TH07 – A New Novel Topical Treatment for Androgenic Alopecia

ABSTRACT

Objectives:

Androgenic alopecia (AGA) is common among men. Currently, topical minoxidil and oral finasteride are approved by the FDA for the treatment of AGA. Unfortunately, neither of them is completely effective and systemic adverse events have been reported after finasteride administration. Triple Hair Inc. has developed a new topical treatment regimen using a combination of finasteride, latanoprost and minoxidil – TH07. Each of the compounds was effective and safe as a topical treatment in animal models and clinical studies of AGA. The aim of this proof-of-concept study was to evaluate the effectiveness of the TH07 in comparison to the 3 drugs as monotherapy on hair growth in men with AGA.

Methods:

Patients with light to moderate AGA were randomized to be treated topically, once daily, for 6 months with TH07, 0.1% finasteride, 0.03% latanoprost, or 5% minoxidil. Data of investigators’ assessment based on pictures, as well as patients’ self-assessment and satisfaction, were collected.

Results:

A moderate hair re-growth in the majority of the participant treated with TH07 in comparison to the retreatment with its active components administered as monotherapy was reported by the investigators. Most of the patients treated with TH07 were satisfied with their hair appearance in comparison to the other treatments. No systemic adverse events were reported and the TH07 was well tolerated.

Conclusions:

The data of the current study demonstrated that the topical administration of TH07 resulted in an improved efficacy in the treatment of the AGA compared to treatment with each of the ingredients administered separately.

INTRODUCTION

Male androgenetic alopecia (AGA) is the most common type of baldness. AGA is characterized by progressive patterned hair loss from the scalp, starting in the frontal area and the vertex, following a defined pattern.[1] The disease is expressed by the shortening of the anagen phase (hair growth) of the hair cycle and prolongation of the telogen phase (no hair growth/quiescent follicular stage), leading to progressive miniaturization of the hair follicle.[2] The diagnosis of AGA is based on clinical presentation (i.e., Hamilton–Norwood Scale progression of hair loss), clinical and family history of AGA.[3,4]

Genetic and androgenic factors play roles in the pathophysiology of the disease. Androgens bind to intracellular androgen receptors, which activate various cell growth factors and calcium/K influx in the dermal papilla cells.[5,6,7] The metabolite 5-dihydrotestosterone (DHT) affects the dermal papilla cells, causing progressive hair follicle miniaturization and hair cycle abnormalities leading to the development of AGA.[1] In addition, there is a cross-talk between the dermal papilla and the hair follicle cells, which results from the secretion of numerous growth factors and/or extracellular matrix factors from the dermal papilla cells, such as insulin-like growth factor 1 (IGF-1) and the basic vascular endothelial growth factor (VEGF), that stimulate hair growth.[8,9,10]

A variety of pharmacotherapeutic agents aiming to efficiently and safely treat AGA are being tested. Finasteride is a DTH-suppressing 5-alfa-reductase inhibitor.[11] In addition, the drug was found to be involved in the protein kinase B (PKB-AKT)/β-catenin-dependent cell growth mechanism, as well as up-regulating the expression of IGF-1.[12] Finasteride has been approved by US Food and Drug Administration (FDA) since 1997 for the treatment of mild-to-moderate AGA as an oral drug (1 mg/day). However, complications such as depression and gynecomastia, decreased libido, erectile dysfunction, and a reduction in the volume of ejaculation have been reported on its use.[13] To overcome the side effects that occur upon the oral use of finasteride, the efficacy, and safety of topically administered finasteride on various characterizations of AGA have been evaluated in several human clinical studies. A significant improvement in the status of scalp hair was observed and the treatment was tolerable.[14,15,16,17,18] Latanoprost is an eye drop solution, containing prostaglandin F2α analogs used in the treatment of ocular hypertension and open-angle glaucoma.[19] Hypertrichosis was detected in the ipsilateral terminal and regional intermediate hairs of the upper and lower eyelids, as well as of the vellus hair of the lower eyelid skin on treatment with the drug.[20] Latanoprost stimulates VEGF protein synthesis in human dermal papilla[21] and activates the Protein kinase C proteins family, which are overexpressed in the mid-anagen and mature anagen stages of the hair follicle.[22] These properties could play an important role in promoting hair growth. Data from animal models and a human clinical study of patients with AGA revealed that topical treatment of latanoprost induced hair growth, while no serious adverse events were reported.[23,24,25] Minoxidil is a pyrimidine derivative that induces hair growth by prolonging anagen duration, shortening telogen, and enlarging miniaturized follicles.[26] The drug was found to increase VEGF production, induce cell growth factors secretion in dermal papilla cells, as well as increasing Ca2⁺ influx and opening potassium channels.[27,28,29,30,31] Data from clinical studies demonstrated that minoxidil, administered topically, once or twice daily for a period of up to 5 years, was safe and stimulates new nonvellus hair growth.[32,33,34,35]

