Efficacy and Safety of Microencapsulated Benzoyl Peroxide Cream, 5%, in Papulopustular Rosacea in Elderly Patients: Post-hoc Analysis of Results from Two Randomized, Phase III, Vehicle-controlled Trials

J Clin Aesthet Dermatol. 2024;17(10):41–44.

by Lawrence J. Green, MD; Hilary Baldwin, MD; Jeffrey Sugarman, MD, PhD; Bill Andriopoulos; Ori Nov, PhD; Ofra Levy-Hacham, PhD; Neal Bhatia, MD; and William P. Werschler, MD

Dr. Green is with the George Washington University School of Medicine in Washington, District of Columbia. Dr. Baldwin is with the Acne Treatment & Research Center in Brooklyn, New York. Dr. Sugarman is with the University of California, San Francisco School of Medicine in San Francisco, California. Dr. Andriopoulos is with Galderma Laboratories Ltd. in Boston, Massachusetts. Drs. Nov and Levy-Hacham are with Sol-Gel Technologies Ltd in Ness Ziona, Israel. Dr. Bhatia is with Therapeutics Clinical Research in San Diego, California. Dr. Werschler is with Spokane Dermatology Clinic and Werschler Aesthetics in Spokane, Washington.

FUNDING: This study was sponsored by Sol-Gel Technologies Ltd. All authors were involved in the conduct of these trials and, as such, have received study-related funding. Medical writing and editorial support for this manuscript was provided by Simpson Healthcare and was funded by Galderma Laboratories.

DISCLOSURES: Dr. Baldwin is an investigator, advisor, and speaker for Galderma; an investigator, advisor, and speaker for Bausch Health, and an investigator and advisor for Sol-Gel Technologies Ltd. Dr. Bhatia is an advisor, consultant, and investigator for Galderma and Sol-Gel Technologies Ltd. Dr. Green is an investigator, speaker, and consultant for Galderma and Ortho Dermatologics. Dr. Sugarman is a consultant for  Sol-Gel Technologies Ltd., Galderma, and Bausch Health.

ABSTRACT: Objective. We sought to compare the efficacy and safety of encapsulated benzoyl peroxide (E-BPO) cream, 5%, versus vehicle in subjects <65 years of age versus subjects ≥65 with moderate to severe papulopustular rosacea.

Methods. This analysis used pooled results from two 12-week, randomized, vehicle-controlled Phase III trials (NCT03564119, NCT03448939) of E-BPO cream, 5%. These trials included 733 subjects randomized 2:1 to E-BPO or vehicle. The primary endpoints were success in the Investigator’s Global Assessment (IGA) score and reduction in mean inflammatory lesion count at Week 12.

Results. Our analysis shows that E-BPO cream, 5%, was significantly superior to vehicle in achieving IGA success and reducing inflammatory lesions in both age groups. IGA success was achieved in 48.3% of subjects who received E-BPO versus 25.4% for vehicle in the intent-to-treat population. The E-BPO and vehicle IGA success percentages for subjects <65 were 45.7% and 23.8%, respectively, and those for subjects ≥65 were 60.0% and 28.1%, respectively. The absolute reduction from baseline in inflammatory lesions was –19.3 for subjects who received E-BPO versus –11.4 for those who received vehicle. The E-BPO and vehicle absolute reduction values for subjects <65 were –19.6 and –11.2, respectively, and 17.5 and –10.4 for subjects ≥65. There were no significant differences in the frequencies of adverse events or cutaneous tolerability.

Limitations. E-BPO was not compared to nonencapsulated BPO.

Conclusion. This combined analysis of results from the two Phase III, randomized, double-blind controlled studies of E-BPO cream, 5%, showed it was efficacious, tolerable, and safe, regardless of age.

