Topical treatment of vitiligo with JAK inhibitors

Abstract

We provide drug treatment for vitiligo. [Solution] A pharmaceutical composition for treating vitiligo in a patient is provided, comprising 0.5% w / w to 1.5% w / w of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, wherein the pharmaceutical composition further comprises water, an oil component, an emulsifier component, a stabilizer component, and a solvent component, and the pharmaceutical composition is administered topically to the affected skin area of ​​the patient twice daily, the affected skin area comprising at least one of the patient's lower limbs, trunk, and feet, and the patient does not receive phototherapy during administration of the pharmaceutical composition.

Description

Technical Field

[0001] Cross-Reference to Related Applications This application claims priority to U.S. Provisional Application No. 62 / 859,584 filed on June 10, 2019, U.S. Provisional Application No. 62 / 894,564 filed on August 30, 2019, U.S. Provisional Application No. 62 / 911,845 filed on October 7, 2019, U.S. Provisional Application No. 62 / 967,879 filed on January 30, 2020, U.S. Provisional Application No. 62 / 859,601 filed on June 10, 2019, U.S. Provisional Application No. 62 / 894,514 filed on August 30, 2019, U.S. Provisional Application No. 62 / 859,495 filed on June 10, 2019, U.S. Provisional Application No. 62 / 894,581 filed on August 30, 2019, U.S. Provisional Application No. 62 / 859,506 filed on June 10, 2019, U.S. Provisional Application No. 62 / 894,496 filed on August 30, 2019, U.S. Provisional Application No. 62 / 859,532 filed on June 10, 2019, and U.S. Provisional Application No. 62 / 894,541 filed on August 30, 2019, each of which is incorporated herein by reference in its entirety.

[0002] Technical Field The present disclosure relates to topical treatment of vitiligo using ruxolitinib or a pharmaceutically acceptable salt thereof.

Background Art

[0003] Vitiligo occurs when melanin-producing cells die or cease to function, resulting in patchy loss of skin pigmentation. Non-segmental vitiligo involves spotted depigmentation of the skin across the whole body. Depigmentation typically occurs on the face, neck and scalp, and around body orifices. Loss of pigmentation is also frequently seen in areas prone to friction, impact or other trauma, such as the hands and arms. Segmental vitiligo is associated with small patches of depigmented skin that appear in a limited area on one side of the body.

[0004] Vitiligo is estimated to affect 0.5% to 2% of the world's population (Krueger C, Schallreuter KU. A review of the worldwide prevalence of vitiligo in children / adolescents and adults. Int J Dermatol 2012;51:1206-1212). There is no difference in prevalence between sexes, and no differences in symptoms based on skin type or race are known. Nearly 50% of patients develop symptoms before the age of 20, and many of them develop symptoms before the age of 10 (Rodrigues M, Ezzedine K, Hamzavi I, Pandya AG, Harris JE, Vitiligo Working Group. New discoveries in the pathogenesis and classification of vitiligo. J Am Acad Dermatol 2017;77:1-13). Generalized (non-segmental) vitiligo is the most common type, accounting for up to 90% of cases (Taieb A, Picardo M. Clinical practice. Vitiligo. N Engl J Med 2009;360:160-169). Vitiligo is associated with Sutton's nevus, thyroid disorders, juvenile diabetes, pernicious anemia, and autoimmune diseases such as Addison's disease. The natural course of the disease is generally unpredictable, but it is often progressive. Some degree of spontaneous repigmentation may occur in 10-20% of patients; however, this is generally unacceptable cosmetically (Castanet J, Ortonne JP. Pathophysiology of vitiligo. Clin Dermatol 1997:15:845-851).

[0005] Vitiligo is a serious disease due to its significant psychological impact on patients' daily functions and its progressive course if left untreated. Studies have shown that the impact of vitiligo on quality of life, particularly psychological impairment, is similar to that of other skin diseases such as psoriasis and atopic dermatitis (AD) (Linthorst Homan MW, Spuls PI, de Korte J, Bos JD, Sprangers MA, van der Veen JP. The burden of vitiligo: patient characteristics associated with quality of life. J Am Acad Dermatol 2009;61:411-420). Involvement of exposed skin such as the face and hands can significantly affect self-esteem, ultimately leading to psychological burden and quality of life (Silverberg JI, Silverberg NB. Association between vitiligo extent and distribution and quality of life impairment. JAMA Dermatol 2013;149:159-164). In some societies, acceptance and understanding of the disease are so insufficient that it leads to discrimination against those affected (Yazdani Abyaneh MA, Griffith R, Falto-Aizpurua L, Nouri K. The dark history of white spots. JAMA Dermatol 2014;150:936).Approximately 75% of patients with vitiligo feel their appearance is moderate to severely unbearable, and 41% feel they can do little to improve their condition, with feelings of despair increasing over time (Salzer BA, Schallreuter KU. Investigation of the personality structure in patients with vitiligo and a possible association with impaired catecholamine metabolism. Dermatology 1995;190:109-115). In a study, 66% of patients reported being troubled by their disease, and 92% reported having experienced stigma (Krueger C, Panske A, Schallreuter KU. Disease-related behavioral patterns and experiences affect quality of life in children and adolescents with vitiligo. Int J Dermatol 2014;53:43-50). Feelings of shame and fear of rejection can cause vitiligo patients to withdraw, leading to social isolation in both personal and professional relationships. The majority of vitiligo patients report feeling anxious or embarrassed when meeting strangers or starting new sexual relationships (Porter J, Beuf A and Lerner A et al. The effect of vitiligo on sexual relationship. J Am Acad Dermatol 1990;22:221-222). Furthermore, clinical depression and depressive symptoms are associated with vitiligo.Patients with vitiligo were approximately five times more likely to develop depression than healthy controls (Lai YC, Yew YW, Kennedy C, Schwartz RA. Vitiligo and depression: a systematic review and meta-analysis of observational studies. Br J Dermatol 2017;177:708-718; Osinubi O, Grainge MJ, Hong L, et al. The prevalence of psychological comorbidity in people with vitiligo: a systematic review and meta-analysis. Br J Dermatol 2018;178:863-878). A recent analysis showed that the combined prevalence of depression across 17 distinct populations (n=1711) was 29% (Wang G, Qiu D, Yang H, Liu W. The prevalence and odds of depression in patients with vitiligo: a meta-analysis [published online ahead of print December 9, 2017]. J Eur Acad Dermatol Venereol. doi: 10.1111 / jdv.14739).

[0006] The research also suggests that the onset of vitiligo, which begins in childhood, may be associated with significant psychological trauma that can have long-lasting effects on self-esteem. The severity of vitiligo is associated with quality of life (QOL) impairment in children and adolescents, particularly self-consciousness, but also with bullying and teasing. Teenagers aged 15 to 17 appear to experience the highest levels of self-consciousness among all pediatric age groups (Silverberg, previously cited). In a study comparing social development and health-related quality of life between young adult patients with childhood vitiligo and healthy controls, vitiligo patients who reported negative childhood experiences reported significantly more problems in social development than those who did not. Negative childhood experiences were significantly associated with health-related quality of life impairment in early adulthood (Linthorst Homan MW, De Korte J, Grootenhuis MA, Bos JD, Sprangers MA, Van Der Veen JP. Impact of childhood vitiligo on adult life. Br J Dermatol 2008;159(4):915-20). Vitiligo is considered one of the most psychologically devastating diseases in dermatology.

[0007] Currently, there are no approved drug therapies for vitiligo. Drugs are used off-label; however, the clinical evidence obtained consists of several small, randomized controlled trials. Off-label topical therapies used for vitiligo include corticosteroids, calcineurin inhibitors, and vitamin D analogs. Other treatments include oral medications, phototherapy, and some surgical methods (e.g., melanocyte transplantation into depigmented lesions). Due to the low level of evidence for any of these treatments, it is not possible to propose definitive clinical recommendations for the treatment of vitiligo, and the management of vitiligo is empirical and based on the latest consensus guidelines.

[0008] The pathogenesis of vitiligo involves endogenous defects within melanocytes and autoimmunity targeting these cells. When melanocytes are stressed, they release inflammatory signals that activate innate immunity, which can be the initiation event of vitiligo. Janus kinase is an intracellular signaling enzyme that acts downstream of the major inflammatory cytokines involved in the pathogenesis of vitiligo. Subsequently, oxidative stress, cell damage, and cytokines secreted from innate immune cells trigger CXCL10 release by skin cells, recruiting CD8+ T cells to that site. Activated CD8+ T cells produce IFN-γ and other inflammatory mediators to target and destroy melanocytes (Frisoli ML, Harris JE. Vitiligo: mechanistic insights lead to novel treatments. J Allergy Clin Immunol 2017;140:654-662). IFN-γ signaling utilizes the Janus kinase-signaling and activator of transcription (JAK-STAT) pathway. Inhibition of JAK signaling may play a role in the treatment of vitiligo. Case reports of JAK inhibitors administered to patients with vitiligo include a patient with both alopecia areata and vitiligo who experienced hair regrowth and repigmentation of vitiligo lesions after 20 weeks of treatment with oral ruxolitinib 20 mg BID (Harris JE, Rashighi M, Nguyen N, et al. Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA). J Am Acad Dermatol 2016;74:370-371).Another report described how patients with widespread and progressive vitiligo who did not respond to topical steroids, tacrolimus ointment, and NB-UVB phototherapy were treated with oral tofacitinib 5 mg QD, resulting in near-complete pigment regrowth after 5 months of treatment (Craiglow BG, King BA. Tofacitinib citrate for the treatment of vitiligo: a pathogenesis-directed Therapy. JAMA Dermatol 2015;151:1110-1112). There was also a 20-week open-label trial using topical ruxolitinib cream in 12 participants with vitiligo who had at least 1% BSA. The results showed that in 7 out of 9 participants who completed the trial, there was a 76% improvement in the Face Vitiligo Area Scoring Index (F-VASI) and a 26% improvement in the Total Body Vitiligo Area Scoring Index (T-VASI) (Rothstein B, Joshipura D, Saraiya A, et al. Treatment of vitiligo with the topical Janus kinase inhibitor ruxolitinib. J Am Acad Dermatol 2017;76:1054-1060). The same group conducted an additional 32-week extension study with optional NB-UVB treatment (Joshipura D, Alomran A, Zancanaro P, Rosmarin D. Treatment of vitiligo with the topical Janus kinase inhibitor ruxolitinib: a 32-week open-label extension study with optional narrow-band ultraviolet B. J Am Acad Dermatol 2018;78:1205-1207). Five participants completed the study, three of whom received NB-UVB.At week 52 (weeks 20 + 32), the results showed a 92% improvement in F-VASI and a 37% improvement in T-VASI. The results also showed that two participants who had previously failed phototherapy and topical cream monotherapy for trunk lesions responded after combination therapy. Furthermore, participants were followed up 6 months after treatment discontinuation, and all five participants maintained a response with the longest duration exceeding 40 weeks. However, the results were from an open-label trial and from a very small sample size. Therefore, the efficacy of ruxolitinib cream in the treatment of vitiligo has not yet been clinically demonstrated in randomized, double-blind, vehicle-controlled trials excluding different treatment regimens. [Overview of the project]

[0009] overview Therefore, the present invention provides, in particular, a method for treating patients suffering from vitiligo with ruxolitinib cream 0.15% QD, 0.5% QD, 1.5% QD, or 1.5% BID.

[0010] This disclosure also provides ruxolitinib compositions or creams for use in any of the methods described herein.

[0011] This disclosure also provides the use of a ruxolitinib composition or cream for the manufacture of a pharmaceutical product for use in any of the methods described herein.

[0012] Details of one or more embodiments of the present invention are shown in the accompanying figures and the following description. Other features, purposes, and advantages of the present invention will become apparent from the description and drawings, as well as from the claims. [Brief explanation of the drawing]

[0013] [Figure 1]Figure 1 shows graphs of F-VASI-50 response (%) at weeks 4, 8, 12, 18, and 24 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order). [Figure 2] Figure 2 shows graphs of F-VASI-75 response (%) at weeks 4, 8, 12, 18, and 24 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order). [Figure 3] Figure 3 is a graph of clear or nearly clear (%) F-PhGVA at week 12 (first bar) and week 24 (second bar) for vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream. [Figure 4] Figure 4 is a graph of the mean (SEM) percentage change from baseline at baseline, weeks 4, 8, 12, 18, and 24 for F-VASI for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream. [Figure 5]Figure 5 is a graph showing the percentage of subjects who achieved an F-VASI50 response in the visit and treatment group at weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order) in the intent-to-treat subjects population in the double-blind period. [Figure 6] Figure 6 is a graph showing the percentage of subjects who achieved an F-VASI50 response in the outpatient treatment group at weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order), in the treatment intention analysis population during the double-blind period, using the Last Observation Carried Forward (LOCF) imputation method. [Figure 7] Figure 7 is a graph showing the percentage of subjects who achieved an F-VASI25 response with outpatient treatment at weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order) in the intention-to-treat analysis population during the double-blind period. [Figure 8]Figure 8 is a graph showing the percentage of subjects who achieved an F-VASI25 response in the outpatient treatment group at weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order), in the treatment intention analysis population during the double-blind period, using the LOCF imputation method. [Figure 9] Figure 9 is a graph showing the percentage of subjects who achieved an F-VASI75 response with outpatient treatment at weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order) in the intention-to-treat population during the double-blind period. [Figure 10] Figure 10 is a graph showing the percentage of subjects who achieved an F-VASI75 response in the outpatient treatment group at weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order), in the treatment intention analysis population during the double-blind period, using the LOCF imputation method.

[0014] [Figure 11]Figure 11 is a graph showing the percentage of subjects who achieved an F-VASI90 response with outpatient treatment at weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order) in the treatment intention analysis population during the double-blind period. [Figure 12] Figure 12 is a graph showing the percentage of subjects who achieved an F-VASI90 response in the outpatient treatment group at weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order), in the treatment intention analysis population during the double-blind period, using the LOCF imputation method. [Figure 13] Figure 13 is a graph showing the mean change from baseline in the F-VASI score for the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (bars for each group are shown in order) in the intention-to-treat population during the double-blind period. [Figure 14]Figure 14 is a graph showing the mean percentage change from baseline in F-VASI scores by outpatient treatment group at baseline, week 4, week 8, week 12, week 18, week 24, week 28, week 34, week 40, week 46 and week 52 for vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream and 1.5% BID ruxolitinib cream (bars for each group are shown in order) for the intention-to-treat analysis population during the double-blind period. [Figure 15] Figure 15 is a graph showing the mean change from baseline in T-VASI scores by outpatient treatment group at baseline, week 4, week 8, week 12, week 18, week 24, week 28, week 34, week 40, week 46 and week 52 for vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream and 1.5% BID ruxolitinib cream (bars for each group are shown in order) for the intention-to-treat analysis population during the double-blind period. [Figure 16] Figure 16 is a graph showing the mean percentage change from baseline in T-VASI scores by outpatient treatment group at baseline, week 4, week 8, week 12, week 18, week 24, week 28, week 34, week 40, week 46 and week 52 for vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream and 1.5% BID ruxolitinib cream (bars for each group are shown in order) for the intention-to-treat analysis population during the double-blind period. [Figure 17]Figure 17 is a graph showing the proportion of subjects who achieved a T-VASI50 response in the outpatient treatment group at weeks 4, 8, 12, 18, 24, 28, 34, 40, 46 and 52 for vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream and 1.5% BID ruxolitinib cream (bars for each group are shown in order) for the intention-to-treat analysis population in the double-blind period. [Figure 18] Figure 18 is a graph showing the proportion of subjects who achieved a T-VASI50 response in the outpatient treatment group at weeks 4, 8, 12, 18, 24, 28, 34, 40, 46 and 52 for vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream and 1.5% BID ruxolitinib cream (bars for each group are shown in order) for the intention-to-treat analysis population in the double-blind period, obtained by the LOCF imputation method. [Figure 19] Figure 19 is a graph showing the proportion of subjects who achieved a T-VASI25 response in the outpatient treatment group at weeks 4, 8, 12, 18, 24, 28, 34, 40, 46 and 52 for vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream and 1.5% BID ruxolitinib cream (bars for each group are shown in order) for the intention-to-treat analysis population in the double-blind period. [Figure 20]Figure 20 is a graph showing the percentage of subjects who achieved a T-VASI25 response in the outpatient treatment group at weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order), in the treatment intention analysis population during the double-blind period, using the LOCF imputation method.

[0015] [Figure 21] Figure 21 is a graph showing the mean change from baseline in T-BSA scores for the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (bars for each group are shown in order) in the intention-to-treat population during the double-blind period. [Figure 22] Figure 22 is a graph showing the mean percentage change from baseline in T-BSA scores for the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (bars for each group are shown in order) in the treatment intention analysis population during the double-blind period. [Figure 23]Figure 23 is a graph showing the percentage of subjects who achieved a T-VASI25 response (head and neck only) in the outpatient treatment group at weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order) in the intention-to-treat population during the double-blind period. [Figure 24] Figure 24 is a graph showing the percentage of subjects who achieved a T-VASI50 response (head and neck only) in the outpatient treatment group at weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order) in the intention-to-treat population during the double-blind period. [Figure 25] Figure 25 is a graph showing the percentage of subjects who achieved a T-VASI75 response (head and neck only) in the outpatient treatment group at weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order) in the intention-to-treat population during the double-blind period. [Figure 26]Figure 26 is a graph showing the mean change from baseline in the T-VASI score (head and neck only) for the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order) during the double-blind intention-to-treat analysis period. [Figure 27] Figure 27 is a graph showing the mean percentage change from baseline in the T-VASI score (head and neck only) for the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order) in the intention-to-treat population during the double-blind period. [Figure 28] Figure 28 is a graph showing the proportion of T-VASI25 responses (hands only) in the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (bars for each group are shown in order) in the intention-to-treat analysis population during the double-blind period. [Figure 29]Figure 29 is a graph showing the proportion of T-VASI50 responses (hands only) in the outpatient treatment groups at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the treatment intention analysis population during the double-blind period, for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (bars for each group are shown in order). [Figure 30] Figure 30 is a graph showing the proportion of T-VASI75 responses (hands only) in the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (bars for each group are shown in order) in the intention-to-treat analysis population during the double-blind period.

[0016] [Figure 31] Figure 31 is a graph showing the mean change from baseline in the T-VASI score (hand only) for the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (bars for each group are shown in order) during the double-blind intention-to-treat analysis period. [Figure 32]Figure 32 is a graph showing the mean percentage change from baseline in the T-VASI score (hand only) for the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the treatment intention analysis population during the double-blind period, for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (bars for each group are shown in order). [Figure 33] Figure 33 is a graph showing the proportion of T-VASI25 responses (upper limbs only) in the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (bars for each group are shown in order) in the treatment intention analysis population during the double-blind period. [Figure 34] Figure 34 is a graph showing the proportion of T-VASI50 responses (upper limbs only) in the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the treatment intention analysis population during the double-blind period, for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order). [Figure 35]Figure 35 is a graph showing the proportion of T-VASI75 responses (upper limbs only) in the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the treatment intention analysis population during the double-blind period, for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order). [Figure 36] Figure 36 is a graph showing the mean change from baseline in the T-VASI score (upper limbs only) for the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (bars for each group are shown in order) during the double-blind period for the intention-to-treat analysis population. [Figure 37] Figure 37 is a graph showing the mean percentage change from baseline in the T-VASI score (upper limbs only) for the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (bars for each group are shown in order) during the double-blind period for the intention-to-treat analysis population. [Figure 38]Figure 38 is a graph showing the proportion of T-VASI25 responses (trunk only) in the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the treatment intention analysis population during the double-blind period, for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order). [Figure 39] Figure 39 is a graph showing the proportion of T-VASI50 responses (trunk only) in the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the treatment intention analysis population during the double-blind period, for vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order). [Figure 40] Figure 40 is a graph showing the proportion of T-VASI75 responses (trunk only) in the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the treatment intention analysis population during the double-blind period, for vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order).

