Emerging treatments in alopecia.

Review

Emerging treatments in alopecia Leyre Falto-Aizpurua, Sonal Choudhary & Antonella Tosti† †

Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Dicle Univ. on 11/08/14 For personal use only.

University of Miami, Miller School of Medicine, Department of Dermatology and Cutaneous Surgery, Miami, FL, USA

1.

Background

2.

Existing treatments

3.

Medical need

4.

Current research goals

5.

Scientific rationale

6.

Competitive environment

7.

Potential developmental issues

8.

Conclusion

9.

Expert opinion

Introduction: Alopecia is a common concern encountered in the medical practice. Treatment approach varies according to the type and severity of alopecia. However, available treatment options have limited efficacy and several adverse effects. Presently, there are different treatment options being studied to overcome these limitations. Additionally, cellular pathways involved in the pathophysiology of alopecia are further being clarified to potentially target pathogenic molecules. Areas covered: We searched the literature for recently published articles discussing new treatment options as well as mechanisms involved in alopecia. We discuss the use of stem cells, growth factors, cellular pathways and robotic hair transplant, among other emerging therapies used for alopecia. Expert opinion: Future looks very promising and new effective treatments such as janus kinase inhibitors could possibly be available for alopecia areata. The stem-cell technology is advancing and companies involved in hair follicle neogenesis are starting clinical trials on patients with androgenetic alopecia. Keywords: abatacept, alopecia areata, androgenetic alopecia, bimatoprost, chemotherapy-induced alopecia, dutasteride, excimer laser, finasteride, hair transplant, IL-2, iron, janus kinase inhibitors, micropigmentation, minoxidil, pioglitazone, platelet-rich plasma, prostaglandin, retinoids, ruxolitinib, scalp cooling, scarring alopecia, stem cells, tofacitinib, trichotillomania, vitamin D, wnt pathway Expert Opin. Emerging Drugs [Early Online]

1.

Background

Alopecia is a common complaint seen in the dermatologic practice. Androgenetic alopecia (AGA) is seen in about 70% of the population. Another commonly observed type is alopecia areata (AA), which can be localized or generalized. Scarring and other types of alopecia are less frequently encountered but very concerning to patients. 2.

Existing treatments

[1,2]

Currently approved treatment options typically require a great degree of compliance for long periods of time to achieve effectiveness. Approved medications for AGA include finasteride and topical minoxidil [3]. Finasteride’s most concerning side effects are sexual dysfunction, mood disorders and increased risk of high-grade prostate cancer in men [4] and its use is contraindicated in pregnancy or women with personal or family history of breast or ovarian cancer. Minoxidil can cause irritation and/or allergies at the site of application and is usually required to be applied twice daily for long periods of time. Women can use the 5% solution once a day achieving the same effectiveness, while men could also apply it once a day if combined with topical tretinoin 0.01% [5]. Treatment for AA is mostly based on experience as randomized, controlled clinical trials are limited [6]. Treatment depends on disease involvement and some options are topical [7], intralesional [8] or systemic [9] steroids, and topical

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L. Falto-Aizpurua et al.

immunotherapy or systemic immunomodulators. None of these treatments are curative and treatment response is very variable. Chemotherapy-induced alopecia (CIA) is a very big concern as it affects 65% of patients undergoing chemotherapy. Nonetheless, it can only be prevented with scalp cooling systems, which are not effective for all regimens and readily available only in a few cancer centers. In trichotillomania, the first line of treatment is behavioral intervention, although the use of several drugs has been described with different success rates. Treatments for scarring alopecia are limited, and mainly concentrate on prevention or halting disease progression with anti-inflammatory or immunomodulatory agents. Oral cetirizine has also been utilized [10]. 3.

Medical need

Unfortunately, adverse effects of medications and lack of persistence are the most common reasons for noncompliance. Therefore, new medications with decreased side effects and easier to use are needed to enhance patient compliance. To do this, the pathophysiology behind the different types of alopecia has to be further clarified. In this review, we discuss new drugs for alopecia as well as potential targets for new drugs.

finasteride 1 mg, dutasteride 0.02 mg, 0.1 mg and placebo. Dutasteride was overall well tolerated and adverse effects were similar among the different treatment groups with no dose-dependent adverse effects associated to dutasteride [13]. A study by Jung et al. demonstrated that a 6-month therapy with dutasteride 0.5 mg significantly improved hair density by 10.3% and hair thickness by 18.9% in 24 out of 31 (77.4%) patients who had previously been treated with finasteride 1 mg for 6 months with poor results. The main adverse effect encountered was transient sexual dysfunction in six patients (17.1%) [14]. Prostaglandins In 2008, bimatoprost, a prostaglandin F2a-related analog, was approved by the FDA for the treatment of hypotrichosis of the eyelashes. Recently, it was shown that scalp hair follicles also express prostanoid receptors mostly in the dermal papilla and connective tissue sheath surrounding the hair bulb [15]. Another potential drug target is prostaglandin-D2, which, contrary to prostamide F2a, inhibits hair growth in mouse and human hair follicles through the G-protein-coupled receptor 44 (GPCR44) [16-18]. Drugs that block GPCR44 are currently under clinical trials for asthma and may be a possible future treatment of AGA. 5.1.2

