SLIDE KIT SUPPORTED BY AN UNRESTRICTED EDUCATIONAL SPONSORSHIP

SLIDE KIT SUPPORTED BY AN UNRESTRICTED EDUCATIONAL SPONSORSHIP FROM

Update on JAK Inhibition for Vitiligo Presented by David Rosmarin, MD Tufts Medical Center, Boston, MA, USA Developed by Infomedica – Medical Education & Information 2020 AAD Virtual Meeting Experience content is made available to an international audience through a licensing agreement between Infomedica and the American Academy of Dermatology. Infomedica is an independent medical education provider that delivers medical information to healthcare professionals through conference coverage and online educational programs and activities.

AMERICAN ACADEMY OF DERMATOLOGY VIRTUAL MEETING EXPERIENCE OFFICIAL HIGHLIGHTS Key messages • Vitiligo is a common condition that places a heavy burden on sufferers. • JAK inhibitors have broad efficacy, and may be a good treatment fit for vitiligo. • There is emerging evidence from case studies and Phase 2 trials that both oral and topical JAK inhibitors can re-pigment affected areas. DEVELOPED BY

AMERICAN ACADEMY OF DERMATOLOGY VIRTUAL MEETING EXPERIENCE OFFICIAL HIGHLIGHTS Background What do we already know about this topic? • JAK inhibitors are currently approved for several inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and many more indication approvals are expected. DEVELOPED BY

AMERICAN ACADEMY OF DERMATOLOGY VIRTUAL MEETING EXPERIENCE OFFICIAL HIGHLIGHTS Vitiligo – overview • Vitiligo is a common condition where an overactive immune system destroys the skin pigmentation. Globally, it affects around 1% of people. • The disease has a large societal and economic burden. 1, 2 • At present, there are no Food and Drug Administration-approved treatments that can deliver re-pigmentation, and treatment relies on topical steroids and calcineurin inhibitors, UV therapies, bleaching agents, or simply make-up and camouflage. 1. Bickers DR, Lim HW, Marglois D, et al. The Burden of Skin Diseases: 2004 a Joint Project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol 2006; 55(3): 490– 500. 2. Elbuluk N, Ezzedine K. Quality of Life, Burden of Disease, Co-morbidities, and Systemic Effects in Vitiligo Patients. Dermatol Clin 2017; 35(2): 117– 28. DEVELOPED BY

AMERICAN ACADEMY OF DERMATOLOGY VIRTUAL MEETING EXPERIENCE OFFICIAL HIGHLIGHTS Immune pathogenesis • Vitiligo is driven predominately by overactivation of the Th 1 pathway, with interferon-γ signaling through JAK 1/JAK 2 playing a key role. 3 -7 • In addition to the immune elements, WNT – an important factor in melanocyte differentiation – has been implicated in the lack of re-pigmentation in vitiligo lesions. 8 • Studies in alopecia have shown that – in addition to immune suppression – JAK inhibitors can be pro-melanogenic, and actively stimulate the WNT pathway. 9 3. Van den Boorn JG, Konijnenberg D, Dellemijn TAM, et al. Autoimmune Destruction of Skin Melanocytes by Perilesional T Cells From Vitiligo Patients. J Invest Dermatol 2009; 129(9): 2220– 32. 4. Harris JE, Harris TH, Weninger W, et al. A Mouse Model of Vitiligo With Focused Epidermal Depigmentation Requires IFN-γ for Autoreactive CD 8⁺ T-cell Accumulation in the Skin. J Invest Dermatol 2012; 132(7): 1869– 76. 5. Rashighi M, Harris JE. Interfering With the IFN-γ/CXCL 10 Pathway to Develop New Targeted Treatments for Vitiligo. Ann Transl Med 2015; 3(21): 343. 6. Rothstein B, Joshipura D, Saraiya A, et al. Treatment of Vitiligo With the Topical Janus Kinase Inhibitor Ruxolitinib. J Am Acad Dermatol 2017; 76(6): 1054– 60. 7. 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(6): 1205– 07. 8. Regazzetti C, Joly F, Marty C, et al. Transcriptional Analysis of Vitiligo Skin Reveals the Alteration of WNT Pathway: A Promising Target for Repigmenting Vitiligo Patients. J Invest Dermatol 2015; 135(12): 3105– 14. 9. Harel S, Higgins CA, Cerise JE, et al. Pharmacologic Inhibition of JAK-STAT Signaling Promotes Hair Growth. Sci Adv 2015; 1: e: 1500973. DEVELOPED BY

AMERICAN ACADEMY OF DERMATOLOGY VIRTUAL MEETING EXPERIENCE OFFICIAL HIGHLIGHTS Clinical study data • Ruxolitinib is the JAK inhibitor currently in the most advanced phase of development for vitiligo. • 157 patients have been treated in a randomized, double-blind Phase 2 study examining three doses of topical ruxolitinib versus vehicle. • At Week 24, up to 50% of ruxolitinib patients achieved a facial VASI 50, compared to just 3% with vehicle. At the 52 -week mark, one-third of patients on the highest dose had achieved facial VASI 90; there were also good results for total VASI on other body sites. • Ruxolitinib was well tolerated, with no clinically significant or serious treatmentemergent adverse events. DEVELOPED BY

AMERICAN ACADEMY OF DERMATOLOGY VIRTUAL MEETING EXPERIENCE OFFICIAL HIGHLIGHTS Conclusions • Unlike alopecia, vitiligo affects the epidermis, rather than deeper layers, and as such it lends itself to a topical rather than systemic treatment for many patients. • JAK inhibitors have potential to substantially re-pigment the face and body in vitiligo. • Ruxolitinib is currently recruiting for a Phase 3 study. DEVELOPED BY