20201210_DelRosso_Phase 3 efficacy and safety EFFICACY AND SAFETY OF MICROENCAPSULATED BENZOYL PEROXIDE 3% AND MICROENCAPSULATED TRETINOIN 0.1% (E-BPO/E-ATRA) IN ACNE VULGARIS: RESULTS FROM TWO RANDOMIZED CONTROLLED CLINICAL TRIALS Del Rosso J1, Sugarman J2, Levy-Hacham O3, Mizrahi R3 1. JDR Research, Las Vegas, NV. 2. University of California - San Francisco, San Francisco, CA. 3. Sol-Gel Technologies Ltd, Ness Ziona, Israel. METHODS Design RESULTS Patients • In Study 65-04, 281 patients were randomized to E-BPO/E-ATRA and 143 to Vehicle; 249 (88.6%) and 131 (91.6%) completed the trial. In Study 65-05, 290 patients were randomized to E-BPO/E-ATRA and 144 to Vehicle; 242 (83.4%) and 131 (91.6%) completed the trial. Baseline patient characteristics were balanced across groups in both trials (Table 1) Safety • Nearly all AEs were mild or moderate in severity. • A total of 18 subjects discontinued from Studies 65-04 and 65-05 due to a treatment-emergent AE: 18 (2%) in E-BPO/E-ATRA and 0 in Vehicle. • No treatment-related serious AEs (SAEs) were identified in either study. • 2 subjects reported SAEs in Study 65-05; (1) E-BPO/E-ATRA subject reported depression. • Prospective evaluations indicated very good skin tolerability for E-BPO/E-ATRA (Table 2). CONCLUSIONS E-BPO/E-ATRA successfully met all primary efficacy endpoints demonstrating statistically significant improvements over Vehicle. There were no treatment-related SAEs. E-BPO/E-ATRA was well tolerated, with results similar to Vehicle at 12 weeks. Efficacy IGA • In each of the two trials, E-BPO/E-ATRA was significantly superior to Vehicle for the percentage of patients achieving IGA success (Figures 2 and 3). Lesions • Results from both trials indicated that E-BPO/E-ATRA was significantly superior to Vehicle for decreasing the number of inflammatory lesions (Figure 4) and non-inflammatory lesions (Figure 5) from baseline at week 12. Endpoints Co-Primary Efficacy Endpoints • Proportion of patients who achieved a two-grade reduction from baseline and grade 0 (Clear) or grade 1 (Almost Clear) at Week 12 on a 5-point IGA scale. • Absolute change in inflammatory lesion counts from baseline at Week 12. • Absolute change in non-inflammatory lesion counts from baseline at Week 12. Safety Endpoints • Safety was assessed through cutaneous safety assessment, local tolerability assessment, adverse event (AE) reporting, physical examination, and vital signs. Data Analysis • All efficacy analyses were carried out using the intent-to-treat population. Safety analyses were carried out using the safety population. Figure 1. Study design INTRODUCTION • Benzoyl peroxide (BPO) is recommended for treatment of acne of all severities.1 It is bactericidal against C. acnes on the skin and within hair follicles with no risk for development of resistance,1,2 and it also has sebostatic and keratolytic effects.3 • BPO is widely used as a single agent in many different vehicles,4 and in combination with other medications.3,5 