PRP and platelet-rich fibrin matrix PRP is rich in growth factors and other bioactive molecules obtained from the a granules of platelet concentrate. PRP has been used since the 1980s in medicine, and now seems promising for the treatment of hair loss, although its mechanism of action for this purpose had not been completely elucidated until recently [19]. A study by Li et al. demonstrated that PRP increases the expression of b-catenin (inducing the differentiation of bulge stem cells into hair follicles), FGF-7 (prolonging anagen phase) and Bcl-2 expression (protecting cells from apoptosis) in treated dermal papilla cells [20]. They also demonstrated significant hair growth after PRP injections performed for 3 weeks in a mouse model. Others were able to demonstrate an increased number of newly formed follicles as well as accelerated the time of hair formation after grafts treated with PRP in nude mice [21]. Platelet plasma growth factors have been used as an adjunctive therapy in male patients undergoing hair restoration surgery to improve hair density and follicular growth [22]. A similar compound, platelet-rich fibrin matrix (PRFM), was used in a prospective cohort study, where 15 patients with AGA received 3 intradermal injections of PRFM on a monthly basis with a significant improvement in the hair density index at 6 months [23]. 5.1.3

4.

Current research goals

Current research is intended to further elucidate the exact pathophysiology of the different types of alopecia in order to develop drugs that specifically target the disease. Additionally, better models for drug testing have to be developed as well as better, more specific drug delivery systems to decrease the side-effect profile. In this article, we discuss some new drugs (i.e., dutasteride, janus kinase [JAK] inhibitors, among others) and new modalities of administration of existing drugs (i.e., IL-2, valproic acid) that look promising for the treatment of alopecia. We also review the role of stem cells and their activation pathways (i.e., platelet-rich plasma [PRP], follicular unit extraction [FUE]) in the treatment of alopecias. The role of vitamins and other nutritional supplements in the management of alopecia will also be discussed. 5.

Scientific rationale

5.1

Androgenetic alopecia [11] Finasteride and dutasteride

5.1.1

Finasteride, a type II 5-a-reductase inhibitor, is approved for the treatment of AGA in men at the dose of 1 mg per day [12]. Dutasteride, a type I and II 5-a-reductase inhibitor, has been shown to be more effective than finasteride. A Phase III clinical trial (NCT01231607) showed that dutasteride 0.5 mg resulted in significantly increased hair growth and restoration in men with AGA after 24 weeks of treatment, compared to 2

Stem cells The use of hair follicle stem cells (HFSCs) located in the bulge area is promising for the treatment of non-scarring alopecia [24]. Contrary to scarring alopecia, the inflammation in non-scarring alopecia does not affect the bulge area of hair 5.1.4

Expert Opin. Emerging Drugs (2014) 19(4)


Emerging treatments in alopecia

follicles [25,26]. The bulge area is an immune privileged zone mostly because of downregulation of MHC I molecules and upregulation of immunosuppressant molecules, protecting HFSCs from aggressive autoimmune attacks [27]. HFSCs can differentiate into cells of a hair follicle, sebaceous gland or interfollicular epidermis, depending on the surrounding chemical environment [28-34]. Moreover, the hair cycle can be affected by alterations of the pathways involved in the activation and suppression of HFSCs. One of the main pathways currently being studied is the wnt/b-catenin pathway. The activation of this pathway induces the differentiation of bulge stem cells into hair follicles. Lee et al. demonstrated that topical application of valproic acid, which inhibits GSK3b, promotes hair formation in a mice model and on human hair follicle in vitro by increasing b-catenin [35,36]. Recently, in a randomized, double-blind, placebo-controlled trial, men with moderate AGA were treated with a spray containing 8.3% valproic acid or placebo for 24 weeks resulting in significant increase in total hair count in the experimental group [37]. Adipose-derived stem cells have also been studied; however, their survival and regeneration potential are induced by hypoxia, and alternative methods of induction have been looked for. Therefore, preconditioning adipose stem cells with ultraviolet B (UVB) to stimulate the hair-growth--promoting effects was studied [38]. It was found that only low-dose UVB (< 20 mJ/cm2) was able to increase cell survival, migration, angiogenic differentiation and paracrine effects. By performing this technique prior to cell transplantation, it was observed that mice had increased hair follicle formation and hair weight. UVB preconditioning promotes these effects by generating reactive oxygen species and upregulating NADPH oxidase 4. Hair transplant Several studies have demonstrated successful, functional, bioengineered hair follicle transplantation in vivo [39-41]. Given the increasing interest in stem-cell therapies, Kumar et al. performed a preliminary pilot study to compare the average stem-cell yield obtained with FUE with follicular plucking [42]. They found that with FUE a greater number of stem cells were obtained. FUE being the better option for hair transplants, adjustments to the surgical process have been described to optimize overall results [43] and robotic devices have been added to fasten the process. Older robotic devices were able to successfully decrease the harvest time and transection rate. Newer devices (ARTAS Robotic System, Restoration Robotics, Inc., San Jose, California) include a microscope, a follicular unit identification system and a high precision rate two-step punch harvest device [44,45]. 5.1.5