Taken together, the 3 drugs have safely induced hair growth when administered topically in cases of AGA. However, the efficiency of finasteride was found to vary from 31% to 66% and minoxidil averaged only 38% effectiveness for hair re-growth.[34,36] In addition, the beneficial results of topical minoxidil are evident after continuous topical application of at least 4 months and up to 12 months and if the treatment is discontinued, increased hair loss occurs within 2 or 3 months. Thus, attempts have been invested to attain improved outcomes using different topical combinations of the drugs, such as minoxidil with finasteride[37,38,39,40] or with latanoprost.[41] The data from the studies clearly demonstrated that the combination regimen was superior to either of the monotherapies. In addition, the combinations were safe and well tolerated. Following that, Triple Hair Inc. company developed the TH07 formula which contained finasteride, latanoprost, and minoxidil. The goal of the current clinical trial was to evaluate the ability of TH07 to promote hair re-growth, while still being safe, compared to each of the components used as a monotherapy.

METHODS

Test product

The TH07 product and all the ingredients were manufactured by Triple Hair in a cGMP manufacturing facility. The product comprises a clear homogeneous solution of 5% minoxidil, 0.1% finasteride and 0.03% latanoprost dissolved in a solvent vehicle comprising absolute alcohol, propylene glycol, and diethyl glycol. The 5% strength for minoxidil was selected as this concentration is the maximum that the FDA allows for topical use and is approved by various regulatory agencies. Latanoprost at the concentration of 0.03% is approved as an ocular drop (Latisse) to treat ocular hypertension. Finasteride tablets (1 mg) taken orally daily are also approved by the US FDA, EU, and Health Canada for treating AGA. A concentration of 0.1%, which represents 1 mg/cc, was chosen. The product was packaged in 60 mL opaque white bottles filleted with metered pumps, calibrated to dispense 100 μL per spray. The test product was stored at temperatures between 15°C and 30°C.

Patients

Participants were recruited through radio advertisements, meetings with managers and hair stylists in beauty salons in the Dieppe, Moncton, and the Riverview areas, New Brunswick, Canada. The Triple Hair Inc. website featured a complete online registration form with specifications of the study and enrollment criteria.

Study inclusion criteria were: men between 19 and 65 years old; diagnosis of AGA; alopecia levels between 2 and 5 on the Norwood Scale Classification (llight-to-moderate hair loss); participant had to be available once a month for 15 min for 6 months; sign a consent and medical form at the beginning of the study; could not dye their hair for the duration of the study; and had to bring their medication for the first appointment.

Study exclusion criteria were: the use of another hair loss prevention product in the previous year; the use of the following substances in the previous 6 months: steroids, vasodilators, cytotoxic agents, topical antiseptic and/or antifungals, antibiotics, antihypertensive agents, diuretics, or specifically contraindicated agents (such as spironolactone, cimetidine, diazoxide, cyclosporine, or ketoconazole); previous scalp correction surgery; presence of skin infections on the scalp; the existence of an allergy or hypersensitivity to colorant and skin cancer.

Study design

The effect of topical TH07 on hair regrowth was compared with the daily topical application of each drug in a randomized, double-blind study in men with AGA.

The patients were randomized to four topical treatment groups: TH07, 0.1% finasteride, 0.03% latanoprost, and 5% minoxidil. On the first visit, the distance between the base of the nose and the middle of the hair crown, as well as the distance separating the most distal part of the helix and the hair crown were measured. A square area of 2 cm × 2 cm was measured around the middle point of the hair crown (marked by a washable felt crayon). Then, pictures of the scalp from different angles and distances were taken by a professional photographer.

The patients were instructed to apply a dosage of 1 ml (10 metered dose sprays of 0.1 ml) to the scalp once a day after cleansing. The same scalp-measuring and photo-taking method was repeated in the following five sessions to properly evaluate the product’s efficacy. At the end of the treatment, the participants were asked to fill out a self-assessment questionnaire about the treatment’s success and their satisfaction regarding the change in their appearance. This questionnaire has been validated by Barber et al.[42]

The investigators’ assessment of hair growth was conducted from the pictures taken from each patient before and at the end of the treatment. A growth is sufficient to achieve a less pronounced pattern of baldness was classified as a minimal improvement of hair growth. Moderate growth meant that there was a visible change. As for the dense level, it was described as sufficient growth to be cut and combed.

Statistical analysis

Patients’ self-assessment and satisfaction and investigators’ assessment are presented in the percentage of subjects who specified their agreement with each of the questionnaires’ declarations.