[0017] [Figure 41]Figure 41 is a graph showing the mean change from baseline in the T-VASI score (trunk only) for the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order) during the double-blind intention-to-treat analysis period. [Figure 42] Figure 42 is a graph showing the mean percentage change from baseline in the T-VASI score (trunk only) for the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the treatment intention analysis population during the double-blind period, for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order). [Figure 43] Figure 43 is a graph showing the proportion of T-VASI50 responses (trunk only) in the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the treatment intention analysis population during the double-blind period, for vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order). [Figure 44]Figure 44 is a graph showing the proportion of T-VASI25 responses (trunk only) in the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (bars for each group are shown in order) in the intention-to-treat analysis population during the double-blind period. [Figure 45] Figure 45 is a graph showing the proportion of T-VASI75 responses (trunk only) in the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the treatment intention analysis population during the double-blind period, for vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order). [Figure 46] Figure 46 is a graph showing the mean change from baseline in the T-VASI score (trunk only) for the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order) during the double-blind intention-to-treat analysis period. [Figure 47]Figure 47 is a graph showing the mean percentage change from baseline in the T-VASI score (trunk only) for the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the treatment intention analysis population during the double-blind period, for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order). [Figure 48] Figure 48 is a graph showing the proportion of T-VASI50 responses (feet only) in the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the treatment intention analysis population during the double-blind period, for vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order). [Figure 49] Figure 49 is a graph showing the proportion of T-VASI25 responses (feet only) in the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the treatment intention analysis population during the double-blind period, for vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order). [Figure 50]Figure 50 is a graph showing the proportion of T-VASI75 responses (feet only) in the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the treatment intention analysis population during the double-blind period, for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order).

[0018] [Figure 51] Figure 51 is a graph showing the mean change from baseline in the T-VASI score (foot only) for the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the treatment intention analysis population during the double-blind period, for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order). [Figure 52] Figure 52 is a graph showing the mean percentage change from baseline in T-VASI scores (feet only) for the outpatient treatment group at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the treatment intention analysis population during the double-blind period, for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order). [Figure 53] Figure 53 is a table showing the p-values ​​from Fisher's exact method for T-VASI25, T-VASI50, and T-VASI75 between the combination therapy group and the vehicle therapy group at week 24. [Figure 54]Figure 54 is a graph showing the T-VASI50 response for patients treated with vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (bars for each group are shown in order) at weeks 8, 12, 24, 34, and 52, with all depigmented skin treated. The T-VASI50 response has been reported for a subset of patients with baseline T-BSA ≤20%, because the treatment was limited to lesions constituting ≤20% T-BSA. [Figure 55] Figure 55 is a graph showing the mean percentage change in F-BSA from baseline at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream (the bars for each group are shown in order). [Figure 56]Figure 56 shows graphs of F-PhGVA (A) and T-PhGVA (B) by disease category at baseline, 24 weeks, and 52 weeks for vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream. The bars, from bottom to top, represent clear (C), nearly clear (AC), mild disease (MiD), moderate disease (MoD), severe disease (SD), and loss (M). A / Baseline: Vehicle, 0.15% QD, 0.5% QD, 1.5% QD, 1.5% BID (MiD, MoD, SD). A / Week 24: Vehicle (MiD, MoD, SD, M), 0.15% QD (AC, MiD, MoD, M), 0.5% QD, 1.5% QD, 1.5% BID (AC, MiD, MoD, SD, M). A / Week 52: 0.5% QD, 1.5% QD (C, AC, MiD, MoD, SD), 1.5% BID (AC, MiD, MoD, SD). B / Baseline: Vehicle, 0.15% QD, 0.5% QD (MiD, MoD, SD), 1.5% QD (MoD, SD), 1.5% BID (MiD, MoD). For week 24 of B: Vehicle, 1.5% QD (MiD, MoD, SD), 0.15% QD (MiD, MoD), 0.5% QD, 1.5% BID (AC, MiD, MoD). For week 52 of B: 0.5% QD, 1.5% BID (AC, MiD, MoD), 1.5% QD (MiD, MoD). [Figure 57]Figure 57 shows graphs of F-PaGVA (A) and T-PaGVA (B) by disease category at baseline, 24 weeks, and 52 weeks for vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream. The bars, from bottom to top, represent no vitiligo (NW), mild (Mi), moderate (Mo), severe (S), very severe (VS), and loss (M). A / Baseline: Vehicle, 0.15% QD, 0.5% QD, 1.5% QD, 1.5% BID (Mi, Mo, S, VS). A / Week 24: Vehicle, 0.15%QD, 0.5%QD, 1.5%QD, 1.5%BID (Mi, Mo, S, VS, M). A / Week 52: 0.5%QD, 1.5%QD (Mi, Mo, S, VS), 1.5%BID (NW, Mi, Mo, S, VS). B / Baseline: Vehicle, 0.15%QD, 0.5%QD, 1.5%QD, 1.5%BID (Mi, Mo, S, VS). B / Week 24: Vehicle, 1.5%QD, 1.5%BID (Mi, Mo, S, M), 0.15%QD (Mi, Mo, S, VS, M), 0.5%QD (NW, Mi, Mo, S, VS). For week 52 of B: 0.5% QD, 1.5% QD, 1.5% BID (Mi, Mo, S). [Figure 58] Figure 58 shows representative clinical images of the patient's hand (upper part) and trunk (lower part) at day 1, week 24, and week 52 (from left to right). [Figure 59] Figure 59 is a table of TEAEs over 52 weeks of treatment. [Figure 60] Figure 60 is a graph showing mean hemoglobin (g / L) at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream. At week 52, the top row is for 0.5% QD, the middle row is for 1.5% QD, and the bottom row is for 1.5% BID.

[0019] [Figure 61] Figure 61 is a graph showing the mean platelet count (10⁹ / L) at baseline, weeks 4, 8, 12, 18, 24, 28, 34, 40, 46, and 52 for the vehicle, 0.15% QD ruxolitinib cream, 0.5% QD ruxolitinib cream, 1.5% QD ruxolitinib cream, and 1.5% BID ruxolitinib cream. At week 52, the top row is for 1.5% QD, the middle row is for 1.5% BID, and the bottom row is for 0.5% QD. [Figure 62] Figure 62 is a chart showing the F-VASI50 response to ruxolitinib cream 1.5% BID at week 24, broken down by patient demographics and skin type. [Figure 63] Figure 63 is a chart showing the F-VASI50 response to ruxolitinib cream 1.5% BID at week 24, categorized by baseline vitiligo lesion characteristics. [Figure 64] Figure 64 is a chart showing the F-VASI50 response to ruxolitinib cream 1.5% BID at week 24, categorized by disease characteristics and previous treatment. [Modes for carrying out the invention]

[0020] Detailed explanation Ruxolitinib ((R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-3-cyclopentylpropanenitrile) (often referred to as INCB018424), having the structure shown below, and pharmaceutically acceptable salts thereof, have been previously described in U.S. Patent No. 7,598,257 (which, with due attribution, is part of this specification in whole). Ruxolitinibulinate salts are described in U.S. Patent No. 8,722,693 (which, with due attribution, is part of this specification in whole). This disclosure describes, in particular, a method for treating generalized vitiligo using ruxolitinib or a pharmaceutically acceptable salt thereof. [ka]

[0021] Treatment method Accordingly, the present invention provides a treatment for patients suffering from vitiligo using ruxolitinib cream 0.15% QD, 0.5% QD, 1.5% QD, or 1.5% BID. All percentages are based on ruxolitinib or a pharmaceutically acceptable salt thereof (e.g., ruxolitinibulinate) in the cream on a free base basis (w / w).

[0022] In another embodiment, the Disclosure provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 0.15 w / w% ruxolitinib or a pharmaceutically acceptable salt thereon on a free base basis, once daily. In another embodiment, the Disclosure provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 0.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereon on a free base basis, once daily. In another embodiment, the Disclosure provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereon on a free base basis, once daily. In another embodiment, the present disclosure provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily.

[0023] In some embodiments, the patient is administered ruxolitinib cream 1.5% BID for up to 24 weeks.

[0024] In some embodiments, the patient is administered ruxolitinib cream 1.5% BID for up to 52 weeks.

[0025] In some embodiments, the patient is administered ruxolitinib cream 1.5% QD for up to 24 weeks.

[0026] In some embodiments, the patient is administered ruxolitinib cream 1.5% QD for up to 52 weeks.

[0027] In some embodiments, the patient is administered ruxolitinib cream 0.5% QD for up to 24 weeks.

[0028] In some embodiments, the patient is administered ruxolitinib cream 0.5% QD for up to 52 weeks.

[0029] In some embodiments, the patient is administered ruxolitinib cream 0.15% QD for up to 24 weeks.

[0030] In some embodiments, the patient is administered ruxolitinib cream 0.15% QD for up to 52 weeks.

[0031] In another embodiment, the Disclosure provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a cream containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis twice daily. In some embodiments, the cream contains 1.5 w / w% ruxolitinibulinate on a free base basis. In some embodiments, the patient achieves an improvement of 25% or more in the facial vitiligo area scoring index. In some embodiments, the patient achieves an improvement of 50% or more in the facial vitiligo area scoring index. In some embodiments, the patient achieves an improvement of 75% or more in the facial vitiligo area scoring index. In some embodiments, the patient achieves an improvement of 90% or more in the facial vitiligo area scoring index. In some embodiments, the patient achieves an improvement of 25% or more in the generalized vitiligo area scoring index. In some embodiments, the patient achieves an improvement of 50% or more in the generalized vitiligo area scoring index. In some embodiments, the patient achieves an improvement of 75% or more in the generalized vitiligo area scoring index. In some embodiments, the patient achieves a score of 0 (no vitiligo) or 1 (mild) on the Facial Patient's Global Vitiligo Assessment, and a reduction of at least 1 point from baseline. The patient achieves a score of 0 (clear) or 1 (almost clear) on the Facial Physician's Global Vitiligo Assessment. In some embodiments, the patient achieves a score of 0 (clear) or 1 (almost clear) on the Total Physician's Global Vitiligo Assessment. In some embodiments, the patient achieves a score of 1 (very much improved) or 2 (much improved) on the Patient global impression of change for vitiligo.

[0032] In a further embodiment, the present disclosure provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a cream containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, once daily.

[0033] In some embodiments, the cream contains 1.5 w / w% ruxolitinibulinate on a free base basis. In some embodiments, the patient achieves a 25% or greater improvement in the facial vitiligo area scoring index. In some embodiments, the patient achieves a 50% or greater improvement in the facial vitiligo area scoring index. In some embodiments, the patient achieves a 75% or greater improvement in the facial vitiligo area scoring index. In some embodiments, the patient achieves a 90% or greater improvement in the facial vitiligo area scoring index. In some embodiments, the patient achieves a 25% or greater improvement in the generalized vitiligo area scoring index. In some embodiments, the patient achieves a 50% or greater improvement in the generalized vitiligo area scoring index. In some embodiments, the patient achieves a 75% or greater improvement in the generalized vitiligo area scoring index. In some embodiments, the patient achieves a 0 (no vitiligo) or 1 (mild) response to the patient's comprehensive assessment of facial vitiligo, and a decrease of at least 1 point from baseline. In some embodiments, the patient achieves a 0 (clear) or 1 (nearly clear) response to the physician's comprehensive assessment of facial vitiligo. In some embodiments, the patient achieves a score of 0 (clear) or 1 (almost clear) in the physician's overall comprehensive assessment of vitiligo. In some embodiments, the patient achieves a score of 1 (very improved) or 2 (greatly improved) in the patient's overall impression of the change in vitiligo.

[0034] In another embodiment, the Disclosure provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a cream containing about 0.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, once daily. In some embodiments, the cream contains 0.5 w / w% ruxolitinibulinate on a free base basis. In some embodiments, the patient achieves an improvement of 25% or more in the facial vitiligo area scoring index. In some embodiments, the patient achieves an improvement of 50% or more in the facial vitiligo area scoring index. In some embodiments, the patient achieves an improvement of 75% or more in the facial vitiligo area scoring index. In some embodiments, the patient achieves an improvement of 90% or more in the facial vitiligo area scoring index. In some embodiments, the patient achieves an improvement of 25% or more in the generalized vitiligo area scoring index. In some embodiments, the patient achieves an improvement of 50% or more in the generalized vitiligo area scoring index. In some embodiments, the patient achieves an improvement of 75% or more in the generalized vitiligo area scoring index. In some embodiments, the patient achieves a score of 0 (no vitiligo) or 1 (mild) in the patient's comprehensive assessment of facial vitiligo, and a reduction of at least 1 point from baseline. In some embodiments, the patient achieves a score of 0 (clear) or 1 (almost clear) in the physician's comprehensive assessment of facial vitiligo. In some embodiments, the patient achieves a score of 0 (clear) or 1 (almost clear) in the physician's overall comprehensive assessment of vitiligo. In some embodiments, the patient achieves a score of 1 (very improved) or 2 (greatly improved) in the patient's overall impression of the change in vitiligo.

[0035] In another embodiment, the Disclosure provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a claim containing about 0.15 w / w% of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, once daily. In some embodiments, the cream contains 0.15 w / w% of ruxolitinibulinate on a free base basis. In some embodiments, the patient achieves a 25% or greater improvement in the facial vitiligo area scoring index. In some embodiments, the patient achieves a 50% or greater improvement in the facial vitiligo area scoring index. In some embodiments, the patient achieves a 75% or greater improvement in the facial vitiligo area scoring index. In some embodiments, the patient achieves a 90% or greater improvement in the facial vitiligo area scoring index. In some embodiments, the patient achieves a 25% or greater improvement in the generalized vitiligo area scoring index. In some embodiments, the patient achieves a 50% or greater improvement in the generalized vitiligo area scoring index. In some embodiments, the patient achieves a 75% or greater improvement in the generalized vitiligo area scoring index. In some embodiments, the patient achieves a score of 0 (no vitiligo) or 1 (mild) on the patient's comprehensive assessment of facial vitiligo, and a reduction of at least 1 point from baseline. In some embodiments, the patient achieves a score of 0 (clear) or 1 (almost clear) on the physician's comprehensive assessment of facial vitiligo. In some embodiments, the patient achieves a score of 0 (clear) or 1 (almost clear) on the physician's overall comprehensive assessment of vitiligo. In some embodiments, the patient achieves a score of 1 (very improved) or 2 (greatly improved) on the patient's overall impression of the change in vitiligo.

[0036] In a further embodiment, the present disclosure provides a treatment for vitiligo in a patient, comprising topically administering a pharmaceutical composition (e.g., a cream) to the affected area of ​​the patient's skin, wherein the composition comprises, on a free base basis, about 0.15%, about 0.5%, or about 1.5% (w / w) of ruxolitinib or a pharmaceutically acceptable salt thereof based on the weight of the composition (or cream).

[0037] In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate. In some embodiments, the composition is a cream.

[0038] In some embodiments, the composition (or cream) contains 0.15% ruxolitinibrinate on a free base basis and is administered to the patient's skin once daily (QD).

[0039] In some embodiments, the composition (or cream) contains 0.5% ruxolitinibrinate on a free base basis and is administered to the patient's skin once daily (QD).

[0040] In some embodiments, the composition (or cream) contains 1.5% ruxolitinibrinate on a free base basis and is administered to the patient's skin once daily (QD).

[0041] In some embodiments, the composition (or cream) contains 1.5% ruxolitinibrinate on a free base basis and is administered to the patient's skin twice daily (BID).

[0042] In some embodiments, 60 g or less of the composition (or cream) is administered over a period of 4 days.

[0043] In some embodiments, the affected area of ​​the patient's skin is the affected skin on the patient's face.

[0044] In some embodiments, the affected skin area of ​​the patient is the affected skin on the patient's face and body.

[0045] In some embodiments, the affected area of ​​the patient's skin is the affected skin on the patient's trunk.

[0046] In some embodiments, the affected area of ​​the patient's skin is the affected skin on the upper limb.

[0047] In some embodiments, the affected area of ​​the patient's skin is the affected skin of the lower limb.

[0048] In some embodiments, the affected area of ​​the patient's skin is the affected skin on the hand.

[0049] In some embodiments, the affected area of ​​the patient's skin is the affected skin on the foot.

[0050] In some embodiments, the affected area of ​​the patient's skin is the affected skin of the head and neck.

[0051] In some embodiments, patients achieve a 50% or greater improvement in their head and neck vitiligo area scoring index score. In some embodiments, patients achieve a 50% or greater improvement in their head and neck vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0052] In some embodiments, patients achieve a 50% or greater improvement in their upper limb vitiligo area scoring index score. In some embodiments, patients achieve a 50% or greater improvement in their upper limb vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0053] In some embodiments, patients achieve a 50% or greater improvement in their lower extremity vitiligo area scoring index score. In some embodiments, patients achieve a 50% or greater improvement in their lower extremity vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0054] In some embodiments, patients achieve a 50% or greater improvement in their hand vitiligo area scoring index score. In some embodiments, patients achieve a 50% or greater improvement in their hand vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0055] In some embodiments, patients achieve a 50% or greater improvement in their vitiligo area scoring index score. In some embodiments, patients achieve a 50% or greater improvement in their vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0056] In some embodiments, patients achieve a 75% or greater improvement in their head and neck vitiligo area scoring index score. In some embodiments, patients achieve a 75% or greater improvement in their head and neck vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0057] In some embodiments, patients achieve an improvement of 75% or more in their upper limb vitiligo area scoring index score. In some embodiments, patients achieve an improvement of 75% or more in their upper limb vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0058] In some embodiments, patients achieve a 75% or greater improvement in their lower extremity vitiligo area scoring index score. In some embodiments, patients achieve a 75% or greater improvement in their lower extremity vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52. In some embodiments, patients achieve a 75% or greater improvement in their hand vitiligo area scoring index score.

[0059] In some embodiments, patients achieve a 75% or greater improvement in their vitiligo area scoring index score. In some embodiments, patients achieve a 75% or greater improvement in their vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0060] In some embodiments, patients achieve a 25% or greater improvement in their head and neck vitiligo area scoring index score. In some embodiments, patients achieve a 25% or greater improvement in their head and neck vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0061] In some embodiments, patients achieve an improvement of 25% or more in their upper limb vitiligo area scoring index score. In some embodiments, patients achieve an improvement of 25% or more in their upper limb vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0062] In some embodiments, patients achieve a 25% or greater improvement in their lower extremity vitiligo area scoring index score. In some embodiments, patients achieve a 25% or greater improvement in their lower extremity vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0063] In some embodiments, patients achieve a 25% or greater improvement in their hand vitiligo area scoring index score. In some embodiments, patients achieve a 25% or greater improvement in their hand vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0064] In some embodiments, patients achieve a 25% or greater improvement in their vitiligo area scoring index score. In some embodiments, patients achieve a 25% or greater improvement in their vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0065] In some embodiments, the patient suffers from generalized vitiligo.

[0066] In some embodiments, the patient suffers from segmental vitiligo.

[0067] In some embodiments, the patient has segmental vitiligo and achieves a 25% or greater improvement in the Facial Vitiligo Area Scoring Index score. In some embodiments, the patient has segmental vitiligo and achieves a 25% or greater improvement in the Facial Vitiligo Area Scoring Index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0068] In some embodiments, the patient has segmental vitiligo and achieves a 50% or greater improvement in the facial vitiligo area scoring index score. In some embodiments, the patient has segmental vitiligo and achieves a 50% or greater improvement in the facial vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0069] In some embodiments, the patient has segmental vitiligo and achieves a 75% or greater improvement in the facial vitiligo area scoring index score. In some embodiments, the patient has segmental vitiligo and achieves a 75% or greater improvement in the facial vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0070] In some embodiments, the patient has segmental vitiligo and achieves a 90% or greater improvement in the facial vitiligo area scoring index score. In some embodiments, the patient has segmental vitiligo and achieves a 90% or greater improvement in the facial vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0071] In some embodiments, the patient has segmental vitiligo and achieves a 25% or greater improvement in the generalized vitiligo area scoring index score. In some embodiments, the patient has segmental vitiligo and achieves a 25% or greater improvement in the generalized vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0072] In some embodiments, the patient has segmental vitiligo and achieves a 50% or greater improvement in the generalized vitiligo area scoring index score. In some embodiments, the patient has segmental vitiligo and achieves a 50% or greater improvement in the generalized vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0073] In some embodiments, the patient has segmental vitiligo and achieves a 75% or greater improvement in the generalized vitiligo area scoring index score. In some embodiments, the patient has segmental vitiligo and achieves a 75% or greater improvement in the generalized vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0074] In some embodiments, the patient has segmental vitiligo and achieves a 90% or greater improvement in the generalized vitiligo area scoring index score. In some embodiments, the patient has segmental vitiligo and achieves a 90% or greater improvement in the generalized vitiligo area scoring index score at week 4, or week 8, or week 12, or week 18, or week 24, or week 28, or week 34, or week 40, or week 46, or week 52.