Micropigmentation When available treatments have failed or are not possible to pursue, hair micropigmentation is an alternative to camouflage hair loss in AGA or scars in the scalp [46]. Varying 5.1.6

pigments, depending on the hair and scalp skin colors, can be used to tattoo the scalp in the areas where thinner hair, or scars, is present. The procedure should be carefully performed to introduce the pigment at the correct depth (1 -- 2 mm) and at the appropriate distance in the scalp. Possible side effects include infection, tattoo allergy, color fading over time, and the fact that future removal may be difficult and lead to scarring. Improving drug testing and delivery systems A significant limitation encountered when testing drugs using mice or in vitro models is that these are imperfect and incomplete representation of human skin model since the affected pathways and/or drug interactions when tested in humans are not necessarily the same. Therefore, Guo et al. have suggested to create a complete skin model [47]. They aim to create a multicellular skin model by using induced pluripotent stem cells, create a vascular network to simulate systemic drug delivery with hydrogels, integrate the skin with other organs within a microphysiological system, as well as to maximize the lifespan of model in order to be sufficient for drug testing. In the search of improved drug delivery systems and preserve treatment efficacy while minimizing side effects, Gomes et al. aimed to develop, characterize and evaluate the stability and penetration of lipid nanocarriers containing minoxidil and finasteride in vitro [48]. They achieved good drug characteristics but limited drug penetration into ear pig skin. Further studies should be performed to overcome these limitations. 5.1.7

Alopecia areata 5.2.1 IL-2 5.2

An increased amount of CD4- and CD8-positive cells are observed in AA secondary to an impaired function of T regulatory cells [49]. IL-2 at low dosages has been shown to activate T regulatory lymphocytes. A prospective study (NCT018 40046) performed in five patients with AA universalis, unresponsive to systematic therapies, demonstrated improvement in four patients 6 months after receiving subcutaneous administration of low-dose IL-2. Adverse events were mild to moderate and included asthenia, arthralgia, urticaria, and local reactions at injection site. JAK inhibitors IL-15 is an inflammatory cytokine increased in AA. It promotes the survival of CD8 T lymphocytes, including the self-reactive memory T cells, facilitates the production of some immunoglobulins and plays a key role in the survival of natural killer cells. Two of the signaling pathways involved in these functions include the JAK1 and JAK3. Therefore, by interfering with JAK pathways, IL-15 effects can be diminished in several autoimmune disorders. The JAK inhibitors tofacitinib and ruxolitinib were effective in preventing and treating AA in a mouse model both after oral and topical administration [50]. 5.2.2


3



Tofacitinib citrate is a JAK1/3 inhibitor approved by the FDA for the treatment of rheumatoid arthritis and currently in clinical trials for treatment of psoriasis. A recent paper reports a patient with refractory psoriasis and concomitant AA universalis who had complete regrowth of hair after 8 months of therapy with tofacitinib [51]. The JAK 1/2 inhibitor, ruxolitinib, is FDA approved for the treatment of myelofibrosis [50]. Three patients with moderate to severe AA received oral therapy of 20 mg ruxolitinib twice daily for 3 -- 5 months achieving near-complete hair growth by the end of the treatment [50]. Biopsies performed 12 weeks after treatment showed a decrease in perifollicular T-cell infiltration, a decrease in follicular expression of human leukocyte antigen class I and reduction of the dermal inflammation as compared to baseline.

