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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Schulich School of Medicine and Dentistry, Western University, Windsor, ON, Canada

Conflict of interest: Karen Michael has no conflicts. Jerry Tan is an advisor, consultant, speaker and/or trialist for Bausch, Cipher, Cutera, Galderma and Sun Pharma. Funding sources: None.

Abstract:
Oral isotretinoin continues to be unsurpassed in efficacy for acne. However, it is associated with potential adverse events including risk of fetal defects, necessitating appropriate mitigation strategies. Furthermore, the variance in bioavailability of the original formulation when ingested in fed versus fasted conditions can lead to differences in daily dosing and duration of exposure. Advances in formulation, with lidose encapsulation and subsequently with micronization, have led to iterative improvements in reducing bioavailability variation between fed and fasted conditions. Differences in bioavailability during fasting were 60% less for originator oral isotretinoin, 33% less for lidose-encapsulated form, and 20% less for micronized-isotretinoin formulation. The latter also demonstrated overall greater bioavailability such that a 20% dose reduction was required compared to the originator and lidose-encapsulated formulations. By reducing the effect of high-fat/high calorie food co-ingestion, this micronized formulation may facilitate clarity in determining appropriate oral isotretinoin dose requirements in achieving optimal patient outcomes.

Keywords: acne, isotretinoin, lidose, micronized, bioavailability

Oral isotretinoin was and continues to be the standard of treatment for severe or recalcitrant acne since regulatory approval was granted in the United States and Canada in 1982 and 1983, respectively ^1,2 While its efficacy remains unsurpassed, the past 4 decades have witnessed a barrage of reports regarding potential serious adverse events and attendant litigation. This began with the teratogenic potential of isotretinoin and consequential requirements for rigorous consenting and monitoring to mitigate pregnancy risks. Subsequent concerns including associations with depression, suicide, and inflammatory bowel disease led to studies to address these topics in a rigorous scientific manner and develop risk mitigation measures. It is thus a testament to the enduring value of this medication for people with acne and their caregivers that it remains an available therapy.

Mechanism of Action

Oral isotretinoin is a potent sebo-suppressive agent, likely due to its apoptotic effect on human sebocytes.³ Furthermore, it normalizes monocyte toll-like receptor 2 responses to Cutibacterium acnes (C. acnes).⁴ It has recently been found to induce expression of the transcription factor p53, which controls other pathways involved in the pathogenesis of acne vulgaris such as FoxO1, androgen receptor and genes involved in the induction of autophagy and apoptosis.⁵ These effects likely lead to downstream impacts including reduction in C. acnes proliferation, pro-inflammatory lipid mediators and direct and indirect anti-inflammatory effects in the pilosebaceous unit.⁵

Formulations (Table 1)

As isotretinoin is a lipophilic molecule, the originator product Accutane^® (Roche) was formulated with solubilization ingredients including hydrogenated vegetable oil and soybean oil.⁶ Nevertheless, it is only marginally soluble in the intestinal aqueous environment.⁶ Hence, co-administration with fatty meals was encouraged for greater absorption.⁶ Ingestion of a fatty meal can double drug bioavailability compared to the fasting state.⁶ Accordingly, important considerations include recognizing how varying dietary habits can influence drug absorption, which may in turn affect tolerability, safety, and efficacy.⁶

Subsequently, innovative formulations of isotretinoin have been developed to address the variability in absorption in fed and fasted states. The first iteration was lipid encapsulation, lidose-isotretinoin (Epuris^®, Cipher Pharma; Absorica^®, Sun Pharma), approved by the US FDA and Health Canada in 2012. Lipid encapsulation enhances bioavailability of isotretinoin with less dependency on high-fat, high-calorie meals. In this process, isotretinoin is presolubilized in a lipid matrix leading to greater and faster absorption with less food dependency.⁶ When compared with the conventional formulation of isotretinoin, lidose-isotretinoin was absorbed to a greater extent in the fasting state but equivalent in absorption when coadministered with a high-fat/calorie meal.⁷ It has been shown that lidose-isotretinoin delivered almost twice as much isotretinoin after an overnight fast.⁷ During fasting, isotretinoin bioavailability was 67% of that in the fed state with lidose-isotretinoin compared to 40% for conventional isotretinoin.^7,8 Moreover, lidose-isotretinoin was found to be noninferior to the conventional formulation in a blinded randomized controlled trial in efficacy and safety for severe recalcitrant nodular acne.⁹