Multiple analyses have indicated that the efficacy of BPO is enhanced when used in combination with topical retinoids, such as tretinoin (ATRA).6,7 However, BPO causes degradation of tretinoin, reducing its effectiveness.8 • BPO and ATRA can also result in significant skin irritation when applied to the face of patients with acne,9,10 and there is some evidence suggesting that their irritative effects may be additive.11 • E-BPO/E-ATRA is an investigational, antibiotic-free, fixed-dose combination of microencapsulated tretinoin 0.1% and microencapsulated BPO 3% cream. The use of Sol-Gel’s microencapsulation technology platform provides a stable combination of BPO and ATRA, extending drug delivery time, and reducing potential irritation caused by direct application of the drugs to the skin. • Two multicenter, randomized, double-blind, parallel-group vehicle-controlled trials (SGT-65-04 and SGT-65-05) carried out at 63 sites across the United States (Figure 1). ACKNOWLEDGMENTS: The authors gratefully acknowledge the editorial and data analysis contributions of Robert Rhoades, PhDand Thomas Prunty, CMPP of AraMed Strategies whose assistance was funded by Sol-Gel Technologies, Ltd. REFERENCES: 1. Zaenglein AL, et al. J Am Acad Dermatol. 2016;74:945-973 e933; 2. Walsh TR, et al. Lancet Infect Dis.2016;16:e23-33; 3. Matin T, Goodman MB. 2019. Available from http://www.ncbi.nlm.nih.gov/books/ NBK537220/; 4. Kawashima M, et al. JDermatol. 2017;44:1212-1218; 5. Kircik LH. J Drugs Dermatol. 2013;12:s73-76; 6. Sagransky M, et al. Expert Opin Pharmacother. 2009;10:2555-2562; 7. Fakhouri T, et al. J Drugs Dermatol. 2009;8:657-661; 8. Martin B, et al. Br J Dermatol. 1998;139 (Suppl 52):8-11; 9. Patel VB, et al. Drug Dev Ind Pharm. 2001;27:863-869; 10. Quigley JW, Bucks DA. J Am Acad Dermatol. 1998;38:S5-10; 11. Brand B, et al. J Am Acad Dermatol. 2003;49 (3 Suppl):S227-232. Table 1. Baseline patient characteristics Study 65-04 Study 65-05 E-BPO/E-ATRA (n=281) Vehicle (n=143) E-BPO/E-ATRA (n=290) Vehicle (n=144) 20.9 (8.48) 18.0 (11-67) 106 (37.7%) 175 (62.3%) 102 (36.3%) 178 (63.3%) 1 (0.4%) 251 (89.3%) 30 (10.7%) 33.5 (14.62) 28.0 (20-97) 48.6 (20.24) 42.0 (30-148) 21.4 (8.62) 18.0 (10-57) 20.1 (6.96) 18.0 (10-51) 117 (40.3%) 173 (59.7%) 85 (29.3%) 204 (70.3%) 1 (0.3%) 262 (90.3%) 28 (9.7%) 28.2 (8.70) 25.0 (20-62) 44.6 (18.03) 39.0 (23-149) 20.3 (6.67) 18.5 (9-42) 60 (42.0%) 83 (58.0%) 67 (46.5%) 77 (53.5%) 44 (30.8%) 98 (68.5%) 1 (0.7%) 56 (38.9%) 87 (60.4%) 1 (0.7%) 132 (92.3%) 11 (7.7%) 133 (93.0%) 10 (7.0%) 33.5 (14.69) 78 0 (20-90) 27.5 (8.52) 75 (20-75) 47.1 (19.97) 41.0 (30-140) 44.9 (18.82) 38.0 (30-123) Age, years Mean (SD) Median (range Sex, n (%) Male Female Ethnicity, n (%) Hispanic/Latino Not Hispanic or Latino Unknown/Not Reported IGA severity Moderate Severe Inflammatory lesion count Mean (SD) Median (range) Non-inflammatory lesion count Mean (SD) Median (range) Number of sites 32 31 • Age ≥ 9 years • ≥20 to ≤100 Inflammatory lesions • ≥30 