Recent work by Panicker et al. showed that cholesterol pathways are altered in all subtypes of primary scarring alopecia [59]. Excimer laser The use of 308 nm excimer laser has been proven effective for several inflammatory cutaneous diseases including psoriasis and AA by decreasing the T-cell population and altering the inflammatory cytokine profile. Navarini et al. treated 13 patients with LPP unresponsive to conventional therapies with excimer laser twice a week for a total mean dose of 4300 mJ/cm2 [60]. A significant reduction in clinical signs of inflammation was noted at the end of treatment. 5.3.3

5.4

Chemotherapy-induced alopecia Scalp cooling

5.4.1

Platelet-rich plasma A study performed by Trink et al. demonstrated that PRP significantly increased hair growth in 45 patients with chronic AA, compared to intralesional triamcinolone administration, although both were better than controls [52]. PRP induced hair regrowth in 60% of treated patients. The authors were able to demonstrate the growth-promoting effect of PRP by measuring an increase in Ki-67, a cell proliferation marker. They also hypothesized that the benefits of PRP for AA might be due to its anti-inflammatory effects. 5.2.3

Scarring alopecia Due to the nature of the disease and unknown pathogenesis, treatment options for scarring alopecia are limited and only focused to prevent disease progression. 5.3

Biofilms as a possible target in folliculitis decalvans

5.3.1

A recent study suggests that biofilms can be a possible drug target in folliculitis decalvans. Matard et al. observed bacterial infra infundibular biofilms in situ, consisting mostly of bacilli, particularly Propyonobaterium acnes [53]. The authors hypothesize that the disease may be caused by a pathogenic shift within the infundibular biofilm, and anti-staphylococcal antibiotics are effective just because they also act on P. acnes. Pioglitazone Normal expression of PPARg, a transcription factor that regulates lipid metabolism and inflammation, is crucial for healthy pilosebaceous unit [54,55]. In the scalp affected by lichen planopilaris (LPP), there is a decrease in genes that modulate lipid metabolism with progressive loss of peroxisomes, accumulation of proinflammatory lipids and inflammatory infiltrates with subsequent destruction of the pilosebaceous unit [54]. Therefore, PPARg agonist therapy might be a possible, targeted treatment option for LPP. Pioglitazone 15 mg daily has been utilized with variable results [56-58]. 5.3.2

4

The use of scalp cooling for the prevention of CIA has been well documented in the literature, and recent studies show that 50% of patients can avoid wearing a wig with this treatment. Scalp cooling is effective for most regimens except for TAC (taxotere, adriamycin and cyclophosphamide). Other factors that influence the efficacy of scalp cooling include duration of cooling and cooling method and temperature [61]. A randomized trial compared a precooling temperature of 3 and 8 C using a computer-controlled scalp cooling system, to achieve a hair follicle temperature < 22 C with no significant difference between them in preventing alopecia [62]. However, the lower temperature resulted in a higher rate of side effects. A prospective, nonrandomized clinical trial (NCT0100 8774) attempted to compare two different scalp cooling systems (Paxman PSC-2 machine [PAX] or cold cap [CC]) in preventing CIA [63]. A total of 238 patients receiving docetaxel therapy at 3-week intervals for solid tumors were enrolled. It was determined that both systems, PAX and CC, lead to a 78% risk reduction of alopecia compared to no cooling. Adverse events were reported in 5% of the cases, with sensation of cooling being the most common. Topical vasoconstrictors Given the amount of variables present with scalp cooling and the side effects, newer options are being searched for. Soref et al. demonstrated that the application of topical vasoconstrictors, epinephrine or norepinephrine, in mice could effectively suppress alopecia after radiation or chemotherapy [64]. Transient cutaneous vasoconstriction and secondary hypoxia protect hair follicles from radiation- or chemotherapy-induced DNA damage. 5.4.2

Parathyroid hormone agonists An alternate way of modulating the hair follicle response in CIA is with the use of parathyroid hormone (PTH) agonists. The effects of PTH on hair follicles have been previously proven but to achieve appropriate concentration in the skin, Katikaneni et al. combined a PTH agonist with a 5.4.3



bacterial-derived collagen-binding domain (CBD) [65]. They tested the PTH-CBD effect in mice given prophylactically (prior to chemotherapy) or therapeutically. Both protocols were effective for CIA when compared to control, but prophylaxis with PTH-CBD resulted in better hair appearance and no dystrophic follicles, while the treatment resulted in partial recovery with some dystrophic hair follicles.

and wnt/b-catenin signals, on isolated hair follicles and keratinocytes from patients with AA [77]. It was demonstrated that a decreased expression of vitamin D receptors in hair follicle and epidermal keratinocytes was associated with a suppression of the wnt/b-catenin pathway and therefore of the proliferation and differentiation of hair follicles. Vitamin A Vitamin A promotes strong immune responses and its deficiency or excess can result in alopecia [78]. Duncan et al. demonstrated that expression of retinoid synthesis enzymes and binding proteins is increased in patients with AA and in two rodent models. They also showed that a moderate threefold increase in dietary vitamin A accelerated AA onset, possibly by inducing anagen, the target of AA. However, absence of vitamin A in the diet resulted in more severe disease by the end of the study [79]. This duality of responses suggests that precise vitamin A levels are needed. Everts et al. demonstrated that genes involved in the retinoid metabolism were increased in scarring alopecia and high dietary vitamin A may worsen the disease [80]. High intake of Vitamin A can be a triggering event in central centrifugal cicatricial alopecia. 5.6.3

