Regulatory Decision Summary for Winlevi

This New Drug Submission (NDS) was submitted to obtain market authorization for Winlevi (clascoterone cream 1%) for the topical treatment of acne vulgaris in patients 12 years of age or older.

The Canadian regulatory decision on the review of Winlevi was based on a critical assessment of the data package submitted to Health Canada. The primary sources of evidence that supported the efficacy and safety of Winlevi were two almost identically designed Phase 3 studies in participants with moderate to severe acne. The foreign review completed by the United States Food and Drug Administration (FDA) was used as an added reference.

Acne vulgaris affects more than 5 million Canadians: primarily between the ages of 12 and 24 years. Current acne-treatment guidelines recommend using approved and effective topical and systemic acne treatments; however, there is a role for a new, alternative acne treatments.

Winlevi (clascoterone) is a topical anti-androgen that acts locally. Winlevi’s efficacy and safety in treating acne was evaluated primarily in two pivotal Phase 3 randomized controlled trials (RCTs): CB-03-01/25, and CB-03-01/26. Safety was further assessed in an open-label follow-up study (CB-03-01/27) with an additional 9 months of treatment of the face and, if indicated, the trunk. Phase 1 and 2 studies (in particular, 171-7151-202 and CB-03-01/28) were considered supportive.

The pivotal Phase 3 studies assessing the efficacy and safety of Winlevi were nearly identical multicenter, randomized, allocation-concealed, double-blind, vehicle-controlled, parallel-group studies of 12 weeks duration that compared topical Winlevi 1% twice daily (BID) to vehicle BID on the face. These studies included 1,440 participants 9 years of age and older with moderate-to-severe acne (excluding participants with nodular acne). 1,421 participants were ≥ 12 years of age: 62% female, 91% White, and 55% 18 years of age or older (range: 12 to 58 years).

In the pivotal studies, there were three co-primary outcome measures that were tested hierarchically, followed by hierarchical testing of the four secondary outcome measures. The 3 co-primary outcomes were, in order, the proportion of participants with “success” (defined as ≥ 2-point reduction from baseline in Investigator’s Global Assessment [IGA] score and IGA score of clear [0] or almost clear [1]); the absolute change from baseline in non-inflammatory lesion count (NILC); and the absolute change from baseline in inflammatory lesion count (ILC).

Both in the individual pivotal Phase 3 studies, and in the pooled analysis, all of the primary and secondary efficacy outcomes were statistically significant. In the 1,421 participants aged ≥ 12 years, pooled adjusted proportions of participants with end-of-study IGA success were 19.8% with Winlevi and 7.8% with vehicle (odds ratio 2.9, p< 0.0001). From a mean baseline of 62 non-inflammatory lesions, the pooled mean difference in change from baseline in NILC was -7.9 (-19.8 with Winlevi versus -11.9 with vehicle). From a mean baseline of 42 inflammatory lesions, the pooled mean difference in change from baseline in ILC was -5.7 (-19.7 with Winlevi versus -13.9 with vehicle).

In the pivotal Phase 3 studies, the inclusion of only 19 participants aged 9 to < 12 years old made this subgroup’s effect estimates uncertain. In two Phase 2 studies, instances of asymptomatic (mild biochemical) hypothalamic-pituitary-adrenal (HPA) axis suppression were observed in 5% of adults (≥ 18 years), 9% of adolescents (12 to < 18 years), and 9% of pediatric subjects (9 to < 12 years) following 2 weeks of treatment under maximum dose conditions. Additionally, 33% of pediatric subjects (9 to < 12 years) experienced shifts from normal to elevated plasma potassium levels (i.e., hyperkalemia) following treatment. Overall, these studies indicated that pediatric patients may be more susceptible to systemic toxicity than adults when treated with Winlevi. Therefore, the proposed indication was recommended to be limited to participants ≥ 12 years of age.

The primary safety analysis from the two Phase 3 studies included a total of 1,440 participants (722 Winlevi, 718 vehicle): 1,421 were aged ≥ 12 years old. In the Phase 3 studies, participants taking Winlevi had a smaller total number of treatment-emergent adverse events (TEAEs), and fewer TEAEs leading to dose modification or discontinuation than participants receiving vehicle. There were no serious TEAEs with Winlevi. In the long-term extension study (CB-03-01/27) with Winlevi, there were 7 serious TEAEs in 6 participants, none of which were deemed to be related to Winlevi.

In participants ≥ 12 years of age, new or worsening local skin reactions (defined as eight types of investigator-identified adverse skin changes) were common, including erythema (12.2%), scaling/dryness (10.5%), pruritis (7.7%), stinging/burning (4.2%), edema (3.6%), and striae rubrae (2.5%); however, these were assessed to be mostly trace/mild in severity.

Biochemical hypothalamic-pituitary-adrenal (HPA) axis suppression was an identified risk in maximal-dose studies. This risk was mitigated through labelling by limiting the dose and the area of use.

A Risk Management Plan (RMP) for Winlevi (clascoterone) was submitted by Sun Pharmaceutical Industries Limited to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimize risks associated with the product.

Taken together, there is substantial evidence to demonstrate a reduction of acne severity with Winlevi. On the basis of the information reviewed, Winlevi presents an acceptable and manageable safety profile in consideration of the intended population. Based on the benefit-risk-uncertainty profile of the product, it is recommended that Winlevi be granted authorization.

For further details about Winlevi, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.