SKIN September 2021 Volume 5 Issue 5 Copyright 2021 The National Society for Cutaneous Medicine 524 RESEARCH LETTER Brodalumab in The Treatment of Moderate-To-Severe Psoriasis in Patients Refractory to Anti-Interleukin-17A Therapies: Evaluation of Secondary Endpoints Grace Kimmel, MD1, Margot Chima, MD1, Hee Jin Kim, MD1, Jennifer Bares, MD1, Alex Yaroshinsky, PhD2, Giselle Singer, BS1, Soo Jung Kim, MD3, Jerry Bagel, MD4, Mark Lebwohl, MD1 1 Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 2 Ziropa, Inc, Sunnyvale, CA 3 Department of Dermatology, Baylor College of Medicine, Houston, TX 4 Psoriasis Treatment Center of Central New Jersey, East Windsor, NJ Brodalumab is an interleukin-17 receptor A antagonist approved for the treatment of moderate-to-severe plaque psoriasis. In our previous publication, we reported that the majority of patients who had previously failed treatment with an anti-IL-17A agent had significant improvement with brodalumab. As-observed (AO) results showed Psoriasis Area and Severity Index (PASI)-75, PASI-90, and PASI-100 scores in 76%, 50%, and 32% of patients, respectively, at week 16. Using a non- responder imputation (NRI), PASI-75, PASI- 90, and PASI-100 scores were seen in 67%, 44%, and 28% of patients1. ABSTRACT Background: Brodalumab is an interleukin-17 receptor A antagonist approved for the treatment of moderate-to-severe plaque psoriasis. Our prior publication reported significant disease improvement with brodalumab in psoriasis patients who had previously failed treatment with an anti-IL-17A agent. Methods: We conducted an Institutional Review Board (IRB)-approved open-label study of a total of 39 subjects enrolled at 3 sites with moderate-to-severe psoriasis. All patients previously failed treatment with an IL-17A agent. Subjects received brodalumab 210 mg via subcutaneous injection at weeks 0, 1, and 2, followed by 210 mg every 2 weeks, up to week 16. Subjects were evaluated monthly for improvement in PASI and sPGA. Results: Of the baseline comorbidities assessed, the only statistically significant difference between responders and non-responders was the presence of higher weight/BMI in non-responders in the AO dataset; this trend disappeared in the NRI dataset. Of the patients that dropped out of the trial early, 3 of the 5 had PASI improvements of >60%. A rapid onset to disease improvement was seen in the trial. Conclusion: These results indicate that brodalumab may be a good treatment choice for psoriasis patients, including those with severe disease and/or underlying comorbidities. SKIN September 2021 Volume 5 Issue 5 Copyright 2021 The National Society for Cutaneous Medicine 525 Although the majority of these patients improved on brodalumab treatment, we sought to investigate factors that differed between the patients who had treatment success with brodalumab and those who did not, as well as other secondary endpoints. An Institutional Review Board (IRB)- approved open-label study was conducted on a total of 39 subjects enrolled at 3 sites with moderate-to-severe psoriasis. All investigators were Risk Evaluation and Mitigation (REMS) certified. Subjects received brodalumab 210 mg via subcutaneous injection of prefilled syringes at weeks 0, 1, and 2, followed by 210 mg every 2 weeks, up to week 16. All patients previously failed treatment with an IL-17A agent, defined as treatment with either secukinumab or ixekizumab for > 3 months without achieving PASI-75 response, or a 50% loss of original improvement. Endpoints of this extension study included evaluation of baseline characteristics and comorbidities of responders vs non- responders, including weight, body mass index (BMI), smoking status, baseline PASI and static Physician’s Global Assessment (sPGA) scores, and body sites involved. Other endpoints included the extent of improvement in non-responders, characterization of the patients who discontinued early from the trial, time to improvement in PASI scores, and the proportion of patients achieving a >2-point reduction in sPGA at Week 16. For the purposes of these endpoints, “responders” were defined as patients who met sPGA 0 or 1 (clear or almost clear) or