[0075] In some embodiments, the patient is Caucasian.

[0076] In some embodiments, the patient is non-white.

[0077] In some embodiments, the patient is female.

[0078] In some embodiments, the patient is male.

[0079] In some embodiments, the patient has a Fitzpatrick scale type I, II, or III skin type.

[0080] In some embodiments, the patient has a facial BSA of 1.5% or less at baseline.

[0081] In some embodiments, patients have an F-VASI score of 0.75 to less than 1.5 at baseline.

[0082] In some embodiments, patients have stable vitiligo at baseline.

[0083] In some embodiments, the patient has progressive vitiligo at baseline. For example, a patient with progressive vitiligo experiences new lesions and / or other objective clinical signs of active disease (e.g., confetti-like macules and / or trichrome lesions).

[0084] In some embodiments, the patient has had the disease for at least 5 years at baseline.

[0085] In some embodiments, the patient has had the disease for at least 10 years at baseline.

[0086] In some embodiments, the patient has a baseline duration of at least 20 years.

[0087] In some embodiments, the patient has previously been treated with topical corticosteroids.

[0088] In some embodiments, the patient has a total BSA of 20% or less.

[0089] In some embodiments, the patient has a total BSA of 10% or more.

[0090] In some embodiments, the patient has a total BSA of 15% or more.

[0091] In some embodiments, the patient has a total BSA of 20% or more.

[0092] In some embodiments, the patient has suffered from vitiligo for many years.

[0093] In some embodiments, the patient has a facial surface area (F-BSA) of more than 1.5% affected by vitiligo.

[0094] In some embodiments, the patient has a facial surface area percentage (F-BSA) affected by vitiligo exceeding 1.5%, and achieves a 50% or greater improvement in the facial vitiligo area scoring index score at 24 weeks.

[0095] In some embodiments, the patient suffers from generalized vitiligo with (i) a body surface area (BSA) of 0.5% or more on the face, (ii) a BSA of 3% or more in non-facial areas, and (iii) a generalized area of ​​depigmentation not exceeding 10% BSA.

[0096] In some embodiments, the patient suffers from generalized vitiligo, which has (i) a body surface area (BSA) of 0.5% or more on the face, (ii) a BSA of 3% or more in non-facial areas, and (iii) a generalized area of ​​depigmentation not exceeding 20% ​​BSA.

[0097] The total BSA% (including facial and non-facial areas) in patients with vitiligo can be approximated to the closest 0.1% using the Palmar Method, where the palm and five fingers are considered 1% BSA and the thumb 0.1% BSA.

[0098] In some embodiments, the patient is an individual aged 12 years or older.

[0099] In some embodiments, the patient is an individual under 50 years of age.

[0100] In some embodiments, the patient is an individual between the ages of 12 and 50.

[0101] In some embodiments, the patient is an adult.

[0102] In some embodiments, the patient is a young person.

[0103] In some embodiments, the patient has a Fitzpatrick Scale Type I or II skin type.

[0104] In some embodiments, the patient has a Fitzpatrick Scale type III, IV, V, or VI skin type.

[0105] In some embodiments, the patient is not the following patient: (i) Patients who do not have pigmented hairs on the affected area of ​​the face; (ii) Patients with non-generalized vitiligo (including, but not limited to, segmental vitiligo) or other differential diagnoses of vitiligo or other skin depigmentation disorders (including, but not limited to, macular leukoderma, pityriasis leukemia, leprosy, post-inflammatory hypopigmentation, progressive macule hypomelanosis, nevus anemicus, chemical leukoderma, and tinea versicolor); (iii) Patients who have previously undergone depigmentation treatment other than bleaching for the treatment of vitiligo or other areas of hyperpigmentation; and (iv) Patients who have previously used any of the following: (a) an active acute bacterial, fungal, or viral skin infection; (b) a history of thrombosis (including deep vein thrombosis (DVT), pulmonary embolism (PE), or arterial thrombosis); (c) clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial infarction within 6 months of day 1 to day 6 of administration of the study drug, congestive heart failure of New York Heart Association class III or IV, and arrhythmias or uncontrolled hypertension (blood pressure >150 / 90 mmHg) requiring treatment; (d) current liver disease (including known hepatitis B or C with liver or biliary abnormalities); (e) a history of alcohol or drug dependence within one year prior to screening, or current alcohol or drug use that, in the physician's opinion, would interfere with the patient's ability to adhere to the administration schedule and treatment evaluation; and (f) a mental health facility as ordered by law enforcement or administrative authorities. (v) Patients with any of the following test values ​​at the time of screening: (a) hemoglobin (<10 g / dL); (b) liver function tests: aspartate aminotransferase or alanine aminotransferase at more than twice the upper limit of normal; or alkaline phosphatase and / or bilirubin at more than 1.5 times the upper limit of normal; (c) severe renal disease requiring dialysis (serum creatinine >2 mg / dL); (d) clinically significant thyroid-stimulating hormone or free T4 abnormalities at the time of screening as determined by the physician; or (e) a positive serological test result for HIV antibodies at the time of screening; (vi) Body Mass Index <17 or >40 kg / m 2 Patients; and (vii) Pregnant or breastfeeding.

[0106] In some embodiments, the patient is not the following patient: (i) Patients who do not have pigmented hairs on the affected area of ​​the face; (ii) Patients with non-generalized vitiligo (including, but not limited to, segmental vitiligo) or other differential diagnoses of vitiligo or other skin depigmentation disorders (including, but not limited to, mottled plaque, pityriasis leukemia, leprosy, post-inflammatory depigmentation, progressive macular hypomelaninosis, anemic nevi, chemical vitiligo, and tinea versicolor); (iii) Patients who have previously undergone depigmentation treatment other than bleaching for the treatment of vitiligo or other areas of hyperpigmentation; and (iv) Patients who have previously used any of the following: (a) an active acute bacterial, fungal, or viral skin infection; (b) a history of thrombosis (including deep vein thrombosis (DVT), pulmonary embolism (PE), or arterial thrombosis); (c) clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial infarction within 6 months of day 1 to day 6 of administration of the study drug, congestive heart failure of New York Heart Association class III or IV, and arrhythmias or uncontrolled hypertension (blood pressure >150 / 90 mmHg) requiring treatment; (d) current liver disease (including known hepatitis B or C with liver or biliary abnormalities); (e) a history of alcohol or drug dependence within one year prior to screening, or current alcohol or drug use that, in the physician's opinion, would interfere with the patient's ability to adhere to the administration schedule and treatment evaluation; and (f) a mental health facility as ordered by law enforcement or administrative authorities. (v) Patients with any of the following test values ​​at the time of screening: (a) hemoglobin (<10 g / dL); (b) liver function tests: aspartate aminotransferase or alanine aminotransferase at more than twice the upper limit of normal; or alkaline phosphatase and / or bilirubin at more than 1.5 times the upper limit of normal; (c) severe renal disease requiring dialysis (serum creatinine >2 mg / dL); (d) clinically significant thyroid-stimulating hormone or free T4 abnormalities at the time of screening as determined by the physician; or (e) a positive serological test result for HIV antibodies at the time of screening; (vi) Body Mass Index <17 or >40 kg / m 2 Patients; or (vii) Pregnant or breastfeeding.

[0107] In some embodiments, the patient has not previously received systemic or topical JAK inhibitors.

[0108] In some embodiments, the method does not involve administering topical drugs (including, but not limited to, corticosteroids, calcineurin, and phosphodiesterase type 4 inhibitors or retinoids) to the affected area. In some embodiments, the method does not involve administering topical drugs (including, but not limited to, corticosteroids, calcineurin, and phosphodiesterase type 4 inhibitors or retinoids) to the affected area within one week of initiating treatment with the composition (or cream).

[0109] In some embodiments, the method does not involve administering melanocyte stimulants (including but not limited to afamelanotide), systemic immunomodulators (including but not limited to corticosteroids, methotrexate, and cyclosporine), systemic therapies that may increase skin sensitivity to UV / visible light or affect skin pigmentation (including but not limited to tetracycline and methoxypsoralen), and live vaccines within four weeks of initiating treatment with the composition (or cream).

[0110] In some embodiments, the method does not involve the application of a laser or any type of phototherapy (including, but not limited to, tanning beds or intentional UV exposure). In some embodiments, the method does not involve the application of a laser or any type of phototherapy (including, but not limited to, tanning beds or intentional UV exposure) within eight weeks of the commencement of treatment with the composition (or cream).

[0111] In some embodiments, the method does not involve administering a biological agent for the treatment of vitiligo. In some embodiments, the method does not involve administering a biological agent for the treatment of vitiligo within 12 weeks after the commencement of treatment with the composition (or cream).

[0112] In some embodiments, the patient has previously received phototherapy (including, for example, narrowband ultraviolet B phototherapy, psoralen ultraviolet A photochemotherapy, or excimer laser).

[0113] In some embodiments, patients achieve a 50% or greater improvement in the facial vitiligo area scoring index (F-VASI50). In some embodiments, patients achieve a 75% or greater improvement in the facial vitiligo area scoring index (F-VASI75). In some embodiments, patients achieve a 90% or greater improvement in the facial vitiligo area scoring index (F-VASI90).

[0114] In some embodiments, patients achieve a 75% or greater improvement in the facial vitiligo area scoring index (F-VASI75) at 24 weeks.

[0115] In some embodiments, patients achieve a 75% or greater improvement in the facial vitiligo area scoring index (F-VASI75) at week 52.

[0116] In some embodiments, patients achieve a 50% or greater improvement in the facial vitiligo area scoring index (F-VASI50) at 24 weeks.

[0117] In some embodiments, patients achieve a 50% or greater improvement in the facial vitiligo area scoring index (F-VASI50) at 52 weeks.

[0118] In some embodiments, patients achieve a 90% or greater improvement in the facial vitiligo area scoring index (F-VASI90) at 24 weeks.

[0119] In some embodiments, patients achieve a 90% or greater improvement in the facial vitiligo area scoring index (F-VASI90) at 52 weeks.

[0120] In some embodiments, patients achieve a 25% or greater improvement in the generalized vitiligo area scoring index (T-VASI25). In some embodiments, patients achieve a 50% or greater improvement in the generalized vitiligo area scoring index (T-VASI50). In some embodiments, patients achieve a 75% or greater improvement in the generalized vitiligo area scoring index (T-VASI75).

[0121] In some embodiments, patients achieve a 25% or greater improvement in the whole-body vitiligo area scoring index (T-VASI25) at 24 weeks.

[0122] In some embodiments, patients achieve a 25% or greater improvement in the whole-body vitiligo area scoring index (T-VASI25) at week 52.

[0123] In some embodiments, patients achieve a 50% or greater improvement in the whole-body vitiligo area scoring index (T-VASI50) at 24 weeks.

[0124] In some embodiments, patients achieve a 50% or greater improvement in the whole-body vitiligo area scoring index (T-VASI50) at week 52.

[0125] In some embodiments, patients achieve a 75% or greater improvement in the whole-body vitiligo area scoring index (T-VASI75) at 24 weeks.

[0126] In some embodiments, patients achieve a 75% or greater improvement in the whole-body vitiligo area scoring index (T-VASI75) at week 52.

[0127] In some embodiments, patients achieve a score of 4 or 5 on the Vitiligo Noticeability Scale (VNS). The VNS is a 5-point scale patient-reported outcome measure of vitiligo treatment success (Batchelor JM, Tan W, Tour S, Yong A, Montgomery AA, Thomas KS. Validation of the Vitiligo Noticeability Scale: a patient-reported outcome measure of vitiligo treatment success. Br J Dermatol 2016;174:386-394): (1) More noticeable, (2) As noticeable, (3) Slightly less noticeable, (4) A lot less noticeable, and (5) No longer noticeable.

[0128] In some embodiments, patients achieve improvement from baseline in facial surface area % (F-BSA) affected by vitiligo.

[0129] In some embodiments, the improvement from baseline in F-BSA is approximately 10 percentage points.

[0130] In some embodiments, the improvement from baseline in F-BSA is approximately 15 percentage points.

[0131] In some embodiments, the improvement from baseline in F-BSA is approximately 20 percentage points.

[0132] In some embodiments, the Disclosure also provides a method for treating non-facial vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily.

[0133] In some embodiments, the Disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein the patient has previously received phototherapy for vitiligo.

[0134] In some embodiments, the Disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein the patient had a high inflammatory load prior to the administration step.

[0135] In some embodiments, the Disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein the composition (e.g., a cream) is applied to the patient's hands, feet, or both.

[0136] In some embodiments, the Disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein the patient is female and under 50 years of age.

[0137] In some embodiments, the Disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein a female patient under 50 years of age responds better than a male of the same age 24 weeks after administration of the composition (e.g., a cream).

[0138] In some embodiments, the Disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein the patient is female.

[0139] In some embodiments, the Disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein the patient being female responds better than males 24 weeks after administration of the composition (e.g., a cream).

[0140] In some embodiments, the Disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein the patient has had vitiligo for more than 20 years prior to the administration step.

[0141] In some embodiments, the Disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein patients who have had vitiligo for more than 20 years prior to the administration step respond better 24 weeks after administration of the composition (e.g., a cream) than patients who have not had vitiligo for more than 20 years prior to the administration step.

[0142] In some embodiments, the Disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein the patient has skin types I to III.

[0143] In some embodiments, the Disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein the patient has skin type I to II.

[0144] In some embodiments, the Disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein patients with skin types I–III respond better to the composition (e.g., a cream) 24 weeks after administration than patients without skin types I–III.

[0145] In some embodiments, the disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein there is no substantial difference in response between Caucasian and non-Caucasian patients.

[0146] In some embodiments, the Disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein there is no substantial difference in response between patients with stable vitiligo and patients with progressive vitiligo.

[0147] In some embodiments, the Disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein the patient has progressive vitiligo.

[0148] In some embodiments, the Disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein there is no substantial difference in response between patients with BSA of 20 or less and patients with BSA of 20 or more.

[0149] In some embodiments, the Disclosure also provides a method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a composition (e.g., a cream) containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily, wherein the patient has more than 20 BSAs.

[0150] The severity of vitiligo can be assessed by a physician using the Physician's Global Vitiligo Assessment (PhGVA), which has a five-point scale as shown in the table below. Reactions can be reported for the face or the entire body (F-PhGVA or T-PhGVA).

[0151] [Table 1]

[0152] In some embodiments, patients achieve a 1 (very improved) or 2 (greatly improved) in the patient's overall impression of the change in vitiligo. PaGIC-V is a 7-point scale rating of the patient's improvement, comparing the vitiligo area at baseline with the treated vitiligo area of ​​the participant: (1) very improved, (2) greatly improved, (3) slightly improved, (4) no change, (5) slightly worsened, (6) greatly worsened, and (7) very worsened. The response may be reported for the face or whole body (F-PaGVA or T-PaGVA).

[0153] In some embodiments, the mean plasma concentration of ruxolitinib is less than 150 nM 2 hours after BID administration.

[0154] In some embodiments, the mean plasma concentration of ruxolitinib is less than 120 nM 2 hours after BID administration.

[0155] In some embodiments, the mean plasma concentration of ruxolitinib is less than 80 nM 2 hours after QD administration.

[0156] In some embodiments, the mean plasma concentration of ruxolitinib is less than 60 nM 2 hours after QD administration.

[0157] As used herein, the terms “human subject,” “individual,” or “patient” as they are interchangeable mean an animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans. In some embodiments, the patient is a human. In some embodiments, the patient is a human being 12 years of age or older.

[0158] As used herein, embodiments referring to a single patient can be combined with embodiments referring to multiple patients, and vice versa. In some embodiments, “patient” means one patient. In some embodiments, “patient” means a group of patients. In some embodiments, “patient” means one or more patients. In some embodiments, “patient” means one patient. In some embodiments, “patient” means a group of patients. In some embodiments, “patient” means one or more patients.

[0159] As used herein, "contains" is equivalent to "includes".

[0160] Pharmaceutical composition In some embodiments, the pharmaceutical composition is a cream formulation. In some embodiments, the cream formulation is an oil-in-water emulsion. In some embodiments, the cream formulation is described in U.S. Patent Application Publication No. 2015 / 0250790, which is included as a whole in this specification with due attribution.

[0161] In some embodiments, the oil-in-water emulsion comprises water, an oil component, an emulsifier, and 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis. In some embodiments, the oil-in-water emulsion comprises water, an oil component, an emulsifier, and 1.5% by weight of ruxolitinibrinate on a free base basis.

[0162] In some embodiments, the pH of the cream formulation is approximately 2.8 to approximately 3.9. In some embodiments, the pH of the cream formulation is approximately 2.8 to approximately 3.6. In some embodiments, the pH of the cream formulation is approximately 2.9 to approximately 3.6. In some embodiments, the pH of the cream formulation does not exceed 3.6.

[0163] As used herein, the term “emulsifier component” means, in one embodiment, a substance or mixture of substances that maintains elements or particles in a suspended state in a fluid medium. In some embodiments, the emulsifier component enables the oil phase to form an emulsion when combined with water. In some embodiments, the emulsifier component means one or more nonionic surfactants.

[0164] Furthermore, transport tests using newly extracted mouse skin showed a general tendency for increased permeability of the oil-in-water formulation as the strength of the solubilized cream was increased from 0.5% w / w to 1.5% w / w. The formulations described herein are also relatively easy to manufacture through a repeatable formulation process. The resulting products are easily packaged. The formulations appear to possess good stability and a relatively consistent permeability profile.

[0165] In some embodiments, the oil component is present in an amount of about 10% to about 40% by weight of the formulation.

[0166] In some embodiments, the oil component is present in an amount of about 17% to about 27% by weight of the formulation.

[0167] In some embodiments, the oil component is present in an amount of about 20% to about 27% by weight of the formulation.

[0168] In some embodiments, the oil component is present in an amount of about 17% to about 24% by weight of the formulation.

[0169] In some embodiments, the oil component comprises one or more substances independently selected from petrolatum, aliphatic alcohols, mineral oils, triglycerides, and silicone oils.

[0170] In some embodiments, the oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium-chain triglycerides, and dimethicone.

[0171] In some embodiments, the oil component includes an occlusive agent component.

[0172] In some embodiments, the occlusive agent component is present in an amount of about 2% to about 15% by weight of the formulation.

[0173] In some embodiments, the occlusive agent component is present in an amount of about 5% to about 10% by weight of the formulation.

[0174] As used herein, the term "occlusive agent component" refers to a hydrophobic agent or mixture of hydrophobic agents that forms an occlusive film on the skin that reduces transepidermal water loss (TEWL) by preventing the evaporation of water from the stratum corneum.

[0175] In some embodiments, the occlusive agent component comprises one or more substances selected from fatty acids (e.g., lanolinic acid), aliphatic alcohols (e.g., lanolin alcohol), hydrocarbon oils and waxes (e.g., petrolatum), polyhydric alcohols (e.g., propylene glycol), silicones (e.g., dimethicone), sterols (e.g., cholesterol), vegetable or animal fats (e.g., cocoa butter), vegetable waxes (e.g., carnauba wax), and wax esters (e.g., beeswax).

