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A. Tosti et al. (eds.)Hair and Scalp Treatmentshttps://doi.org/10.1007/978-3-030-21555-2_22

22. New Drugs for Alopecias

Jacob Griggs¹, Rodrigo Pirmez² and Antonella Tosti³

(1)

Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Leonard M. Miller School of Medicine, Miami, FL, USA

(2)

Department of Dermatology Santa Casa da Misericordia, Rio De Janeiro, Brazil

(3)

Fredric Brandt Endowed Professor of Dermatology, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

Jacob Griggs

Email: jwg63@med.miami.edu

Keywords

AlopeciaAlopecia areataAndrogenetic alopeciaBricitinibBimatoprostBNZ-1JAK inhibitorsLatanoprostRuxolitinibSetipiprantTofacitinib

Introduction

Treatment for alopecia is continuously an active area of research and development. Elsewhere in this book, we have discussed emerging treatments including platelet-rich plasma (PRP), microneedling, stem cells, and light therapy. This chapter will center on new drugs in development, with a focus on the two types of alopecia most heavily researched: androgenetic alopecia (AGA) and alopecia areata (AA).

Androgenetic Alopecia

Introduction

Androgenetic alopecia, also referred to as male pattern hair loss or female pattern hair loss, is the most common form of progressive hair loss [1]. The goal of treatment is to cease the miniaturization of hair follicles and to induce hair to thicken and regrow [2, 3]. Current treatment typically revolves around topical minoxidil and oral finasteride, both of which are effective with long-term daily use. These treatments essentially require lifelong treatment to see sustained effects, and patients often fear side effects, particularly the sexual side effects of oral finasteride. As a result, there is a demand for novel treatment options, with many potential new treatment options currently being studied.

PGF2 Analogs

Bimatoprost is a PGF2 analog which is currently FDA-approved for eyelash hypotrichosis in a 0.03% solution [4], marketed under the trade name Latisse®. Latanoprost is another PGF2 analog that has been used in eye drops to stimulate eyelash growth [5]. The mechanism of which PGF2 analogs can induce hair growth is unclear, but proposed mechanisms include prolonging anagen and the conversion of telogen follicles to anagen [6]. Topical formulations of PGF2 analogs have been investigated for the treatment of AGA with mixed results, with some studies showing superiority to placebo and others showing no difference [5, 7–10]. Studies comparing topical PGF2 analogs to topical minoxidil appear to show that they are less effective than topical minoxidil [8, 10]. See Table 22.1 for a summary of clinical trials involving topical PGF2 analogs in the treatment for AGA.

Table 22.1

Clinical trials investigation of PGF2 analogs in the treatment of AGA

Drug	Clinical trial ID	Subjects	Design	Results
0.03% Bimatoprost solution [7]	NCT02170662	9 men (age 18–45)	Phase 2, randomized, double-blinded, crossover study (16-week treatment periods with 10-day washout period between)	% Change in Target Area Total Hair Count (TAHC): Placebo then Bimatoprost (n = 3): Week 0–17: −2.6 Week 17–34: 4.9 Bimatoprost then placebo (n = 6) Week 0–17: 27.4 Week 17–34: −5.8
Bimatoprost solution [10]	NCT01325350	306 women (age 18–59)	Phase 2, randomized, double-blinded. Three formulations of bimatoprost solution (A, B, and C) were compared with vehicle and minoxidil 2% solution. Treatment period of 6 months	Change from baseline in TAHC Formulation A (n = 61) −0.4 Formulation B (n = 60) −3.5 Formulation C (n = 60) 4.3 Vehicle placebo (n = 61) 1.1 Minoxidil 2% (n = 61) 13.6
Bimatoprost solution [8]	NCT01325337	307 men (age 18–49)	Phase 2, randomized, double-blinded. Three formulations of bimatoprost solution (A, B, C) were compared with vehicle and minoxidil 5% solution. Treatment period of 6 months	Change from baseline in TAHC Formulation A (n = 60) 13.1 Formulation B (n = 61) 6.1 Formulation C (n = 61) 6.3 Vehicle placebo (n = 61) 4.1 Minoxidil 5% (n = 61) 21.9
Bimatoprost solution [9]	NCT01904721	244 men (age 18–49)	Phase 2, randomized, double-blinded. Subjects treated for 6 months twice daily with bimatoprost solution 1, 2, or vehicle.	Change from baseline in TAHC Formulation 1 (n = 62) 12.7 Formulation 2 (n = 63) 9.3 Vehicle placebo (n = 60) 5.8
0.1% latanoprost solution [5]	N/A	16 men (age 23–35)	Randomized, double-blinded. 24-week treatment of topical latanoprost versus placebo in different zones of scalp on the same patient	Based on clinical evaluation of hair density, length, thickness, and pigmentation: Good clinical response (latanoprost > placebo): 8/16 (50%) No clinical response (latanoprost = placebo): 7/16 (44%) Bad clinical response (latanoprost < placebo): 1/16 (6%)

