(19) TZZ¥__T (11) EP 3 178 465 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 14.06.2017 Bulletin 2017/24 A61K 8/00 (2006.01) (21) Application number: 16195263.5 (22) Date of filing: 06.12.2011 (84) Designated Contracting States: • PROUTY, Stephen, M. AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Doylestown, PA Pennsylvania 18901 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • SCHWEIGER, Eric PL PT RO RS SE SI SK SM TR New York, NY New York 10016 (US) • LEDERMAN, Seth (30) Priority: 06.12.2010 US 420282 P New York, NY New York 10021 (US) 17.03.2011 US 201161453919 P • OSBAKKEN, Mary 17.03.2011 US 201161453902 P Philadelphia, PA Pennsylvania 19144 (US) 25.04.2011 US 201161478689 P • SCHINAZI, Alan, D. 01.08.2011 US 201161513906 P Providence, RI Rhode Island 02906 (US) (62) Document number(s) of the earlier application(s) in (74) Representative: Jones Day accordance with Art. 76 EPC: Rechtsanwälte,Attorneys-at-Law, Patentanwälte 11847079.8 / 2 648 676 Prinzregentenstrasse 11 80538 München (DE) (71) Applicant: Follica, Inc. Mendham, NJ 07945 (US) Remarks: •This application was filed on 24.10.2016 as a (72) Inventors: divisional application to the application mentioned • BARMAN, Shikha, P. under INID code 62. Bedford, MA Massachusetts 01730 (US) •Claims filed after the date of filing of the application • JU, William, D. / after the date of receipt of the divisional application Mendham, NJ New Jersey 07945 (US) (Rule 68(4) EPC) • KELLOGG, Scott, C. Mattapoisett, MA Massachusetts 02739 (US) (54) METHODS FOR TREATING BALDNESS AND PROMOTING HAIR GROWTH (57) The invention relates to a hair growth promoting agent to the subject. The methods comprise the integu- agentfor use in amethod for treating baldnessin ahuman mental perturbation of an affected area of skin of the hu- subject. The invention further relates to a method for man subject, wherein the integumental perturbation is non-therapeutic treatment of baldness in a subject com- accomplished by microneedling. The hair growth promot- prising the administration of a hair growth promoting ing agent is minoxidil. EP 3 178 465 A1 Printed by Jouve, 75001 PARIS (FR) EP 3 178 465 A1 Description [0001] This application claims priority to U.S. provisional application Serial No. 61/420,282, filed December 6, 2010, U.S. provisional application Serial No. 61/453,919, filed March 17,2011, U.S. provisional application Serial No. 5 61/453,902, filed March 17,2011, U.S. provisional application Serial No. 61/478,689, filed April 25, 2011, and U.S. provisional application Serial No. 61/513,906, filed August 1, 2011, the entire contents of each of which is incorporated herein by reference in its entirety. 1. INTRODUCTION 10 [0002] The invention relates to methods of treating baldness, treating alopecia, promoting hair growth, and/or promoting hair follicle development and/or activation on an area of the skin of a subject (for example, a human) by subjecting said area of the skin to integumental perturbation. Integumental perturbation can be used in combination with other treatments for promoting hair growth. The invention provides devices for integumental perturbation for promoting hair growth, and 15 provides pharmaceutical compositions for use in combination with integumental perturbation for promoting hair growth. 2. BACKGROUND [0003] The skin of an adult human is essentially covered with hair follicles and contains approximately five million hair 20 follicles, with approximately 100,000 - 150,000 covering the scalp. The portions of human skin that lack visible hair contain, for the most part, hair follicles that produce "vellus hair" while certain other hair follicles may contain or produce no hair (see Figure 1). Essentially, only the glaborous skin on palmar and plantar aspects of hands and feet, respectively, and the lips and labia lack hair follicles. Only a minority of human hair follicles produce a hair fiber that can be readily appreciated visibly (a "terminal hair") and these specialized follicles are localized on specific regions of skin; on the 25 normal scalp, terminal hair follicles typically outnumber vellus hair follicles by 7:1. Accordingly, both the presence and absence of visible hair on human non-glaborous skin is mediated by regulation of activity of specialized follicles. [0004] Hair follicles, and particularly human hair follicles, are crypt structures comprised of distinct components, each comprised of several different specialized cells (see Figures 2 and 3). In addition to the cells and structures associated with making and anchoring the hair shaft, the vast majority of hair follicles contain units called sebaceous glands (which 30 produce sebum). Some hair follicles have apocrine glands attached to them, and are located in the axilla and other specific areas of the body. [0005] In addition to the hair shaft, the structures of the hair follicle include the follicular papilla (FP) and the