Topical treatment of vitiligo by a jak inhibitor

Abstract

This invention relates to the topical treatment of vitiligo using ruzotinib or a medically acceptable salt thereof.

Description

[Technical Field] This invention relates to the topical treatment of vitiligo using ruzotinib or a medically acceptable salt thereof. [Previous Technology] Vitiligo occurs when melanin-producing cells die or cease functioning, causing spots of skin depigmentation. Non-segmental vitiligo involves spots of depigmentation of the skin throughout the body. Depigmentation commonly occurs on the face, neck, scalp, and around body openings. Loss of pigmentation is also frequently seen in areas that frequently experience friction, impact, or other trauma, such as the hands and arms. Segmental vitiligo is associated with smaller spots of depigmented skin appearing in a limited area on one side of the body. It is estimated that vitiligo affects 0.5% to 2% of the global population (Krüger C, Schallreuter KU. A review of the worldwide prevalence of vitiligo in children / adolescents and adults. Int J Dermatol 2012;51:1206-1212). The incidence is similar between men and women, and there are no known differences in presentation based on skin type or ethnicity. Up to 50% of patients develop vitiligo before the age of 20, with many developing it 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 autoimmune diseases such as sutton nevus, thyroid disorders, juvenile diabetes, pernicious anemia, and Addison's disease. The natural course of the disease is usually unpredictable, but it is typically progressive. Some degree of spontaneous repigmentation may occur in 10% to 20% of patients; however, it is usually not cosmetically acceptable (Castanet J, Ortonne JP. Pathophysiology of vitiligo. Clin Dermatol 1997:15:845-851). Vitiligo is a serious disease due to its substantial psychological impact on patients' daily functioning and its progressive course if left untreated. Studies have shown that the impact of vitiligo on quality of life (specifically, 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). Exposed skin, such as the face and hands, can have a significant impact on self-esteem and is ultimately linked 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, low acceptance and understanding of the disease leads to discrimination against individuals with the condition (Yazdani Abyaneh MA, Griffith R, Falto-Aizpurua L, Nouri K. The dark history of white spots. JAMA Dermatol 2014;150:936). Approximately 75% of vitiligo patients find their appearance moderate to severe and intolerable, and 41% feel powerless 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).Studies have reported that 66% of patients experience depression due to their illness, and 92% have experienced humiliation (Krüger 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). The embarrassment and fear of rejection can lead to withdrawal in vitiligo patients and social isolation in personal and professional relationships. It has been reported that most vitiligo patients experience anxiety and embarrassment 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 or depressive symptoms are associated with vitiligo. Patients with vitiligo are approximately five times more likely to suffer from 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).Recent analysis indicates that the comorbidity rate of depression was 29% in 17 distinct populations (n=1711) (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). Studies have also shown that the onset of vitiligo in childhood can be associated with significant psychological trauma, which may have long-term effects on self-esteem. The severity of vitiligo is associated with reduced quality of life (QOL) in children and adolescents, especially with self-esteem, and is also associated with bullying and ridicule. Adolescents aged 15 to 17 appear to be the most self-conscious of all pediatric age groups (Silverberg, see above). In a study comparing social development and health-related quality of life in adolescents with childhood vitiligo to healthy controls, vitiligo patients who reported negative childhood experiences reported significantly more problems in social development than their counterparts who did not report negative experiences. Negative childhood experiences are significantly associated with impaired health-related quality of life 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. Currently, there are no approved drug treatments for vitiligo. Off-label medications have been used; however, the clinical evidence generated consists of several small randomized controlled studies. Off-label topical treatments for vitiligo include corticosteroids, calcineurin inhibitors, and vitamin D analogs. Other therapies include oral medications, phototherapy, and some surgical procedures (e.g., implantation of melanocytes into depigmented lesions). Due to the low level of evidence for any of these treatments, no definitive clinical recommendations for the treatment of vitiligo can be made, and the control of vitiligo is empirical and based on the latest consensus guidelines. The pathogenesis of vitiligo involves intrinsic defects within melanocytes and autoimmunity targeting these cells. Upon stress, melanocytes release inflammatory signals that activate the innate immune system, representing the initiating event in vitiligo. Janus kinases are intracellular signaling enzymes acting downstream of key pro-inflammatory cytokines involved in the pathogenesis of vitiligo. Oxidative stress, cell damage, and cytokines secreted by innate immune cells subsequently trigger the release of CXCL10 from skin cells, recruiting CD8+ T cells to the site. Activated CD8+ T cells produce IFN-γ and other inflammatory mediators that 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 signal transducer and the JAK-STAT pathway. Inhibition of JAK signaling may play a role in the treatment of vitiligo. Case reports of administering JAK inhibitors to patients with vitiligo include patients with both alopecia areata and vitiligo who were treated with oral ruxolitinib 20 mg BID for 20 weeks, followed by hair regrowth and repigmentation of the vitiligo-affected areas (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). In another report, patients with extensive and progressive vitiligo who did not respond to topical steroids, tacrolimus ointment, and NB-UVB phototherapy with 5 mg QD of oral tofacitinib developed almost complete repigmentation 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). A 20-week open-label study was conducted in 12 participants with vitiligo who had at least 1% diseased BSA and used topical ruzoutinib cream.The results showed that 7 out of 9 participants who completed the study achieved a 76% improvement in the Facial Vitiligo Area Score Index (F-VASI) and a 26% improvement in the Total Vitiligo Area Score 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). An additional 32-week extension study was conducted in the same group using optional narrow-band ultraviolet B (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, with three receiving NB-UVB. At week 52 (weeks 20 and 32), results showed a 92% improvement in F-VASI and a 37% improvement in T-VASI. Results also indicated a response in two participants who had previously failed phototherapy and topical cream monotherapy for trunk lesions following combination therapy. Furthermore, participants were followed up for 6 months after treatment cessation, and all five participants maintained a response, with the longest duration exceeding 40 weeks. However, these results are from an open-label study and from an extremely small sample size. Therefore, the efficacy of ruzotinib cream in treating vitiligo has not been clinically proven in randomized, double-blind, mediator-controlled trials excluding different treatment regimens. [Summary of the Invention] Therefore, the present invention particularly provides a method for treating patients with vitiligo using ruzotinib cream at 0.15% QD, 0.5% QD, 1.5% QD or 1.5% BID. The present invention further provides a ruzotinib composition or cream for use in any of the methods described herein. The present invention also provides the use of a ruzotinib composition or cream for the manufacture of a pharmaceutical agent for use in any of the methods described herein. Details of one or more embodiments of the invention are set forth in the accompanying drawings and the following description. Other features, objectives, and advantages of the invention will become apparent from the embodiments, the illustrations, and the claims.

