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Long-term Efficacy and Safety of Microencapsulated Benzoyl Peroxide Cream, 5%, in Rosacea: Results From an Extension of Two Phase III, Vehicle-controlled Trials

J Clin Aesthet Dermatol. 2023;16(8):27–33.

by William P. Werschler, MD; Jeffrey Sugarman, MD, PhD; Neal Bhatia, MD; Hilary Baldwin, MD;
Lawrence J. Green, MD; Ori Nov, PhD; Vered Ram, MChem; Ofra Levy-Hacham, PhD; and Linda Stein-Gold, MD

Dr. Werschler is with Spokane Dermatology Clinic and Werschler Aesthetics in Spokane, Washington. Dr. Sugarman is with the University of California San Francisco School of Medicine

in San Francisco, California. Dr. Bhatia is with Therapeutics Clinical Research in San Diego, California. Dr. Baldwin is with the Acne Treatment and Research Center in Brooklyn, New York, and Robert Wood Johnson Medical Center in New Brunswick, New Jersey. Dr. Green is with the George Washington University School of Medicine in Washington, DC. Dr. Nov, Mr. Ram, and Dr.  Levy-Hacham are with Sol-Gel Technologies Ltd in Ness Ziona, Israel. Dr. Stein Gold is with Henry Ford Health in Detroit, Michigan.

FUNDING: Funding was provided by Sol-Gel Technologies Ltd. Additionally, medical writing and editorial support was provided by Simpson Healthcare and funded by Galderma.

DISCLOSURES: Dr. Sugarman is a consultant and speaker for Arcutis, Pfizer, Regeneron, Sanofi, and Incyte; a consultant for Bausch Heath and Sol-Gel; and a medical safety monitor for Galderma clinical research trials and Dermavant clinical studies. Dr. Bhatia is an advisor, consultant, investigator, and speaker for Galderma. Dr. Baldwin is a speaker at Galderma, Bausch Health, Almirall, EPI, and Sun Pharma. Dr. Green is a speaker, consultant, investigator for Galderma and Ortho Dermatologics. Mr. Ram reports no conflict of interest. Dr. Nov is an employee of Sol-Gel Technologies. Dr. Stein Gold is an investigator, speaker, and advisor for Galderma, Ortho Derm, Sun Pharma, and Almirall. Dr. Werschler, Mr. Ram, and Dr. Levy-Hacham report no conflict of interest. 

ABSTRACT: Obecjtive. We sought to assess the long-term safety and tolerability of microencapsulated benzoyl peroxide cream, 5% (E-BPO cream, 5%), in subjects with rosacea. Efficacy and tolerability have been previously demonstrated in two 12-week, randomized, double-blind, vehicle-controlled Phase III trials.

Methods. In this open-label extension study (NCT03564145; clinicaltrials.gov), all subjects from the initial placebo-controlled Phase III trials could receive E-BPO cream, 5%, for up to an additional 40 weeks, up to a total of 52 weeks of E-BPO cream, 5%, exposure. If a subject was assessed at study visits as “clear” or “almost clear” using the 5-point Investigator Global Assessment (IGA) scale (IGA 0 or 1), E-BPO cream, 5%, was not dispensed. If a subject was assessed as “mild to severe” (IGA 2+), E-BPO cream, 5%, was applied daily until they reached “clear” or “almost clear.”

Results. The safety and tolerability profile for E-BPO cream, 5%, was similar to that reported in the Phase III studies. Five subjects (0.9%) discontinued study drug due to treatment-related adverse events, and 17 subjects (3.2%) experienced an adverse event considered related to study drug. IGA success after 40 weeks of active treatment was 66.5 percent for subjects continuing from the Phase III vehicle group (n=172) and 67.6 percent for subjects who continued Phase III E-BPO cream, 5% (n=363). The study ended early in accordance with the protocol.

Limitations. Safety and tolerability of E-BPO were not compared with those of unencapsulated BPO.

Conclusion. E-BPO cream, 5%, showed a favorable safety and tolerability profile during this 40-week, open-label extension study.