germinative epithelium (GE) (together, the bulb). The FP is comprised of mesenchymal cells (and connective tissue). The other cells of the follicle are epithelial and include at least 8 cellular lineages including the outer root sheath (ORS), the companion 35 layer (CL), the internal root sheath Henle’s layer (He), internal root sheath Huxley’s layer (Hu), the cuticle of the internal root sheath (Csth), the cuticle of the hair shaft (Csft), the cortex of the hair shaft, and the medulla of the shaft (Med). (Stenn & Paus, 2001, Physiol. Revs. 81: 449-494.) (See also Figures 2-4.) [0006] Scalp and certain other hair in humans tend to grow in follicular units. A follicular unit of scalp hair is typically composed of two to four terminal hair follicles; one, rarely two vellus hair follicles; their associated sebaceous glands, 40 neurovascular plexus, an erector pilorum muscle and a circumferential band of adventitial collagen, termed the "perifol- liculum" (Headington JT, 1984, Arch. Dermatol. 120:449-456; Bernstein RM, 2005, "Follicular Unit Hair Transplantation," Ch. 34 in Surgery of the Skin, Robinson et al., eds., St. Louis: Mosby, pp. 549-574). [0007] Hair follicles are believed to produce approximately 20 individual hair shafts over the life of the follicle as the follicle progresses through cycles of hair production, shedding (ejection), involution and new growth. The regulation of 45 hair growth and follicle regeneration have been investigated in murine systems. However, the biology of hair follicles in the mouse is different from those of the human in several important aspects. In the mouse, a thick fur coating is essential to healthy life (because hair plays roles in thermoregulation and other functions.) Mouse skin is covered with hair follicles that produce terminal hair (fur), whereas significant regions of human skin are covered with hair follicles that produce vellus hair, which is much less visible or even invisible. Mouse and other non-primate mammals have synchronous 50 Follicle Cycles in early life, although the hair follicle cycles become less synchronous with age. Human follicles progress through the Follicle Cycle in an asynchronous fashion. On an adult human scalp, at any particular time approximately 80-90% are in anagen; 10-20% in telogen and 1-2% in catagen. While the mouse has certain specialized follicles (e.g., whiskers, guard, awl, auchene, and zigzag hair), mouse follicles are generally not subject to developmental and gender- specific hair patterning. In contrast, a significant number of human follicles are individual participants in choreographed 55 hair patterning that affects the type, length and color of shaft produced at different times in development and aging and in a gender specific manner. 2 EP 3 178 465 A1 2.1 HAIR FOLLICLE MORPHOGENESIS AND REGENERATION [0008] It is believed that follicle formation occurs but once in a lifetime (in utero), so that a mammal, and particularly a human, is born with a fixed number of follicles, which does not normally increase thereafter. Despite suggestions of 5 the regenerative capacity of the adult mammalian skin to recreate the embryonic follicle, until recently, follicle neogenesis was not proven because of the lack of tools needed to demonstrate the occurrence or hair follicle neogenesissee ( , Argyris et al., 1959, Dev. Biol. 1: 269-80; Miller, 1973, J. Invest. Dermatol. 58:1-9; and Kligman, 1959, Ann NY Acad Sci 83: 507-511). [0009] It has been proposed, however, that hair follicle neogenesis can be associated with wound healing in animals 10 (e.g., rabbits, mice). See, Stenn & Paus, 2001, Physiol. Revs. 81:449-494. More recently, a series of murine experiments definitively showed that hair follicle-derived epithelial stem cell progenitors migrate out of the follicle and contribute to the re-epithelialization of injured skin ( see, Morris et al., 2004, Nature Biotechnology 22:411-417; Ito et al., 2004, Differ- entiation 72:548-57; and Ito et al., 2005, Nature Medicine 11:1351-1354). In animal studies designed to explore the role of Wnt in hair follicle development, Fathke showed that prolonged activation of Wnt signaling during wound healing in 15 mice resulted in generation of rudiments of hair follicles but did not result in the formation of hair follicles or growth of more hair (Fathke et al., 2006, BMC Cell Biol. 7:4). [0010] As noted by Fathke, cutaneous repair in adult mammals following full thickness wounding is understood to result in scar tissue and the loss of the regenerative capability of the hair follicle. Severe wounds and bums are usually associated with a form of cutaneous repair that results in scar tissue and no hair follicles ( see, Fathke et al., 2006, BMC 20 Cell Biol. 7:4). However, in a mouse study, Cotsarelis showed that physically disrupting the skin and existing follicles, in a defined fashion, can lead to follicle neogenesis (Ito et al., 2007, Nature 447:316-321).