A one-way analysis of variance (ANOVA) was used to test the difference in means between the four groups. This test was used to determine whether there was any significant difference between the mean values of the four groups. In addition, the Tukey Honestly Significant Difference (HSD) test was used to assess the difference in results between two groups. Finally, a comparison of the mean values to determine which group offered the best results was conducted by weighting the test subject’s responses using the following scale: a status of “High Growth” was scaled as 3, a status of “Moderate Growth” was scaled as 2, a status of “Minimal Growth” was scaled as 1, and a status of “No Growth” was scaled as 0.

RESULTS

Drop outs

Of a total of 40 patients recruited initially for the study, 6 subjects withdrew from the study. Overall, 34 patients completed the study [Table 1].

Table 1.

Participants follow-up

	TH07	Finasteride 0.1%	Latanoprost 0.03%	Minoxidil 5%
Total number of participants at beginning of study	27	4	4	5
Total number of drop outs during the study	4	0	1	1
Total number of participants who finished the 6 months study	23	4	3	4

Patients’ self-assessment

Most of the patients treated with TH07 (61%) strongly agreed, while most of the patients in the latanoprost (66%) and minoxidil (50%) agreed that the size of their bald spot has been reduced. Half (52%) of the TH07 group reported that the general appearance of the hair seems a lot better, whereas 100% of the finasteride group felt that it was a little better. The appearance of the hair looked the same for half of the patients in the finasteride and minoxidil groups. The majority of the TH07 treated patients (52%) saw a moderate increase in their hair growth, a slight change was reported from the latanoprost (100%) and the minoxidil (75%) groups and no change by the finasteride group (50%). A very effective slowing down of hair loss was reported by the TH07 treated patients (83%), while a somewhat effective slowing down was achieved in the finasteride (75%), latanoprost (66%), and minoxidil (75%) groups [Table 2].

Table 2.

Patient’s self-assessment

	Satisfaction	TH07 (n=23)	Finasteride 0.1% (n=4)	Latanoprost 0.03% (n=3)	Minoxidil 5% (n=4)
Reduced size of bald spot	Strongly agree	61%
	Agree	35%	50%	66%	50%
	Disagreed		50%	33%	25%
	No opinion	4%			25%
General appearance of hair	A lot better	52%
	Somewhat better	30%
	A little better	17%	25%	100%	50%
	The same		50%		50%
	A little worse		25%
Hair growth	A great increase	30%
	Moderate increase	52%	25%
	A slight increase	17%	25%	100%	75%
	No change		50%		25%
Slowing down hair loss	Very effective	83%		33%
	Somewhat effective	17%	75%	66%	75%
	Not effective at all		25%		25%

Patients’ satisfaction

When asked about their satisfaction concerning the appearance of front hairline compared to before treatment, 57% of the respondents in the TH07 treatment group said that they were very satisfied. Among the responders in the latanoprost treatment group, 66% declared that they were satisfied with their front hairline. Of the respondents in the minoxidil treatment group, 75% were neutral with regard to the front hairline.

When describing their satisfaction with their hair on top of their head 57% of responders in the TH07 treatment group said that they were very satisfied and 66% of the latanoprost treatment group were neutral. Of the respondents in the minoxidil treatment group, 75% were neutral with regard to the effect of treatment on the hair at the top crown of their head.

Concerning the overall appearance and hair, 52% of the responders in the TH07 treatment group were satisfied. When asked about their satisfaction with their overall hair appearance, all participants of the latanoprost treatment group were satisfied. When asked what they thought about the appearance of parts of their head before and after treatment, all respondents in the minoxidil treatment group said they were neutral about their hair growth overall.

The data are presented in Table 3.

Table 3.

Patient’s satisfaction

	Satisfaction	TH07 (n=23)	Finasteride 0.1% (n=4)	Latanoprost 0.03% (n=3)	Minoxidil 5% (n=4)
Appearance of certain parts of the head (particularly the front hairline)	Very satisfied	57%	25%
	Satisfied	26%		66%	25%
	Neutral	8%	75%	33%	75%
Appearance of hair on top of the head	Very satisfied	57%	25%
	Satisfied	39%	25%	33%	25%
	Neutral	4%	50%	66%	75%
Overall hair appearance	Very satisfied	39%			100%
	Satisfied	52%		100%
	Neutral	4%

Investigators’ assessment

In the TH07 treatment group, 52% of the patients demonstrated a dense level of hair growth and 30% moderate growth. No growth was observed in most of the subjects in the finasteride, latanoprost, and minoxidil treatment groups (50%, 77%, and 75%, respectively).

A representative picture of two patients, before and after the treatment with TH07 is presented in Figure 1 and the data are presented in Table 4.

Figure 1.

A representative picture of 2 patients, before and after the treatment with TH07

Table 4.