Implementation Method

Claims

1. Use of a pharmaceutical composition comprising about 1.5% w / w ruxolitinib or a pharmaceutically acceptable salt thereof, calculated as a free base, for the preparation of an agent for treating vitiligo in a patient in need, wherein the pharmaceutical composition is applied topically twice daily to a diseased skin area of ​​the patient; wherein the diseased skin area includes at least one of the patient's lower extremities, trunk, and feet; wherein the agent is administered for 52 weeks; wherein the treatment does not involve laser or any type of phototherapy; and wherein the patient achieves a 25% or greater improvement in the Vitiligo Area Score (VASI) of the diseased skin area.

2. As requested in claim 1, wherein the affected skin area is the patient’s lower limb.

3. As requested in claim 1, wherein the affected skin area is the patient’s torso.

4. As requested in claim 1, wherein the affected skin area is the patient's foot.

5. For the purpose of any of the requests 1 to 4, wherein the patient: a) achieves a 50% or greater improvement in the vitiligo area score index of the patient's feet at week 52; or b) achieves a 50% or greater improvement in the vitiligo area score index of the patient's lower extremities at week 52; or c) achieves a 50% or greater improvement in the vitiligo area score index of the patient's trunk at week 52.

6. As in the purpose of request item 1, wherein: The affected area was selected from the lower extremities, trunk, and feet; the patient suffered from generalized vitiligo with the following depigmented areas: (i) 0.5% or more of the body surface area (BSA) on the face, (ii) 3% or more of the BSA on non-facial areas, and (iii) no more than 10% of the BSA on the entire body area; the treatment did not involve laser or any type of phototherapy; and the patient achieved a 50% or greater improvement in the vitiligo area score index of the affected skin area.

7. As requested in item 1, wherein the patient’s vitiligo disease has lasted for at least 20 years.

8. For any of the uses of items 1 to 4, 6 and 7, wherein the patient has a total body surface area (T-BSA) of not more than 10% affected by vitiligo.

9. For any of the uses of items 1 to 4, 6 and 7, wherein the patient has been clinically diagnosed with vitiligo.

10. For any of the requests in items 1 through 4, 6 and 7, wherein the patient’s age is: a) 12 years or older; or b) 18 years or older; or c) 18 to 75 years; or d) 50 years or younger.

11. For any of the purposes requested in items 1 to 4, 6 and 7, wherein the patient has: a) at least 0.5% of the facial body surface area affected by vitiligo; or b) at least 3% of the non-facial body surface area affected by vitiligo; or c) not more than 10% of the total body surface area affected by vitiligo.

12. As requested in any of items 1 to 4 and 6, wherein the patient has a disease duration of at least 10 years at baseline.

13. As requested in any of items 1 to 4, 6 and 7, wherein the patient is not given any other reagents for the treatment of vitiligo.

14. The use of any of claims 1 to 4, 6 and 7, wherein the ruzotinib or a pharmaceutically acceptable salt thereof is ruzotinib phosphate.

15. The use of any of claims 1 to 4, 6 and 7, wherein the pharmaceutical composition is a cream, and where applicable, wherein the cream is an oil-in-water emulsion.

16. As claimed in claim 15, wherein the cream contains about 1.5% w / w ruzotinib phosphate based on free base, and wherein, where applicable, the pH of the cream is about 2.8 to about 3.9.

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