PASI-75 at week 16. Of the baseline characteristics (tables 1, 2), the only statistically significant difference between responders and non-responders was the presence of higher weight/BMI in non-responders, seen in the AO dataset. This trend disappears in the NRI dataset. This is consistent with the known efficacy of brodalumab for obese patients- in its phase III trials, the efficacy of brodalumab did not differ between nonobese vs obese patients (BMI >30 kg/m2)2. There was also a non- statistically significant trend toward more severe disease in the non-responders. A total of 5 patients discontinued participation in the trial. The most common reason for early discontinuation was lack of efficacy. Percent improvement in PASI scores at early termination were 81% (week 4), and 60%, 35%, 4%, and 61% (week 12). The BMI of the patients who discontinued participation ranged from 20.9 to 29.8. For those patients who were non- responders at week 16, we observed a partial response (PASI-50) in 50% (AO)/30.8% (NRI). A rapid onset of disease improvement was observed. By week 4, 53.8% and 23.1% of patients achieved PASI-50 and PASI-75, respectively; increasing to 88.2% and 76.5% at week 16 (AO). A >2-grade improvement in sPGA at week 16 was achieved by 61.5% of patients (both AO, NRI). In conclusion, the only statistically significant difference between responders and non- responders was the presence of higher weight/BMI in the AO dataset; this effect disappeared in the NRI dataset. These data suggest that brodalumab may be a good treatment option for psoriasis patients who have failed other biologics, including the anti-IL-17A class, regardless of their underlying disease severity or comorbidities. SKIN September 2021 Volume 5 Issue 5 Copyright 2021 The National Society for Cutaneous Medicine 526 Abbreviations: AO: As-observed PASI: Psoriasis Area and Severity Index NRI: Non-responder imputation IRB: Institutional Review Board REMS: Risk Evaluation and Mitigation Strategy sPGA: static Physician’s Global Assessment Conflict of Interest Disclosures: Grace Kimmel, MD: Advisory Board Member: Bristol Myers Squibb (May 2020); Pfizer (Jan 2021) Margot Chima, MD: None. Hee Jin Kim, MD: None. Jennifer Bares, MD: None. Alex Yaroshinsky, PhD: Consultant, owns equity: Ziropa. Consultant: Dermoforce, Mesoblast, Maplight, AMO, Neuren, Novo Ventures. Giselle Singer, BS: None. Soo Jung Kim, MD: None Jerry Bagel, MD: Dr. Bagel has received research funds payable to the Psoriasis Treatment Center of New Jersey from AbbVie, Amgen, Arcutis Biotherapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Corrona LLC, Dermavant Sciences, LTD, Dermira/UCB, Eli Lilly and Company, Glenmark Pharmaceuticals Ltd, Janssen Biotech, Kadmon Corporation,LEO Pharma Lycera Corp, Menlo Therapeutics, Novartis, Pfizer, Regeneron Pharmaceuticals, Sun Pharma, Taro Pharmaceutical Industries Ltd, and Valeant Pharmaceuticals; consultant fees from AbbVie, Amgen, Celgene Corporation, Eli Lilly and Company, Janssen Biotech, Novartis, Sun Pharmaceutical Industries Ltd, and Valeant Pharmaceuticals; and fees for speaking from AbbVie, Celgene Corporation, Eli Lilly, Janssen Biotech, and Novartis. . Mark Lebwohl, MD: Mark Lebwohl is an employee of Mount Sinai and receives research funds from: Abbvie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Dermavant Sciences, Eli Lilly, Incyte, Janssen Research & Development, LLC, Ortho Dermatologics, Regeneron, and UCB, Inc. Dr. Lebwohl is also a consultant for Aditum Bio, Almirall, AltruBio Inc., AnaptysBio, Arcutis, Inc., Aristea Therapeutics, Arrive Technologies, Avotres Therapeutics, BiomX, Boehringer-Ingelheim, Bristol- Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Dr. Reddy’s Laboratories, Evelo Biosciences, Evommune, Inc., Facilitatation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Helsinn Therapeutics, Hexima Ltd., LEO Pharma, Meiji Seika Pharma, Mindera, Pfizer, Seanergy, and Verrica. Funding: This study received funding from Ortho Dermatologics. Corresponding Author: Grace Kimmel, MD Department of Dermatology Icahn School of Medicine at Mount Sinai 1425 Madison Ave Box 1047, L2-17 New York, NY 10029 Email: gracewkimmel@gmail.com References: 1. Kimmel, G., et al., Brodalumab in the treatment of moderate to severe psoriasis in patients when previous anti-interleukin 17A therapies have failed. J Am Acad Dermatol, 2019. 