Investigator’s assessment

	TH07 (n=23)	Finasteride 0.1% (n=4)	Latanoprost 0.03% (n=3)	Minoxidil 5% (n=4)
Dense level	52%
Moderate growth	30%	25%
Minimal improvement	17%	25%	33%	25%
No regrowth		50%	77%	75%

Analyses of the hair growth status according to the weighting scale (ranging from 0 for “No Growth” to 4 for “High Growth”) revealed that TH07 had the highest average of 2.35 ± 0.78, demonstrating a moderate hair growth. The cooperative ingredients demonstrated a low status of minimal growth (0.1% finasteride – 0.25 ± 0.50, 0.03% latanoprost – 0.33 ± 0.58, and 5% minoxidil – 0.75 ± 0.96).

The ANOVA analysis resulted in a significant difference between the four groups of treatments (P < 0.0001). The Tukey HSD test results showed a significant difference between the TH07 treatment and the 5% minoxidil treatment (P < 0.05, as well as with the 0.1% finasteride treatment (P < 0.01) and the 0.03% latanoprost treatment (P < 0.01). However, comparisons between the 5% minoxidil and the 0.03% latanoprost treatments, between the 5% minoxidil and the 0.1% finasteride treatments, as well as between the 0.03% latanoprost and the 0.1% finasteride treatments were not statistically significant.

Safety

None of the participants in the TH07 treatment group noticed any change in their sexual activities. Only 3 participants had itching and eruption problems which were deemed a reaction to propylene glycol, 2 after 1 month and 1 after more than 5 months of treatment.

DISCUSSION

The rationale for the development of TH07 came from cumulative evidence, demonstrating that the efficacy of each of the ingredients was limited. The data from the current study indicate that the topical use of TH07 is more effective at promoting hair growth than the component administered as monotherapy. No systemic side effects were reported by participants. Pharmacokinetic studies report a low rate of absorption in a topical route of administration than when taken orally, which results in fewer systemic side effects while still being effective at promoting hair growth.[17,43,44]

It is suggested that the TH07 formula’s mechanisms of action (direct and indirect) affects simultaneously some elements of the disease’s pathophysiology [Figure 2]. The direct mechanism of action of the combined treatment includes an anti-androgenic effect and increasing the levels of growth factors. Minoxidil was found to hamper the activity of androgen receptors in the dermal papilla cells.[29] Furthermore, increased IGF-1 expression in minoxidil-treated mice was observed compared to saline-treated mice.[45] Increased levels of MAPK and AKT phosphorylation were detected posttreatment with minoxidil in dermal papilla cell cultures.[46] Finasteride alters the conversion of testosterone to DHT in the dermal papilla cell, leading to the decreased androgenic activation and to the reversal of the follicular miniaturization of the hair.[47] Increased levels of IGF-1 were detected in patients who demonstrated a moderate hair growth improvement after 12 months of treatment with finasteride.[48] Finasteride treatment significantly raised the levels of phosphorylated AKT in dermal papilla cell line and in 2 human primary dermal papilla cells.[12] The addition of latanoprost to human ciliary muscle cells cultures increased ERK1/2 levels.[22] The indirect mechanism of action of the combined treatment includes induction off VEGF production, increased supply of oxygen, blood and nutrients to the hair follicle, opening of the Ca2⁺/K channels, and increased absorption and penetration of the drugs. Both VEGF mRNA and protein were significantly elevated in Minoxidil-treated dermal papilloma cells.[27] Minoxidil enhanced the growth of cultured isolated red deer anagen follicle[49] and raised the amount of intracellular Ca2⁺ and VEGF production in cultures.[50] It might also be suggested these activities of the minoxidil could enhance the absorption of the finasteride, resulting in the improved efficiency of hair growth and density. VEGF protein synthesis was elevated in a dose-dependent manner in Latanoprost-treated human dermal papilla cells.[21] Taken together, it seems that when the 3 drugs are applied simultaneously, various pathophysiological processes of the diseased are affected. Figure 2 presents a scheme of the suggested TH07 mechanism of action.

Figure 2.

Rational for a combined therapy in AGA. AGA: androgenetic alopecia

CONCLUSIONS

The data of the current study demonstrated that the topical treatment of TH07 resulted in improved efficacy in the treatment of the AGA compared to each of the ingredients administered separately, as monotherapy. The superiority of the TH07 might be due to affecting simultaneously various mechanisms, playing a role in the development of AGA, resulting with an additive/synergistic effect on hair growth.

TH07 offers an option to meet the unmet demand for safe and effective treatments for AGA, as this new drug combination has the potential of hair growth with very little potential of side effects.

Limitation

Our study has some limitations as well. The size of the samples was small, especially in the single drugs treatments. There is no vehicle arm, even though all 3 drugs and the TH07 were prepared with the same vehicle. A longer period of treatment may have further refined the differences between the treated groups. Larger and longer clinical studies are needed to establish the advantage of the TH07 combined treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.