CB-03-01

CB-03-01 (clascoterone; cortexolone 17alpha-propionate; 11-deoxycortisol 17alpha-propionate) is a synthetic pregnane steroid that functions as a competitive antagonist of the androgen receptor (AR) with submicromolar potency (IC50 approximately 0.4 to 1 micromolar in AR transactivation assays) and peripheral selectivity conferred by rapid enzymatic hydrolysis to the inactive parent compound cortexolone (11-deoxycortisol) in human skin, plasma, and hepatic tissue. The compound was identified from a structure-activity series of cortexolone 17alpha-monoesters screened for topical antiandrogen activity in the hamster flank organ test, in which CB-03-01 demonstrated potency approximately four times greater than progesterone, three times greater than flutamide, two times greater than finasteride, and approximately equivalent to cyproterone acetate, while lacking systemic antiandrogenic, antianabolic, or glucocorticoid activity after subcutaneous administration in rats. The molecular pharmacology centers on competitive displacement of dihydrotestosterone (DHT) from the androgen receptor in sebocytes and dermal papilla cells, resulting in suppression of androgen-responsive gene transcription, reduction of sebaceous lipid synthesis, inhibition of inflammatory cytokine production (including interleukin-6), and attenuation of androgen-driven miniaturization of scalp hair follicles. In human dermal papilla cell cultures, CB-03-01 demonstrated significantly greater inhibition of DHT-stimulated IL-6 synthesis than the direct AR antagonist enzalutamide.

The compound received its first regulatory approval from the United States Food and Drug Administration in August 2020 as a 1% topical cream (Winlevi) for the treatment of acne vulgaris in patients aged 12 years and older, representing the first new mechanism of action approved for acne in approximately 40 years and the first topical antiandrogen approved for acne in any jurisdiction. Two pivotal Phase 3 randomized, double-blind, vehicle-controlled trials enrolling a total of 1440 patients with moderate to severe facial acne demonstrated statistically significant treatment success rates (Investigator Global Assessment score of 0 or 1 with at least a two-grade reduction) of approximately 18 to 20 percent for clascoterone versus 7 to 9 percent for vehicle at 12 weeks, with concurrent reductions in both inflammatory and noninflammatory lesion counts. Long-term safety data through 12 months demonstrated a favorable tolerability profile dominated by local application site reactions (erythema, dryness, pruritus) without clinically meaningful systemic antiandrogen effects.

A second clinical program in androgenetic alopecia (AGA) has advanced through Phase 2 dose-ranging studies (2.5%, 5%, and 7.5% solutions applied twice daily) demonstrating statistically significant improvements in target area hair count (TAHC) at 6 and 12 months, and into Phase 3 registration trials (SCALP-1 and SCALP-2) using a 5% topical solution in 1465 male patients with mild to moderate AGA. The Phase 3 topline results reported statistically significant improvements in TAHC relative to vehicle, with a 5.39-fold relative improvement in one study and a 1.68-fold relative improvement in the second, the divergence attributable to baseline hair count differences rather than inconsistent drug performance. The safety profile in the AGA trials was comparable to vehicle, with no evidence of systemic androgen blockade.

Pharmacokinetics following topical application are characterized by minimal systemic absorption. At maximal clinical use conditions (6 grams of 1% cream applied twice daily), steady-state plasma concentrations of clascoterone average 3.1 plus or minus 1.9 ng/mL with Cmax values of 4.5 plus or minus 2.9 ng/mL. The compound is rapidly hydrolyzed in plasma to cortexolone, which is detectable at concentrations generally near or below the lower limit of quantitation (0.5 ng/mL). Plasma protein binding is 84 to 89 percent. The principal safety signal is reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, observed in approximately 7 percent of adolescent and adult subjects in maximal-use pharmacokinetic studies, with all cases resolving within 4 weeks of discontinuation. This monograph reviews the chemistry, synthesis, and structural pharmacology of CB-03-01; the competitive androgen receptor antagonist mechanism in molecular detail; the pharmacokinetic profile including systemic absorption, metabolism, and HPA axis considerations; the preclinical pharmacology in hamster, rat, and human tissue models; the clinical evidence base across acne and androgenetic alopecia indications; sourcing and quality verification; reconstitution and handling; stack-interaction considerations; adverse-event signal; and a comparative assessment of five alternative antiandrogen or androgen-modulating agents against CB-03-01 on five competency standards.