A more recent development was a formulation combining isotretinoin micronization with a lidose vehicle carrier system (micronized-isotretinoin; Absorica LD^®, Sun Pharma) that was approved by the FDA in 2019 and Health Canada in 2023. This advancement was based on recognition that drug solubility is also dependent on particle size, with smaller sizes resulting in higher penetration and distribution across a larger total surface area. In micronization, isotretinoin particles are reduced to micrometer or nanometer size. The newest formulation of isotretinoin combines both micronization and lipid encapsulation to enhance solubility, absorption, and bioavailability.⁶ For comparison, conventional formulations of isotretinoin have a mean particle size of about 100 μm while micronized isotretinoin can reach a particle size of 10 μm and the median size (D50) is less than 15 μm.^6,10

Bioequivalence

This micronized formulation was evaluated as an abbreviated new drug application as isotretinoin with lidose encapsulation had been previously approved by the FDA. The demonstration of bioequivalence required pharmacokinetic studies evaluating concentration maximum (Cmax; peak serum concentration after administration) and extent of absorption (AUC; area under the curve).¹¹

The pivotal trial for micronized-isotretinoin comprised 2 open-label, crossover pharmacokinetic studies comparing bioavailability of micronized-isotretinoin 32 mg against lidose-isotretinoin 40 mg in healthy adults. A prior internal study by the sponsor determined that micronized-isotretinoin 0.8 mg/kg would achieve similar plasma levels to lidose-isotretinoin 1 mg/kg, or a 20% dose reduction.¹² One study assessed bioequivalence in the fed state and assessed the effect of food (Figure 1A), and the second evaluated bioavailability in the fasted state (Figure 1B).¹² The fed state was based on administration of a standardized high-fat, high-calorie breakfast as defined by the FDA containing 150 protein calories, 250 carbohydrate calories, and 500 fat calories. In practice, this comprised 2 fried eggs, 2 bacon strips, 4 oz hash browns, 2 slices buttered toast, and 8 oz whole milk.¹²

In the first study, healthy adults of both genders aged 18 years or greater were enrolled in a 3 treatment, 3 period, crossover study. Subjects were sequentially exposed to a single dose of either micronized-isotretinoin 32 mg after an overnight fast (minimum 10 hours); micronized-isotretinoin 32 mg after a high-fat/caloric meal; or lidose-isotretinoin 40 mg after a high-fat/caloric meal. For each subject, crossover was undertaken with intervening durations of 21 days for exposure to each of the 3 treatments. Data were available for 65 subjects. In the fed state, Cmax and AUC parameters were similar for those receiving micronized-isotretinoin 32 mg and for lidose-isotretinoin 40 mg. The comparative results fell within the 80-125% range for bioequivalence, inferring that micronizedisotretinoin 32 mg was bioequivalent to lidose-isotretinoin 40 mg under fed conditions.¹²

The pharmacokinetic effect of food on micronized-isotretinoin 32 mg showed that the high-fat/calorie meal delayed maximum isotretinoin absorption (Tmax) by 1.5 hours. Furthermore, food increased AUC by just over 20%. By comparison, the food effect was 60% for originator isotretinoin and was 33% for lidoseisotretinoin.¹²

The second study evaluated relative bioavailability in the fasted state. Data from 18 subjects were available. Cmax and AUC results for micronized-isotretinoin 32 mg were almost double those for lidose-isotretinoin 40 mg. Under fasted conditions, micronizedisotretinoin 32 mg had almost 2 times greater bioavailability compared with lidose-isotretinoin 40 mg.¹²

Conclusion

Prior literature on oral isotretinoin regarding benefit/risk profiles of low versus conventional isotretinoin dosing and the utility of cumulative dosing in achieving remissions focused on originator and conventional formulations. The present micronized-isotretinoin formulation, due to greater bioavailability, requires transforming these metrics into doses 20% lower than those published for originator and conventional formulations. The pivotal trials for micronized-isotretinoin were comprised of fed bioequivalence, food effect and fasting studies compared to lidose-isotretinoin. As micronized-isotretinoin 32 mg was found to be bioequivalent to lidose-isotretinoin 40 mg under fed conditions, these formulations are not interchangeable. Furthermore, in fasted conditions, micronized-isotretinoin confers 2 times greater bioavailability compared with lidose-isotretinoin 40 mg. In comparing absorption during fed versus fasting conditions, a 20% increase was observed with micronized-isotretinoin compared to 33% with lidoseisotretinoin. Thus, micronized-isotretinoin bioavailability was less food dependent. Micronized-isotretinoin substantially reduced the food effect for oral isotretinoin bioavailability.

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