81(3): p. 857- 859. 2. Hsu, S., et al., Comparable efficacy and safety of brodalumab in obese and nonobese patients with psoriasis: analysis of two randomized controlled trials. Br J Dermatol, 2020. 182(4): p. 880-888. mailto:gracewkimmel@gmail.com SKIN September 2021 Volume 5 Issue 5 Copyright 2021 The National Society for Cutaneous Medicine 527 Table 1 Baseline characteristics of responders and non-responders, AO dataset Baseline Characteristics Week 16 Responder (N=26) Week 16 Non- Responder (N=8) Week 16 Missing (N=5) Age (years) N 26 8 5 Mean (SE) 53.2 (3.43) 49.9 (3.98) 38.2 (6.71) Median 51.50 50.00 34.00 Min, Max 19, 91 28, 66 24, 56 p-value [a] 0.6149 Weight (lb) N 26 8 5 Mean (SE) 191.3 (7.46) 252.1 (31.56) 160.8 (14.61) Median 188.0 241.00 158.00 Min, Max 122, 267 155, 425 118, 208 p-value [a] 0.0085 BMI (kg/m2) N 26 8 5 Mean (SE) 28.6 (0.90) 37.4 (3.95) 25.0 (1.50) Median 28.55 35.45 25.00 Min, Max 21, 39 25, 59 21, 30 p-value [a] 0.0023 Smoking Status, n(%) No 17 (65.4%) 5 (62.5%) 4 (80.0%) Yes- current 2 (7.7%) 2 (25.0%) 0 Yes- former 7 (26.9%) 1 (12.5%) 1 (20.0%) p-value [b] 1.0000 PASI at Baseline N 26 8 5 Mean (SE) 21.2 (2.61) 19.3 (5.75) 17.6 (7.42) Median 18.15 12.20 10.50 Min, Max 5, 51 7, 55 4, 43 p-value [a] 0.7447 sPGA at Baseline, n(%) 3 17 (65.4%) 3 (37.5%) 3 (60.0%) 4 9 (34.6%) 5 (62.5%) 2 (40.0%) p-value [b] 0.2278 Comorbidities, n(%) Diabetes Mellitus 6 (23.1%) 3 (37.5%) 0 p-value [b] 0.6488 Hypertension 13 (50.0%) 3 (37.5%) 2 (40.0%) p-value [b] 0.6933 Hyperlipidemia 9 (34.6%) 3 (37.5%) 0 p-value [b] 1.0000 Psoriatic Arthritis 2 (7.7%) 0 3 (60.0%) p-value [b] 1.0000 History of Depression 5 (19.2%) 0 0 p-value [b] 0.3086 Locations, n(%) Head 17 (65.4%) 6 (75.0%) 3 (60.0%) p-value [b] 1.0000 Trunk 21 (80.8%) 6 (75.0%) 4 (80.0%) p-value [b] 1.0000 Upper Extremities 22 (84.6%) 8 (100.0%) 3 (60.0%) p-value [b] 0.5515 Lower Extremities 25 (96.2%) 8 (100.0%) 4 (80.0%) p-value [b] 1.0000 [a] p-value is from a t-test comparing Week 16 Responder with Week 16 Non-Responder; [b] p-value is from the Fisher's exact test comparing Week 16 Responder with Week 16 Non-Responder. SKIN September 2021 Volume 5 Issue 5 Copyright 2021 The National Society for Cutaneous Medicine 528 Table 2 Baseline characteristics of responders and non-responders, NRI dataset Baseline Characteristics Week 16 Responder (N=26) Week 16 Non- Responder (N=13) Age (years) N 26 13 Mean (SE) 53.2 (3.43) 45.4 (3.76) Median 51.50 47.00 Min, Max 19, 91 24, 66 p-value [a] 0.1655 Weight (lb) N 26 13 Mean (SE) 191.3 (7.46) 217.0 (23.44) Median 188.00 194.00 Min, Max 122, 267 118, 425 p-value [a] 0.1963 BMI (kg/m2) N 26 13 Mean (SE) 28.6 (0.90) 32.7 (2.99) Median 28.55 29.80 Min, Max 21, 39 21, 59 p-value [a] 0.1019 Smoking Status, n(%) No 17 (65.4%) 9 (69.2%) Yes- current 2 (7.7%) 2 (15.4%) Yes- former 7 (26.9%) 2 (15.4%) p-value [b] 1.0000 PASI at Baseline N 26 13 Mean (SE) 21.2 (2.61) 18.7 (4.36) Median 18.15 12.00 Min, Max 5, 51 4, 55 p-value [a] 0.6016 sPGA at Baseline, n(%) 3 17 (65.4%) 6 (46.2%) 4 9 (34.6%) 7 (53.8%) p-value [c] 0.2497 Comorbidities, n(%) Diabetes Mellitus 6 (23.1%) 3 (23.1%) p-value [b] 1.0000 Hypertension 13 (50.0%) 5 (38.5%) p-value [b] 0.7342 Hyperlipidemia 9 (34.6%) 3 (23.1%) p-value [b] 0.7144 Psoriatic Arthritis 2 (7.7%) 3 (23.1%) p-value [b] 0.3102 History of Depression 5 (19.2%) 0 p-value [b] 0.1488 Locations, n(%) Head 17 (65.4%) 9 (69.2%) p-value [b] 1.0000 Trunk 21 (80.8%) 10 (76.9%) p-value [b] 1.0000 Upper Extremities 22 (84.6%) 11 (84.6%) p-value [b] 1.0000 Lower Extremities 25 (96.2%) 12 (92.3%) p-value [b] 1.0000 [a] p-value is from a t-test comparing Week 16 Responder with Week 16 Non-Responder; [b] p-value is from the Fisher's exact test comparing Week 16 Responder with Week 16 Non-Responder; [c] p-value is from the Chi- square test comparing Week 16 Responder with Week 16 Non-Responder SKIN September 2021 Volume 5 Issue 5 Copyright 2021 The National Society for Cutaneous Medicine 529