] [Table 17]

Claims

1. A method for treating a human adult patient with vitiligo, comprising administering 15 mg of upadacitinib orally to the patient once daily.

2. The method according to claim 1, wherein the patient has non-segmental vitiligo (NSV).

3. The method according to claim 2, wherein the NSV is stable.

4. The method according to claim 2, wherein the NSV is active.

5. The method according to any one of claims 1 to 4, wherein the patient has a facial vitiligo area scoring index (F-VASI) of 0.5 or higher before the start of treatment.

6. The method according to any one of claims 1 to 5, wherein the patient has a total vitiligo area scoring index (T-VASI) of 5 or more prior to the start of treatment.

7. The method according to any one of claims 1 to 6, wherein the patient has not received any immunomodulatory biological therapy prior to the initiation of treatment.

8. The method according to any one of claims 1 to 7, wherein the patient has not received any topical JAK inhibitor within 12 weeks prior to the start of treatment.

9. The method according to any one of claims 1 to 8, wherein the patient has leukotritis in 33% or less of the affected area.

10. The method according to any one of claims 1 to 9, wherein the patient achieves F-VASI 75 at 24 weeks after the first daily administration.

11. The method according to any one of claims 1 to 10, wherein the patient achieves one or more of T-VASI50, T-VASI75, T-VASI90, F-VASI50, and F-VASI90 at 36 weeks after the first daily administration.

12. The method according to any one of claims 1 to 11, wherein the patient achieves improvement in the overall impression change (PaGIC-V) for generalized vitiligo at 36 weeks after the first daily administration.

13. The method according to any one of claims 1 to 12, wherein the patient achieves a Vitiligo Sampling Scale (VNS) score of “Not Significantly Significant (4)” or “Not Significantly Significant (5)” at 36 weeks after the first daily dose.

14. The method according to any one of claims 1 to 13, wherein the patient achieves improvement from baseline in the vitiligo extent score (VES) at 36 weeks after the first daily dose.

15. The method according to any one of claims 1 to 14, wherein the patient achieves improvement from baseline in VitiQoL at 36 weeks after the first daily dose.

16. The method according to any one of claims 1 to 15, wherein the patient achieves a total dermatological quality of life index (DLQI) score of "0" or "1" at 36 weeks after the first daily administration.

17. The method according to any one of claims 1 to 16, wherein the patient achieves an improvement from baseline in the Hospital Anxiety and Depression Scale (HADS) score at 36 weeks after the first daily dose.

18. The method according to any one of claims 1 to 17, wherein the patient achieves an improvement in the time to the onset of pigment redeposition compared to a patient not treated with upadacitinib.

19. The method according to any one of claims 1 to 18, wherein the patient achieves improvement in itching or burning within 36 weeks of the start of treatment.

20. The method according to any one of claims 1 to 19, wherein the patient achieves a physician's global impression change (PhGIC-V) score of “much better (1)” or “somewhat better (2)” for vitiligo at 36 weeks after the first daily dose.

21. The method according to any one of claims 1 to 20, wherein the patient achieves a "much better (1)" or "somewhat better (2)" Patient Global Impression Change (PaGIC-V) score for vitiligo at 36 weeks after the first daily dose.

22. The method according to any one of claims 1 to 21, wherein a patient achieves a facial-physician-generalized vitiligo (F-PhGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks after the first daily administration.

23. The method according to any one of claims 1 to 21, wherein the patient achieves a total body-to-physician generalized vitiligo assessment (T-PhGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks after the first daily administration.

24. The method according to any one of claims 1 to 23, wherein the patient achieves a facial-total vitiligo assessment (F-PaGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks after the first daily administration.

25. The method according to any one of claims 1 to 24, wherein the patient achieves a total vitiligo assessment (T-PaGVA) score of “no depigmentation (0)” or “limited depigmentation (1)” at 36 weeks after the first daily administration.

26. The method according to any one of claims 1 to 25, wherein the progression of vitiligo is stopped within 36 weeks of the start of treatment.

27. The method according to any one of claims 1 to 26, wherein a reduction from baseline in one or more biomarkers of vitiligo is achieved within 36 weeks of initiation of treatment.

28. The method according to claim 27, wherein the biomarker is an inflammatory chemotactic protein or a T cell activation marker.

29. The method according to claim 27 or 28, wherein the biomarker is CXCL9, CXCL10, IL12B, TNFSF9, or a combination thereof.

30. The method according to any one of claims 1 to 29, further comprising treating the patient in combination with exposure to ultraviolet light.

31. A method for treating vitiligo in pediatric human patients, comprising administering a therapeutically effective dose of upadacitinib to the pediatric patient, If a pediatric patient weighs between approximately 10 kg and less than approximately 20 kg, (i) Upadacitinib is administered twice daily at doses of 3 mg each (3 mg BID), or (ii) Upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID). If a pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, (i) Upadacitinib is administered twice daily at doses of 4 mg each (4 mg BID), or (ii) Upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID). If a pediatric patient weighs approximately 30 kg or more, (i) Upadacitinib is administered twice daily at a dose of 6 mg each (6 mg BID). (ii) Upadacitinib is administered twice daily at a dose of 8 mg each (8 mg BID), or (ii) A method in which upadacitinib is administered once daily at a dose of 15 mg (15 mg QD).

32. The method according to claim 31, wherein upadacitinib is administered to pediatric patients as a stable oral liquid preparation at a dose of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, or 8 mg twice daily.