Keywords. Rosacea, topical, papulopustular rosacea, encapsulation, microencapsulation, benzoyl peroxide, BPO

Rosacea is a highly prevalent, chronic, relapsing inflammatory skin disease that affects up to 16 million people in the United States.^1,2 Assessments of different phenotypes suggest that about 30 percent of people have disease characterized by papules and pustules.³ Several recent epidemiological studies have indicated that the prevalence of rosacea is high in older adults. Results from a survey carried out in Finland showed that 25 percent of participants aged 70 years or older had rosacea.⁴ Similarly, a cross-sectional study of 2,701 unselected individuals in Germany showed that 33.7 percent of those aged 60 to 69 years had rosacea, as did 32.9 percent of participants aged 70 years or older.⁵ A second German epidemiological study noted that the prevalence of rosacea was age-dependent, with the mean age of participants with rosacea being significantly higher than the mean age of those without rosacea.⁶ A wide range of topical and systemic therapies have been employed for treating rosacea.^7–9 Still, to our knowledge, no controlled trials have provided any quantitative information regarding the efficacy and safety of any of these treatments in patients over 65 years of age, who often have more sensitive skin due to the structural and physiological changes associated with age.¹⁰  

Microencapsulated benzoyl peroxide cream, 5% (E-BPO cream, 5%), is a novel formulation of BPO developed using the sol gel process in which the drug is enclosed in silica microcapsules.¹¹ Results from two Phase III randomized, controlled trials and a long-term extension of these studies have demonstrated significant superiority of this treatment over a vehicle cream for decreasing papulopustular lesions and improving the Investigator’s Global Assessment (IGA) in subjects with rosacea.^12,13 In this report, data from the two randomized controlled studies were further analyzed to compare the efficacy and safety of E-BPO cream, 5%, versus vehicle in subjects younger than 65 years versus subjects aged 65 years or older. 

Methods

The design for the two Phase III trials (NCT03564119, NCT03448939) has been described in detail.¹² In brief, the subjects were males and females aged 18 years or older with a clinical diagnosis of moderate to severe rosacea with a baseline IGA score of 3 (moderate severity) or 4 (severe) on a severity scale of 0 to 4. The subjects had a minimum of 15 and a maximum of 70 total inflammatory lesions (papules and/or pustules), including those present on the nose, and 2 or fewer nodules (defined as a papule or pustule >5mm in diameter). 

The two trials were randomized (2:1), double-blind, multicenter, parallel-group, vehicle-controlled studies that included a screening visit and 12 weeks of treatment. Treatment was to be applied once daily at approximately the same time. After screening, randomization, and a baseline evaluation (Day 1), subjects returned to study sites for four evaluation visits (Weeks 2, 4, 8, and 12) during the double-blind period. Safety was monitored throughout the study. The studies were conducted in compliance with United States Food and Drug Administration (FDA) regulations, the ethical principles of the Declaration of Helsinki, and the current International Council for Harmonisation Good Clinical Practice guidelines. The protocol, informed consent documents, any information provided to subjects, recruitment advertisements, and any amendments to these items had Institutional Review Board approval prior to their use in the study. Voluntary informed consent was given by every patient before the initiation of any study-related procedures. 

Each study had two coprimary endpoints. The first was treatment success as determined by the IGA, administered at screening/baseline and Weeks 2, 4, 8, and 12. Success was defined as achieving an IGA rating of “clear” (0) or “almost clear” (1) on the five-point IGA scale (0=clear, 1=almost clear, 2=mild disease, 3=moderate disease, and 4=severe disease) at Week 12. The second coprimary endpoint was the absolute change in inflammatory lesion count from baseline to Week 12. Safety was assessed by recording vital signs and monitoring the incidence of adverse events (AEs). At each study evaluation, cutaneous safety was assessed by evaluating itching, scaling, dryness, and burning/stinging on a four-point scale. The primary population for efficacy analysis was the intent-to-treat population, which consisted of all randomized subjects who received study treatment. The safety population consisted of subjects in the randomized population who were presumed to have used the study product at least once and provided at least one post-baseline safety evaluation.

Results

Study subjects and demographics. A total of 733 subjects were enrolled, including 493 who were treated with E-BPO cream, 5%, and 240 who received vehicle. There were 606 subjects younger than 65 years, with 403 in the E-BPO group and 203 subjects in the vehicle group. There were 127 subjects aged 65 years or older, with 90 in the E-BPO group and 37 subjects in the vehicle group.

Efficacy. The analysis showed that E-BPO cream, 5%, was superior to vehicle in achieving IGA success and reducing inflammatory lesions in both age groups. IGA success was achieved in 48.3 percent of subjects of all ages who received E-BPO versus 24.5 percent for vehicle. The IGA success percentage for E-BPO subjects younger than 65 was 45.7 percent, and 23.8 percent for vehicle subjects. In subjects aged 65 or older, the IGA success percentage was 60.0 percent for E-BPO and 28.1 percent for vehicle (Figure 1). 