[0176] In some embodiments, the occlusive agent component comprises one or more substances selected from lanolinic acid aliphatic alcohol, lanolin alcohol, petrolatum, propylene glycol, dimethicone, cholesterol, cocoa butter, carnauba wax, and beeswax.

[0177] In some embodiments, the occlusive agent component includes petrolatum.

[0178] In some embodiments, the occlusive agent component includes white petrolatum.

[0179] In some embodiments, the oil component includes a curing agent component.

[0180] In some embodiments, the curing agent component is present in an amount of about 2% to about 8% by weight of the formulation.

[0181] In some embodiments, the curing agent component is present in an amount of about 3% to about 6% by weight of the formulation.

[0182] In some embodiments, the curing agent component is present in an amount of about 4% to about 7% by weight of the formulation.

[0183] As used herein, the term “curing agent component” means a substance or mixture of substances that increases the viscosity and / or consistency of a formulation or improves the rheology of a formulation.

[0184] In some embodiments, the curing agent component comprises one or more substances independently selected from aliphatic alcohols.

[0185] In some embodiments, the curing agent component is C 12-20 It contains one or more substances independently selected from aliphatic alcohols.

[0186] In some embodiments, the curing agent component is C 16-18 It contains one or more substances independently selected from aliphatic alcohols.

[0187] In some embodiments, the curing agent component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol.

[0188] In some embodiments, the oil component includes a skin-softening component.

[0189] In some embodiments, the skin-softening component is present in an amount of about 5% to about 15% by weight of the formulation.

[0190] In some embodiments, the skin-softening component is present in an amount of about 7% to about 13% by weight of the formulation.

[0191] As used herein, the term "skin softening agent" refers to an agent that softens or soothes the skin, or soothes an irritated internal surface.

[0192] In some embodiments, the skin-softening component comprises one or more substances independently selected from mineral oil and triglycerides.

[0193] In some embodiments, the skin-softening component comprises one or more substances independently selected from light mineral oil and medium-chain triglycerides.

[0194] In some embodiments, the skin-softening component comprises one or more substances independently selected from light mineral oil, medium-chain triglycerides, and dimethicone.

[0195] In some embodiments, water is present in an amount of about 35% to about 65% by weight of the formulation.

[0196] In some embodiments, water is present in an amount of about 40% to about 60% by weight of the formulation.

[0197] In some embodiments, water is present in an amount of about 45% to about 55% by weight of the formulation.

[0198] In some embodiments, the emulsifier component is present in an amount of about 1% to about 9% by weight of the formulation.

[0199] In some embodiments, the emulsifier component is present in an amount of about 2% to about 6% by weight of the formulation.

[0200] In some embodiments, the emulsifier component is present in an amount of about 3% to about 5% by weight of the formulation.

[0201] In some embodiments, the emulsifier component is present in an amount of about 4% to about 7% by weight of the formulation.

[0202] In some embodiments, the pharmaceutical formulation comprises an emulsifier component and a curing agent component, wherein the amounts of the emulsifier component and the curing agent component constitute at least about 8% by weight of the formulation.

[0203] In some embodiments, the emulsifier component comprises one or more substances independently selected from glyceryl fatty acid esters and sorbitan fatty acid esters.

[0204] In some embodiments, the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20.

[0205] In some embodiments, the pharmaceutical formulation also includes a stabilizing agent component.

[0206] In some embodiments, the stabilizing component is present in an amount of about 0.05% to about 5% by weight of the formulation.

[0207] In some embodiments, the stabilizing agent component is present in an amount of about 0.1% to about 2% by weight of the formulation.

[0208] In some embodiments, the stabilizing component is present in an amount of about 0.3% to about 0.5% by weight of the formulation.

[0209] As used herein, the term “stabilizing component” means a substance or mixture of substances that improve the stability of a pharmaceutical formulation and / or the compatibility of components within the formulation. In some embodiments, the stabilizing component prevents the aggregation of emulsions and stabilizes droplets in an oil-in-water emulsion.

[0210] In some embodiments, the stabilizing component comprises one or more substances independently selected from polysaccharides.

[0211] In some embodiments, the stabilizing component includes xanthan gum.

[0212] In some embodiments, the pharmaceutical formulation also includes a solvent component.

[0213] In some embodiments, the solvent component is present in an amount of about 10% to about 35% by weight of the formulation.

[0214] In some embodiments, the solvent component is present in an amount of about 15% to about 30% by weight of the formulation.

[0215] In some embodiments, the solvent component is present in an amount of about 20% to about 25% by weight of the formulation.

[0216] As used herein, the term “solvent component” refers to a liquid substance or mixture of liquid substances that can dissolve ruxolitinib or other substances in a formulation. In some embodiments, the solvent component is a liquid substance or mixture of liquid substances in which ruxolitinib or a pharmaceutically acceptable salt thereof has a moderate solubility. For example, the solubility of ruxolitinib (free base) or its phosphate is reported in Table 21 of U.S. Patent Application Publication 2015 / 0250790. In some embodiments, the solvent is a substance or mixture thereof in which ruxolitinib or a pharmaceutically acceptable salt thereof (either one is used) has a solubility of at least about 10 mg / mL, at least about 15 mg / mL, or at least about 20 mg / mL, as measured as described in Example 4 of U.S. Patent Application Publication 2015 / 0250790.

[0217] In some embodiments, the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.

[0218] In some embodiments, the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.

[0219] In some embodiments, the therapeutic agent is present in an amount of about 0.5% to about 1.5% by weight of the formulation on a free base basis.

[0220] In some embodiments, the therapeutic agent is present in an amount of about 0.5% by weight of the formulation on a free base basis.

[0221] In some embodiments, the therapeutic agent is present in an amount of about 1% by weight of the formulation on a free base basis.

[0222] In some embodiments, the therapeutic agent is present in an amount of about 1.5% by weight of the formulation on a free base basis.

[0223] In some embodiments, the therapeutic agent is (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]propannitrile phosphate.

[0224] For several reasons, the pharmaceutical formulation is Approximately 35% to 65% by weight of water in the formulation; Oil components making up approximately 10% to 40% by weight of the formulation; Emulsifier component making up approximately 1% to 9% by weight of the formulation; Approximately 10% to 35% by weight of the solvent component in the formulation; Stabilizing agent components in the formulation at a concentration of approximately 0.05% to 5% by weight; and Approximately 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt of the formulation on a free base basis. Includes.

[0225] For several reasons, the pharmaceutical formulation is Approximately 40% to 60% by weight of water in the formulation; Oil components making up approximately 15% to 30% by weight of the formulation; Emulsifier component in the formulation, approximately 2% to 6% by weight; Approximately 15% to 30% by weight of the solvent component in the formulation; Stabilizing agent components in the formulation in an amount of approximately 0.1% to approximately 2% by weight; and Approximately 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt of the formulation on a free base basis. Includes.

[0226] For several reasons, the pharmaceutical formulation is Approximately 45% to 55% by weight of water in the formulation; Oil components making up approximately 17% to 27% by weight of the formulation; Approximately 3% to 5% by weight of the emulsifier component in the formulation; Approximately 20% to 25% by weight of the solvent component in the formulation; Stabilizing agent components in an amount of approximately 0.3% to approximately 0.5% by weight of the formulation; and Approximately 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt of the formulation on a free base basis. comprises.

[0227] In some embodiments, the pharmaceutical formulation is from about 45% to about 55% by weight of the formulation of water; from about 17% to about 27% by weight of the formulation of an oil component; from about 4% to about 7% by weight of the formulation of an emulsifier component; from about 20% to about 25% by weight of the formulation of a solvent component; from about 0.3% to about 0.5% by weight of the formulation of a stabilizer component; and about 1.5% by weight of ruxolitinib, or a pharmaceutically acceptable salt thereof, based on the free base, in the formulation comprises.

[0228] In some embodiments, the pharmaceutical formulation is from about 45% to about 55% by weight of the formulation of water; from about 17% to about 24% by weight of the formulation of an oil component; from about 4% to about 7% by weight of the formulation of an emulsifier component; from about 20% to about 25% by weight of the formulation of a solvent component; from about 0.3% to about 0.5% by weight of the formulation of a stabilizer component; and about 1.5% by weight of ruxolitinib, or a pharmaceutically acceptable salt thereof, based on the free base, in the formulation comprises.

[0229] In some embodiments, the oil component comprises one or more substances independently selected from petrolatum, aliphatic alcohols, mineral oil, triglycerides, and dimethicone; the emulsifier component comprises one or more substances independently selected from glyceryl fatty acid esters and sorbitan fatty acid esters; the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols; the stabilizer component comprises one or more substances independently selected from polysaccharides.

[0230] In some embodiments, said oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium-chain triglycerides, and dimethicone; said emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20; said solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol; said stabilizer component comprises xanthan gum.

[0231] In some embodiments, the pharmaceutical formulation comprises: from about 35% to about 65% by weight of the formulation of water; from about 2% to about 15% by weight of the formulation of an occlusive component; from about 2% to about 8% by weight of the formulation of a hardener component; from about 5% to about 15% by weight of the formulation of an emollient component; from about 1% to about 9% by weight of the formulation of an emulsifier component; from about 0.05% to about 5% by weight of the formulation of a stabilizer component; from about 10% to about 35% by weight of the formulation of a solvent component; and about 1.5% by weight of the formulation, based on free base, of ruxolitinib or a pharmaceutically acceptable salt thereof .

[0232] In some embodiments, the pharmaceutical formulation comprises: from about 40% to about 60% by weight of the formulation of water; from about 5% to about 10% by weight of the formulation of an occlusive component; from about 2% to about 8% by weight of the formulation of a hardener component; from about 7% to about 12% by weight of the formulation of an emollient component; from about 2% to about 6% by weight of the formulation of an emulsifier component; from about 0.1% to about 2% by weight of the formulation of a stabilizer; from about 15% to about 30% by weight of the formulation of a solvent component; and about 1.5% by weight of the formulation, based on free base, of ruxolitinib or a pharmaceutically acceptable salt thereof Includes.

[0233] For several reasons, the pharmaceutical formulation is Approximately 45% to 55% by weight of water in the formulation; Approximately 5% to 10% by weight of the occlusive agent component in the formulation; A curing agent component making up approximately 3% to 6% by weight of the formulation; Skin softening ingredients making up approximately 7% to 13% by weight of the formulation; Approximately 3% to 5% by weight of the emulsifier component in the formulation; Stabilizing agent component in the formulation, approximately 0.3% to 0.5% by weight; Approximately 20% to 25% by weight of solvent components in the formulation; and Approximately 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt of the formulation on a free base basis. Includes.

[0234] For several reasons, the pharmaceutical formulation is Approximately 45% to 55% by weight of water in the formulation; Approximately 5% to 10% by weight of the occlusive agent component in the formulation; A curing agent component making up approximately 4% to 7% by weight of the formulation; Skin softening ingredients making up approximately 7% to 13% by weight of the formulation; Approximately 4% to 7% by weight of the emulsifier component in the formulation; Stabilizing agent component in the formulation, approximately 0.3% to 0.5% by weight; Approximately 20% to 25% by weight of solvent components in the formulation; and Approximately 1.5% by weight of ruxolitinib or a pharmaceutically acceptable salt of the formulation on a free base basis. Includes.

[0235] For several reasons, the pharmaceutical formulation is Approximately 45% to 55% by weight of water in the formulation; Approximately 7% by weight of the occlusive agent component of the formulation; Approximately 4.5% to 5% by weight of the curing agent component in the formulation; Approximately 10% by weight of the formulation is a skin-softening ingredient; Approximately 4% to 4.5% by weight of the emulsifier component in the formulation; a stabilizer component in an amount of about 0.4% by weight of the formulation; a solvent component in an amount of about 22% by weight of the formulation; and ruxolitinib or a pharmaceutically acceptable salt thereof, in an amount of about 1.5% by weight of the formulation on a free base basis comprising.

[0236] In some embodiments, the combined amount of the hardener component and the emulsifier component is at least about 8% by weight of the formulation.

[0237] In some embodiments, the occlusive component comprises petrolatum; the hardener component comprises one or more substances independently selected from one or more aliphatic alcohols; the emollient component comprises one or more substances independently selected from mineral oil and triglycerides; the emulsifier component comprises one or more substances independently selected from glyceryl fatty acid esters and sorbitan fatty acid esters; the stabilizer component comprises one or more substances independently selected from polysaccharides; the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.

[0238] In some embodiments, the occlusive component comprises white petrolatum; the hardener component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol; the emollient component comprises one or more substances independently selected from light mineral oil, medium-chain triglycerides, and dimethicone; the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20; the stabilizer component comprises xanthan gum; the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.

[0239] In some embodiments, the pharmaceutical formulation also includes an antimicrobial preservative component.

[0240] In some embodiments, the antimicrobial preservative component is present in an amount of about 0.05% to about 3% by weight of the formulation.

[0241] In some embodiments, the antimicrobial preservative component is present in an amount of about 0.1% to about 1% by weight of the formulation.

[0242] As used herein, the term "antimicrobial preservative component" refers to a substance or mixture of substances that inhibit the growth of microorganisms in a formulation.

[0243] In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from alkylparabens and phenoxyethanol.

[0244] In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from methylparaben, propylparaben, and phenoxyethanol.

[0245] In some embodiments, the pharmaceutical formulation also includes a chelating agent component.

[0246] As used herein, the term "chelating agent component" means a compound or mixture of compounds that has the ability to strongly bind to metal ions.

[0247] In some embodiments, the chelating agent component includes disodium edetate.

[0248] As used herein, "weight percent of the formulation" means that the concentration percentage of an ingredient in the formulation is on a weight / weight basis. For example, 1 w / w% of ingredient A = [(mass of ingredient A) / (total mass of the formulation)] × 100.

[0249] As used herein, “w / w% of the formulation on a free base basis” for ruxolitinib or a pharmaceutically acceptable salt means that the w / w% is calculated based on the weight of ruxolitinib in the entire formulation. For example, “0.5 w / w% on a free base basis” of ruxolitinibrate means that for every 100 g of the entire formulation, there are 0.66 g of ruxolitinibrate present in the formulation (equal to 0.5 g of ruxolitinib as a free base).

[0250] In some embodiments, the component is present exactly within a specified range (for example, the term "approximately" does not exist). In some embodiments, "approximately" means ±10% of the value.

[0251] As can be understood, some components of the pharmaceutical formulations described herein may have multiple functions. For example, a given substance may act as both an emulsifier and a stabilizer. In some such cases, the function of a given component can be considered to be only one, even if its properties enable multiple functions. In some embodiments, each component of the formulation comprises a different substance or a mixture of substances.

[0252] As used herein, the term “component” may mean one substance or a mixture of substances.

[0253] As used herein, the term “fatty acid” means a saturated or unsaturated aliphatic acid. In some embodiments, the fatty acid is a mixture of different fatty acids. In some embodiments, the fatty acid has an average of about 8 to about 30 carbon atoms. In some embodiments, the fatty acid has an average of about 12 to 20, 14 to 20, or 16 to 18 carbon atoms. Suitable fatty acids include, but are not limited to, cetyl acid, stearic acid, lauric acid, myristic acid, erucic acid, palmitic acid, palmitoleic acid, capric acid, caprylic acid, oleic acid, linoleic acid, linolenic acid, hydroxystearic acid, 12-hydroxystearic acid, cetostearic acid, isostearic acid, sesquioleic acid, sesqui-9-octadecanoic acid, sesquiisooctadecanoic acid, behenic acid, isobehenic acid, and arachidonic acid, or mixtures thereof.

[0254] As used herein, the term “aliphatic alcohol” refers to saturated or unsaturated aliphatic alcohols. In some embodiments, the aliphatic alcohol is a mixture of different aliphatic alcohols. In some embodiments, the aliphatic alcohol has an average of about 12 to about 20 carbon atoms, about 14 to about 20 carbon atoms, or about 16 to about 18 carbon atoms. Suitable aliphatic alcohols include, but are not limited to, stearyl alcohol, lauryl alcohol, palmityl alcohol, cetyl alcohol, caprylyl alcohol, oleyl alcohol, linoleyl alcohol, arachidonic alcohol, behenyl alcohol, isovenyl alcohol, selachyl alcohol, chimyl alcohol, and linoleyl alcohol, or mixtures thereof.

[0255] As used herein, the term "polyalkylene glycol," when used alone or in combination with other terms, refers to a polymer containing oxyalkylene monomer units having 2 to 6, 2 to 4, or 2 to 3 carbon atoms in an alkylene group, or a polymer containing copolymers of different oxyalkylene monomer units. As used herein, the term "oxyalkylene," when used alone or in combination with other terms, refers to a group of the formula -O-alkylene. In some embodiments, polyalkylene glycol is polyethylene glycol.

[0256] As used herein, the term "sorbitan fatty acid ester" includes sorbitan esters and polyethoxylated sorbitan esters, and products derived from sorbitan or sorbitol and fatty acids and, optionally, poly(ethylene glycol) units. In some embodiments, the sorbitan fatty acid ester is a polyethoxylated sorbitan ester.

[0257] As used herein, the term "sorbitan ester" means a compound or mixture of compounds derived by the esterification of sorbitol with at least one fatty acid. Fatty acids useful for deriving sorbitan esters include, but are not limited to, those listed herein. Suitable sorbitan esters include Span 20 (sorbitan monolaurate), 40 (sorbitan monopalmitate), 60 (sorbitan monostearate), 65 (sorbitan tristearate), 80 (sorbitan monooleate), and 85 (sorbitan trioleate), which are available from Uniqema. TM Examples of suitable sorbitan esters include, but are not limited to, the series (available from Uniqema). Other suitable sorbitan esters are listed in RC Rowe and PJ Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed. (which, with proper attribution, are included as part of this specification).

[0258] As used herein, the term “polyethoxylated sorbitan ester” means a compound or mixture of compounds derived by the ethoxylation of a sorbitan ester. The polyoxyethylene portion of the compound may be between a fatty acid ester and a sorbitan portion. As used herein, the term “sorbitan ester” means a compound or mixture of compounds derived by the esterification of sorbitol with at least one fatty acid. Fatty acids useful for deriving polyethoxylated sorbitan esters include, but are not limited to, those described herein. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 2 to about 200 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 2 to about 100 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4 to about 8 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4 to about 40 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4 to about 20 oxyethylene units. Suitable polyethoxylated sorbitan esters include Tween 20 (POE(20) sorbitan monolaurate), 21 (POE(4) sorbitan monolaurate), 40 (POE(20) sorbitan monopalmitate), 60 (POE(20) sorbitan monostearate), 60K (POE(20) sorbitan monostearate), 61 (POE(4) sorbitan monostearate), 65 (POE(20) sorbitan tristearate), 80 (POE(20) sorbitan monooleate), 80K (POE(20) sorbitan monooleate), 81 (POE(5) sorbitan monooleate), and 85 (POE(20) sorbitan trioleate). TMExamples include, but are not limited to, the series (available from Uniqema). As used herein, the abbreviation "POE" means polyoxyethylene. The number following the abbreviation POE indicates the number of oxyethylene repeating units in the compound. Other suitable polyethoxylated sorbitan esters include polyoxyethylene sorbitan fatty acid esters listed in RC Rowe and PJ Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed. (which are included herein as a whole with due attribution). In some embodiments, the polyethoxylated sorbitan ester is polysorbate. In some embodiments, the polyethoxylated sorbitan ester is polysorbate 20.

[0259] As used herein, the term “glyceryl fatty acid ester” means a monoglyceride, diglyceride, or triglyceride of a fatty acid. Glyceryl fatty acid esters may be substituted with a sulfonic acid group or a pharmaceutically acceptable salt thereof. Suitable fatty acids for the derivatized glycerides of fatty acids include, but are not limited to, those described herein. In some embodiments, the glyceryl fatty acid ester is a monoglyceride of a fatty acid having 12 to 18 carbon atoms. In some embodiments, the glyceryl fatty acid ester is glyceryl stearate.

[0260] As used herein, the term “triglyceride” refers to a fatty acid triglyceride. In some embodiments, the triglyceride is a medium-chain triglyceride.

[0261] As used herein, the term "alkylene glycol" means a compound of the formula -O-alkylene- (wherein the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms). In some embodiments, the alkylene glycol is propylene glycol (1,2-propanediol).

