Topical hair loss treatments: what is the difference between RU58841 and CB-03-01?
Male-pattern baldness, more properly called androgenic alopecia, affects a significant proportion of the male population and quite a few women. In this condition, inherited genetic factors cause the hair follicles on the head to be abnormally sensitive to the presence of a hormone called dihydrotestosterone (DHT). An enzyme called 5-alpha-reductase turns testosterone into DHT. The DHT then binds to androgen receptors in the hair follicles. In susceptible hair follicles, prolonged exposure to DHT causes the hair follicle to spend more time resting rather than growing hair, and over time, the follicle undergoes a gradual miniaturization process, eventually producing only tiny fine hair called vellum.
Many researchers have identified the androgen receptors as good targets for treating androgenic alopecia. If the androgen receptors in the hair follicles can be blocked or disabled, then DHT cannot affect the hair follicles. However, systemic administration of androgen receptor blockers, such as the drugs used to treat prostate cancer, cause a lot of serious side effects. Since baldness affects the skin, which is readily accessible, topical application of an effective androgen receptor blocker should stop the balding process without causing any systemic side-effects. Researchers have already identified molecules that function in exactly this way.
RU58841, a short review
RU58841 is an androgen receptor blocker that was first discovered in the early 1990s, and it has been extensively studied in animal models. When applied topically, it is highly effective in stopping the progression of balding and can even stimulate some hair re-growth (1, 2). No systemic side effects have been found in monkeys treated topically with RU58841. However, due to issues unrelated to RU58841 itself, it has never gone through the formal human testing processes to allow it to be approved by the FDA and other regulatory agencies for marketing as a balding treatment. It is available for purchase as a research chemical, and many individuals have been using it to treat balding over the last few decades. It is reported to be very effective in stopping hair loss with minimal side effects. A few individuals report that it stimulates hair re-growth as well.
Cortexolone 17 Alpha-Propionate, or “CB-03-01″
CB-03-01 is an androgen receptor blocker first discovered in the 2000s. Initial studies in animal models found it could block androgen receptors when applied topically but not when given systemically (3). Its lack of activity when applied systemically means it exhibited no systemic anti-androgenic side effects in rats injected with the drug. Its ability to block topical androgen activity was described by the early researchers as being about three times more potent than flutamide. The fact that it has no anti-androgenic activity when applied systemically is probably due to the fact that after it enters the body it is almost immediately metabolized into an inactive form.
Early studies of RU588541 also compared its efficacy to other androgen receptor blockers, such as flutamide, nilutamide, and bicalutamide. When taken systemically, RU58841 has strong side effects similar to any oral androgen receptor blocker. In studies of RU58841, it was found to a much more potent blocker of androgen receptors than any previously-known androgen receptor blockers; in fact, the researchers concluded it was the “most potent antiandrogen” known at that time (1998), with up to 100 times the activity of flutamide, suggesting it is a much more potent androgen receptor blocker than CB-03-01 (4).
Although the two agents have never been directly compared, they have both been evaluated in similar tests against reference drugs. Hamsters have a special glands in their skin that develop in response to male hormones. The ability of anti-androgenic drugs to block this gland development is commonly used in the laboratory. In hamster skin gland tests, at a dose of 400 micrograms per day, CP-03-01 was less effective than flutamide (84% vs. 55%, respectively) in blocking development of the organ in response to male hormones but it was slightly more effective than cyproterone acetate (only 93% blockage) (3) [just see below].
However, at a dose of only 10 micrograms per day, RU58841 was capable of blocking development of the gland by 60%, and it was found to be a much more potent topical androgen receptor blocker than either flutamide or cyproterone acetate (5). Simple deduction suggests it is also a much more potent agent than CP-03-01.
Unlike RU58841, which appears to have been abandoned by the pharmaceutical industry, CB-03-01 is being actively studied, primarily as a treatment for acne (6). CB-03-01 is manufactured by Cosmo Pharmaceuticals, an Italian company. The company licensed the drug to Medicis in 2012 for development in the US. Early studies of the drug as a hair loss treatment required a special method of delivering the drug to the hair follicles using an electrical current (iontophoresis), but once delivered, it did seem to be reasonably effective in treating hair loss (7) [see below]. However, few patients are going to be willing to be treated several times a week for decades by iontophoresis.
The study evaluated the efficacy of CB-03-01 in 40 men with androgenetic alopecia grade 1-4 according to the Hamilton scale, and in 30 post-menopausal women with androgenetic alopecia grade 1 according to the Ludwig scale.
A presentation by Cosmo in 2013 indicates they may have solved the delivery problem. They have performed skin permeation tests, and have shown that a 5% solution of the drug in a special carrier cream is able to penetrate the hair follicles. They have also performed toxicity and irritation tests in pigs. The 2013 presentation suggested they were about to begin studies in human volunteers (8). A more recent report from the company indicated that the results of a trial comparing it to minodoxil in 120 human volunteers will be available in late 2015 (9).
Although both RU58841 and CB-03-01 are available for purchase as research chemicals for individual use, it is difficult for a casual purchaser to “try out” CB-03-01 at home. Unlike RU58841, which can be dissolved in alcohol or other readily available carriers, CB-03-01 apparently needs to be prepared in a special carrier cream in order to get it to enter the hair follicles. Therefore, because none of Cosmo’s studies on hair loss have been published as of yet, and no one has been able to “try out” CB-03-01 at home, it is unclear how effective it is relative to RU58841 for treating balding. CB-03-01 appears to have a much shorter half-life than RU58841, and it may be a less potent blocker of androgen receptors. When applied topically, neither product should exhibit any systemic side-effects.
(1) Endocrine. 1998 Aug;9(1):39-43. Evaluation of RU58841 as an anti-androgen in prostate PC3 cells and a topical anti-alopecia agent in the bald scalp of stumptailed macaques.
(2) Br J Dermatol. 1997 Nov;137(5):699-702. A controlled study of the effects of RU58841, a non-steroidal antiandrogen, on human hair production by balding scalp grafts maintained on testosterone-conditioned nude mice.
(3) Arzneimittelforschung. 2004;54(12):881-6. Biological profile of cortexolone 17alpha-propionate (CB-03-01), a new topical and peripherally selective androgen antagonist.
(4) J Steroid Biochem Mol Biol. 1998 Jan;64(1-2):103-11. Pharmacological profile of RU 58642, a potent systemic antiandrogen for the treatment of androgen-dependent disorders.
(5) Ann N Y Acad Sci. 1995 Jun 12;761:56-65. Local inhibition of sebaceous gland growth by topically applied RU 58841
(6) Br J Dermatol. 2011 Jul;165(1):177-83. doi: 10.1111/j.1365-2133.2011.10332.x. Epub 2011 Jun 2. Cortexolone 17α-propionate 1% cream, a new potent antiandrogen for topical treatment of acne vulgaris. A pilot randomized, double-blind comparative study vs. placebo and tretinoin 0·05% cream.