Pharmacokinetic Profile, Safety, and Tolerability of Clascoterone (Cortexolone 17-alpha propionate, CB-03-01) Topical Cream, 1% in Subjects With Acne Vulgaris: An Open-Label Phase 2a Study

June 2019 | Volume 18 | Issue 6 | Original Article | 563 | Copyright © June 2019

Alessandro Mazzetti MD,a Luigi Moro PhD,a Mara Gerloni PhD,a Martina Cartwright PhDb

aCassiopea SpA, via Cristoforo Colombo 1, Lainate, Italy bCassiopea Inc., San Diego, CA

Abstract
Clascoterone (cortexolone 17α-propionate, CB-03-01) 1% cream, a topical, androgen receptor (AR) inhibitor under investigation for the treatment of acne vulgaris, is rapidly metabolized to cortexolone in human plasma. The primary objectives of this study were to determine the pharmacokinetic (PK) properties and adrenal suppression potential of clascoterone topical cream, 1% in subjects with acne vulgaris.

Study Design: This study was an open-label, multicenter study in 42 subjects ≥12 years of age with moderate-to-severe acne (Grade 3-4 on the Investigator’s Global Assessment [IGA]), on the face, chest and/or back. Cohort 1(>18 years of age) and Cohort 2 (12-18 years of age) applied clascoterone topical cream, 1% twice daily (BID) for 14 days. Primary safety endpoints included hypothalamic-pituitary-adrenal (HPA) axis response to cosyntropin via a Cosyntropin Stimulation Test (CST) upon screening (day 1) and at day 14 (HPA axis suppression was defined as a post-stimulation serum cortisol level <18 μg/dL at day 14); and PK evaluation including concentration-time profiles of clascoterone and cortexolone in plasma—PK parameters were determined using “non-compartmental” analysis. Secondary safety endpoints included clinical laboratory testing, local and systemic adverse events (AEs), physical examination/vital signs, and electrocardiogram (ECG).

Results: 42 subjects (Cohort 1=20, Cohort 2= 22) enrolled. Cohort 1 was comprised of 15 females (15/20, 75%) and 5 males (5/20, 25%), non-Hispanic/Latino (20/20, 100%), mean age is 24.4 years. Cohort 2 was comprised of 12 females (12/22, 54.5%) and 10 males (10/22, 45.5%), non-Hispanic/Latino (21/22, 95.5%), and mean age is 15.6 years. Three subjects (3/42,7%), 1 adult and 2 adolescents, demonstrated an abnormal HPA axis response with post-stimulation serum cortisol levels ranging from 14.9 to 17.7 μg/dL at day 14. All returned to normal HPA axis function, four weeks after day 14. None showed clinical evidence of adrenal suppression. Clascoterone plasma concentrations achieved PK steady-state by day 5. Clascoterone systemic exposure was similar between both cohorts. At steady-state, plasma concentrations increased ~1.8 to 2.1 fold versus first dose with mean (coefficient of variation [CV] %) maximum plasma concentrations of 4.4 ng/mL (67%) and 4.6 ng/mL (103%) in Cohort 1 and Cohort 2, respectively. Cortexolone plasma concentrations trended below the lower limit of quantitation (0.5 ng/mL) in both cohorts. Local skin reactions (LSRs) were mostly mild, with only one moderate case of pruritus. There were nine AEs categorized as follows: definitely related (N=2), probably related (N=4), unlikely/not related (N=3), to clascoterone.

Conclusion: This study demonstrates the safety and tolerability of clascoterone topical cream, 1% in adolescents and adults with acne vulgaris treated BID for 14 consecutive days.

J Drugs Dermatol. 2019;18(6):563-568.

INTRODUCTION

Acne is a chronic inflammatory skin condition of the pilosebaceous glands that typically begins at puberty and may continue through adulthood, with flares often coinciding with increases of serum androgens.1,2 Over 85% of adolescents3 and 40% of adults develop late onset acne.4 It is one of the most common dermatological disorders in the world5 with its incidence and severity influenced by genetics and environment.1,6 Endogenous androgens, particularly testosterone and dihydrotestosterone (DHT), mediate excess sebum production in the skin, driving abnormal keratinization and desquamation leading to obstruction of the pilosebaceous duct which allows Cutibacterium acnes (formerly Propionibacterium acnes) to proliferate.7,8 Proinflammatory mediators are released in response, triggering localized inflammation and exacerbation of acne lesion eruption.7