Keywords: Rosacea, microencapsulation, benzoyl peroxide, topicals, papulopustular rosacea, BPO, erythema

It has been estimated that of the approximately 16 million people in the United States with rosacea,1 one-fourth experience papulopustular disease.2 Rosacea is a chronic, relapsing disease3,4 associated with a high patient burden.5–10 A wide range of topical and systemic therapies have been employed to treat rosacea,11–13 but efficacy and tolerability concerns have lowered patient satisfaction.14 These concerns have prompted the exploration of new alternatives for rosacea treatment. Unencapsulated benzoyl peroxide (BPO) has been used as monotherapy or as combination therapy in patients with rosacea and has demonstrated efficacy in treating this condition; however, it is poorly tolerated by patients, who complain of local skin irritation, such as stinging, burning, and itching.15–21

The poor tolerability and variable efficacy of unencapsulated BPO in individuals with rosacea may be related to transient high concentrations on the skin and a short residence time after the drug is applied, respectively.22–24 These limitations have been addressed by the development of a BPO formulation designed to control the release of the drug through microencapsulation. This BPO formulation, microencapsulated BPO cream, 5% (E-BPO cream, 5%), was developed using the Sol-Gel microencapsulation process. The result is a silica-based capsule that provides gradual release of BPO to the skin with the potential to improve both the tolerability and efficacy versus the conventional bolus delivery of the drug.23–25 The efficacy, safety, and tolerability of E-BPO cream, 5%, have been studied in two identical, parallel, 12-week, randomized, double-blind Phase III trials. These trials demonstrated significant superiority of this E-BPO preparation over vehicle in the percentage of subjects achieving success (“clear” or “almost clear”) according to the Investigator Global Assessment (IGA) scale (IGA score of 0 or 1, respectively) and in the percentage of subjects experiencing a reduction in the number of inflammatory lesions.26 

 Due to the chronic nature of rosacea, it is important to understand the long-term safety and tolerability of its treatment. Despite this, there are few studies of more than six months and no long-term studies of any BPO formulations in rosacea.27–30

This report summarizes results from the 40-week extension of the two 12-week Phase III trials of E-BPO cream, 5%, in subjects with moderate to severe papulopustular rosacea. The primary objective was to evaluate the long-term safety and tolerability, but long-term efficacy was also captured.

Methods

Subjects. Subjects enrolled in this long-term extension study met the following inclusion criteria when entering the 12-week Phase III trials. They had to be at least 18 years of age with a clinical diagnosis of moderate to severe rosacea and a baseline IGA score of 3 (“moderate”) or 4 (“severe”) on a severity scale of 0 to 4.18 Subjects were required to have a minimum of 15 and a maximum of 70 total inflammatory lesions (papules and/or pustules), including those present on the nose, and no more than two nodules (defined as a papule or pustule >5mm in diameter) at baseline. Sexually active women of childbearing potential were required to use an accepted method of birth control. 

Study design and treatment. All eligible subjects in this single-arm, long-term extension study were assigned to treatment with E-BPO cream, 5%. Additionally, all the subjects enrolled in the 12-week Phase III trials were eligible to enroll in this extension study, including the subjects assigned to the vehicle arm. The subjects were followed for up to 40 weeks in the extension study for a total of up to 52 weeks, including the time in the 12-week Phase III trials. The investigators evaluated the subjects’ IGA scores at 4-week intervals throughout the extension study. If a patient was assessed as “clear” (IGA 0) or “almost clear” (IGA 1), they were instructed not to apply E-BPO cream, 5%, and it was not dispensed. If a patient was assessed as “mild,” “moderate,” or “severe” (IGA 2–4), E-BPO cream, 5%, was dispensed, and the patient was instructed to apply the product daily until the following assessment. 

This study was conducted in compliance with the United States Food and Drug Administration (FDA) regulations, the ethical principles of the Declaration of Helsinki, and the current International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. The protocol, informed consent documents, information provided to the subjects, recruitment advertisements, and amendments to these items had institutional review board approval before their use in the study. Voluntary informed consent was given by every subject before the initiation of any study-related procedure. 

Assessments. Investigator Global Assessment. At each extension study visit (baseline and Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and end of study), subjects were assessed for rosacea severity using the 5-point IGA scale. The scale was used to measure the number of papules and pustules and erythema severity ranging from 0 (skin clear of inflammatory papules or pustules) to 4 (numerous small and/or large papules or pustules and severe, bright to deep red erythema).

