Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Cassiopea S.p.A., Via C. Colombo, 1, Lainate, 20045, Milan, Italy
Pharmacotherapeutic group: Anti-acne preparations, other anti-acne preparations for topical use
ATC code: D10AX06
Clascoterone is an androgen receptor inhibitor. In vitro studies showed that it potently antagonizes the effects of androgens in primary human sebocytes to reduce sebum production and accumulation and inflammatory mediators which are known drivers of the acne pathogenesis.
In the dedicated phase 2 study 171-7151-202 aimed at investigating the potential effects of clascoterone cream 10 mg/g on the HPA axis and pharmacokinetics in adults and adolescents with acne vulgaris, HPA axis suppression was evaluated in adults (n=20) and adolescents from 12 years of age (n=22) following application of supratherapeutical doses of clascoterone cream with a mean daily amount of 11.3 g in adults and 9.3 g in adolescents for 2 weeks (see section 5.2). HPA axis suppression indicated by 30-minute post-stimulation serum cortisol level of ≤18 mcg/dL was observed in 1/20 (5%) of adult subjects and 2/22 (9%) of adolescent subjects at Day 14. All subjects returned to normal HPA axis function at follow-up 4 weeks after the end of treatment.
At approximately 9-times the maximum treatment adult dose (5 g/day of cream), clascoterone does not prolong the QT interval to any clinically relevant extent.
The safety and efficacy of clascoterone cream 10 mg/g applied twice daily for 12 weeks for the treatment of acne vulgaris were assessed in two identically-designed phase 3, multicentre, randomised, double-blind, vehicle-controlled clinical trials (CB-03-01/25 and CB-03-01/26) enrolling in total 1 440 subjects with facial acne vulgaris. The trials enrolled subjects with Investigator's Global Assessment (IGA) of moderate or severe facial acne vulgaris (score of 3 or 4), 30 to 75 inflammatory lesions (papules, pustules and nodules), and 30 to 100 non-inflammatory lesions (open and closed comedones).
Of these 1 440 randomised subjects, 19 (1.3%) were 9 to 11 years of age, 641 (44.5%) were 12 to 17 years of age, and 780 (54.2%) were 18 years of age or older. Among adults and adolescents, 62% of the subjects were female and 91% were Caucasian. At baseline, subjects had a mean inflammatory lesion count of 42.4 and a mean non-inflammatory lesion count of 61.4. Approximately 83% of subjects had an IGA score of 3.
Efficacy was assessed by three co-primary endpoints: proportion of subjects in each treatment group achieving "success" at Week 12, with "success" defined as an IGA score of "clear (score=0)" or "almost clear (score=1)" AND at least a 2-point reduction in IGA compared to baseline, absolute change from baseline in non-inflammatory lesions count (NILC) in each treatment group at Week 12, and absolute change from baseline in inflammatory lesions count (ILC) in each treatment group at Week 12.
The IGA success rate and mean absolute and percent reduction from baseline in acne lesion counts after 12 weeks of treatment for patients 12 years of age and older are presented in Table 2.
Table 2. Clinical efficacy of clascoterone cream 10 mg/g in adult and adolescent patients with facial acne vulgaris at week 12:
| Study CB-03-01/25 | Study CB-03-01/26 | |||
| Clascoterone cream N=342 | Vehicle cream N=350 | Clascoterone cream N=367 | Vehicle cream N=362 | |
| IGA Successa | 18.8% | 8.7% | 20.9% | 6.6% |
| Difference from vehicle | 10.1% | 14.3% | ||
| (95% CI) | (4.1%, 16.0%) | (8.9%, 19.7%) | ||
| Non-inflammatory lesions count (NILC) | ||||
| Mean absolute reduction | 20.4 | 13.0 | 19.5 | 10.8 |
| Difference from vehicle | 7.3 | 8.7 | ||
| (95% CI) | (3.5, 11.1) | (4.5, 12.4) | ||
| Mean percent reduction | 32.6% | 21.8% | 29.6% | 15.7% |
| Difference from vehicle | 10.8% | 13.8% | ||
| (95% CI) | (3.9%, 17.6%) | (7.5%, 20.1%) | ||
| Inflammatory lesions count (ILC) | ||||
| Mean absolute reduction | 19.3 | 15.4 | 20.1 | 12.6 |
| Difference from vehicle | 3.9 | 7.5 | ||
| (95% CI) | (1.3, 6.5) | (5.2, 9.9) | ||
| Mean percent reduction | 44.6% | 36.3% | 47.1% | 29.7% |
| Difference from vehicle | 8.3% | 17.5% | ||
| (95% CI) | (2.2%, 14.4%) | (11.8%, 23.1%) | ||
a Investigator Global Assessment (IGA) success was defined as at least a 2-point reduction in IGA compared to baseline and an IGA score of 0 (clear) or 1 (almost clear).
Among the 641 subjects aged 12 to <18 years enrolled in phase 3 vehicle-controlled studies for facial acne vulgaris, 316 and 325 subjects were randomized to clascoterone cream and to vehicle, respectively.
Clascoterone cream was superior to vehicle in all the three co-primary endpoints: in the IGA success rate at Week 12 (14.9% vs 3.7%, respectively; Adjusted Odds Ratio [95% CI]: 4.3 [2.2; 8.4]; p-value: <0.0001), in the absolute change from baseline in NILC at Week 12 (-17.6 vs -11.4, respectively; LS mean difference [95% CI]: -6.2 [-10.6; -1.9]; p-value: 0.0050) and in the absolute change from baseline in ILC at Week 12 (-17.9 vs -12.5, respectively; LS mean difference [95% CI]: -5.4 [-8.2; -2.7]; p-value: 0.0001).