Setipiprant

Setipiprant is a selective antagonist to the PGD2 receptor [11]. PGD2 is highly expressed in the bald scalp of men with AGA, and in mice, high levels of PGD2 have been shown to induce follicular miniaturization, sebaceous gland hyperplasia, and alopecia [12]. Setipiprant has been investigated in clinical trials for allergic disorders and has been demonstrated to be safe and well-tolerated [13]. A phase 2A study of oral setipiprant to treat AGA in males was completed (NCT02781311), but results are not yet available.

SM04554

SM04554 is a small-molecule activator of the Wnt pathway, which is involved in the regulation of hair growth. Abnormal regulation of Wnt leads to hair loss in AGA, and it is proposed that increasing Wnt signaling may extend the anagen phase and delay the transition to catagen phase [14]. Table 22.2 shows the two phase 2 clinical trials investigating SM04554 in a topical formulation for the treatment of AGA; final results are not yet available, but preliminary results have been released. According to the drug company’s website (Samumed), a phase 3 clinical trial involving 625 patients started recently [15].

Table 22.2

Phase 2 clinical trials investigating SM04554 in the treatment of AGA

Clinical trial ID	Subjects	Design	Results
NCT02275351 [16]	302 men (age 18–55)	Phase 2, randomized, placebo-controlled, double-blind. Three treatment groups: 0.15% topical SM04554, 0.25% topical SM04554, and vehicle control. Treatment period of 90 days	At day 135, significant increase of mean hair count and mean hair density seen in 0.15% SM04554 topical formulation compared to vehicle control
NCT02503137 [17]	49 men (age 18–65)	Phase 2, randomized, placebo-controlled, double-blind, single-center study. Three treatment groups: 0.15% topical SM04554, 0.25% topical SM04554, and vehicle control. Treatment period of 90 days	Significant increase of total follicle counts at days 90 and 135 for 0.25% topical formulation. Significant increase of total follicle counts at day 135 for 0.15% topical formulation

Clinical trial ID

Subjects

Design

Results

NCT02275351 [16]

302 men (age 18–55)

Phase 2, randomized, placebo-controlled, double-blind. Three treatment groups: 0.15% topical SM04554, 0.25% topical SM04554, and vehicle control. Treatment period of 90 days

At day 135, significant increase of mean hair count and mean hair density seen in 0.15% SM04554 topical formulation compared to vehicle control

NCT02503137 [17]

49 men (age 18–65)

Phase 2, randomized, placebo-controlled, double-blind, single-center study. Three treatment groups: 0.15% topical SM04554, 0.25% topical SM04554, and vehicle control. Treatment period of 90 days

Significant increase of total follicle counts at days 90 and 135 for 0.25% topical formulation.

Significant increase of total follicle counts at day 135 for 0.15% topical formulation

CB-03-01

CB-03-01 (also called cortexolone 17a-propionate, clascoterone, Breezula™) is a selective androgen receptor antagonist. It has a very good safety profile as it has minimal systemic bioavailability. Two phase 2 clinical trials have been performed for CB-03-01 in a topical solution for the treatment of AGA (Table 22.3), one of which is currently ongoing. Current evidence supports efficacy compared to placebo, though topical minoxidil appears to be superior [18].

Table 22.3

Clinical trials investigating CB-03-01 in the treatment of AGA

Clinical trial ID	Subjects	Design	Results
NCT02279823 [18]	95 men (age 18–50)	Phase 2, double-blind, randomized. Three parallel arms: CB-03-01 5% solution, minoxidil 5% solution, placebo solution. Applied 2×/day for 26 weeks	At 6 months: Increase in total hair count. Minoxidil: 18.8 CB-03-01: 12.7 Placebo: 2.9
2016-003733-23 [19]	404 men (age 18–55)	Phase 2, double-blind, randomized, multicenter. Five treatment groups for 12 months: 2.5% CB-03-01 solution BID 5.0% CB-03-01 solution BID 7.5%CB-03-01 solution BID 7.5% CB-03-01 solution daily Vehicle solution BID	Currently ongoing. Interim analysis at 6 months: Mean changes of TAHC from baseline 2.5% BID: 13.01 5% BID: 12.21 7.5% BID: 20.79 7.5% QD: 11.52 Vehicle: −0.11

Clinical trial ID

Subjects

Design

Results

NCT02279823 [18]

95 men (age 18–50)

Phase 2, double-blind, randomized. Three parallel arms: CB-03-01 5% solution, minoxidil 5% solution, placebo solution. Applied 2×/day for 26 weeks

At 6 months:

Increase in total hair count.