to ≤150 Non-inflammatory lesions • IGA grade 3 (Moderate) or grade 4 (Severe) • Cysts/nodules ≤ 2 In cl us io n cr ite ri a Randomization Baseline 2 4 Weeks 8 12 12 weeks of treatment 63 Total Sites Study 65 04: 424 Study 65-05: 434 QD, Self-applied Vehicle cream E-BPO/E-ATRA cream (3% E-BPO, 0.1% E-ATRA) 2:1 E-ATRA, microencapsulated tretinoin; E-BPO, microencapsulated benzoyl peroxide; IGA, Investigator’s Global Assessment; QD, once daily. To interact with and explore these data more intimately, please click here: https://www.solgelposters.com 38.5% 11.5% 0% 10% 20% 30% 40% P er ce nt o f s ub je ct s ac hi ev in gI G A su cc es s at w ee k 12 E-BPO/E-ATRA(n=281) E-BPO/E-ATRA(n=290)Vehicle(n=143) 25.4% 14.7% 0% 10% 20% 30% 40% Study 65-05 Vehicle(n=144) Figure 2. Success in IGA at week 12 P<0.001 Study 65-04 Erythema Scaling Pigmentation Dryness Itching Burning Stinging Study 65-05 Erythema Scaling Pigmentation Dryness Itching Burning Stinging 62.0% 78.8% 61.6% 71.2% 86.0% 92.4% 92.4% 57.8% 83.2% 70.5% 73.0% 88.1% 91.4% 96.7% 33.2% 19.6% 32.8% 22.0% 12.8% 6.0% 7.2% 32.8% 13.1% 21.7% 22.5% 9.4% 5.7% 3.3% 4.4% 1.6% 4.8% 6.0% 1.2% 1.6% 0.4% 9.4% 3.7% 7.8% 4.5% 2.5% 2.9% 0.0% 0.4% 0 0.8% 0.8% 0 0 0 0 0 0 0 0 0 0 65.9% 83.3% 67.4% 78.0% 89.4% 95.5% 94.7% 64.4% 89.4% 70.5% 84.1% 87.9% 96.2% 99.2% 25.8% 15.9% 27.3% 18.9% 7.6% 3.8% 3.8% 28.0% 9.8% 25.8% 14.4% 9.8% 30% 0.0% 8.3% 0.8% 5.3% 3.0% 3.0% 0.8% 1.5% 7.6% 0.8% 3.8% 1.5% 2.3% 0.8% 0.8% 0 0 0 0 0 0 0 0 0 0 0 0 0 0 None Mi l d Moderate Severe None Mi l d Moderate Severe E-BPO/E-ATRA (n=274) % Vehicle (n=139) % Table 2. Skin tolerability for E-BPO/E-ATRA and vehicle -21.6 -14.8 -25 -15 -5 M ea n re du ct io n in in fla m m at or y le si on co un t fr om b as el in e at W ee k1 2 Vehicle (n=143) Study 65-04 E-BPO/E-ATRA(n=281) -14.1 -16.2 P=0.018 -25 -15 -5 Study 65-05 E-BPO/E-ATRA(n=290) Vehicle (n=144) Figure 4. Reduction in inflammatory lesion count at week 12 2x trials / 12 weeks / 63 sites acrossUS -29.7 -19.8 -35 -25 -15 -5 M ea n re du ct io n in n on -in fla m m at or y le si on c ou nt fr om b as el in e at W ee k1 2 Study 65-04 E-BPO/E-ATRA(n=281) Vehicle (n=143) -24.2 -17.4 -35 -25 -15 -5 Study 65-05 E-BPO/E-ATRA(n=290) Vehicle (n=144) Figure 5. Reduction in non-inflammatory lesion count at week 12 Figure 3. Improvement in IGA and reduction in lesion count with E-BPO/E-ATRA Subject: Age: 18 years old. Gender: Female. Although this patient did not achieve success as defined by the trial protocol, this represents a real-world clinical success and the authors note the improvement is unusual for topical monotherapy Baseline Week 12 Subject: Age: 19 years old. Gender: Male. Race: Hispanic or Latino. Baseline Week 12 Lesions count 50 4 Study 65-04 P=0.017 P<0.001 P<0.001 P<0.001 http://www.ncbi.nlm.nih.gov/books/ EFFICACY AND SAFETY OF MICROENCAPSULATED BENZOYL PEROXIDE 3% AND MICROENCAPSULATED TRETINOIN 0.1% (E-BPO/E-ATRA) IN ACNE VULGARIS: RESULTS FROM TWO RANDOMIZED CONTROLLED CLINICAL TRIALS