Moderate and Severe Inflammatory Acne Vulgaris Effectively Treated with Single-Agent Therapy by a New Fixed-Dose Combination Adapalene 0.3 %/Benzoyl Peroxide 2.5 % Gel: A Randomized, Double-Blind, Parallel-Group, Controlled Study

Acne represents a substantial disease burden, and thus effective treatment is crucial. The Global Burden of Disease study covering 187 countries found acne to be among the top ten most prevalent diseases worldwide in 2010, and skin conditions were one of the top causes of years lived with disability [1]. There is growing evidence that acne negatively affects quality of life [2]. Early, effective treatment of acne is essential and is important to avoid later complications, including scarring and psychosocial issues [3].

A need exists for topical treatments in the management of patients with more severe inflammatory acne. A variety of topical therapies already exist for the treatment of mild to moderate acne vulgaris, and a variety of treatments are used in combination [4]. The efficacy and safety of adapalene 0.1 % gel has been demonstrated in multiple randomized controlled trials (RCTs). A higher concentration of the formulation, adapalene 0.3 % gel, expanded treatment options and, in phase III studies, demonstrated superior efficacy and a safety profile similar to that of adapalene 0.1 % gel and its vehicle [5, 6]. Its long-term safety and efficacy have been shown over 12 months [7]. Moreover, noninferior efficacy and superior tolerability were found compared with tazarotene 0.1 % gel [8].

The rationale for combination therapy with a topical retinoid and antimicrobial agent is well-documented, particularly for adapalene 0.1 %/benzoyl peroxide (BPO) 2.5 % fixed-dose combination gel (hereafter, 0.1 % A/BPO, Epiduo^®, Galderma Laboratories, LP, Fort Worth, TX, USA), in the interests of limiting antibiotic resistance and simplifying therapy by targeting several etiopathogenic factors of acne. BPO is the gold standard bactericidal agent and is not associated with antibiotic resistance. Adapalene exerts comedolytic, anti-comedogenic effects (the microcomedo being the precursor lesion targeted by retinoids), and demonstrates anti-inflammatory properties in both in vitro and in vivo research as well as clinical studies [8‐12]. Moreover, adapalene has been found to down-regulate the expression of toll-like receptor 2 (TLR₂) [10, 12], a receptor involved in the pathogenesis of acne lesions through Propionibacterium acnes-mediated activation, which subsequently induces proinflammatory cytokines [13].

Combining a topical retinoid with BPO is supported by the Global Alliance to Improve Outcomes in Acne guidelines [4, 14] and European guidelines for acne treatment [15]. To date, topical therapies alone, including 0.1 % A/BPO, have been recommended for the treatment of mild to moderate papulopustular acne, and in combination with an oral antibiotic for moderate to severe papulopustular acne. According to more recent pediatric treatment guidance from Eichenfield et al. [16], the recommendations diverge for treatment of moderate acne, where topical combination therapy (topical retinoid and BPO with or without a topical antibiotic) is advised as an additional option to the traditional oral antibiotic with topical retinoid and BPO. All of these guidelines suggest the following limited choices in severe, non-nodulocystic acne treatment: either oral isotretinoin or a topical combination (retinoid and BPO) with oral antibiotics used for all but the most severe forms of acne. Thus, a topical therapy in a single formulation that is strong enough to improve severe inflammatory acne as a standalone or adjunct alternative treatment choice for a significant number of acne patients without the need for oral isotretinoin (and its associated side effects) or concomitant antibiotic therapy (to reduce microbial resistance) represents a substantial unmet need.

Data from three RCTs among 3855 subjects in total, of whom 983 received 0.1 % A/BPO, demonstrated that it provided synergistic and significantly greater efficacy than its monotherapies in the treatment of acne vulgaris, with an acceptable safety profile [17]. Synergism was defined as the benefit of the combination greater than the sum of benefits of adapalene and BPO monotherapies [17]. Furthermore, the benefit of A/BPO relative to vehicle has been shown to increase with higher lesion counts at baseline [18]. A synergistic and potent anti-inflammatory effect could thus be inferred with a higher concentration of adapalene combined with BPO, which would be essential in a more severe population.

To date, topical treatments alone are not perceived as suited for treatment of the severe papulopustular, non-nodulocystic acne population. To evaluate the potential for a higher concentration of adapalene in a fixed-dose combination with BPO in meeting this need in a broader segment of patients, the current study aimed to evaluate the efficacy and safety of adapalene 0.3 %/benzoyl peroxide 2.5 % (0.3 % A/BPO) gel as single-agent therapy in subjects with moderate and severe inflammatory acne.