Trichotillomania 5.5.1 N-acetylcysteine


5.5

Recently, N-acetylcysteine was investigated as a potential drug given that it increases glutamate extracellular concentration in the nucleus accumbens [66]. It was proven to successfully diminish compulsive behavior of hair pulling in a randomized placebo-controlled trial without adverse effects [66]. After this study, several case reports have further supported its efficacy [67]. Olanzapine Olanzapine has also been tested and proved effective for treating trichotillomania but with greater side effects, although its mechanism of action has not been completely elucidated [68]. 5.5.2

Naltrexone The use of naltrexone has also been studied as it may modulate the mesolimbic dopaminergic circuit, diminishing the urges to incur in the behavior. However, controlled studies have had conflicting results [69,70]. 5.5.3

5.6

Nutritional supplementation Iron

5.6.1

Attempting to elucidate the discrepancy of iron as a possible treatment for alopecia, a retrospective study demonstrated that men and women with AGA had overall lower iron store levels compared to controls, with premenopausal women having the most significant lower levels [71]. In another study, women with AGA and chronic telogen effluvium were found to have significant low iron stores as well as vitamin D when compared against control group [72]. Vitamin D Vitamin D modulates the innate and immune reactions because of their effect on lymphocytes and, although controversial, its deficiency has been implicated in several autoimmune diseases, including AA [73]. A cross-sectional study demonstrated that vitamin D deficiency directly correlated with AA and its level inversely correlated with disease severity [74]. Another group of authors have demonstrated that there are seasonal variations observed in AA and that those that have frequent relapses or chronic AA have reduced vitamin D levels, although the latter was not statistically significant [75]. However, it has also been shown that hair cycle generation cannot occur without a functional vitamin D receptor in keratinocytes, independent from vitamin D levels [76]. Lim et al. studied the expression of vitamin D receptors 5.6.2

6.

Competitive environment

6.1

Androgenetic alopecia Dutasteride

6.1.1

A multicenter, open-label, Phase III clinical trial (NCT0 1831791) is currently ongoing to assess the safety, efficacy and tolerability of dutasteride 0.5 mg in men with AGA types III vertex, IV and V according to Norwood-Hamilton classification for 52 weeks. Estimated completion date is October 2014 (summarized in Table 1). Another Phase III, double-blind, placebo-controlled clinical trial (NCT02014584) aims to assess the impact of dutasteride 0.5 mg on sexual function of men with AGA using the International Index of Erectile Function. This study will also assess subject satisfaction with hair growth and quality of life. It is estimated to enroll 700 men with AGA Type III vertex, IV or V Norwood-Hamilton classification and be completed by October 2015. Bimatoprost An ongoing Phase II, randomized, double-blind clinical trial (NCT01904721) attempts to measure the safety and efficacy of bimatoprost in males with mild to moderate AGA. The authors will be using different solutions of bimatoprost and compare them against bimatoprost vehicle. Different experimental groups are to apply the solutions for 28 days or 6 months. The primary outcome is a change from baseline in target area hair count (TAHC) and the subject selfassessment in alopecia Score on a 7-point scale at 6 months. Up to date, 246 patients have been enrolled, and it is estimated that the study will be completed on November 2014. 6.1.2


5


Table 1. Summary of clinical trials discussed in the competitive environment section. Indication


Androgenetic alopecia

Alopecia areata

Compound

Structure

Stage (phase) of development

Dutasteride

GlaxoSmithKline

Oral

3

Bimatoprost

Allergan

Topical

2

Hair--stimulating complex

Histogen

Intradermal injection

1/2

Platelet-rich plasma

N/A


1/2

Human platelet lysate N/A


1/2

Human autologous hair follicle dermal sheath cup cells

TrichoScience Innovations, Inc./Replicel


1/2

Minoxidil 5% Minoxidil 5% Mesotherapy & minoxidil 5% IL-2

Johnson & Johnson Topical foam Applied Biology, Inc. Topical foam N/A Topical

2 2 3

N/A

Subcutaneous

1/2

Abatacept

Bristol-Myers Squibb

Subcutaneous

2

Ruxolitinib

Incyte

Oral

2

Stem Cell Educator

Tianhe Stem Cell Intravenous Biotechnologies, Inc. N/A Topical

Psoralen ultraviolet A

Excimer laser Methotrexate Chemotherapy-induced Paxman hair loss prevention system alopecia DigniCap system Trichotillomania Inositol