Relapse and retreatment. Relapse was defined as a subject no longer having an IGA score of “clear” (0) or “almost clear” (1) after a previous visit IGA score of clear or almost clear. The number of retreatments was defined as the number of times a subject was instructed to restart the E-BPO cream, 5%, due to an IGA score of 2 or more. For subjects previously treated with the vehicle in the 12-week Phase III trials, this was the number of retreatments after the initial treatment in the current extension. For subjects previously treated with E-BPO cream, 5%, in the 12-week Phase III trials, this was the number of treatments in the extension following the cessation of the treatment at the end of the Phase III trials. 

The number of treatment-free days until the first retreatment (relapse) was calculated for each subject. The number of treatment-free days until first retreatment was defined as the number of days between an initial IGA score of “clear” or “almost clear” while the subject received E-BPO cream, 5%, until an IGA score of “mild,” “moderate,” or “severe” (IGA 2–4) was reached. For subjects previously treated with vehicle in the Phase III trials, the number of treatment-free days was the number of days between the end of their first treatment of E-BPO cream, 5%, in the extension (when the subject had an IGA score of “clear” or “almost clear”) and the start of the next treatment in the extension (when the subject had an IGA score of 2+, indicating they should dose). For subjects previously treated with E-BPO cream, 5%, in the Phase III trials, the number of treatment-free days was the number of days between the end of the treatment that began in the 12-week Phase III trials (when the subject had an IGA score of 0 [“clear”] or 1 [“almost clear”]) and the start of the next treatment in the extension (when the subject had an IGA score of 2+, indicating they should dose). The maximum number of retreatments was four.

Erythema and telangiectasia. Erythema was evaluated at baseline and at each study visit. It was scored on a scale of 0 (no visible erythema) to 3 (bright to deep red, either centrofacial or generalized to the whole face). Telangiectasia was also evaluated at baseline and at each study visit. It was also rated on a scale of 0 (no telangiectasia) to 3 (numerous and prominent fine and/or coarse vessels involving more than 30% of the facial area).

Safety and tolerability. At each visit, the following safety measures were recorded: any adverse events (AEs), including local and systemic events; the investigators’ cutaneous safety assessment ratings (dryness and scaling); the subjects’ local tolerability assessment ratings (itching and burning/stinging) on a scale ranging from 0 (none) to 3 (severe); physical examinations; and vital signs.

Data analysis. All analyses were performed using the safety population, which included all subjects who received at least one confirmed dose of E-BPO cream, 5%, and had at least one assessment. The results for all measures are summarized with descriptive statistics, and inferential analyses were not carried out. The confidence interval (CI) for the median time to relapse was calculated using the Kaplan–Meier method. 

Results

Study termination. On October 31, 2019, the sponsor terminated the study early in accordance with the study protocol. Per the protocol, 300 or more subjects for 28 weeks and 100 subjects for 52 weeks had to be followed in order to complete an adequate assessment of long-term safety as specified in the ICH E1A guidance. At study termination, 478 (87.4%) had been followed for 28 weeks, 395 (72.2%) had been followed for 40 weeks, and 209 (57.6%) had been followed for 52 weeks of once-daily E-BPO cream, 5%, treatment. The analysis visits at Week 28 in this extension study corresponded to treatment Week 28 for those treated with vehicle in the Phase III trials and treatment Week 16 for those treated with E-BPO cream, 5%, because that group had already received 12 weeks of treatment in the double-blind studies. The analysis visit at Week 52 in the extension study was unavailable to those treated with the vehicle in the Phase III trials because treatment was not provided beyond 40 weeks. For those treated with E-BPO cream, 5%, in the double-blind studies, the analysis visits at Week 52 corresponded to Week 40 of treatment in this extension study because that group had already received 12 weeks of treatment. 

