Clascoterone

Clascoterone (cortexolone 17α-propionate), also known as CB-03-01 or Breezula, is a novel topical androgen receptor (AR) antagonist with a dual mechanism of action for treating androgen-dependent skin conditions. Although technically not a peptide but rather a synthetic pregnane steroid derived from cortexolone, it represents a first-in-class topical antiandrogen approved by the FDA in August 2020 as Winlevi (1% cream) for treating acne vulgaris in patients aged 12 years and older. The compound works by competitively binding to androgen receptors in sebaceous glands, dermal papilla cells, and hair follicles, thereby blocking the effects of dihydrotestosterone (DHT) and reducing sebum production, inflammatory cytokine synthesis (particularly IL-6), and hair follicle miniaturization. Clinical trials have demonstrated statistically significant improvements in both acne lesion counts and hair growth parameters, with 18-20% treatment success rates for acne compared to 7-9% with placebo. For androgenetic alopecia, Phase II studies showed significant increases in target area hair count (TAHC) with 7.5% solution applied twice daily, and Phase III trials in males are currently underway with results expected in 2025. The medication exhibits a favorable safety profile with predominantly mild, localized skin reactions (erythema, dryness) comparable to vehicle control, and notably demonstrates no systemic antiandrogenic effects, distinguishing it from oral antiandrogen therapies. Long-term studies up to 12 months confirm sustained efficacy and tolerability across diverse patient populations.

Acne Treatment Effects

• FDA-Approved Efficacy: First-in-class topical androgen receptor inhibitor approved for acne vulgaris in patients ≥12 years, achieving 18.4-20.3% treatment success versus 6.5-9.0% with vehicle in two Phase III trials (n=1,440)^[8]
• Lesion Reduction: Statistically significant reductions in both inflammatory and noninflammatory acne lesions by week 12 compared to placebo across multiple clinical trials^[4][8]
• Sebum Regulation: Antagonizes androgen-regulated lipid production in human primary sebocytes in a dose-dependent manner, directly addressing sebum overproduction that drives acne pathogenesis^[6][7]
• Anti-inflammatory Action: Inhibits DHT-induced inflammatory cytokine production, particularly interleukin-6 (IL-6), from sebocytes and performs significantly better than spironolactone at suppressing inflammatory mediator synthesis^[6][11]

Hair Loss Treatment Effects

• Androgen Receptor Blockade: Functions as AR antagonist in dermal papilla cells with efficacy similar to finasteride in inhibiting AR-regulated transcription, offering topical alternative to systemic 5α-reductase inhibitors^[11]
• Hair Growth Promotion: Phase II clinical trials in males (n=400+) demonstrated statistically significant improvements in target area hair count (TAHC), hair length, and hair width with 7.5% concentration applied twice daily^[11]
• IL-6 Suppression: Significantly superior to enzalutamide at inhibiting IL-6 synthesis from DHT-stimulated dermal papilla cells, targeting inflammatory pathways involved in follicular miniaturization^[11]
• Female Efficacy: 5% formulation showed significant hair growth improvement in women under 30 years old with androgenetic alopecia (n=293)^[1]
• Prostaglandin Reduction: Reduces production of prostaglandin D2, a mediator implicated in hair miniaturization and pattern baldness progression^[1][11]

Multi-Indication Versatility

• Real-World Applications: Beyond acne and alopecia, demonstrated effectiveness for hirsutism, hidradenitis suppurativa, retinoid-induced dermatitis, folliculitis, postinflammatory hyperpigmentation, and laser-induced acne flares in case series
• Treatment Flexibility: Effective as monotherapy, adjunctive therapy with other topical/systemic agents or laser treatments, and as maintenance therapy to prevent acne relapse^[14]
• Broad Demographics: Well-tolerated and effective regardless of acne severity, age, gender, and ethnicity in real-world clinical experience

Clinical Safety Profile

• Favorable Tolerability: Safety profile similar to vehicle (placebo) across Phase III trials, with predominantly mild adverse events and low frequency of treatment-emergent adverse events (TEAEs) over 9-12 months of use^[8][12][13]
• Local Skin Reactions: Most common treatment-related effects are mild erythema (8% of patients), scaling/dryness (10%), itching, and application site reactions, with majority being trace/minimal in severity^[8][12][13]
• No Systemic Effects: Demonstrates local antiandrogenic effects without systemic antiandrogenic activity; no reported reduction in libido, feminization, or hormonal disturbances in male patients during clinical trials^[3][4][5][7]
• Long-term Safety: Up to 12-month studies confirm sustained favorable safety profile with treatment-emergent adverse events in approximately 18% of patients, comparable to many topical dermatological therapies^[13]

Regulatory Status and Warnings

• FDA Approval: Approved in August 2020 as Winlevi (1% clascoterone cream) for acne vulgaris in patients aged 12 years and older; designated as "first-in-class medication"^[2][3][5]
• European Rejection: European Medicines Agency (EMA) recommended refusing marketing authorization in April 2025 due to concerns about potential risks to growth and sexual maturation in adolescents, despite FDA approval^[2]
• HPA Axis Suppression: Hypothalamic-pituitary-adrenal (HPA) axis suppression occurred in approximately 7% of adolescents and adults, though effects reversed within 4 weeks after discontinuation^[2]
• Electrolyte Monitoring: Elevated potassium levels observed in 5% of users versus 4% in placebo groups; monitoring may be warranted in patients with renal conditions or taking potassium-sparing medications^[2]
• Hair Loss Development: 7.5% solution for androgenetic alopecia remains investigational; Phase III trials (SCALP 1 and SCALP 2) are ongoing with approximately 1,500 male subjects, with topline results expected in 2025^[1][2]

Common Adverse Events

• Systemic TEAEs: Most frequent treatment-emergent adverse events were nasopharyngitis, headache, and oropharyngeal pain (all mild-moderate severity and comparable to vehicle)^[8][12]
• Application Site: Mild application site pain, dryness, and hypersensitivity reactions reported but infrequent^[8][12]
• Pediatric Use: Well-tolerated in patients as young as 9-12 years in clinical trials, though EMA raised concerns about adolescent safety that require further evaluation^[8][12]

Contraindications and Precautions

• Pregnancy Category: No human pregnancy data available; animal studies indicate potential risks; should be used during pregnancy only if clearly needed and benefits outweigh risks^[2]
• Pediatric Safety: While FDA-approved for ages 12+, the EMA's rejection highlights ongoing debate about developmental safety in adolescents undergoing puberty^[2]
• Drug Interactions: Theoretical concern for interactions with other medications affecting potassium levels or HPA axis, though no significant drug interactions reported in clinical trials^[2][12]