[0262] As used herein, the term "polyethylene glycol" refers to a polymer containing ethylene glycol monomer units represented by the formula -O-CH2-CH2-. Preferred polyethylene glycols may have free hydroxyl groups at each end of the polymer molecule, or one or more hydroxyl groups etherified with a lower alkyl group (e.g., a methyl group). Derivatives of polyethylene glycol having esterifiable carboxyl groups are also preferred. Polyethylene glycols useful in the present invention may be polymers of any chain length or molecular weight and may include branching. In some embodiments, the average molecular weight of polyethylene glycol is about 200 to about 9000. In some embodiments, the average molecular weight of polyethylene glycol is about 200 to about 5000. In some embodiments, the average molecular weight of polyethylene glycol is about 200 to about 900. In some embodiments, the average molecular weight of polyethylene glycol is about 400. Suitable polyethylene glycols include, but are not limited to, polyethylene glycol-200, polyethylene glycol-300, polyethylene glycol-400, polyethylene glycol-600, and polyethylene glycol-900. The number following the dash in the name represents the average molecular weight of the polymer.

[0263] In some embodiments of the methods described herein, the biological sample is blood, serum, plasma, urine, cerebrospinal fluid, saliva, tears, or sweat. In some embodiments, the biological sample is blood, serum, or plasma.

[0264] In some embodiments of the methods described herein, the protein concentration is measured by immunological methods (e.g., selected from the group consisting of enzyme-linked immunosorbent assay, enzyme immunoassay, radioimmunoassay, chemiluminescence immunoassay, electrochemiluminescence immunoassay, latex turbidimetry immunoassay, Lux photometric immunoassay, immunochromatography, and Western blotting).

[0265] In some embodiments of the method described herein, the protein concentration is measured by mass spectrometry.

[0266] The term "baseline concentration" of protein refers to the concentration of protein in a subject before the initiation of treatment with ruxolitinib.

[0267] The term "decreased concentration" means that the concentration of the protein being analyzed is lower than the concentration of that protein in the control or in previous samples. For example, the concentration of the protein being analyzed may be at least 1 / 1.5, 1 / 2, 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 20, 1 / 25, 1 / 50, 1 / 75, or 1 / 100 of the concentration of that protein in the control, or at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1,000%, 1,500%, 2,000%, 2,500%, 3,000%, 3,500%, 4,000%, 4,500%, or 5,000% lower.

[0268] The term "increased concentration" means that the concentration of the protein being analyzed is higher than the concentration of that protein in the control or in previous samples. For example, the concentration of the protein being analyzed may be at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 25, 50, 75, or 100 times higher than the concentration of that protein in the control, or at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1,000%, 1,500%, 2,000%, 2,500%, 3,000%, 3,500%, 4,000%, 4,500%, or 5,000% higher.

[0269] "Responding to therapy" means that a subject who has received the therapy shows a positive reaction to the ruxolitinib therapy provided.

[0270] Combination therapy One or more additional pharmaceutical agents, such as anti-inflammatory agents, steroids, immunosuppressants, and Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors, such as those described in International Publication No. 2006 / 056399, may be used in combination with the formulation of the present invention for vitiligo. These one or more additional pharmaceutical agents may be administered to the patient simultaneously or sequentially.

[0271] Examples of steroids include corticosteroids such as dexamethasone or prednisone.

[0272] Examples of Bcr-Abl inhibitors include compounds of the genera and species disclosed in U.S. Patent No. 5,521,184, International Publication No. 04 / 005281, and U.S. Patent Application No. 60 / 578,491, as well as their pharmaceutically acceptable salts.

[0273] Examples of suitable Flt-3 inhibitors include the compounds disclosed in International Publication Nos. 03 / 037347, 03 / 099771, and 04 / 046120, and their pharmaceutically acceptable salts.

[0274] Examples of suitable RAF inhibitors include the compounds described in International Publication Nos. 00 / 09495 and International Publication Nos. 05 / 028444 and their pharmaceutically acceptable salts.

[0275] Examples of suitable FAK inhibitors include the compounds described in International Publication Nos. 04 / 080980, 04 / 056786, 03 / 024967, 01 / 064655, 00 / 053595, and 01 / 014402, and their pharmaceutically acceptable salts.

[0276] In some embodiments, the formulations of the present invention may be used in combination with one or more other kinase inhibitors, including imatinib, particularly to treat patients resistant to imatinib or other kinase inhibitors.

[0277] In some embodiments, a corticosteroid such as dexamethasone is administered to the patient in combination with the compound of the present invention, and the dexamethasone is administered intermittently, as opposed to being administered continuously.

[0278] The following embodiments are provided:

[0279] Embodiment 1. A method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a cream containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily.

[0280] Embodiment 2. The method according to Embodiment 1, wherein the cream contains 1.5 w / w% ruxolitinibrinate on a free base basis.

[0281] Embodiment 3. The method according to any one of Embodiments 1 to 2, wherein the patient achieves a 25% or greater improvement in the facial vitiligo area scoring index.

[0282] Embodiment 4. The method according to any one of Embodiments 1 to 2, wherein the patient achieves a 50% or greater improvement in the facial vitiligo area scoring index.

[0283] Embodiment 5. The method according to any one of Embodiments 1 to 2, wherein the patient achieves a 75% or greater improvement in the facial vitiligo area scoring index.

[0284] Embodiment 6. The method according to any one of Embodiments 1 to 2, wherein the patient achieves a 90% or greater improvement in the facial vitiligo area scoring index.

[0285] Embodiment 7. The method according to any one of Embodiments 1 to 6, wherein the patient achieves a 25% or greater improvement in the whole-body vitiligo area scoring index.

[0286] Embodiment 8. The method according to any one of Embodiments 1 to 6, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index.

[0287] Embodiment 9. The method according to any one of Embodiments 1 to 6, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index.

[0288] Embodiment 10. The method according to any one of Embodiments 1 to 9, wherein the patient achieves a score of 0 (no vitiligo) or 1 (mild) on the Patient's Comprehensive Assessment Response for Facial Vitiligo, and a reduction of at least 1 point from baseline.

[0289] Embodiment 11. The method according to any one of Embodiments 1 to 9, wherein the patient achieves a score of 0 (clear) or 1 (nearly clear) in a comprehensive assessment of facial vitiligo by a physician.

[0290] Embodiment 12. The method according to any one of Embodiments 1 to 9, wherein the patient achieves a score of 0 (clear) or 1 (nearly clear) in a comprehensive evaluation of vitiligo by a physician.

[0291] Embodiment 13. The method according to any one of Embodiments 1 to 9, wherein the patient achieves a 1 (very improved) or 2 (greatly improved) in the overall impression of the change in the vitiligo.

[0292] Embodiment 14. The method according to any one of Embodiments 1 to 13, wherein the patient has a baseline duration of illness of at least 10 years.

[0293] Embodiment 15. The method according to any one of Embodiments 1 to 13, wherein the patient has a baseline duration of illness of at least 20 years.

[0294] Embodiment 16. The method according to any one of Embodiments 1 to 13, wherein the patient has progressive vitiligo at baseline.

[0295] Embodiment 17. The method according to any one of Embodiments 1 to 13, wherein the patient has segmental vitiligo.

[0296] Embodiment 18. The method according to any one of Embodiments 1 to 17, wherein the administration is for a maximum of 24 weeks.

[0297] Embodiment 19. The method according to any one of Embodiments 1 to 17, wherein the administration is for a maximum of 52 weeks.

[0298] Embodiment 20. The method according to Embodiment 1, wherein the patient has segmental vitiligo and achieves a 50% or greater improvement in the facial vitiligo area scoring index score at 52 weeks.

[0299] Embodiment 21. The method according to Embodiment 1, wherein the patient has segmental vitiligo and achieves a 75% or greater improvement in the facial vitiligo area scoring index score at 52 weeks.

[0300] Embodiment 22. The method according to any one of Embodiments 1 and 20-21, wherein the patient has segmental vitiligo and achieves a 50% or greater improvement in the whole-body vitiligo area scoring index score at 52 weeks.

[0301] Embodiment 23. The method according to Embodiment 1, wherein the patient achieves a 25% or greater improvement in the upper limb vitiligo area scoring index score at 24 weeks.

[0302] Embodiment 24. The method according to Embodiment 1, wherein the patient achieves a 50% or greater improvement in the upper limb vitiligo area scoring index score at 24 weeks.

[0303] Embodiment 25. The method according to Embodiment 1, wherein the patient achieves a 75% or greater improvement in the upper limb vitiligo area scoring index score at 24 weeks.

[0304] Embodiment 26. The method according to Embodiment 1, wherein the patient achieves a 25% or greater improvement in the upper limb vitiligo area scoring index score at 52 weeks.

[0305] Embodiment 27. The method according to Embodiment 1, wherein the patient achieves a 50% or greater improvement in the upper limb vitiligo area scoring index score at 52 weeks.

[0306] Embodiment 28. The method according to Embodiment 1, wherein the patient achieves a 75% or greater improvement in the upper limb vitiligo area scoring index score at 52 weeks.

[0307] Embodiment 29. The method according to Embodiment 1, wherein the patient achieves a 25% or greater improvement in the lower extremity vitiligo area scoring index score at 24 weeks.

[0308] Embodiment 30. The method according to Embodiment 1, wherein the patient achieves a 50% or greater improvement in the lower extremity vitiligo area scoring index score at 24 weeks.

[0309] Embodiment 31. The method according to Embodiment 1, wherein the patient achieves a 75% or greater improvement in the lower extremity vitiligo area scoring index score at 24 weeks.

[0310] Embodiment 32. The method according to Embodiment 1, wherein the patient achieves a 25% or greater improvement in the lower extremity vitiligo area scoring index score at 52 weeks.

[0311] Embodiment 33. The method according to Embodiment 1, wherein the patient achieves a 50% or greater improvement in the lower extremity vitiligo area scoring index score at 52 weeks.

[0312] Embodiment 34. The method according to Embodiment 1, wherein the patient achieves a 75% or greater improvement in the lower extremity vitiligo area scoring index score at 52 weeks.

[0313] Embodiment 35. The method according to Embodiment 1, wherein the patient achieves a 25% or greater improvement in the hand vitiligo area scoring index score at 24 weeks.

[0314] Embodiment 36. The method according to Embodiment 1, wherein the patient achieves a 50% or greater improvement in the hand vitiligo area scoring index score at 24 weeks.

[0315] Embodiment 37. The method according to Embodiment 1, wherein the patient achieves a 75% or greater improvement in the hand vitiligo area scoring index score at 24 weeks.

[0316] Embodiment 38. The method according to Embodiment 1, wherein the patient achieves a 25% or greater improvement in the hand vitiligo area scoring index score at 52 weeks.

[0317] Embodiment 39. The method according to Embodiment 1, wherein the patient achieves a 50% or greater improvement in the hand vitiligo area scoring index score at 52 weeks.

[0318] Embodiment 40. The method according to Embodiment 1, wherein the patient achieves a 75% or greater improvement in the hand vitiligo area scoring index score at 52 weeks.

[0319] Embodiment 41. The method according to Embodiment 1, wherein the patient achieves a 25% or greater improvement in the vitiligo area scoring index score of the foot at 24 weeks.

[0320] Embodiment 42. The method according to Embodiment 1, wherein the patient achieves a 50% or greater improvement in the vitiligo area scoring index score of the foot at 24 weeks.

[0321] Embodiment 43. The method according to Embodiment 1, wherein the patient achieves a 75% or greater improvement in the vitiligo area scoring index score of the foot at 24 weeks.

[0322] Embodiment 44. The method according to Embodiment 1, wherein the patient achieves a 25% or greater improvement in the vitiligo area scoring index score of the foot at 52 weeks.

[0323] Embodiment 45. The method according to Embodiment 1, wherein the patient achieves a 50% or greater improvement in the vitiligo area scoring index score of the foot at 52 weeks.

[0324] Embodiment 46. The method according to Embodiment 1, wherein the patient achieves a 75% or greater improvement in the vitiligo area scoring index score of the foot at 52 weeks.

[0325] Embodiment 47. The method according to any one of Embodiments 1 to 46, wherein the cream is an oil-in-water emulsion.

[0326] Embodiment 48. The method according to any one of Embodiments 1 to 47, wherein the cream has a pH of about 2.8 to about 3.9.

[0327] Embodiment 49. The method according to any one of Embodiments 1 to 48, wherein the patient has a facial surface area percentage (F-BSA) of more than 1.5% affected by vitiligo.

[0328] Embodiment 50. The method according to any one of Embodiments 1 to 48, wherein the patient has a facial surface area percentage (F-BSA) affected by vitiligo exceeding 1.5%, and achieves a 50% or greater improvement in the facial vitiligo area scoring index score at 24 weeks.

[0329] Embodiment 51. The method according to any one of Embodiments 1 to 50, wherein the patient is an individual under 50 years of age.

[0330] Embodiment 52. The method according to any one of Embodiments 1 to 51, wherein the patient is female.

[0331] Embodiment 53. The method according to any one of Embodiments 1 to 52, wherein the patient has previously received phototherapy.

[0332] Embodiment 54. A method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a cream containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, twice daily.

[0333] Embodiment 55. The method according to Embodiment 54, wherein the cream contains 1.5 w / w% ruxolitinibrinate on a free base basis.

[0334] Embodiment 56. The method according to Embodiment 54, wherein the patient achieves a 25% or greater improvement in the facial vitiligo area scoring index.

[0335] Embodiment 57. The method according to Embodiment 54, wherein the patient achieves a 50% or greater improvement in the facial vitiligo area scoring index.

[0336] Embodiment 58. The method according to Embodiment 54, wherein the patient achieves a 75% or greater improvement in the facial vitiligo area scoring index.

[0337] Embodiment 59. The method according to Embodiment 54, wherein the patient achieves a 90% or greater improvement in the facial vitiligo area scoring index.

[0338] Embodiment 60. The method according to Embodiment 54, wherein the patient achieves a 25% or greater improvement in the whole-body vitiligo area scoring index.

[0339] Embodiment 61. The method according to Embodiment 54, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index.

[0340] Embodiment 62. The method according to Embodiment 54, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index.

[0341] Embodiment 63. The method according to Embodiment 54, wherein the patient achieves a score of 0 (no vitiligo) or 1 (mild) on the Patient's Comprehensive Assessment Response for Facial Vitiligo, and a reduction of at least 1 point from baseline.

[0342] Embodiment 64. The method according to Embodiment 54, wherein the patient achieves a score of 0 (clear) or 1 (nearly clear) in a comprehensive assessment of facial vitiligo by a physician.

[0343] Embodiment 65. The method according to Embodiment 54, wherein the patient achieves a score of 0 (clear) or 1 (nearly clear) in a comprehensive evaluation of vitiligo by a physician.

[0344] Embodiment 66. The method according to Embodiment 54, wherein the patient achieves an overall impression of the change in vitiligo as 1 (very improved) or 2 (greatly improved).

[0345] Embodiment 67. A method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a cream containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, once daily.

[0346] Embodiment 68. The method according to Embodiment 67, wherein the cream contains 1.5 w / w% ruxolitinibrinate on a free base basis.

[0347] Embodiment 69. The method according to Embodiment 67, wherein the patient achieves a 25% or greater improvement in the facial vitiligo area scoring index.

[0348] Embodiment 70. The method according to Embodiment 67, wherein the patient achieves a 50% or greater improvement in the facial vitiligo area scoring index.

[0349] Embodiment 71. The method according to Embodiment 67, wherein the patient achieves a 75% or greater improvement in the facial vitiligo area scoring index.

[0350] Embodiment 72. The method according to Embodiment 67, wherein the patient achieves a 90% or greater improvement in the facial vitiligo area scoring index.

[0351] Embodiment 73. The method according to Embodiment 67, wherein the patient achieves a 25% or greater improvement in the whole-body vitiligo area scoring index.

[0352] Embodiment 74. The method according to Embodiment 67, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index.

[0353] Embodiment 75. The method according to Embodiment 67, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index.

[0354] Embodiment 76. The method according to Embodiment 67, wherein the patient achieves a score of 0 (no vitiligo) or 1 (mild) on the Patient's Comprehensive Assessment Response for Facial Vitiligo, and a reduction of at least 1 point from baseline.

[0355] Embodiment 77. The method according to Embodiment 67, wherein the patient achieves a score of 0 (clear) or 1 (nearly clear) in a comprehensive assessment of facial vitiligo by a physician.

[0356] Embodiment 78. The method of Embodiment 67, wherein the patient achieves a score of 0 (clear) or 1 (nearly clear) in a comprehensive evaluation of vitiligo by a physician.

[0357] Embodiment 79. The method according to Embodiment 67, wherein the patient achieves an overall impression of the change in vitiligo by the patient of 1 (very improved) or 2 (greatly improved).

[0358] Embodiment 80. A method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a cream containing about 0.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, once daily.

[0359] Embodiment 81. The method according to Embodiment 80, wherein the cream contains 0.5 w / w% ruxolitinibulinate on a free base basis.

[0360] Embodiment 82. The method according to Embodiment 80, wherein the patient achieves a 25% or greater improvement in the facial vitiligo area scoring index.

[0361] Embodiment 83. The method according to Embodiment 80, wherein the patient achieves a 50% or greater improvement in the facial vitiligo area scoring index.

[0362] Embodiment 84. The method according to Embodiment 80, wherein the patient achieves a 75% or greater improvement in the facial vitiligo area scoring index.

[0363] Embodiment 85. The method according to Embodiment 80, wherein the patient achieves a 90% or greater improvement in the facial vitiligo area scoring index.

[0364] Embodiment 86. The method according to Embodiment 80, wherein the patient achieves a 25% or greater improvement in the whole-body vitiligo area scoring index.

[0365] Embodiment 87. The method according to Embodiment 80, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index.

[0366] Embodiment 88. The method according to Embodiment 80, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index.

[0367] Embodiment 89. The method according to Embodiment 80, wherein the patient achieves a score of 0 (no vitiligo) or 1 (mild) on the Patient's Comprehensive Assessment Response for Facial Vitiligo, and a reduction of at least 1 point from baseline.

[0368] Embodiment 90. The method according to Embodiment 80, wherein the patient achieves a score of 0 (clear) or 1 (nearly clear) in a comprehensive assessment of facial vitiligo by a physician.

[0369] Embodiment 91. The method according to Embodiment 80, wherein the patient achieves a score of 0 (clear) or 1 (nearly clear) in a comprehensive evaluation of vitiligo by a physician.

[0370] Embodiment 92. The method according to Embodiment 80, wherein the patient achieves a 1 (very improved) or 2 (greatly improved) in the overall impression of the change in the vitiligo.

[0371] Embodiment 93. A method for treating vitiligo in a patient, comprising administering to the patient in need of such treatment a cream containing about 0.15 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis, once daily.

[0372] Embodiment 94. The method according to Embodiment 93, wherein the cream contains 0.15 w / w% ruxolitinibrinate on a free base basis.

[0373] Embodiment 95. The method according to Embodiment 93, wherein the patient achieves a 25% or greater improvement in the facial vitiligo area scoring index.

[0374] Embodiment 96. The method according to Embodiment 93, wherein the patient achieves a 50% or greater improvement in the facial vitiligo area scoring index.

[0375] Embodiment 97. The method according to Embodiment 93, wherein the patient achieves a 75% or greater improvement in the facial vitiligo area scoring index.

[0376] Embodiment 98. The method according to Embodiment 93, wherein the patient achieves a 90% or greater improvement in the facial vitiligo area scoring index.

[0377] Embodiment 99. The method according to Embodiment 93, wherein the patient achieves a 25% or greater improvement in the whole-body vitiligo area scoring index.

[0378] Embodiment 100. The method according to Embodiment 93, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index.

[0379] Embodiment 101. The method according to Embodiment 93, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index.

[0380] Embodiment 102. The method according to Embodiment 93, wherein the patient achieves a score of 0 (no vitiligo) or 1 (mild) on the Patient's Comprehensive Assessment Response for Facial Vitiligo, and a reduction of at least 1 point from baseline.