The absolute reduction from baseline in inflammatory lesions was –19.2 for subjects in the E-BPO cream, 5%, group versus –11.0 for the vehicle group. The values for subjects younger than 65 were –19.6 for E-BPO and –11.2 for vehicle, and for subjects aged 65 or older, the reduction values were –17.5 for E-BPO and –10.4 for vehicle (Figure 2).

Safety and tolerability. Safety results for the subjects younger than 65 and 65 or older were similar (Table 1). In both trials, roughly 20 percent of subjects treated with E-BPO cream, 5%, had treatment-emergent AEs (TEAEs), and approximately two percent of subjects discontinued due to AEs. The most commonly reported TEAEs involved the application site and were mild or moderate in severity.

Local tolerability was assessed by the investigator at each study visit. Subjects in both age groups reported improved cutaneous tolerability (dryness, scaling, itching, and burning/stinging) at Week 12 compared to baseline (Figure 3). Similar results were seen in the E-BPO and vehicle groups. For all treatment groups at both ages, the mean tolerability stayed below 1 (on a 0 to 3 scale) and was not statistically different.

Discussion

This post-hoc analysis of pooled results from the two Phase III trials of E-BPO cream, 5%, demonstrated efficacy versus vehicle in improving IGA success and decreasing inflammatory lesions in subjects younger than 65 and 65 or older. A higher percentage of subjects over 65 achieved IGA success with E-BPO compared to those under 65 (60% vs. 48.3%), with similar results for vehicle (28.1% vs. 24.5%). The absolute reduction in inflammatory nodules was similar for E-BPO (–17.5 vs. –19.6) and vehicle (–10.4 vs. –11.2). Safety and cutaneous tolerability were consistent between the two groups evaluated in this study and the Phase III results.¹²

Receptor activation by triggers leads to the physical signs of rosacea and can cause increased sensitivity in rosacea skin.¹⁴ Burning, stinging, and dryness are secondary signs of disease experienced by many with rosacea,¹⁵ which can negatively impact quality of life.^16–18 Avoiding products that can irritate the already sensitive skin is important for these patients. Increased age also leads to sensitive skin, regardless of the presence of a dermatologic disease. Structural and physiological changes due to age result in physiological changes to the skin, including reduced skin integrity and degenerative changes,¹⁰ which add to the challenges of treating rosacea in this population. 

The tolerability of E-BPO cream, 5%, was similar to that reported for vehicle cream in both age groups. Application-site reactions occurred in less than five percent of older and younger subjects in the present analysis. However, unencapsulated BPO products have historically been poorly tolerated. In a small-scale study that included 26 subjects with rosacea treated with the combination of BPO and clindamycin, 15.4 percent reported application-site burning with active treatment versus zero percent for vehicle.¹⁹ Results from a retrospective cohort study using medical and pharmacy claims from the MarketScan Commercial Claims and Encounters database and the Medicare Supplemental database from January 1, 2008, to December 31, 2013, also indicated poor tolerability of BPO in subjects with rosacea. Overall, 22.5 percent of 1,084 subjects treated with BPO had AEs versus 12.9 percent of 10,721 subjects treated with azelaic acid and 12.3 percent of 35,868 subjects who received metronidazole.²⁰ Similarly, results from a large-scale clinical trial of subjects with acne indicated that unencapsulated BPO, 5%, was associated with application-site irritation in 12.3 percent of subjects and application-site erythema in 10.8 percent.²¹ In another study of 360 subjects with acne, more subjects who received unencapsulated BPO experienced dryness, itching, burning/stinging, and peeling than those in the vehicle group from Week 1 to Week 12.²²

Limitations. This post-hoc analysis shares the same limitations as the Phase III trials: E-BPO was not compared to unencapsulated BPO, and the length of treatment was only 12 weeks, which limits the understanding of the durability and tolerability of E-BPO in these age groups. A third limitation is the smaller group size in the ≥65-year-old population compared to the <65 population. 

Conclusion

This combined analysis of results from the two Phase III, randomized, double-blind controlled studies of E-BPO cream, 5%, showed results were consistent in both age groups and indicated that E-BPO was efficacious, safe, and well tolerated in both those over and under 65 years of age with papulopustular rosacea, demonstrating that E-BPO cream, 5%, is a viable option in older patients with sensitive skin.

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