33. The method according to claim 31 or 32, wherein the stable oral pharmaceutical solution comprises upadacitinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

34. The method according to any one of claims 31 to 33, wherein the oral solution contains upadacitinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

35. The method according to any one of claims 31 to 34, wherein upadacitinib at a dose of 15 mg is administered to a pediatric patient once daily as a sustained-release tablet.

36. The method according to any one of claims 31 to 35, wherein a pediatric patient has non-segmental vitiligo (NSV).

37. The method according to claim 36, wherein the NSV is stable.

38. The method according to claim 36, wherein the NSV is active.

39. The method according to any one of claims 31 to 38, wherein the pediatric patient has a facial vitiligo area scoring index F-VASI of 0.5 or higher before the start of treatment.

40. The method according to any one of claims 31 to 39, wherein the pediatric patient has a total vitiligo area scoring index (T-VASI) of 5 or more before the start of treatment.

41. The method according to any one of claims 31 to 40, wherein the pediatric patient has not received any immunomodulatory biological therapy prior to the initiation of treatment.

42. The method according to any one of claims 31 to 41, wherein the pediatric patient has not received any topical JAK inhibitor within 12 weeks prior to the start of treatment.

43. The method according to any one of claims 31 to 42, wherein the pediatric patient has alopecia in 33% or less of the affected area.

44. The method according to any one of claims 31 to 43, wherein a pediatric patient achieves F-VASI 75 at 24 weeks after the first daily administration.

45. The method according to any one of claims 31 to 44, wherein a pediatric patient achieves one or more of T-VASI50, T-VASI75, T-VASI90, F-VASI50, or F-VASI90 at 36 weeks after the first daily administration.

46. The method according to any one of claims 31 to 45, wherein a pediatric patient achieves improvement in the overall impression change (PaGIC-V) for generalized vitiligo at 36 weeks after the first daily administration.

47. The method according to any one of claims 31 to 46, wherein a pediatric patient achieves a Vitiligo Splendor Scale (VNS) score of "Not Significantly Significant (4)" or "No Longer Significant (5)" at 36 weeks after the first daily administration.

48. The method according to any one of claims 31 to 47, wherein a pediatric patient achieves improvement from baseline in the vitiligo extent score (VES) at 36 weeks after the first daily administration.

49. The method according to any one of claims 31 to 48, wherein a pediatric patient achieves improvement from baseline in VitiQoL at 36 weeks after the first daily administration.

50. The method according to any one of claims 31 to 49, wherein a pediatric patient achieves a total dermatological quality of life index (DLQI) score of "0" or "1" at 36 weeks after the first daily administration.

51. The method according to any one of claims 31 to 50, wherein a pediatric patient achieves improvement from baseline in the Hospital Anxiety and Depression Scale (HADS) score at 36 weeks after the first daily administration.

52. The method according to any one of claims 31 to 51, wherein pediatric patients achieve an improvement in the time to the onset of pigment redeposition compared to patients not treated with upadacitinib.

53. The method according to any one of claims 31 to 52, wherein a pediatric patient achieves improvement in itching or burning sensation within 36 weeks of the start of treatment.

54. The method according to any one of claims 31 to 53, wherein a pediatric patient achieves a physician's global impression change (PhGIC-V) score of “much better (1)” or “somewhat better (2)” for vitiligo at 36 weeks after the first daily administration.

55. The method according to any one of claims 1 to 54, wherein a pediatric patient achieves a "much better (1)" or "somewhat better (2)" global impression change (PaGIC-V) score for vitiligo at 36 weeks after the first daily administration.

56. The method according to any one of claims 1 to 55, wherein a pediatric patient achieves a facial-physician-generalized vitiligo (F-PhGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks after the first daily administration.

57. The method according to any one of claims 1 to 56, wherein a pediatric patient achieves a total body-to-physician generalized vitiligo assessment (T-PhGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks after the first daily administration.

58. The method according to any one of claims 1 to 57, wherein a pediatric patient achieves a facial-total vitiligo assessment (F-PaGVA) score of "no depigmentation (0)" or "limited depigmentation (1)" at 36 weeks after the first daily administration.

59. The method according to any one of claims 31 to 58, wherein a pediatric patient achieves a total vitiligo assessment (T-PaGVA) score of “no depigmentation (0)” or “limited depigmentation (1)” at 36 weeks after the first daily administration.

60. The method according to any one of claims 31 to 59, wherein the progression of vitiligo is stopped within 36 weeks of the start of treatment.

61. The method according to any one of claims 31 to 60, wherein a reduction from baseline in one or more biomarkers of vitiligo is achieved within 36 weeks of the start of treatment.

62. The method according to claim 61, wherein the biomarker is an inflammatory chemotactic protein or a T cell activation marker.

63. The method according to claim 61 or 62, wherein the biomarker is CXCL9, CXCL10, IL12B, TNFSF9, or a combination thereof.

64. The method according to any one of claims 21 to 63, further comprising treating a pediatric patient in combination with exposure to ultraviolet light.

65. The method according to any one of claims 1 to 9, wherein the patient achieves T-VASI 50 at 48 weeks after the first daily administration.

66. The method according to any one of claims 1 to 9, wherein the patient achieves F-VASI 75 at 48 weeks after the first daily administration.

67. The method according to any one of claims 1 to 9, wherein the patient achieves T-VASI 50 at 52 weeks after the first daily administration.

68. The method according to any one of claims 1 to 9, wherein the patient achieves F-VASI 75 at 52 weeks after the first daily administration.

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