[0381] Embodiment 103. The method according to Embodiment 93, wherein the patient achieves a score of 0 (clear) or 1 (nearly clear) in a comprehensive assessment of facial vitiligo by a physician.

[0382] Embodiment 104. The method according to Embodiment 93, wherein the patient achieves a score of 0 (clear) or 1 (nearly clear) in a comprehensive evaluation of vitiligo by a physician.

[0383] Embodiment 105. The method according to Embodiment 93, wherein the patient achieves a 1 (very improved) or 2 (greatly improved) in the overall impression of the change in the vitiligo.

[0384] Embodiment 106. A method for treating vitiligo in a patient, comprising topically administering a pharmaceutical composition containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis to the affected area of ​​the patient's skin requiring treatment, twice daily.

[0385] Embodiment 107. The method according to Embodiment 106, wherein the vitiligo is generalized vitiligo.

[0386] Embodiment 108. A method for treating vitiligo in a patient, comprising topically administering a pharmaceutical composition containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis to a skin area of ​​the patient requiring treatment, wherein the affected area is selected from the lower limbs, trunk, hands, upper limbs, and feet.

[0387] Embodiment 109. The method according to Embodiment 108, wherein the affected skin area is the patient's lower limb.

[0388] Embodiment 110. The method according to Embodiment 108, wherein the affected area of ​​skin is the torso of the patient.

[0389] Embodiment 111. The method according to Embodiment 108, wherein the affected skin area is the patient's hand.

[0390] Embodiment 112. The method according to Embodiment 108, wherein the affected skin area is the patient's upper limb.

[0391] Embodiment 113. The method according to Embodiment 108, wherein the affected area of ​​skin is the patient's foot.

[0392] Embodiment 114. The method according to any one of Embodiments 108 to 113, wherein the patient achieves a 25% or greater improvement in the vitiligo area scoring index in the affected skin area.

[0393] Embodiment 115. The method according to any one of Embodiments 108 to 114, wherein the patient achieves a 50% or greater improvement in the vitiligo area scoring index in the affected skin area.

[0394] Embodiment 116. The method according to any one of Embodiments 108 to 115, wherein the patient achieves a 75% or greater improvement in the vitiligo area scoring index in the affected skin area.

[0395] Embodiment 117. The method according to any one of Embodiments 108 to 116, wherein the patient achieves a 50% or greater improvement in the patient's hand vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

[0396] Embodiment 118. The method according to any one of Embodiments 108 to 117, wherein the patient achieves a 50% or greater improvement in the patient's upper limb vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

[0397] Embodiment 119. The method according to any one of Embodiments 108 to 118, wherein the patient achieves a 50% or greater improvement in the patient's foot vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

[0398] Embodiment 120. The method according to any one of Embodiments 108 to 119, wherein the patient achieves a 50% or greater improvement in the patient's lower limb vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

[0399] Embodiment 121. The method according to any one of Embodiments 108 to 120, wherein the patient achieves a 50% or greater improvement in the patient's trunk vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

[0400] Embodiment 122. The affected area is selected from the lower limbs, trunk, hands, upper limbs, and feet; The patient has generalized vitiligo with depigmented areas of (i) 0.5% or more of the body surface area (BSA) on the face, (ii) 3% or more of the BSA in non-facial areas, and (iii) not more than 10% of the total body surface area; The method does not involve administering lasers or any type of phototherapy; Patients achieve a 50% or greater improvement in the vitiligo area scoring index score of the affected skin area. The method according to Embodiment 108.

[0401] Embodiment 123. The affected area is selected from the lower limbs, trunk, and feet; The patient has generalized vitiligo with depigmented areas of (i) 0.5% or more of the body surface area (BSA) on the face, (ii) 3% or more of the BSA in non-facial areas, and (iii) not more than 10% of the total body surface area; The method does not involve administering lasers or any type of phototherapy; Patients achieve a 50% or greater improvement in the vitiligo area scoring index score of the affected skin area. The method according to Embodiment 108.

[0402] Embodiment 124. A method for treating generalized vitiligo in a patient, comprising topically administering a pharmaceutical composition containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis to the affected skin area of ​​the patient requiring the treatment, wherein the patient has had vitiligo for at least 20 years, and the patient achieves an improvement of 50% or more in the facial vitiligo scoring index.

[0403] Embodiment 125. The method according to Embodiment 124, wherein the affected area is the face.

[0404] Embodiment 126. The method according to Embodiment 124, wherein the affected area is the head and neck.

[0405] Embodiment 127. The method according to Embodiment 124, wherein the affected area is selected from the lower limbs, trunk, hands, upper limbs, and feet.

[0406] Embodiment 128. A method for treating vitiligo in a patient, comprising topically administering a pharmaceutical composition containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis to the affected area of ​​the patient's skin requiring treatment, wherein the patient is not receiving phototherapy for vitiligo during the administration of the pharmaceutical composition.

[0407] Embodiment 129. The method according to any one of Embodiments 106 to 128, wherein the patient achieves a 25% or greater improvement in the facial vitiligo area scoring index.

[0408] Embodiment 130. The method according to any one of Embodiments 106 to 129, wherein the patient achieves a 50% or greater improvement in the facial vitiligo area scoring index.

[0409] Embodiment 131. The method according to any one of Embodiments 106 to 130, wherein the patient achieves a 75% or greater improvement in the facial vitiligo area scoring index.

[0410] Embodiment 132. The method according to any one of Embodiments 106 to 131, wherein the patient achieves a 90% or greater improvement in the facial vitiligo area scoring index.

[0411] Embodiment 133. The method according to any one of Embodiments 106 to 132, wherein the patient achieves a 25% or greater improvement in the whole-body vitiligo area scoring index.

[0412] Embodiment 134. The method according to any one of Embodiments 106 to 133, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index.

[0413] Embodiment 135. The method according to any one of Embodiments 106 to 134, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index.

[0414] Embodiment 136. The method according to any one of Embodiments 106 to 135, wherein the administration is for a maximum of 24 weeks.

[0415] Embodiment 137. The method according to any one of Embodiments 106 to 136, wherein the administration is for a maximum of 52 weeks.

[0416] Embodiment 138. The method according to any one of Embodiments 106 to 137, wherein the patient has at least 1.5% of the facial body surface area (F-BSA) affected by vitiligo.

[0417] Embodiment 139. The method according to any one of Embodiments 106 to 138, wherein the patient has at least 1.5% of the facial body surface area (F-BSA) affected by vitiligo, and achieves a 50% or greater improvement in the facial vitiligo area scoring index score at 24 weeks.

[0418] Embodiment 140. The method according to any one of Embodiments 106 to 139, wherein the patient has 1.5% of the facial body surface area (F-BSA) affected by vitiligo and achieves a 50% or greater improvement in the facial vitiligo area scoring index score at 52 weeks.

[0419] Embodiment 141. The method according to any one of Embodiments 106 to 140, wherein the patient has 1.5% of the facial body surface area (F-BSA) affected by vitiligo and achieves a 75% or greater improvement in the facial vitiligo area scoring index score at 24 weeks.

[0420] Embodiment 142. The method according to any one of Embodiments 106 to 141, wherein the patient has at least 1.5% of the facial body surface area (F-BSA) affected by vitiligo, and achieves a 75% or greater improvement in the facial vitiligo area scoring index score at 52 weeks.

[0421] Embodiment 143. The method according to any one of Embodiments 106 to 142, wherein the patient achieves a 25% or greater improvement in the whole-body vitiligo area scoring index score at 24 weeks.

[0422] Embodiment 144. The method according to any one of Embodiments 106 to 143, wherein the patient achieves a 25% or greater improvement in the whole-body vitiligo area scoring index score at 52 weeks.

[0423] Embodiment 145. The method according to any one of Embodiments 106 to 144, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index score at 24 weeks.

[0424] Embodiment 146. The method according to any one of Embodiments 106 to 145, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index score at 52 weeks.

[0425] Embodiment 147. The method according to any one of Embodiments 106 to 146, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index score at 24 weeks.

[0426] Embodiment 148. The method according to any one of Embodiments 106 to 147, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index score at 52 weeks.

[0427] Embodiment 149. The method according to any one of Embodiments 106 to 148, wherein the patient has a total body surface area (T-BSA) affected by vitiligo that does not exceed 10%.

[0428] Embodiment 150. The method according to any one of Embodiments 106 to 149, wherein the patient is clinically diagnosed with vitiligo.

[0429] Embodiment 151. The method according to any one of Embodiments 106 to 150, wherein the patient is 12 years of age or older.

[0430] Embodiment 152. The method according to any one of Embodiments 106 to 150, wherein the patient is 18 years of age or older.

[0431] Embodiment 153. The method according to any one of Embodiments 106 to 150, wherein the patient is between 18 and 75 years of age.

[0432] Embodiment 154. The method according to any one of Embodiments 106 to 150, wherein the patient is 50 years of age or younger.

[0433] Embodiment 155. The method according to any one of Embodiments 106 to 154, wherein the patient has progressive vitiligo at baseline.

[0434] Embodiment 156. The method according to any one of Embodiments 106 to 155, wherein the patient has at least 0.5% of their facial surface area affected by vitiligo.

[0435] Embodiment 157. The method according to any one of Embodiments 106 to 156, wherein the patient has at least 3% of the non-facial body surface area affected by vitiligo.

[0436] Embodiment 158. The method according to any one of Embodiments 106 to 157, wherein the patient has a total body surface area affected by vitiligo that does not exceed 10%.

[0437] Embodiment 159. The method according to any one of Embodiments 106 to 158, wherein the patient has a baseline duration of illness of at least 10 years.

[0438] Embodiment 160. The method according to any one of Embodiments 106 to 159, wherein the patient has not received any other medications for the treatment of vitiligo.

[0439] Embodiment 161. The method according to any one of Embodiments 106 to 160, wherein the patient has previously received phototherapy.

[0440] Embodiment 162. The method according to any one of Embodiments 106 to 161, wherein the method does not involve administering a laser or any type of phototherapy.

[0441] Embodiment 163. The method according to any one of Embodiments 106 to 162, wherein the patient's hemoglobin level at week 52 is similar to the patient's hemoglobin level at baseline.

[0442] Embodiment 164. The method according to any one of Embodiments 106 to 163, wherein the patient's platelet level at week 52 is similar to the patient's platelet level at baseline.

[0443] Embodiment 165. The method according to any one of Embodiments 106 to 164, wherein there is no substantial difference in response between patients with vitiligo whose baseline total surface area is 20% or less and patients with vitiligo whose baseline total surface area is greater than 20%.

[0444] Embodiment 166. The method according to any one of Embodiments 106 to 165, wherein ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0445] Embodiment 167. The method according to any one of Embodiments 106 to 166, wherein the pharmaceutical composition is a cream.

[0446] Embodiment 168. The method according to Embodiment 167, wherein the cream is an oil-in-water emulsion.

[0447] Embodiment 169. The method according to Embodiment 168, wherein the cream contains 1.5 w / w% ruxolitinibrinate on a free base basis.

[0448] Embodiment 170. The method according to Embodiment 169, wherein the cream has a pH of about 2.8 to about 3.9.

[0449] Embodiment 171. The method according to Embodiment 106, wherein the vitiligo is segmental vitiligo.

[0450] Embodiment 172. A pharmaceutical composition for use in any of the methods described in Embodiments 106 to 171.

[0451] Embodiment 173. Use of a pharmaceutical composition for the manufacture of a pharmaceutical for use in any of the methods described in Embodiments 106 to 171.

[0452] Embodiment 174. A method for treating vitiligo in a patient, comprising topically administering a pharmaceutical composition containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis to the affected area of ​​the patient in need of treatment, the affected area being selected from the lower limbs, trunk, hands, upper limbs, and feet.

[0453] Embodiment 175. The method according to Embodiment 174, wherein ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0454] Embodiment 176. The method according to Embodiment 174, wherein the method does not involve administering a laser or any type of phototherapy.

[0455] Embodiment 177. The method according to Embodiment 174, wherein the affected area of ​​skin is the patient's lower limb.

[0456] Embodiment 178. The method according to Embodiment 174, wherein the affected area of ​​skin is the torso of the patient.

[0457] Embodiment 179. The method according to Embodiment 174, wherein the affected skin area is the patient's hand.

[0458] Embodiment 180. The method according to Embodiment 174, wherein the affected skin area is the patient's upper limb.

[0459] Embodiment 181. The method according to Embodiment 174, wherein the affected area of ​​skin is the patient's foot.

[0460] Embodiment 182. The method according to Embodiment 174, wherein the patient achieves a 25% or greater improvement in the vitiligo area scoring index in the affected skin area.

[0461] Embodiment 183. The method according to Embodiment 174, wherein the patient achieves a 50% or greater improvement in the vitiligo area scoring index in the affected skin area.

[0462] Embodiment 184. The method according to Embodiment 174, wherein the patient achieves a 75% or greater improvement in the vitiligo area scoring index in the affected skin area.

[0463] Embodiment 185. The method according to Embodiment 174, wherein the patient has at least 0.5% of their facial surface area affected by vitiligo.

[0464] Embodiment 186. The method according to Embodiment 174, wherein the patient has at least 3% of the non-facial body surface area affected by vitiligo.

[0465] Embodiment 187. The method according to Embodiment 174, wherein the patient has at least 0.5% of the facial surface area affected by vitiligo and at least 3% of the non-facial surface area affected by vitiligo.

[0466] Embodiment 188. The method according to Embodiment 174, wherein the patient is clinically diagnosed with vitiligo.

[0467] Embodiment 189. The method according to Embodiment 174, wherein the patient has not received any other medications for the treatment of vitiligo.

[0468] Embodiment 190. The method according to Embodiment 174, wherein the patient is between 18 and 75 years of age.

[0469] Embodiment 191. The method according to Embodiment 174, wherein the patient achieves a 25% or greater improvement in the patient's hand vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

[0470] Embodiment 192. The method according to Embodiment 174, wherein the patient achieves a 25% or greater improvement in the patient's upper limb vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

[0471] Embodiment 193. The method according to Embodiment 174, wherein the patient achieves a 25% or greater improvement in the patient's foot vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

[0472] Embodiment 194. The method according to Embodiment 174, wherein the patient achieves a 25% or greater improvement in the patient's lower limb vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

[0473] Embodiment 195. The method according to Embodiment 174, wherein the patient achieves a 25% or greater improvement in the patient's trunk vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

[0474] Embodiment 196. The method according to Embodiment 174, wherein the patient achieves a 50% or greater improvement in the patient's hand vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

[0475] Embodiment 197. The method according to Embodiment 174, wherein the patient achieves a 50% or greater improvement in the patient's upper limb vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

[0476] Embodiment 198. The method according to Embodiment 174, wherein the patient achieves a 50% or greater improvement in the patient's foot vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

[0477] Embodiment 199. The method according to Embodiment 174, wherein the patient achieves a 50% or greater improvement in the patient's lower limb vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

[0478] Embodiment 200. The method according to Embodiment 174, wherein the patient achieves a 50% or greater improvement in the patient's trunk vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

[0479] Embodiment 201. The method according to Embodiment 174, wherein the patient achieves a 75% or greater improvement in the vitiligo area scoring index score of the patient's lower limbs, upper limbs, feet, hands, or trunk at week 4, 8, 18, 24, 32, 38, 42, 48, or 52.

[0480] Embodiment 202. The method according to Embodiment 174, wherein the pharmaceutical composition is a cream.

[0481] Embodiment 203. The method according to Embodiment 202, wherein the cream is an oil-in-water emulsion.

[0482] Embodiment 204. The method according to Embodiment 203, wherein the cream contains 1.5 w / w% ruxolitinibrinate on a free base basis.

[0483] Embodiment 205. The method according to Embodiment 204, wherein the cream has a pH of about 2.8 to about 3.9.

[0484] Embodiment 206. The method according to Embodiment 174, wherein there is no substantial difference in response between patients with vitiligo whose baseline total body surface area (T-BSA) is 20% or less and patients whose baseline T-BSA is greater than 20%.

[0485] Embodiment 207. A method for treating generalized vitiligo in a patient, comprising topically administering a cream containing 1.5 w / w% ruxolitinibrinate on a free base basis to the affected skin area of ​​the patient requiring treatment twice daily. The affected area is selected from the lower limbs, trunk, hands, upper limbs, and feet; The patient is 18 years of age or older; The patient has generalized vitiligo with (i) a body surface area (BSA) of 0.5% or more on the face, (ii) a BSA of 3% or more in non-facial areas, and (iii) a BSA-depigmented area of ​​no more than 10% of the total body surface area; The method does not involve administering lasers or any type of phototherapy; Patients achieve a 50% or greater improvement in the vitiligo area scoring index score of the affected skin area. method.

[0486] Embodiment 208. A method for treating generalized vitiligo in a patient, comprising topically administering a cream containing 1.5 w / w% ruxolitinibrinate on a free base basis to the affected skin area of ​​the patient requiring treatment twice daily. The affected area is selected from the lower limbs, trunk, and feet; The patient is 18 years of age or older; The patient has generalized vitiligo with (i) a body surface area (BSA) of 0.5% or more on the face, (ii) a BSA of 3% or more in non-facial areas, and (iii) a BSA-depigmented area of ​​no more than 10% of the total body surface area; The method does not involve administering lasers or any type of phototherapy; Patients achieve a 50% or greater improvement in the vitiligo area scoring index score of the affected skin area. method.

[0487] Embodiment 209. A method for treating generalized vitiligo in a patient, comprising topically administering a pharmaceutical composition containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis to the affected skin area of ​​the patient requiring the treatment, wherein the patient has had vitiligo for at least 20 years, and the patient achieves an improvement of 50% or more in the facial vitiligo scoring index.

[0488] Embodiment 210. The method according to Embodiment 209, wherein the ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0489] Embodiment 211. The method according to Embodiment 209, wherein the pharmaceutical composition is a cream.

[0490] Embodiment 212. The method according to Embodiment 211, wherein the cream is an oil-in-water emulsion.

[0491] Embodiment 213. The method according to Embodiment 212, wherein the cream contains 1.5 w / w% ruxolitinibulinate on a free base basis.

[0492] Embodiment 214. The method according to Embodiment 213, wherein the cream has a pH of about 2.8 to about 3.9.

[0493] Embodiment 215. The method according to Embodiment 209, wherein the patient has at least 0.5% of their facial surface area affected by vitiligo.

[0494] Embodiment 216. The method according to Embodiment 209, wherein the patient has at least 3% of the non-facial body surface area affected by vitiligo.

[0495] Embodiment 217. The method according to Embodiment 209, wherein the patient has generalized vitiligo with depigmented areas, wherein (i) at least 0.5% of the facial surface area affected by vitiligo, and (ii) at least 3% of the non-facial surface area affected by vitiligo.

[0496] Embodiment 218. The method according to Embodiment 209, wherein the patient has a total surface area affected by vitiligo that does not exceed 10%.

[0497] Embodiment 219. The method according to Embodiment 209, wherein the patient achieves a 75% or greater improvement in the facial vitiligo area scoring index.

[0498] Embodiment 220. The method according to Embodiment 209, wherein the patient achieves a 90% or greater improvement in the facial vitiligo area scoring index.

[0499] Embodiment 221. The method according to Embodiment 209, wherein the patient achieves a 25% or greater improvement in the whole-body vitiligo area scoring index.

[0500] Embodiment 222. The method according to Embodiment 209, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index.

[0501] Embodiment 223. The method according to Embodiment 209, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index.

[0502] Embodiment 224. The method according to Embodiment 209, wherein the patient has at least 1.5% of their facial surface area affected by vitiligo.

[0503] Embodiment 225. The method according to Embodiment 209, wherein the patient has at least 1.5% of the facial surface area affected by vitiligo, and achieves a 50% or greater improvement in the facial vitiligo area scoring index score at 24 weeks.

[0504] Embodiment 226. The method according to Embodiment 209, wherein the patient has at least 1.5% of the facial surface area affected by vitiligo, and achieves a 50% or greater improvement in the facial vitiligo area scoring index score at 52 weeks.