These are the primary results for the first topical drug developed for severe acne. In this study, 0.3 % A/BPO as single-agent therapy was superior to vehicle in the co-primary endpoints of IGA success rate (clear/almost clear, at least a 2-grade change) and change in IN and NIN lesion counts (consistently p < 0.001) at week 12, which was confirmed in the PP population. In addition, an early onset of action was shown as of week 1, with significantly larger reductions in lesions relative to vehicle. Furthermore, in the severe inflammatory acne population (IGA = 4), where a rigorous 3-grade IGA improvement was required, 0.3 % A/BPO continued to demonstrate statistical superiority over vehicle (p = 0.029). The product was also safe and well-tolerated, and side effects subsided quickly, as can be expected with any retinoid-containing product. The safety profile of 0.3 % A/BPO was similar to that of 0.1 % A/BPO. Furthermore, no increase in incidence of AEs or local tolerability effects for subjects with baseline severe IGA 4 acne was observed compared with the moderate population.

The study design is also original in that other topical therapies do not typically target such a high proportion of patients with severe inflammatory acne (50 %) as single-agent therapy. The subjects enrolled in this study had a relatively higher number of baseline IN and NIN lesions (about 39 and 59 for the 0.3 % A/BPO group, with a total of 98.5 lesions) compared with other topical acne drug studies (e.g., ranging from 65.5 total lesions for clindamycin 1.2 %/BPO 3.75 % to 79 total lesions for dapsone 0.5 % gel at baseline) [19, 20]. In separate phase III studies regarding clindamycin 1.2 %/BPO 2.5 % gel, clindamycin 1.2 %/BPO 3.75 %, clindamycin 1.2 %/tretinoin 0.025 % gel, and tazarotene foam 0.1 %, a range of about 17–20 % of subjects had severe acne at baseline [19, 21‐23]. Clindamycin 1 %/BPO 5 % gel was studied in a population with moderate to moderately severe acne (IGA between 3 and 4), and improvement was only described in terms of at least one grade of improvement [24].

Indeed, 0.3 % A/BPO may fill a gap as a single-agent treatment for moderate to severe inflammatory acne. Pediatric guidelines recommend that an oral antibiotic be started concomitantly with topical combination therapy (i.e., topical retinoid and BPO) promptly to prevent scarring in severe acne, when there is evidence of scarring even in moderate acne, or as a step-up regimen if initial therapeutic response with topical therapy is not adequate [16]. European guidance suggests that for moderate acne, an oral antibiotic should be initiated upon the presentation of more widespread disease [15]. Therefore, 0.3 % A/BPO may be able to substitute antibiotics in the interest of minimizing antibiotic resistance in cases where the addition of systemic antibiotic therapy is considered, particularly as its mechanism of action includes prevention of microcomedone formation. International guidelines for acne management stipulate that oral isotretinoin remains the gold standard for severe acne treatment [4, 14]. Recent guidance for the pediatric population suggests that oral isotretinoin is no longer indicated as first-line treatment, but instead only after inadequate response with initial treatment using combination therapy (topical treatment associated with oral antibiotic) [16]. Therefore, 0.3 % A/BPO may be an appropriate treatment, alone or in combination with other therapies, prior to the potential need for step-up treatment to oral isotretinoin, or while enrolling the patient in the required programs to obtain access to oral isotretinoin. Furthermore, 0.3 % A/BPO may be seen as a replacement for existing topical combination therapies used with oral antibiotics in not only moderate acne but also in severe inflammatory non-nodulocystic acne (although, perhaps not exclusively).

As adapalene has been found to down-regulate the expression of TLR_2, β-defensin 4 and interleukin (IL)-8, as well as to increase CD1d expression [10, 12, 25], with a dose-dependent effect on inflammatory markers [12], it seems logical that a higher potency of A/BPO can demonstrate an even greater anti-inflammatory effect in patients with more severe acne, an effect that has not previously been available. Thus, 0.3 % A/BPO may open the door to more treatment options for patients with severe inflammatory acne and can be considered as a step-up option from 0.1 % A/BPO before considering more aggressive systemic therapies. A once-daily topical treatment regimen may be perceived as easier to integrate into the patient’s existing skin care habits. Patient adherence may be improved with a standalone topical treatment versus an often long-term, oral regimen as in this study. In this trial, 0.3 % A/BPO was effective, and patient adherence was maintained throughout the trial (90.8 % for the 0.3 % A/BPO group).

It is noteworthy that this study was conducted in a diverse patient population with about one-fourth Hispanic or Latino subjects, and over one-third with darker skin phototypes (IV–VI). This is important because Hispanics are the fastest-growing minority group in the USA, and acne is reported as the most common dermatologic diagnosis seen in over 20 % of the Hispanic population [26]. Furthermore, in darker skin phototypes, there is a potential for increased cutaneous irritation and postinflammatory hyperpigmentation (PIH) [27]. The use of 0.3 % A/BPO in this population may be particularly warranted to provide quick control of the disease with good tolerability. A limitation of this study was that in the absence of adapalene and BPO arms, the contribution of each individual component could not be determined. Nevertheless, this may be extrapolated from previous data regarding synergy of 0.1 % A/BPO and the advantage of the combination over its components [17].

Treatment with 0.3 % A/BPO topical gel showed superior efficacy to vehicle, along with a good safety profile in moderate to severe inflammatory non-nodulocystic acne. The availability of a higher concentration of A/BPO will increase patients’ treatment options and allow clinicians to further customize acne management according to the disease presentation.