6

Company

N/A

1/2 2

N/A

Topical Oral Topical

2 3 3

Target Health, Inc. N/A

Topical Powder

3 3


Mechanism of action

Type I and II 5-a reductase inhibitor Prostamide analog that promotes hair growth and prolongs anagen phase Growth factors and soluble precursors that will stimulate resting hair follicles Rich in growth factors and bioactive molecules that induce the differentiation of stem cells into hair follicles by increasing the expression of B-catenin Contains growth factors and cytokines enhancing cell growth and differentiation Cells obtained from punch biopsy are replicated and re-injected into balding areas Vasodilator that enhances hairs in telogen phase shed and go into anagen phase Activates T regulatory lymphocytes Inhibits T-cell activation, therefore reducing the production of inflammatory cytokines Decreases the activity of IL-15 by inhibition of the janus kinase pathway Suggested to reverse autoimmunity In a phototoxic reaction UV radiation may reach hair follicles and inflammatory cells Immunosuppression Immunosuppression Vasoconstriction

Glucose isomer, important in the phosphatydilinositol cycle. Its deficiency has been implicated in several anxiety, depressive and compulsive disorders



A Phase II clinical trial (NCT01325337) completed in 2012 aimed to evaluate the safety and efficacy of three different solutions of bimatoprost, compared to a control as well as to minoxidil 5% solution in 307 men with AGA. One milliliter of the medication was applied to a prespecified site daily for 6 months, except for minoxidil that was applied twice daily. Changes from baseline in TAHC were 13.1 + 21.69 for formulation A, 6.1 + 19.80 for formulation B, 6.3 + 22.05 for formulation C, 21.9 + 19.30 for minoxidil 5% and 4.1 + 15.59 for vehicle. Reported adverse effects include pruritus at the site of application. No serious adverse events were reported. Growth factors and stem cells A clinical trial (NCT01501617) attempts to elucidate the safety and efficacy of intradermal injections of different doses of hair-stimulating complex in men with AGA. This complex, patented by histogen, is a liquid composition consisting of proteins and cofactors secreted by multipotent stem cells. Some of the factors include follistatin, VEGF and KGF. This study aims to measure a change in non-vellus hair count from baseline to 12 weeks of treatment, as well as to assess systemic effects and immunological responses to this complex. An ongoing clinical trial (NCT02074943) aims to assess the effects and safety of PRP in AGA. PRP will be injected to half of the scalp of subjects and the degree of hair growth will be measured using the hair regrowth score for each side of the scalp at 16 weeks. Another clinical trial (NCT02087319) will examine PRP effects and effectiveness on hair loss, specifically in men with AGA. They will measure hair density and newly formed hair length by measurement and photography at 1 month after treatment. A multicenter, open-label, randomized, Phase I/II pilot study (NCT01643629) aims to evaluate the safety and efficacy of human platelet lysate (HPL) in AGA. The experimental group will receive three injections of HPL at 1-month intervals while the control group will receive standard therapy for AGA (minoxidil 2% and/or finasteride). The change in caliber and hair density, assessed with folliscope at 0, 4 and 6 months, will be measured. A Phase I/II clinical trial (NCT01286649) plans to evaluate the safety and efficacy of injections human autologous hair follicle dermal sheath cup cells in women and men with AGA. Cells are acquired from a small punch biopsy taken from the back of the scalp of subjects. These cells are replicated and injected onto the balding areas. Terminal and vellus hair density, cumulative hair thickness and its safety profile will be measured at follow-up visits. This study, sponsored by Replicel, will run through 2015, enrolling about 160 patients. 6.1.3

Minoxidil A Phase II clinical trial (NCT01319370) aimed to show the efficacy of 5% minoxidil topical foam applied twice daily in the temples of males with AGA after 24 weeks of treatment.

As a secondary outcome, this trial also attempted to evaluate the long-term efficacy and safety of this foam applied twice daily to the temple and vertex regions over a period of 2 years. No results have been published. Two prospective, observational clinical trials attempt to test minoxidil 5% topical foam response in men (NCT02198261) and women (NCT02206802) with AGA. Before commencing therapy, sensitivity and specificity of the minoxidil response in vitro diagnostic kit will be used to predict at baseline the treatment efficacy evaluated by expert panel review of global photographs assessing hair regrowth at 16 weeks. These studies are currently recruiting patients, planning to enroll 300, finishing in July 2015. A Phase III clinical trial (NCT01655108) attempts to investigate the effectiveness and safety of minoxidil mesotherapy for female pattern alopecia. Sixty patients will receive either minoxidil 0.5%/2 ml intradermal injection or placebo (saline 0.9%), weekly, for 10 weeks. Scalp biopsies will be performed before and after 6 weeks of treatment to determine terminal-vellus hair ratio, as well as a trichogram to assess the percentage of anagen, telogen and dystrophic hairs, and Trichoscan to assess any improvement on hair density. 6.2

