Regulatory Decision Summary for Cabtreo

This New Drug Submission (NDS) was submitted to request market authorization of Cabtreo (1.2% clindamycin phosphate, 0.15% adapalene and 3.1% benzoyl peroxide gel) for the treatment of acne vulgaris in patients 9 years of age and older. The recommended indication is for the treatment of acne vulgaris in patients 12 years of age and older.

Once daily application of Cabtreo on affected facial areas for 12 weeks was demonstrated to be safe and effective compared to vehicle gel in 2 identical multicenter, randomized, double-blind, vehicle controlled, phase 3 pivotal clinical studies (Study 301 and 302). The co-primary efficacy endpoints were mean absolute change in non-inflammatory and inflammatory facial lesion counts at week 12, and Evaluator’s Global Severity Score (EGSS) treatment success (defined as a 2 grade or more improvement from baseline and a clear or almost clear score) at week 12. These are well-validated efficacy endpoints. In both trials, patients treated with Cabtreo gel had statistically significantly better results for all three endpoints compared to those treated with vehicle gel. In study 301 and 302, respectively, patients treated with Cabtreo gel had a decrease in inflammatory lesion count of 27.7 and 30.1 from baseline compared to a reduction of 21.7 and 20.8 for those treated with vehicle gel. Similarly, decreases in non-inflammatory lesion count were 35.4 and 35.2 from baseline for patients treated with Cabtreo and 23.5 and 22.0 from baseline in patients treated with vehicle gel. EGSS treatment success was achieved in 49.6% and 50.5% of patients treated with Cabtreo compared to 24.9% and 20.5% in those treated with the vehicle gel in studies 301 and 302, respectively. Statistical significance was also achieved for key secondary endpoints in favor of Cabtreo.

Cabtreo was relatively well-tolerated across the clinical program. The vast majority of treatment-related adverse events were administration site and skin-related conditions. In the pivotal clinical studies, 19.8% of patients treated with Cabtreo had application site events compared to 1.7% for vehicle-treated participants. These included pain, dryness, exfoliation and irritation at the site of application. Erythema was also more common in the Cabtreo treated group. Cutaneous tolerability was generally worse during the early weeks of treatment and improved over time. This safety profile is consistent with the known adverse event frequencies associated with the constituent components of this product. Clinicians are familiar with the use of these ingredients and the management of cutaneous tolerability. There were no concerning systemic events attributed to Cabtreo use. A contraindication on use during pregnancy has been added to the Product Monography (PM) as an additional risk mitigation measure because of known potential teratogenic effects of topical adapalene.

A dedicated pharmacokinetic (PK) study was conducted with Cabtreo and demonstrated relatively low levels of systemic exposure of clindamycin and adapalene (approximately 3-fold increase) under maximal daily-use conditions for 28 days. The exposures of each component do not seem to be affected by the presence of the other components as they have independent, non-overlapping pharmacodynamic properties.

The non-clinical pharmacology and toxicology assessments are considered appropriate in establishing a suitable clinical safety margin to support the treatment of acne vulgaris. The majority of non-clinical data provided has been derived from individual or 2-component studies and not with Cabtreo. As these ingredients are well known acne drugs with characterized safety profiles, the provided non-clinical information does not raise any safety issues that would preclude approval of Cabtreo for the proposed indication and relevant risks have been mitigated with appropriate labelling in the Product Monograph.

The Sponsor did not provide any safety or efficacy data beyond 12 weeks of use, therefore the long-term safety profile or persistence of efficacy is unknown. However, as all three components have a long history of use in this disease setting, it is expected that the safety can be extrapolated from other similar topical products. Enhanced compliance and increased efficacy of Cabtreo compared to other products or 2-drug regimens cannot be validated as a direct comparison to standard of care was not assessed.

Finally, the pivotal trials allowed for the inclusion of patients 9 years of age and up and the Sponsor sought an indication that included this age group. However, very few patients aged 9-11 were enrolled in these trials and insufficient PK data was generated in these pediatric patients. Given the lack of data and potential differences in disease progression and response to treatment in a pre-pubescent compared to an adult population, the indication was not extended to this youngest cohort at this time.

Overall, Cabtreo exhibited a favorable benefit-harm-uncertainty profile when used as directed for patients aged 12 years and older for the topical treatment of acne vulgaris.

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