¹Schulich School of Medicine and Dentistry, Western University, Windsor, ON, Canada
²Department of Health Sciences, Brock University, St. Catharines, ON, Canada
³Windsor Clinical Research Inc, Windsor, ON, Canada

Conflict of interest: Karen Michael, Jaefer Mohaad and Nuha Nasir have no conflicts. Jerry Tan is an advisor, consultant, speaker and/or trialist for Bausch, Cipher, Cutera, Galderma and Sun Pharma.

Funding sources: None.

Abstract: Clindamycin phosphate 1.2%/benzoyl peroxide 3.1%/adapalene 0.15% (IDP-126) is a novel fixed-dose triad gel combination approved by the US FDA October 2023 and by Health Canada August 2024 for the treatment of acne vulgaris in patients aged 12 years and older. IDP-126 was efficacious in moderate to severe acne compared to vehicle and component topical dyads in phase 2 and to vehicle in phase 3 randomized controlled studies. Efficacy outcomes were inflammatory and noninflammatory lesion counts and Evaluator’s Global Severity Score. IDP-126 also had a favorable tolerability and safety profile.

Keywords: acne, topical, triple combination, fixed-dose, clindamycin, adapalene, benzoyl peroxide, treatment, Cabtreo™

Introduction

The pathogenesis of acne involves different mechanisms including follicular proliferation of Cutibacterium acnes (C. acnes), follicular hyperkeratinization, inflammation, and increased sebum production.¹ Current topical medications include retinoids, benzoyl peroxide, antibiotics, azelaic acid, and dapsone – either as monads or dyads. Recently, a novel topical fixed-dose triad, combining clindamycin phosphate 1.2%/benzoyl peroxide (BPO) 3.1%/adapalene 0.15% (IDP-126) has been developed. Herein, we summarize pivotal trials leading to regulatory approval in the US and Canada.

Phase 2 Studies

The phase 2 study, conducted in the US and Canada, was randomized, controlled and double-blinded involving participants 9 years or older with moderate [Evaluator’s Global Severity Score (EGSS) of 3] to severe (EGSS 4) facial acne.² Participants were randomized to one of five different treatment groups for 12 weeks: vehicle, IDP-126 (triple combination), and the following dyad formulations: benzoyl peroxide 3.1%/adapalene 0.15% gel (BPO/ ADAP), clindamycin phosphate 1.2%/benzoyl peroxide 3.1% (CLIN/BPO), or clindamycin phosphate 1.2%/adapalene 0.15% gel (CLIN/ADAP).

Treatment success, defined by achievement of ≥2-grade reduction in EGSS and clear/almost clear (EGSS 0 or 1), was achieved by 52.5% of participants at week 12 with IDP-126. This was significantly greater than the three dyad gels (range 27.8-30.5%; P ≤ 0.001, all) and vehicle (8.1%; P < 0.001). IDP-126 resulted in significant mean reductions in inflammatory (29.9) and noninflammatory lesions (35.5) from baseline to week 12 (P < 0.05, all) compared to all dyad treatments and vehicle (Figure 1). Overall, IDP-126 demonstrated over 70% reductions in both inflammatory and noninflammatory lesions.

Phase 3 Studies

Two identical randomized, double-blind, vehicle-controlled 12-week trials were conducted in subjects aged 9 years and older in moderate to severe acne.³ Participants were randomized to IDP-126 or vehicle gel, at a 2:1 ratio. Co-primary outcomes were ≥2-grade reduction from baseline and achievement of clear/almost clear on EGSS, and changes in inflammatory and noninflammatory lesion counts.

All coprimary efficacy endpoints were achieved in both trials with IDP-126 gel outperforming vehicle at week 12. Significantly greater percentages of participants achieved a 2-grade reduction in EGSS and clear/almost clear at week 12 with IDP-126 vs. vehicle (Study 1: 49.6% vs. 24.9%, P ≤ 0.01; Study 2: 50.5% vs. 20.5%; P ≤ 0.001).

When comparing IDP-126 vs. vehicle at week 12, greater reductions were also observed in inflammatory (Study 1: 27.7% vs. 21.7%, P ≤ 0.01; Study 2: 30.1% vs. 20.8%; P ≤ 0.001) and noninflammatory (Study 1: 35.4% vs. 23.5%, P ≤ 0.01; Study 2: 35.2% vs. 22.0%; P ≤ 0.001) lesion counts (Figure 2). Significant differences in inflammatory and noninflammatory lesion counts with IDP-126 vs. vehicle were noted by week 4 (P < 0.05).

Treatment-emergent adverse events (TEAEs) were observed with greater frequency in the IDP-126 group (Study 1: 24.6% vs. 8.2%; Study 2: 30.0% vs. 8.3%) and considered related in a smaller proportion (Study 1: 18.0% vs. 0%; Study 2: 21.7% vs. 3.3%). These were primarily mild-moderate in severity and attributed to application site pain (Study 1: 10%; Study 2: 15.0%), erythema (Study 1: 4.9%; Study 2: 2.5%), dryness (Study 1: 1.6%; Study 2: 4.2%), irritation (Study 1: 0.8%; Study 2: 3.3%), exfoliation (Study 1: 3.3%; Study 2: 0%) and xerosis (Study 1: 0%; Study 2: 2.5%). Three severe adverse events were reported, all in the IDP-126 cohorts (Study 1: application site burn, n = 1, led to study withdrawal; Study 2: application site pain and dryness, n =1; application site pain, n = 1; related). No serious adverse events were reported.

Network Meta-Analysis

A network meta-analysis compared the relative efficacy of commercially available acne treatments for moderate to severe acne.⁴ Inclusion criteria were randomized controlled trials (RCTs) with minimum duration of 4 weeks involving subjects aged 9 years and older. Notably, isotretinoin studies were excluded from this analysis due to either absence of global assessments in current use for regulatory approval, or non-randomized designs. Primary outcomes evaluated were percentage of patients achieving a ≥2-grade reduction in acne severity, almost clear/clear for global severity score, and changes in inflammatory lesion (IL) counts, and noninflammatory (NIL) counts. Treatments were ranked using surface under cumulative ranking (SUCRA) values. SUCRA scores rank treatments based on their effectiveness across studies, simplifying comparison by assigning higher scores to more consistently effective treatments. The top treatments across these outcomes were: (1) IDP-126, a combination of topical antibiotics/ BPO/retinoids (SUCRA 0.96 for Global Assessment, 0.90 for inflammatory lesions, and 0.91 for noninflammatory lesions), (2) fixed-dose dyad topical treatments with oral antibiotics (SUCRA 0.88, 0.98, and 0.99, respectively), and (3) topical retinoid/ BPO combinations (SUCRA 0.74, 0.79, and 0.79, respectively). These rankings highlight the strong overall performance of these treatment combinations across different acne efficacy outcome measures. In addition to efficacy, IDP-126 showed a favorable safety and tolerability profile with lower discontinuation rates (2.8%). It also had fewer patients with TEAEs than dyads.

Conclusion

The topical fixed-dose triad of clindamycin phosphate 1.2%/BPO 3.1%/adapalene 0.15% gel (IDP-126) represents an effective and well-tolerated novel topical treatment option for moderate to severe acne. In comparison to currently available topical and systemic treatments (except for oral isotretinoin), it ranks within the top three of the most effective treatments for moderate to severe acne.

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