[0505] Embodiment 227. The method according to Embodiment 209, wherein the patient has at least 1.5% of the facial surface area affected by vitiligo, and achieves a 75% or greater improvement in the facial vitiligo area scoring index score at 24 weeks.

[0506] Embodiment 228. The method according to Embodiment 209, wherein the patient has at least 1.5% of the facial surface area affected by vitiligo, and achieves a 75% or greater improvement in the facial vitiligo area scoring index score at 52 weeks.

[0507] Embodiment 229. The method according to Embodiment 209, wherein the patient achieves a 25% or greater improvement in the whole-body vitiligo area scoring index score at 24 weeks.

[0508] Embodiment 230. The method according to Embodiment 209, wherein the patient achieves a 25% or greater improvement in the whole-body vitiligo area scoring index score at 52 weeks.

[0509] Embodiment 231. The method according to Embodiment 209, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index score at 24 weeks.

[0510] Embodiment 232. The method according to Embodiment 209, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index score at 52 weeks.

[0511] Embodiment 233. The method according to Embodiment 209, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index score at 24 weeks.

[0512] Embodiment 234. The method according to Embodiment 209, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index score at 52 weeks.

[0513] Embodiment 235. The method according to Embodiment 209, wherein the patient has been clinically diagnosed with vitiligo.

[0514] Embodiment 236. The method according to Embodiment 209, wherein the patient has not received any other medications for the treatment of vitiligo.

[0515] Embodiment 237. The method according to Embodiment 209, wherein the patient is between 18 and 75 years of age.

[0516] Embodiment 238. The method according to Embodiment 209, wherein the patient is 50 years of age or younger.

[0517] Embodiment 239. The method according to Embodiment 209, wherein the patient has previously received phototherapy.

[0518] Embodiment 240. The method according to Embodiment 209, wherein the method does not involve administering a laser or any type of phototherapy.

[0519] Embodiment 241. The method according to Embodiment 209, wherein the patient's hemoglobin level at 52 weeks is similar to the patient's hemoglobin level observed at baseline.

[0520] Embodiment 242. The method according to Embodiment 209, wherein the patient's platelet level at 52 weeks is similar to the patient's platelet level observed at baseline.

[0521] Embodiment 243. The method according to Embodiment 209, wherein there is no substantial difference in response between patients with a baseline total surface area of ​​20% or less and patients with a baseline total surface area of ​​more than 20%.

[0522] Embodiment 244. The method according to Embodiment 209, wherein the affected area is the face.

[0523] Embodiment 245. The method according to Embodiment 209, wherein the affected area is the head and neck.

[0524] Embodiment 246. The method according to Embodiment 209, wherein the affected area is selected from the lower limbs, trunk, hands, upper limbs, and feet.

[0525] Embodiment 247. The method according to Embodiment 209, wherein the patient is not receiving phototherapy for vitiligo during administration of the pharmaceutical composition.

[0526] Embodiment 248. The method according to Embodiment 209, wherein the patient has progressive vitiligo at baseline.

[0527] Embodiment 249. A method for treating generalized vitiligo in a patient, comprising topically administering a pharmaceutical composition containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis to the affected area of ​​the patient's skin requiring treatment, twice daily.

[0528] Embodiment 250. A method for treating vitiligo in a patient, comprising topically administering a pharmaceutical composition containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis to the affected area of ​​the patient's skin requiring treatment, wherein the patient is not receiving phototherapy for vitiligo during the administration of the pharmaceutical composition.

[0529] Embodiment 251. The method according to Embodiment 249 or 250, wherein ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

[0530] Embodiment 252. The method according to Embodiment 249 or 250, wherein the patient achieves a 25% or greater improvement in the facial vitiligo area scoring index.

[0531] Embodiment 253. The method according to Embodiment 249 or 250, wherein the patient achieves a 50% or greater improvement in the facial vitiligo area scoring index.

[0532] Embodiment 254. The method according to Embodiment 249 or 250, wherein the patient achieves a 75% or greater improvement in the facial vitiligo area scoring index.

[0533] Embodiment 255. The method according to Embodiment 249 or 250, wherein the patient achieves a 90% or greater improvement in the facial vitiligo area scoring index.

[0534] Embodiment 256. The method according to Embodiment 249 or 250, wherein the patient achieves a 25% or greater improvement in the whole-body vitiligo area scoring index.

[0535] Embodiment 257. The method according to Embodiment 249 or 250, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index.

[0536] Embodiment 258. The method according to Embodiment 249 or 250, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index.

[0537] Embodiment 259. The method according to Embodiment 249 or 250, wherein the administration is for a maximum of 24 weeks.

[0538] Embodiment 260. The method according to Embodiment 249 or 250, wherein the administration is for a maximum of 52 weeks.

[0539] Embodiment 261. The method according to Embodiment 249 or 250, wherein the patient has at least 1.5% of their facial surface area affected by vitiligo.

[0540] Embodiment 262. The method according to Embodiment 249 or 250, wherein the patient has at least 1.5% of the facial surface area affected by vitiligo, and achieves a 50% or greater improvement in the facial vitiligo area scoring index score at 24 weeks.

[0541] Embodiment 263. The method according to Embodiment 249 or 250, wherein the patient has 1.5% of the facial surface area affected by vitiligo and achieves a 50% or greater improvement in the facial vitiligo area scoring index score at 52 weeks.

[0542] Embodiment 264. The method according to Embodiment 249 or 250, wherein the patient has 1.5% of the facial surface area affected by vitiligo and achieves a 75% or greater improvement in the facial vitiligo area scoring index score at 24 weeks.

[0543] Embodiment 265. The method according to Embodiment 249 or 250, wherein the patient has at least 1.5% of the facial surface area affected by vitiligo, and achieves a 75% or greater improvement in the facial vitiligo area scoring index score at 52 weeks.

[0544] Embodiment 266. The method according to Embodiment 249 or 250, wherein the patient achieves a 25% or greater improvement in the whole-body vitiligo area scoring index score at 24 weeks.

[0545] Embodiment 267. The method according to Embodiment 249 or 250, wherein the patient achieves a 25% or greater improvement in the whole-body vitiligo area scoring index score at 52 weeks.

[0546] Embodiment 268. The method according to Embodiment 249 or 250, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index score at 24 weeks.

[0547] Embodiment 269. The method according to Embodiment 249 or 250, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index score at 52 weeks.

[0548] Embodiment 270. The method according to Embodiment 249 or 250, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index score at 24 weeks.

[0549] Embodiment 271. The method according to Embodiment 249 or 250, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index score at 52 weeks.

[0550] Embodiment 272. The method according to Embodiment 249 or 250, wherein the patient has a total body surface area affected by vitiligo that does not exceed 10%.

[0551] Embodiment 273. The method according to Embodiment 249 or 250, wherein the pharmaceutical composition is a cream.

[0552] Embodiment 274. The method according to Embodiment 273, wherein the cream is an oil-in-water emulsion.

[0553] Embodiment 275. The method according to Embodiment 274, wherein the cream contains 1.5 w / w% ruxolitinibrinate on a free base basis.

[0554] Embodiment 276. The method according to Embodiment 275, wherein the cream has a pH of about 2.8 to about 3.9.

[0555] Embodiment 277. The method according to Embodiment 249 or 250, wherein the patient is 50 years of age or younger.

[0556] Embodiment 278. The method according to Embodiment 249 or 250, wherein the patient has progressive vitiligo at baseline.

[0557] Embodiment 279. The method according to Embodiment 249 or 250, wherein the patient has previously received phototherapy.

[0558] Embodiment 280. The method according to Embodiment 249 or 250, wherein the patient's hemoglobin level at 52 weeks is similar to the patient's hemoglobin level at baseline.

[0559] Embodiment 281. The method according to Embodiment 249 or 250, wherein the patient's platelet level at week 52 is similar to the patient's platelet level at baseline.

[0560] Embodiment 282. The method according to Embodiment 249 or 250, wherein there is no substantial difference in response between patients with a baseline total surface area score of 20% or less and patients with a baseline total surface area score greater than 20%.

[0561] Embodiment 283. The method according to Embodiment 249 or 250, wherein the vitiligo is segmental vitiligo.

[0562] Embodiment 284. The method according to Embodiment 249 or 250, wherein the patient has had vitiligo for at least 20 years.

[0563] Embodiment 285. The method according to Embodiment 249 or 250, wherein the patient has a baseline duration of illness of at least 10 years.

[0564] Embodiment 286. The method according to Embodiment 249 or 250, wherein the affected area of ​​skin is the face.

[0565] Embodiment 287. The method according to Embodiment 249 or 250, wherein the affected area of ​​skin is the head and neck.

[0566] Embodiment 288. The method according to Embodiment 249 or 250, wherein the affected skin area is selected from the lower limbs, trunk, hands, upper limbs, and feet.

[0567] Embodiment 289. The method according to Embodiment 249 or 250, wherein the affected skin area is selected from the non-acral lower limb and the non-acral upper limb.

[0568] Embodiment 290. The method according to Embodiment 249 or 250, wherein the patient has at least 0.5% of their facial surface area affected by vitiligo.

[0569] Embodiment 291. The method according to Embodiment 249 or 250, wherein the patient has at least 3% of the non-facial body surface area affected by vitiligo.

[0570] Embodiment 292. The method according to Embodiment 249 or 250, wherein the patient has at least 0.5% of the facial surface area affected by vitiligo and at least 3% of the non-facial surface area affected by vitiligo.

[0571] Embodiment 293. The method according to Embodiment 249 or 250, wherein the patient has been clinically diagnosed with vitiligo.

[0572] Embodiment 294. The method according to Embodiment 249 or 250, wherein the patient has not received any other medications for the treatment of vitiligo.

[0573] Embodiment 295. The method according to Embodiment 249 or 250, wherein the patient is between 18 and 75 years of age.

[0574] The following are embodiments of the present invention. These should not be construed as limiting the scope of the present invention. [Examples]

[0575] Example 1 - Phase II trial of ruxolitinib for the treatment of vitiligo vulgaris INCB18424-211 was a phase II, randomized, double-blind, vehicle-controlled, three-part study in adults with vitiligo vulgaris having depigmented areas containing at least 0.5% BSA on the face and at least 3% BSA in non-facial areas. A total of 157 participants were equally randomized to receive ruxolitinib cream 1.5% BID, 1.5% QD, 0.5% QD, 0.15% QD, or vehicle BID for 24 weeks. Ruxolitinib in the cream formulations was present as ruxolitinibulinate, with a proportion of w / w% based on free bases. The 0.5% and 1.5% cream formulations were oil-in-water cream formulations as described in Tables 3 and 5 of U.S. Patent Application Publication 2015 / 0250790 (which, by attribution, is incorporated herein as a whole).

[0576] The mean (SD) age was 48.3 (12.9) years, 46.5% of patients were male, and 84.1% were Caucasian. The distribution of baseline disease characteristics was similar between treatment groups. See Table 1 for patient demographics and baseline disease characteristics. Most patients (93.0%) had non-segmental vitiligo, and skin types II–III (63.7%). The median (range) duration of illness was 14.0 (0.3–67.9) years. The mean (SD) percentages of T-BSA and F-BSA involvement at baseline were 22.1% (18.4%) and 1.48% (0.86%), respectively, and the mean (SD) baseline T-VASI and F-VASI scores were 18.0 (15.5) and 1.26 (0.82), respectively. The discontinuation rate was low up to week 52. By week 24, 18 patients (11.5%) had discontinued the study treatment. The main reasons were patient discontinuation (6.4%), adverse events (1.9%), patients lost to follow-up (1.3%), protocol deviation (1.3%), and non-adherence to the study drug (0.6%).

[0577] In the second part of the trial, all participants were initially randomized to a vehicle BID, and participants initially randomized to a 0.15% QD who did not achieve a ≥25% improvement from baseline in F-VASI were re-randomized to one of three high-dose groups for an additional 28 weeks. All other participants maintained the same treatment until week 52. From week 52 onward, participants were eligible to receive an open-label 1.5% BID for an additional 52 weeks. The primary endpoint was the proportion of participants who achieved a ≥50% improvement from baseline in F-VASI50 at week 24. Secondary endpoints included achieving a clear or near-clear score (F-PhGVA score of 0 or 1) in the physician-administered comprehensive assessment of vitiligo (F-PhGVA) at week 24; the percentage of participants who achieved T-VASI50 at week 52; and safety and tolerability assessed by monitoring the frequency, duration, and severity of adverse events (AEs) from at least 30 days after the last dose up to week 120. Subjects receiving any form of phototherapy, including tanning beds, were excluded from this study.The following subjects were also excluded: subjects with other skin conditions besides vitiligo, whose presence or treatment could complicate the assessment of hyperpigmentation; subjects who had previously used skin bleaching treatments for vitiligo or other areas of hyperpigmentation; subjects who had received any of the following treatments within the specified minimum period, e.g., use of biological therapy, investigative treatment or research treatment or procedure for vitiligo within 12 weeks or 5 half-lives (whichever is longer) from screening; use of laser or light-based vitiligo treatment, including tanning beds, within 8 weeks from screening; and immunomodulatory oral or systemic medications (e.g., corticosteroids, methotrexate, cyclosporine) or within 4 weeks from screening. Patients who have used topical medications that may affect vitiligo (e.g., corticosteroids, tacrolimus / pimecrolimus, retinoids); patients who have used prior treatments and combination therapies other than those listed above that may interfere with the objectives of the study at the discretion of the investigator, including drugs that cause photosensitivity or skin pigmentation (e.g., antibiotics such as tetracycline, antifungals) within 8 weeks of screening; subjects with clinically significant thyroid-stimulating hormone or free T4 abnormalities at screening; subjects with cytopenia as defined in the protocol at screening; subjects with severe hepatic impairment; subjects with renal impairment; subjects who have taken potent systemic cytochrome P450 3A4 inhibitors or fluconazole for less than 2 weeks or less than 5 half-lives, whichever is longer, prior to baseline visits; and subjects who have previously received JAK inhibitor therapy (systemic or topical). In this study, the facial area analyzed for F-VASI included the area vertically from the forehead to the hairline, vertically from the cheek to the jawline, and horizontally from the corner of the mouth to the tragus. The analyzed facial area did not include the surface area of ​​the lips, scalp, eyelids, ears, or neck, but it did include the nose.

[0578] [Table 2]

[0579] Week 24 All ruxolitinib treatment groups demonstrated clinically meaningful efficacy and superiority over the vehicle. The proportion of participants achieving F-VASI50 at week 24 was statistically significantly higher in ruxolitinib cream compared to the vehicle, with response rates of 32.3%, 25.8%, 50.0%, 45.5%, and 3.2% for ruxolitinib cream 0.15%QD, 0.5%QD, 1.5%QD, 1.5%BID, and the vehicle, respectively.

[0580] All ruxolitinib treatment groups were generally safe and well-tolerated, with no major TEAEs or application site events, and no clinically relevant hematological changes. Treatment discontinuation up to 24 weeks was low (11.5% overall). Key endpoints obtained from the 24-week analysis are summarized in Table 2.

[0581] [Table 3]

[0582] The results of the analysis at week 24 are shown in Figures 1-4.

[0583] Figure 62 shows the F-VASI50 response to ruxolitinib cream 1.5% BID at week 24, broken down by patient demographics and skin type. Among the 33 patients treated with ruxolitinib cream 1.5% BID, a higher proportion of younger patients (under 50 years old: n=17 [58.8%]) and female patients (n=15 [60.0%]) were F-VASI50 responders at week 24. No substantial differences were observed between Caucasian and non-Caucasian responders, or between responders with skin types I-II and III-VI.

[0584] Figure 63 shows the F-VASI50 response to ruxolitinib cream 1.5% BID at week 24, categorized by baseline vitiligo lesion characteristics. Among patients treated with ruxolitinib cream 1.5% BID, a larger proportion (n=19 [52.6%]) of patients with a baseline F-BSA of ≤1.5% were F-VASI50 responders at week 24. There was no substantial difference between responders with baseline T-BSA ≤20% and those with >20%, indicating that ruxolitinib cream is effective even in patients with a high disease burden.

[0585] Figure 64 shows the F-VASI50 response to ruxolitinib cream 1.5% BID at week 24, categorized by disease characteristics and previous treatment. Among patients treated with ruxolitinib cream 1.5% BID, a higher proportion of patients with longer disease duration (>20 years; n=10 [60.0%]) were F-VASI50 responders. There was no substantial difference between responders with stable disease and those with progressive disease. This indicates that ruxolitinib cream is effective in treating vitiligo in patients with long-term, widespread disease characterized by high inflammatory load (indicated by the degree of depigmentation of the skin surface). In contrast to corticosteroids (n=14 [50.0%]) or calcineurin inhibitors (n=14 [42.9%]), a higher proportion of patients with a history of phototherapy (n=12 [66.7%]) were F-VASI50 responders.

[0586] After the 24-week evaluation, subjects randomized to the vehicle were randomized in a 1:1:1 ratio to one of three high-activity treatment groups while maintaining blindness. Subjects who did not achieve a ≥25% improvement from baseline in F-VASI (F-VASI25 non-responders) in the ruxolitinib (INCB018424) 0.15% QD group were randomized to one of the three high-activity treatment groups while maintaining blindness. Subjects randomized to ruxolitinib 0.15% QD who achieved a ≥25% improvement from baseline in F-VASI continued at the same dose until week 52. Subjects randomized to ruxolitinib 1.5% BID, 1.5% QD, or 0.5% QD continued at the same dose until week 52.

[0587] The primary endpoint, F-VASI50 at week 24, was achieved significantly more frequently in patients treated with any dose of ruxolitinib cream than in the vehicle group (3.1%; Figure 5) (1.5% BID, 45.5% [P<0.001]; 1.5% QD, 50.0% [P<0.001]; 0.5% QD, 25.8% [P<0.05]; 0.15% QD, 32.3% [P<0.01]). A further important secondary endpoint, achieving a clear or near-clear score on F-PhGVA at week 24, was achieved only in patients treated with ruxolitinib cream (3.2% to 13.3% across all doses; Figure 3).

[0588] Subgroup analyses investigated responses based on patient demographics and baseline characteristics; results were largely similar across treatment groups at week 24. Among patients treated with ruxolitinib cream 1.5% BID (n=33; F-VASI50 responders, 45.5%), a greater proportion of patients in the following subgroups were F-VASI50 responders: patients aged 50 years or older (58.8%); female patients (60.0%); patients with skin type I–III (50.0%); patients with affected baseline facial BSA ≥1.5% (52.6%); patients with baseline F-VASI score between 0.75 and <1.5 (75.0%); and patients with duration of illness greater than 20 years (60.0%); as well as recipients who had previously received topical corticosteroids (50.0%). There were no substantial differences between white responders (44.8%) and non-white responders (50.0%), between responders with stable disease (46.2%) and those with progressive disease (45.0%), or between responders with a total BSA of 20% or more (45.0%) and those with a total BSA of more than 20% (46.2%). Ruxolitinib cream was effective in treating vitiligo across all demographic and clinical characteristics, including patients with long-term, widespread disease.

[0589] Week 52 The analysis results for week 52 are shown in Figures 5 to 22 and Table 3. Sub-analyses of T-VASI scores for the head and neck, hands, upper limbs, trunk, lower limbs, and feet were also performed. The results of these sub-analyses are shown in Figures 23 to 53. Further results are shown in Figures 54 to 61.

[0590] [Table 4]

[0591] Persistent improvement was achieved after 52 weeks of ruxolitinib cream monotherapy, with 1.5% BID yielding the highest response rates at F-VASI50 (57.6%), F-VASI75 (51.5%), and F-VASI90 (33.3%) (Figures 5, 9, and 11). In patients with all depigmented skin treated (baseline T-BSA ≤ 20%), the T-VASI50 response rate was 45.0% (1.5% BID) at week 52 (Figure 54). The important secondary endpoint of T-VASI50 at week 52 was achieved in a dose-dependent manner by patients (Figure 17 - 1.5% BID, 36.4%; 1.5% QD, 30.0%; 0.5% QD, 25.8%). The mean percentage change from baseline in VASI (Figure 14 (F-VASI) and Figure 16 (T-VASI)) and BSA (Figure 55 (F-BSA) and Figure 22 (T-BSA)) showed clear separation from the vehicle in the face and throughout the body, starting as early as week 8 of treatment with most ruxolitinib cream doses.

