A Phase I/II Clinical Study of Topical Minoxidil in Acne Vulgaris

1. Background 1.1 Overview of disease pathogenesis, epidemiology and current treatments Patients with acne vulgaris (AV) appeared to be a chronic inflammation with a wide range in teenagers and adult. There are four main components in the pathogenesis of AV: (1) enhancement of sebum secretion (2) keratinization of the middle infundibulum (3) bacterial proliferation of the follicle (4) Inflammation. In sebaceous glands, pro-hormones dehydroepiandrosterone (DHEA) and androstenedione can be metabolized into testosterone and dehydrotestosterone (DHT). Literature identified androgen receptor (AR) expression in sebaceous glands by immunohistochemistry and high sebum secretion associated with high AR expression in sebaceous gland of T-zone than U-zone of face. Via AR, androgen could induce sebocyte sebaceous differentiation. Genomic related studies elucidated AR related genes were associated with severe acne. Imbalanced androgen correlated with AR plays an important role in increasing sebaceous glands excretion and lipogenesis. Triglyceryl hydrolysis is attributed to generate free fatty acid by the anaerobic bacterium Propionibacterium acnes (P. acnes), a key role in inflammatory AV, reflects to the immune response which is stimulated via the toll-like receptor (TLR) 2 to Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, thereafter induces the production of pro-inflammatory cytokines, chemokines and adhesion molecules.

Current therapies for none or slightly inflammatory AV mostly use topical retinoids, moderate or severe acne use topical/oral antibiotics and oral isotretinoin. Topical antibiotics including clindamycin, erythromycin, nadifloxacin and tetracycline, are sometimes used in monotherapy but are more effective in combination with topical retinoids. For additional therapy, benzoyl peroxide, azelaic acid and sodium sulfacetamide, are antiseptic agent can use in combination treatment to decrease the risk of bacterial resistance. Severe acne uses oral antibiotics doxycycline, minocycline, tetracycline, erythromycin, and Trimethoprim/sulfamethoxazole combine topical treatment. Isotretinoin contributes to treat inflammatory papules, pustules and nodules, but it has been reported that isotretinoin has adverse effects teratogenic action in pregnant patients.

More recently, clascoterone, an antiandrogen chemical had been shown efficacy in acne treatment.

1.2 Introduction to investigational treatment(s) and other study treatment(s) 1.2.1 Overview of minoxidil Minoxidil was first used in anti-hypertension in clinical therapy. However, further study found minoxidil had the side effect of hirsutism, an abnormal hair growth over human body. Androgenetic alopecia (AGA) is an androgen-AR pathway may lead to hair loss, most frequent in men. In current clinical therapy, topical 2% or 5% solution of minoxidil have been used for AGA treatment but the therapeutic mechanism of minoxidil working on AGA is uncertain. The previous study showed minoxidil could reduce AR expression in messenger ribonucleic acid (mRNA) and protein level in Human Hair Dermal Papilla Cells (HHDPCs). Furthermore, the investigators demonstrated minoxidil could bind to AR protein structure at α8 and α11 helices which may hinder the association of interacting proteins, therefore disrupting downstream regulation of AR transactivation. 2. Study rationale:

In the investigator's preliminary data, minoxidil could suppress fatty acid synthase activity and lipid formation in androgen-sensitive prostate cancer cell line in vitro. Minoxidil suppressed sebum formation in hamster flank organ in vivo. For P. acnes, minoxidil had a minimal inhibitory concentration of 5mM which was lower than 2% minoxidil (about 100mM). Furthermore, 2% and 5% minoxidil could suppress P. acnes induced infection/inflammation in animal studies. For acne formation, minoxidil could reduce sebum secretion, bacterial activity, and inflammation. 3. Study period (estimated):