Alopecia areata IL-2

6.2.1

A Phase I/II trial (NCT01840046) will evaluate the efficacy and tolerability of low-dose IL-2 in severe or resistant AA. Patients will undergo four cycles of recombinant IL-2 (aldesleukin, Proleukin) subcutaneously Monday to Friday in weeks 1, 3, 6 and 9. The primary outcome will be measured as the number of patients who obtained an improvement of at least 90% of severity of alopecia tool score (SALT) score in 2 months. Abatacept Abatacept is a selective immune modulator that inhibits T-cell activation by binding to CD80 and CD86 receptors, preventing these receptors to bind to CD28 on T cells [81]. It also decreases production of inflammatory cytokines such as TNF-a and interferon-g. The use of abatacept is FDAapproved for the treatment of rheumatoid arthritis. A Phase II clinical trial (NCT02018042) aims to assess the efficacy of abatacept for AA. As a primary outcome the study will measure the proportion of those subjects that have a 50% or greater hair regrowth from baseline using SALT score, after 24 weeks of treatment. Those subjects that respond will be followed for an additional 6 months or until disease recurrence. Scalp biopsies throughout the study will be performed at certain intervals for analysis and therefore attempt to elucidate mechanism of action of abatacept. This trial is currently recruiting subjects and is expected to finish on July 2016. 6.2.2

6.1.4

Ruxolitinib A Phase II, open-label study (NCT01950780) aims to evaluate safety and efficacy of treatment with ruxolitinib 20 mg day 6.2.3


7


in severe AA. Responders are defined as 50% or greater hair regrowth from baseline by SALT score. Study is not yet recruiting patients and is expected to end on August 2015. Stem Cell Educator A Phase I/II clinical trial (NCT01673789) attempts to develop and explore the therapeutic effectiveness of Stem Cell Educator therapy in AA patients. Human cord bloodderived multipotent stem cells can control autoimmune responses by altering regulatory T cells. Stem Cell Educator therapy functions by briefly coculturing the patient’s lymphocytes with cord blood-derived multipotent stem cells in vitro and then returning the educated lymphocytes to the patient’s circulation. For this purpose, the patient’s blood, taken from the median cubital vein, is passed through a blood cell separator, which isolates circulating lymphocytes according to the recommended protocol by the manufacturer. These are then transferred to the Stem Cell Educator and treated by CBSC. After this procedure, the educated cells are returned to the patient’s blood using the dorsal vein of hand. Patients will be then hospitalized for 2 days to monitor for temperature and adverse reactions. Follow-up visits for clinical assessments will be performed at 4, 12, 24, 40 and 54 weeks.


6.2.4

Ultraviolet A and UVB A clinical trial (NCT01559584) attempted to evaluate the effect of topical or phototoxic Psoralen ultraviolet A (UVA) in AA. UVA sessions were performed twice a week with a 0.5% solution of 8-methoxypsoralen applied 20 min before UVA exposure (315 -- 400 nm). The goal is to achieve phototoxic reaction, perceived as erythema or vesiculation. This experimental group will be compared to a control group treated with monthly injections of potent corticosteroids. Treatment success will be defined as effective if there is sustained growth of hair in > 80% of the affected area. Study was finished on March 2014. Two trials are being performed to evaluate the safety and efficacy of excimer lasers for AA. One of them is a Phase II, prospective split-lesion, single-blinded randomized trial (NCT01802177) that plans to assess the efficacy and safety of UVB excimer light in the treatment of AA. Response will be measured based on a change in the percentage of hair regrowth, with a positive response defined as 50% or more hair regrowth. The second trial (NCT01736007) aims to assess the feasibility, safety and response of excimer for patchy AA in children (6 -- 17 years of age). Response during the 12-week treatment will be measured as hair regrowth using the SALT score and two blinded evaluations of photographs. Follow-up visits at 36 and 48 weeks are also scheduled for long-term results. 6.2.5

Methotrexate A Phase III, randomized, double-blind trial (NCT02037191) aims to evaluate the efficacy of methotrexate (MTX) (20 -- 25 mg per week) in patients with severe AA. The rate 6.2.6

8

of complete or almost complete hair regrowth will be measured at 12 months of treatment and compared to placebo group. Experimental arm will be treated with either MTX (20 -- 25 mg per week) or MTX and associated prednisone 0.3 mg/kg/day for 6 months. This study is not yet recruiting and is expected to finish on February 2017. 6.3