[0592] The responses to F-VASI75 and F-VASI90 approximated the patient's desired outcome of complete or near-complete pigment regrowth (Eleftheriadou, et al., Br J Dermatol 2019;180:574-9); these responses paralleled improvements in PhGVA and PaGVA scores at week 52. At week 52, more patients had clear to mild disease on F-PhGVA and T-PhGVA assessments compared to baseline (Figure 56). Similarly, more patients reported mild disease or no vitiligo on F-PaGVA and T-PaGVA after 52 weeks of treatment with ruxolitinib cream compared to baseline (Figure 57). Patients treated with any dose of ruxolitinib cream showed a noticeable improvement in pigmentation redeposition of facial and non-facial vitiligo lesions; pigmentation redeposition was most pronounced in 1.5% QD and 1.5% BID, and patients showed continued improvement up to week 52 (Figure 58, showing trunk and hands).

[0593] In subgroup analyses, the proportion of patients who achieved a ≥50% and ≥75% improvement in total vitiligo area scoring indices (T-VASI50 and T-VASI75) from baseline at week 52 was determined by affected area. Ruxolitinib cream application was limited to total BSA of ≤20%, and the analysis was performed only in these patients. Ruxolitinib cream 1.5% BID yielded the highest response in most body areas. At week 52, 1.5% BID resulted in substantial overall T-VASI50 and T-VASI75 responses (45.0% and 15.0%) across all body regions: head and neck (60.0% and 55.0%) (Figures 24 and 25), trunk (29.4% and 11.8%) (Figures 39 and 40), upper extremities (52.9% and 23.5%) (Figures 34 and 35), lower extremities (52.6% and 26.3%) (Figures 43 and 45), hands (15.0% and 5.0%) (Figures 29 and 30), and feet (29.4% and 17.6%) (Figures 48 and 50). In summary, ruxolitinib cream resulted in pigment redeposition across all body regions, including hands / feet, in patients with vitiligo, a phenomenon not reported with previous treatments.

[0594] Of the 157 subjects, 11 had segmental vitiligo. Four of these patients received either 0.5% QD or 1.5% BID ruxolitinib cream. Two patients who received 1.5% ruxolitinib cream achieved F-VASI75 and T-VASI50 at week 52 (Table 4).

[0595] [Table 5]

[0596] The incidence and types of treatment-related adverse events (TEAEs) were similar across treatment groups (Figure 59). Four patients experienced serious TEAEs unrelated to the study treatment (1.5% BID, subdural hematoma [n=1]; 1.5% QD, seizure [n=1]; 0.5% QD, coronary artery occlusion [n=1] and esophageal achalasia [n=1]). In patients treated with ruxolitinib cream (1.5% BID, n=1 [3.0%]; 1.5% QD, n=3 [10.0%]; 0.5% QD, n=3 [9.7%]; 0.15% QD, n=6 [19.4%]) and vehicle (n=3 [9.4%]; Figure 59), application site pruritus was the most common treatment-related AE. Acne was observed as a treatment-related adverse event (AE) in 13 patients (8.3%) treated with ruxolitinib cream and 1 patient (3.1%) treated with vehicle. All treatment-related AEs were mild (grade 1) or moderate (grade 2) in terms of severity. Three patients experienced TEAEs leading to treatment discontinuation (0.15% QD and vehicle [both n=1], headache [treatment-related for 0.15% QD]; 1.5% QD [n=1], seizure).

[0597] No clinically relevant changes were observed in laboratory values. Transient changes within the normal range of hemoglobin (Figure 60) and platelet (Figure 61) levels were observed throughout the double-blind treatment. At week 52, hemoglobin and platelet levels were nearly the same as those observed at baseline. Systemic exposure to ruxolitinib cream was limited, representing approximately 4%–5% of the applied topical dose.

[0598] Example 2 - Phase III trial of ruxolitinib for the treatment of vitiligo vulgaris A phase III, randomized, vehicle-controlled trial is being conducted in adolescent and adult (12 years and older) participants diagnosed with non-segmental vitiligo and with depigmented areas including at least 0.5% BSA, ≥0.5 F-VASI on the face, at least 3% BSA on non-facial areas, and ≥3 T-VASI. Vitiligo of the entire body (facial and non-facial) must not exceed 10% BSA. Participants are randomized to receive either ruxolitinib cream 1.5% BID or the vehicle, stratified by age (under 40 or over 40) and skin type (Fitzpatrick scale types I and II and types III, IV, V and VI), and receive the study treatment for 24 weeks. Ruxolitinib in the cream formulation was present as ruxolitinibulinate as a percentage as w / w% on a free base basis. The cream formulation was the oil-in-water cream formulation described in Table 5 of U.S. Patent Application Publication 2015 / 0250790 (which, with due attribution, is incorporated herein by reference). Adolescents comprised at least 10% of the study population, and less than 50% of participants were over 40 years of age. In this study, the facial area analyzed for F-VASI included the area from the forehead to the hairline, the area vertically from the cheek to the jawline, and the area horizontally from the corner of the mouth to the tragus. The facial area analyzed did not include the surface area of ​​the lips, scalp, ears, or neck, but it did include the nose and eyelids.

[0599] VASI is based on a composite estimate of the overall area of ​​vitiligo lesions at baseline and the degree of macular repigmentation over time within these lesions. Facial VASI is measured as a percentage of vitiligo involvement (BSA) and the degree of depigmentation. The percentage of vitiligo involvement (BSA) is estimated by the investigator using the palmar method (see Section 8.2.1). The hand unit is based on the participant's hand size. The investigator uses their own hand to mimic the participant's hand size and assesses the percentage of vitiligo involvement. The degree of depigmentation for each vitiligo lesion site is determined and estimated to be the closest of the following percentages: 0, 10%, 25%, 50%, 75%, 90%, or 100%. In 100% depigmentation, no pigment is present; in 90%, pigmented spots are present; in 75%, the depigmented area exceeds the pigmented area; in 50%, the pigmented and pigmented areas are equal; in 25%, the pigmented area exceeds the depigmented area, and in 10%, only depigmented spots are present. Next, the F-VASI is derived by multiplying the value evaluated for vitiligo lesions by the percentage of affected skin in each area of ​​the face, and summing the values ​​for all areas (the possible range is 0 to 3).

[0600] The whole-body VASI is calculated using a formula that includes contributions from the whole-body region (possible range, 0 to 100).

[0601] (Math 1) VASI=Σ[hand unit]×[residual depigmentation] whole body area

[0602] The body is divided into the following six mutually exclusive parts: (1) head and neck, (2) hands, (3) upper limbs (excluding hands), (4) trunk, (5) lower limbs (excluding feet), and (6) feet. The percentage of vitiligo lesions is estimated in hand units (%) of BSA by the same principal investigator throughout the study. Hand units are based on the size of the participant's hand. The principal investigator will use their own hand to mimic the size of the participant's hand and assess the percentage of BSA vitiligo lesions. The degree of depigmentation for each body part is determined and estimated to be the closest of the following percentages: 0%, 10%, 25%, 50%, 75%, 90%, or 100%. Next, the T-VASI is derived by multiplying the value assessed for vitiligo lesions by the percentage of affected skin in each body part, and then summing up the values ​​for all body parts (Hamzavi I, Jain H, McLean D, Shapiro J, Zeng H, Lui H. Parametric modeling of narrowband UV-B phototherapy for vitiligo using a novel quantitative tool: the Vitiligo Area Scoring Index. Arch Dermatol 2004;140:677-683).

[0603] After the 24-week evaluation, participants will be offered the opportunity to receive a further 28-week open-label extension of treatment with ruxolitinib cream 1.5% BID. To be eligible, participants must complete baseline and 24-week outpatient evaluations, adhere to the study drug, and meet all inclusion / exclusion criteria. However, the lower and upper limits of %BSA are not required, and the exclusion criterion of no prior JAK inhibitor treatment does not apply to participants who received ruxolitinib cream during the initial 24-week double-blind vehicle-controlled period. The treatment area must not exceed 10%BSA or 20%BSA. For areas with complete re-pigmentation, participants may discontinue the study drug and continue observation. During the open-label extension period, approval for additional treatment areas (new vitiligo areas or expansion of existing vitiligo areas) may be made by telephone, but the principal investigator may, at their discretion, request participants to make unscheduled outpatient visits. Patients receiving any phototherapy, including laser treatment, tanning beds, or intentional UV exposure, will be excluded from this study. The following subjects will also be excluded: subjects with no pigmented hair in any of the facial vitiligo areas; subjects with other forms of vitiligo (e.g., segmental vitiligo) or other differential diagnoses of vitiligo or other skin depigmentation disorders (e.g., mottled plaque, pityriasis leukemia, leprosy, post-inflammatory depigmentation, progressive macular demelaninosis, anemic nevus, chemical vitiligo, and tinea versicolor); subjects who have previously used depigmentation medications (e.g., monobenzone) for the treatment of vitiligo or other pigmented areas; and subjects who have used therapies defined in the protocol within the prescribed drug-free period prior to baseline.

[0604] The primary endpoint of this study is the proportion of participants who achieve F-VASI75 at week 24. Secondary endpoints include: the percentage change from baseline in F-BSA (Facial Body Surface Area) at week 24; the proportion of participants who achieve F-VASI50 at week 24; the proportion of participants who achieve F-VASI90 at week 24; the proportion of participants who achieve T-VASI50 at week 24; the proportion of participants who achieve F-VASI75 at week 52; the proportion of participants who achieve F-VASI90 at week 52; the proportion of participants who achieve T-VASI50 at week 52; the proportion of participants who achieve T-VASI75 at week 52; and the proportion of patients who achieve a Vitiligo Severity Scale (VNS) score of 4 ("Not very noticeable") or 5 ("No longer noticeable") at week 24; the number of adverse events that occurred under treatment up to week 56 (including adverse events first reported after the first dose of the study drug or exacerbation of pre-existing events); 5 Percentage of participants who achieved F-VASI 25 / 50 / 75 / 90 (≥25% / 50% / 75% / 90% improvement from baseline in F-VASI score) by week 2; Percentage change from baseline in F-VASI by week 52; Percentage change from baseline in F-BSA by week 52; Percentage change from baseline in T-VASI by week 52; Percentage change from baseline in total body surface area (T-BSA) by week 52; Percentage of participants who achieved T-VASI 25 / 50 / 75 / 90 (≥25% / 50% / 75% / 90% improvement in T-VASI) at week 52; Percentage of participants belonging to each category of VNS at week 52; Population-based (trough) plasma concentration of ruxolitinib at week 4; Population-based (trough) plasma concentration of ruxolitinib at week 24; Population-based (trough) plasma concentration of ruxolitinib at week 40. In addition, this study will track the frequency, duration, and severity of adverse events associated with the use of ruxolitinib cream.

Claims

1. A method for treating vitiligo in a patient, comprising topically administering a pharmaceutical composition containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis to the affected skin area of ​​the patient requiring such treatment, twice daily.

2. The method according to claim 1, wherein the vitiligo is generalized vitiligo.

3. A method for treating vitiligo in a patient, comprising topically administering a pharmaceutical composition containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis to the affected area of ​​the patient's skin requiring treatment, the affected area being selected from the lower limbs, trunk, hands, upper limbs, and feet.

4. The method according to claim 3, wherein the affected area of ​​skin is the patient's lower limb.

5. The method according to claim 3, wherein the affected area of ​​skin is the torso of the patient.

6. The method according to claim 3, wherein the affected area of ​​skin is the patient's hand.

7. The method according to claim 3, wherein the affected area of ​​skin is the patient's upper limb.

8. The method according to claim 3, wherein the affected area of ​​skin is the patient's foot.

9. The method according to any one of claims 3 to 8, wherein the patient achieves a 25% or greater improvement in the Vitiligo Area Scoring Index in the affected skin area.

10. The method according to any one of claims 3 to 9, wherein the patient achieves a 50% or greater improvement in the vitiligo area scoring index in the affected skin area.

11. The method according to any one of claims 3 to 10, wherein the patient achieves an improvement of 75% or more in the vitiligo area scoring index in the affected skin area.

12. The method according to any one of claims 3 to 11, wherein the patient achieves a 50% or greater improvement in the patient's hand vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

13. The method according to any one of claims 3 to 12, wherein the patient achieves a 50% or greater improvement in the patient's upper limb vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

14. The method according to any one of claims 3 to 13, wherein the patient achieves a 50% or greater improvement in the vitiligo area scoring index score of the patient's feet at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

15. The method according to any one of claims 3 to 14, wherein the patient achieves a 50% or greater improvement in the patient's lower limb vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

16. The method according to any one of claims 3 to 15, wherein the patient achieves a 50% or greater improvement in the patient's trunk vitiligo area scoring index score at week 4, week 8, week 18, week 24, week 32, week 38, week 42, week 48, or week 52.

17. The affected area is selected from the lower limbs, trunk, hands, upper limbs, and feet; The patient has generalized vitiligo with (i) 0.5% or more of the body surface area (BSA) on the face, (ii) 3% or more of the BSA in non-facial areas, and (iii) no more than 10% of the total body surface area with BSA; The method does not involve administering lasers or any type of phototherapy; Patients achieve a 50% or greater improvement in the vitiligo area scoring index score of the affected skin area. The method according to claim 3.

18. The affected area is selected from the lower limbs, trunk, and feet; The patient has generalized vitiligo with (i) 0.5% or more of the body surface area (BSA) on the face, (ii) 3% or more of the BSA in non-facial areas, and (iii) no more than 10% of the total body surface area with BSA; The method does not involve administering lasers or any type of phototherapy; Patients achieve a 50% or greater improvement in the vitiligo area scoring index score of the affected skin area. The method according to claim 3.

19. A method for treating generalized vitiligo in a patient, comprising topically administering a pharmaceutical composition containing approximately 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis to the affected skin area of ​​the patient requiring such treatment, wherein the patient has had vitiligo for at least 20 years, and the patient achieves an improvement of 50% or more in the Face Vitiligo Scoring Index.

20. The method according to claim 19, wherein the affected area is the face.

21. The method according to claim 19, wherein the affected area is the head and neck.

22. The method according to claim 19, wherein the affected area is selected from the lower limbs, trunk, hands, upper limbs, and feet.

23. A method for treating vitiligo in a patient, comprising topically administering a pharmaceutical composition containing about 1.5 w / w% ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis to the affected area of ​​the patient's skin, wherein the patient is not receiving phototherapy for vitiligo during the administration of the pharmaceutical composition.

24. The method according to any one of claims 1 to 23, wherein the patient achieves a 25% or greater improvement in the Face Vitiligo Area Scoring Index.

25. The method according to any one of claims 1 to 24, wherein the patient achieves a 50% or greater improvement in the facial vitiligo area scoring index.

26. The method according to any one of claims 1 to 25, wherein the patient achieves a 75% or greater improvement in the facial vitiligo area scoring index.

27. The method according to any one of claims 1 to 26, wherein the patient achieves a 90% or greater improvement in the facial vitiligo area scoring index.

28. The method according to any one of claims 1 to 27, wherein the patient achieves a 25% or greater improvement in the Total Body Vitiligo Area Scoring Index.

29. The method according to any one of claims 1 to 28, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index.

30. The method according to any one of claims 1 to 29, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index.

31. The method according to any one of claims 1 to 30, wherein the administration is for a maximum of 24 weeks.

32. The method according to any one of claims 1 to 31, wherein the administration is for a maximum of 52 weeks.

33. The method according to any one of claims 1 to 32, wherein the patient has at least 1.5% of the facial surface area (F-BSA) affected by vitiligo.

34. The method according to any one of claims 1 to 33, wherein the patient has at least 1.5% of the facial body surface area (F-BSA) affected by vitiligo, and achieves a 50% or greater improvement in the Face Vitiligo Area Scoring Index score at 24 weeks.

35. The method according to any one of claims 1 to 34, wherein the patient has 1.5% of the facial body surface area (F-BSA) affected by vitiligo, and achieves a 50% or greater improvement in the facial vitiligo area scoring index score at 52 weeks.

36. The method according to any one of claims 1 to 35, wherein the patient has 1.5% of the facial surface area (F-BSA) affected by vitiligo, and achieves a 75% or greater improvement in the facial vitiligo area scoring index score at 24 weeks.

37. The method according to any one of claims 1 to 36, wherein the patient has at least 1.5% of the facial body surface area (F-BSA) affected by vitiligo, and achieves an improvement of 75% or more in the facial vitiligo area scoring index score at 52 weeks.

38. The method according to any one of claims 1 to 37, wherein the patient achieves a 25% or greater improvement in the whole-body vitiligo area scoring index score at 24 weeks.

39. The method according to any one of claims 1 to 38, wherein the patient achieves a 25% or greater improvement in the whole-body vitiligo area scoring index score at 52 weeks.

40. The method according to any one of claims 1 to 39, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index score at 24 weeks.

41. The method according to any one of claims 1 to 40, wherein the patient achieves a 50% or greater improvement in the whole-body vitiligo area scoring index score at 52 weeks.

42. The method according to any one of claims 1 to 41, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index score at 24 weeks.

43. The method according to any one of claims 1 to 42, wherein the patient achieves a 75% or greater improvement in the whole-body vitiligo area scoring index score at 52 weeks.

44. The method according to any one of claims 1 to 43, wherein the patient's total body surface area (T-BSA) affected by vitiligo does not exceed 10%.

45. The method according to any one of claims 1 to 44, wherein the patient has been clinically diagnosed with vitiligo.

46. The method according to any one of claims 1 to 45, wherein the patient is 12 years of age or older.

47. The method according to any one of claims 1 to 45, wherein the patient is 18 years of age or older.

48. The method according to any one of claims 1 to 45, wherein the patient is between 18 and 75 years of age.

49. The method according to any one of claims 1 to 45, wherein the patient is 50 years of age or younger.

50. The method according to any one of claims 1 to 49, wherein the patient has progressive vitiligo at baseline.

51. The method according to any one of claims 1 to 50, wherein the patient has at least 0.5% of their facial surface area affected by vitiligo.

52. The method according to any one of claims 1 to 51, wherein the patient has at least 3% of the non-facial body surface area affected by vitiligo.

53. The method according to any one of claims 1 to 52, wherein the total surface area affected by vitiligo does not exceed 10% of the patient's body surface.

54. The method according to any one of claims 1 to 53, wherein the patient has had the disease for at least 10 years at baseline.

55. The method according to any one of claims 1 to 54, wherein the patient has not received any other medications for the treatment of vitiligo.

56. The method according to any one of claims 1 to 55, wherein the patient has previously received phototherapy.

57. The method according to any one of claims 1 to 56, wherein the method does not involve administering a laser or any type of phototherapy.

58. The method according to any one of claims 1 to 57, wherein the patient's hemoglobin level at 52 weeks is the same as the patient's baseline hemoglobin level.

59. The method according to any one of claims 1 to 58, wherein the patient's platelet level at 52 weeks is similar to the patient's platelet level at baseline.

60. The method according to any one of claims 1 to 59, wherein there is no substantial difference in response between patients with vitiligo whose baseline total surface area is 20% or less and patients with vitiligo whose baseline total surface area is greater than 20%.

61. The method according to any one of claims 1 to 60, wherein ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinibulinate.

62. The method according to any one of claims 1 to 61, wherein the pharmaceutical composition is a cream.

63. The method according to claim 62, wherein the cream is an oil-in-water emulsion.

64. The method according to claim 63, wherein the cream contains 1.5 w / w% ruxolitinibrinate on a free base basis.

65. The method according to claim 64, wherein the cream has a pH of approximately 2.8 to approximately 3.

9.

66. The method according to claim 1, wherein the vitiligo is segmental vitiligo.

67. A pharmaceutical composition for use in any of the methods described in claims 1 to 66.

68. Use of a pharmaceutical composition for the manufacture of a pharmaceutical for use in any of the methods described in claims 1 to 66.

Images