Minoxidil: 18.8

CB-03-01: 12.7

Placebo: 2.9

2016-003733-23 [19]

404 men (age 18–55)

Phase 2, double-blind, randomized, multicenter. Five treatment groups for 12 months:

2.5% CB-03-01 solution BID

5.0% CB-03-01 solution BID

7.5%CB-03-01 solution BID

7.5% CB-03-01 solution daily Vehicle solution BID

Currently ongoing.

Interim analysis at 6 months:

Mean changes of TAHC from baseline

2.5% BID: 13.01

5% BID: 12.21

7.5% BID: 20.79

7.5% QD: 11.52

Vehicle: −0.11

Topical JAK Inhibitors

In mouse and human skin, topical treatment with JAK inhibitors results in the rapid onset of anagen, resulting in hair growth [20]. AGA is a hair loss disorder involving hair follicles arrested in telogen phase; thus, treatment with topical JAK inhibitors may increase hair growth by promoting hair follicle entry into anagen. ATI-50002 (also called ATI-502) is a topical JAK1/3 inhibitor currently undergoing a phase 2, open- label study assessing its safety, tolerability, and efficacy in both males and females with AGA (NCT03495817). Oral JAK inhibitors have no effect on the androgen-dependent scalp [21].

Topical Finasteride

Oral finasteride is highly effective with widespread use for the treatment of AGA; however, in some patients, it may cause undesirable side effects, particularly sexual side effects. Many patients are hesitant to start treatment based on fear of these possible side effects. In some countries, topical finasteride is available, both as a solo agent and in combination with minoxidil. Topical formulations of finasteride have been created in order to minimize systemic absorption, thereby decreasing the risk of side effects. A topical formulation of 0.25% finasteride called P-3074 was shown to have a much greater impact on scalp DHT levels than on serum DHT levels, theoretically decreasing the risk of sexual side effects [22]. There is a completed phase 3, multicenter, randomized, double-blind clinical trial investigating P-3074 versus a vehicle control in men with AGA, showing increase in the target area hair count at 6 months.

Alopecia Areata

Alopecia areata (AA) is a nonscarring form of hair loss with an autoimmune mechanism, typically with a sudden onset. There are currently no approved treatments for AA that result in a lasting response or permanent remission [23, 24]. However, some promising new treatments are under investigation.

Oral JAK Inhibitors

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is involved in many proinflammatory pathways [25]. Studies of JAK inhibitors in treating AA have thus far been promising [26]. The efficacy of JAK inhibitors in treating AA may be their ability to inhibit cytokines involved in the activation of CD8⁺ NKG2D⁺ T cells, a predominant type of cell found in the follicular infiltrate of AA lesions [27]. Additionally, JAK inhibitors appear to have a direct effect on hair growth by promoting hair follicle entry into anagen phase [20]. The JAK inhibitors shown to be effective in alopecia areata include ruxolitinib, tofacitinib, and baricitinib (see Table 22.4 for more information) [26]. Ruxolitinib and tofacitinib are FDA-approved for the treatment of various hematologic and rheumatologic diseases [28].

Table 22.4

Oral JAK inhibitors studied for the treatment of alopecia areata

Name (brand)	Primary targets [28]	Clinical trials	Design	Results
Ruxolitinib (Jakafi)	JAK1/3	NCT01950780 [29]	12 subjects (age 14–41 years), open-label; moderate to severe AA; 20 mg twice per day, 3–6 months of treatment	9/12: At least 50% regrowth (responders had average of 92% regrowth; Seven of the nine responders achieved >95% regrowth) 3/12 did not respond
Tofacitinib (Xeljanz)	JAK1/2	NCT02312882 [30] NCT02197455 [30]	66 subjects (age 19–65). Two-center, open-label, single-arm. For AA with >50% hair loss, alopecia totalis, and alopecia universalis. Treatment with 5 mg twice daily for 3 months	32% of subjects experienced 50% or greater improvement in SALT score.^a Drug cessation resulted in disease relapse in 8.5 weeks
Tofacitinib (Xeljanz)	JAK1/2	NCT02299297 [31]	12 subjects, open-label pilot study, moderate to severe AA, alopecia totalis, and alopecia universalis. 5–10 mg twice/day, 6–18 months of treatment	8/12: >50% regrowth 3/12: <50% regrowth 1/12: no regrowth
Baricitinib (Olumiant)	JAK1/2	NCT03570749	725 subjects (age 18–70), placebo-controlled, severe or very severe AA	Study currently recruiting

^aSALT Score: Severity of Alopecia Tool [32]

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Mar 23, 2021 | Posted by admin in Dermatology | Comments Off

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Drugs for Alopecias