Chemotherapy-induced alopecia Scalp cooling

6.3.1

A Phase III clinical trial (NCT01986140) attempts to determine that the Orbis Paxman Hair Loss Prevention System is safe and effective in reducing CIA in women with breast cancer undergoing neoadjuvant or adjuvant chemotherapy. The primary endpoint is considered to be the success of hair preservation (CTCAE v4 alopecia grade < 2) at 2 months compared to control (no treatment). In December 2018, 5-year long-term safety will be measured. This study plans to enroll 235 patients and is still recruiting. Another active clinical trial (NCT01831024), although not yet recruiting, attempts to measure the clinical performance, efficacy and safety of the DigniCap system in preventing CIA in women with early-stage breast cancer undergoing adjuvant or neoadjuvant chemotherapeutic therapies. Hair loss and tolerability will be determined at 4 weeks after last chemotherapy cycle while long-term adverse event measures continue until 6 months. 6.4

Trichotillomania Inositol

6.4.1

A Phase II double-blind, placebo-controlled clinical trial (NCT01875445) attempts to measure the safety and efficacy of inositol in trichotillomania. The Trichotillomania Symptom Severity Scale (NIMH-TSS) will be administered every 2 weeks for a total duration of 10 weeks to assess improvement in hair pulling. It is currently enrolling patients and is expected to finish on May 2015. 7.

Potential developmental issues

A frequently encountered difficulty when developing new drugs is when results on mice models or in vitro differ from those on humans as environmental interaction between cells is not the same. Furthermore, systemic absorption and side effects are common hazards to patients. The creation of topical formulations that are effective would be ideal as side effects would be minimal, enhancing patient compliance. Another limitation of targeted immune therapies that are being developed is their cost and availability for patients. 8.

Conclusion

We discussed here new possible targets for the treatment of alopecia, as more molecular studies are possible and cellular pathways involved are elucidated. By better understanding the underlying pathophysiology of alopecia, more targets



could be researched, clarifying and improving current technologies. Improving the drug delivery methods of existing therapies into more localized ones is another option of overcoming current limitations.


9.

Expert opinion

In the last 5 years many new therapeutical approaches have been developed for the treatment of non-scarring alopecias and the number of medications undergoing clinical trails is increasing daily. I believe that in the next few years we will possibly have new effective treatment options for one of the most common and distressing type of alopecia, AA. The genetic studies on AA, published in 2010, provided the clue that led to rationally selecting the JAK pathways as a target for treatment. JAK inhibitors can block TH1 cytokines that drive AA and represent a new promising treatment for the disease. JAK inhibitors look very promising for two main reasons: i) JAK inhibitors were highly effective in animal models and although numbers are small, all patients with severe AA who received this treatment had hair regrowth. ii) These drugs can be delivered as topical agents, which if proven effective in humans might represent optimal way of treatment of the disease. PRP is probably the other treatment that will increase in popularity in the near future, even though we still do not have real evidence of its efficacy. This treatment is highly advertised on the web and by the media and more and more patients will ask our expert opinion on its efficacy. The reality is that we still do not know if PRP is effective or not. Published data on AGA are still not convincing but several clinical trials have just started and I am confident that in 2 years we will have a definitive answer for patients who want to know if PRP is or is not an effective treatment of AGA. On the other hand, published evidence indicates that PRP is of limited value in the treatment of AA as efficacy has been reported Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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only in mild disease, where the placebo effect is difficult to rule out. A recent paper showed no efficacy in chronic severe disease [82]. I do not believe that new topical treatments will make a great difference in the treatment of baldness, patients do not like to apply topical lotions and efficacy of topical prostaglandin agonists looks limited. Topical finasteride can be an option if clinical trials will confirm preliminary data on a new formulation that provides optimal scalp penetration with limited systemic absorption [83]. Advances in stem-cell research might possibly make hair follicle neogenesis a reality, and this would not only be a major step in the treatment of male and female pattern hair loss but also the only possible option for patients with scarring alopecias. How close is this? We do not know, great strides have been done at the level of basic research, but when and how these findings can convert into clinical benefits is still difficult to predict. Will most surgeons utilize robotic technology to harvest and implant hair follicular units? This technology is expensive but undoubtedly makes the transplant faster and more precise. In summary this decade has been full of new discoveries on mechanisms that regulate hair grow and development of new therapies for hair disorders and I foresee that clinicians will have several new effective treatment options for most common diseases, particularly AA and baldness.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Affiliation Leyre Falto-Aizpurua1 MD, Sonal Choudhary2 MD & Antonella Tosti†2 MD † Author for correspondence 1 University of Miami, Miller School of Medicine, Department of Dermatology and Cutaneous Surgery, 1475 NW 12th Avenue, Suite 2175, Miami, FL 33136, USA 2 University of Miami, Miller School of Medicine, Department of Dermatology and Cutaneous Surgery, 1600 NW 10th Avenue, Rosenstiel Medical Science Building, Room 2023, Miami, FL 33136, USA Tel: +1 305 243 6734; E-mail: [email protected]

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