Among the 19 subjects aged 9 to 11 years enrolled in phase 3 vehicle-controlled studies for facial acne vulgaris, 13 and 6 subjects were randomized to clascoterone cream and to vehicle, respectively. No statistically significant differences between clascoterone cream and vehicle were seen in any of the three co-primary endpoints: in the IGA success rate at Week 12 (15.4% vs 18.0%, respectively; Adjusted Odds Ratio [95% CI]: 0.8 [0.1; 11.8]; p-value: 0.8903), in the absolute change from baseline in NILC at Week 12 (7.3 vs -23.4, respectively; LS mean difference [95% CI]: 30.8 [-17.9; 79.4]; p-value: 0.2155) and in the absolute change from baseline in ILC at Week 12 (-20.6 vs -26.3; LS mean difference [95% CI]: 5.7 [-2.5; 13.9]; p-value: 0.1719).
After repeated cutaneous administrations of 4 g to 12 g daily of clascoterone cream 10 mg/g in healthy adults and in adult patients with acne vulgaris for up to 6 consecutive weeks, the systemic exposure was less than 1% of the total administered dose.
No correlation between blood levels and adverse reactions could be established.
Following cutaneous treatment of clascoterone for 2 weeks with a mean dose of approximately 6 g applied twice daily (12 g/day of cream) to adult subjects with moderate to severe acne vulgaris (n=20), systemic concentrations of clascoterone were at steady state by Day 5. On Day 14, the mean ± SD maximum plasma concentrations (Cmax) was 4.5 ± 2.9 ng/mL, the mean ± SD area under the plasma concentration-time over the dosing interval (AUCτ) was 37.1 ± 22.3 h*ng/mL and the mean ± SD average plasma concentration (Cavg) was 3.1 ± 1.9 ng/mL.
In in vitro studies, plasma protein binding of clascoterone was 84% to 89% and was independent of concentrations.
Following cutaneous treatment with clascoterone, the plasma concentrations of cortexolone, the main metabolite of clascoterone, were detectable and generally below or near the lower limit of quantitation (0.5 ng/mL) in subjects with acne vulgaris.
Excretion of clascoterone has not been fully characterised in humans. Because of the relatively low systemic bioavailability of clascoterone, the effects of renal or hepatic impairment were not evaluated.
In adolescent patients with acne vulgaris aged from 12 to <18 years (n=22) after 2 weeks of treatment with a mean dose of approximately 4 g of clascoterone cream 10 mg/g applied twice daily (8 g/day), steady-state concentrations of clascoterone were achieved by Day 14. Clascoterone systemic exposure was similar to that observed in adult patients treated with 6 g twice daily.
Clinical studies of clascoterone cream did not include sufficient number of subjects 65 years of age and older to determine whether they respond differently from younger subjects.
Clascoterone inhibited CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 with an IC50 value of >40 μM. Clascoterone up to 30 μM did not induce CYP 1A2, 2B6, or 3A4. These findings suggest that clascoterone has no clinically meaningful effect on the PK of substances metabolised by CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity studies.
Clascoterone was negative in an in vitro Ames and was aneugenic in an in vitro human lymphocyte micronucleus assay with a threshold of 50 mcg/mL, ˃10 000 fold higher than the clinical Cmax reached with supratherapeutic doses.
In vivo, in male rats after double subcutaneous administration up to 2000 mg/kg, clascoterone was clastogenic in the micronucleous test, corresponding to >100 safety margin calculated on the basis of animal versus clinical Cmax and AUC.
Clascoterone was not carcinogenic after daily topical administration of 0.1, 1 or 5 mg/mL cream (1 mg/g, 10 mg/g, or 50 mg/g) in a 2-year carcinogenicity study in rats. A statistically significant increase in benign sebaceous cell adenoma at the topical application site was observed only in males treated with the highest concentration of 50 mg/g clascoterone cream. An increased incidence of the non-neoplastic finding of atrophy of the skin and subcutis at the application site was reported in males and females treated with 10 mg/g and 50 mg/g clascoterone cream.
In a fertility and early embryonic development study in rats, there was no effect on fertility at subcutaneous doses up to 12.5 mg/kg/day; increased preimplantation loss and sperm count changes were noted at this dose level but not at 2.5 mg/kg/day (4.7 to 8.0 times the human exposure based on AUC comparison).
In an embryofetal development study conducted in rats at subcutaneous doses of 1, 5, or 25 mg/kg/day, clascoterone-related malformations were noted at all dose levels, without a dose relationship: omphalocele was noted in a single foetus at each dose level, and external and visceral malformations (severe dilation of the lateral and third cerebral ventricles; thin skin, small size, and protruding tongue) were noted in two additional fetuses at 1 mg/kg/day (2.5 times the human exposure based on AUC comparison).
In rabbits, postimplantation loss and resorptions were increased at a subcutaneous dose of 1.5 mg/kg/day whereas no treatment-related effect on embryofetal development was observed at doses up to 0.4 mg/kg/day (3.7 times the human exposure based on AUC). In a pre- and postnatal development study performed in rats, no significant developmental toxicity was observed at subcutaneous doses up to 12.5 mg/kg/day.
Based on its endocrine mechanism of action, clascoterone may pose a risk to compartment(s), in particular the aquatic compartment(s).
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