Patient disposition and demographics. The disposition of subjects in the current extension study is summarized in Figure 1. A total of 547 subjects were enrolled, including 363 previously treated with E-BPO cream, 5%, and 184 previously treated with vehicle. According to an ad hoc analysis, 85.7 percent of the subjects completed the study, including those who discontinued early as completers due to the sponsor’s decision to terminate the study early once the minimum number of subjects needed for the long-term safety analysis was reached. The most common reason for discontinuation, besides the sponsor-determined termination, was withdrawal by the subject. The Phase III baseline demographics and clinical characteristics of the subjects who continued to the extension are summarized in Table 1.

Adherence to treatment. Overall, most subjects adhered to the study visits and dosing, and a review of the patient reports did not suggest any trends in misuse or overuse of E-BPO cream, 5%, during the study. Subjects treated with E-BPO cream, 5%, during the 12-week Phase III trials missed a mean of 6.3 noninstructed applications (standard deviation [SD]=14.7) during the current extension versus 4.3 (SD=11.4) for the subjects who received the vehicle during the 12-week Phase III trials. These missed doses were in addition to the doses omitted due to IGA success. Subjects in the E-BPO cream, 5%, group (n=363) applied the drug an average of 218.5 times over 297.4 days. The respective values for subjects in the vehicle group (n=172) in the 12-week Phase III trials were 139.6 times over 190.8 days.

Cutaneous safety and tolerability. These assessments showed good, long-term cutaneous safety and tolerability of E-BPO cream, 5%, for up to 40 weeks or 52 weeks of treatment. For each cutaneous safety and tolerability parameter, there was a small increase in the percentage of subjects with no or mild signs and symptoms over 52 weeks. Analysis of Grade 3 (severe) cutaneous safety and/or tolerability ratings revealed two subjects with dryness, one with itching, and one with burning/stinging at Week 40 (n=387); there were no reports of Grade 3 ratings at Week 52 (n=209) (Figure 2).

Adverse events. A total of 185 subjects (34.6%) reported at least one treatment-emergent AE (TEAE), and a total of 367 individual TEAEs were reported overall (Table 2). Most TEAEs were mild or moderate in severity, and 17 subjects (3.2%) had AEs that were considered by the investigator to be treatment-related. Of the eight subjects (1.5%) who experienced severe TEAEs, two of the TEAEs (0.4%) were considered related and six (1.1%) were considered not related to study treatment. Events (all severity) considered by the investigator to be related to study drug were reported for 17 subjects (3.2%). No deaths were reported in the study. Ten subjects (1.9%) experienced serious AEs (tonsil cancer, arrhythmia, bilateral mastectomy, squamous cell carcinoma, rib fracture, migraine, atrial fibrillation, nephrolithiasis, embolic stroke, and pulmonary embolism), none of which were related to study treatment. Five subjects discontinued the E-BPO cream, 5%, due to TEAEs, and of these, four (0.7%) discontinued the study. 

Investigator global assessment success. IGA success was defined as achieving a “clear” (IGA 0) or “almost clear” (IGA 1) score. At Week 40 or the early-termination visit, 67.2 percent of subjects had achieved success. This success was achieved by 67.6 percent of the subjects in the E-BPO cream, 5%, group and 66.5 percent of those in the vehicle group in the double-blind, 12-week studies who continued into the extension study (Figure 3). These percentages are based on the remaining subjects at the study termination. Here, 478 (87.4%) had been followed for 28 weeks, 395 (72.2%) had been followed for 40 weeks, and 209 (57.6%) had been followed for 52 weeks of the once-daily E-BPO cream, 5%, treatment.

Retreatment. Because they had an IGA assessment of “clear” or “almost clear,” 445 subjects were instructed not to dose. The E-BPO cream, 5%, was not dispensed until an IGA score of “mild” (IGA 2), “moderate” (IGA 3), or “severe” (IGA 4) rosacea was recorded at a subsequent visit. A mean of 1.4 retreatments and a median of 1.0 retreatment were reported for all subjects enrolled in the extension. The number of retreatments was defined as the number of times a subject’s IGA score went from “clear” or “almost clear” to “mild,” “moderate,” or “severe” after the subject was “clear” or “almost clear” while receiving E-BPO cream, 5%. The median number of treatment-free days in the extension until the first retreatment (when a subject received an assessment of “mild,” “moderate,” or “severe”) was 58 (95% CI, 57.0–64.0). 

Erythema and telangiectasia. Facial erythema generally improved during the study (Figure 4A). There was an increase from baseline to Week 40 in the percentage of subjects with no or mild erythema (10.1% to 76.2%). Improvement in facial erythema was noted at each postbaseline evaluation, with the percentage of subjects experiencing no or mild erythema ranging from 55.8 percent to 81.3 percent from Weeks 4 to 52. The proportion of subjects with no or mild telangiectasia at baseline was 58.2 percent and increased to 80.1 percent by Week 40 and to 84.7 percent in subjects enrolled for the full 52 weeks (Figure 4B). No clinically relevant improvement in telangiectasia severity occurred in the safety population.

Vital signs and physical examinations. There were no clinically meaningful changes from baseline to any postbaseline evaluation, and there were no meaningful differences in vital signs, including temperature, respiratory rate, systolic and diastolic blood pressure, and heart rate. In addition, no clinically significant findings from physical examinations were reported.

Discussion

Results from this long-term assessment show that the safety and tolerability profile for E-BPO cream, 5%, was similar to that reported in the 12-week vehicle-controlled trials.26 The mean tolerability parameters of both stayed below 1 on a scale of 1 to 3 and were not statistically different. Ten subjects experienced serious AEs; none were considered related to E-BPO cream, 5%, and five subjects discontinued the study because of AEs. In addition, for each cutaneous safety and tolerability parameter, there was a slight increase in the percentage of subjects with no signs or symptoms throughout the current extension. The present extension study results show that this treatment is an effective and well-tolerated long-term treatment for subjects with rosacea.

Previous results from a small study that included 26 subjects with rosacea treated with a combination of unencapsulated BPO and clindamycin showed that application site burning occurred in 15.4 percent of subjects who received BPO versus none for those receiving vehicle.31 Similarly, a retrospective claims analysis showed that 22.5 percent of 1,084 subjects with rosacea treated with BPO had AEs versus 12.9 percent of 10,721 subjects treated with azelaic acid and 12.3 percent of 35,868 who received metronidazole.17 In the Phase III studies of E-BPO, nine participants treated with E-BPO (1.8%) discontinued compared with one subject in the vehicle group (0.4%). There were no statistically significant differences in mean tolerability parameters between E-BPO and vehicle.26

Evaluation of the long-term efficacy of E-BPO cream, 5%, was not an objective of this long-term extension. Nevertheless, the IGA scoring results demonstrate the sustained efficacy of this microencapsulated BPO preparation. For all subjects entered in the extension, regardless of their response to active treatment or vehicle during the 12-week Phase III trials, IGA success was 67.2 percent, and results for the two groups were similar. Results from this extension study also show improvements in erythema, with the percentage of subjects reporting no or mild erythema increasing from baseline to Week 40. In the 209 subjects who were followed for 52 weeks, 81.3 percent had no or mild erythema. In addition, the percentage of subjects with severe erythema decreased from 14.4 percent to 1.8 percent through 40 weeks and was at 0.5 percent at Week 52. 

Most of the subjects enrolled in the trial required one or more retreatments with E-BPO cream, 5%, during the 40-week extension, but the median number of retreatments was only 1.0 (mean, 1.4). The requirement for retreatment is common and expected due to the natural waxing and waning of rosacea severity12,28,32 and the potential for subjects to be exposed to triggers throughout long-term follow-up.33,34 The median time to first relapse in this extension study for all subjects was 58 days. The results also support the global ROSacea COnsensus 2019 panel recommendation that the goal of treatment for subjects with rosacea should be complete clearance.11

One limitation of this safety extension study, as with both of the 12-week Phase III trials, was that E-BPO was not compared with unencapsulated BPO. The poor tolerability of unencapsulated BPO in rosacea has previously been reported.9,35

Conclusion 

The results from this long-term extension of two 12-week Phase III, randomized, controlled trials demonstrate progressive clinical improvement as reflected by the percentage of subjects who achieved IGA success, a reduction in erythema, and good cutaneous safety and tolerability with E-BPO cream, 5%, applied for up to 52 weeks in subjects with rosacea. This 40-week safety extension study addresses the limitations of the 12-week Phase III trials, whose short duration was not reflective of clinical treatment of a chronic disease.

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