Brodalumab, a Human Anti–interleukin-17 Receptor A Monoclonal Antibody, Shows Low Immunogenicity in Patients With Moderate-to-Severe Psoriasis Kristian Reich,1 Mark Lebwohl,2 Carle Paul,3 Mads Røpke,4 Monika Rosen,4 Klaus Hansen4 1Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany; 2Icahn School of Medicine at Mount Sinai, New York, NY, USA; 3Paul Sabatier University, Toulouse, France; 4LEO Pharma, Ballerup, Denmark Winter Clinical Dermatology Conference - Hawaii® • January 12-17, 2018 • Lahaina, HI INTRODUCTION • Brodalumab is a human anti–interleukin (IL)-17 receptor A monoclonal antibody, which is delivered via subcutaneous injection, that demon- strated high efficacy in the treatment of moderate-to-severe psoriasis1–4 • Biologic therapies, such as brodalumab, have the potential to elicit an immune response in humans, which may result in the production of anti-drug antibodies (ADAs)5 • ADAs may change the pharmacokinetic and/or pharmacodynamic profile of a drug and thereby compromise its efficacy and/or safety profile6 – ADAs have been associated with hypersensitivity and immune reactions,7,8 which may be preceded by localized inflammation at an injection site9,10 – Neutralizing antibodies can prevent the drug from binding to the target receptor11 • This analysis was performed to evaluate immunogenicity and rates of hypersensitivity and injection-site reactions related to brodalumab METHODS Study design • Immunogenicity data from a 12-week Phase II study (NCT00975637),1 its open-label extension (NCT01101100; cut-off date: 16 June 2014),2 and three 52-week Phase III studies (AMAGINE-1,3 -2 and -34) were included • All studies were placebo controlled for the first 12 weeks, and AMAGINE-2 and -3 also included ustekinumab as a comparator up to week 52 – Treatment changes were incorporated into the design of each study; there- fore, patients had exposure to different therapies and experienced different durations of treatment with those therapies – Brodalumab was administered at doses of 70, 140 or 210 mg every 2 weeks (Q2W), with an additional initial dose at week 1, or at a dose of 280 mg every 4 weeks (Q4W) Immunogenicity assessments • In the Phase II study, serum samples were tested at baseline and weeks 4 and 16 • In the Phase II open-label extension, serum samples were tested at the open-label extension baseline and weeks 4, 12, 24, 36, 48 and every 24 weeks thereafter (to a maximum of week 336 or end of treatment) • In the Phase III studies, serum samples were tested at baseline and weeks 0, 4, 12, 24, 48 and 52 • Samples were treated with 300 mM acetic acid to enable antibody complex dissociation prior to analysis and thus increase the probability that anti-brodalumab antibodies would be detected • A highly sensitive (15 ng/mL) electrochemiluminescent bridging immunoassay with a drug tolerance threshold of 100.0 μg/mL, defined by a positive-control antibody, was used to detect brodalumab-specific ADAs in samples • Samples with a positive immunoassay result were tested for brodalumab-specific neutralizing ADAs with a validated cell-based assay that used IL-8 cytokine measurement as a surrogate endpoint – Assay sensitivity was 0.5 μg/mL, with a lower limit of reliable detection of 2.5 μg/mL and a drug tolerance of 0.78–1.25 μg/mL – Confirmatory assays were conducted on positive samples by incubating the sample in the absence of IL-17 and brodalumab Statistical analysis • This analysis included all patients who received at least one dose of brodalumab in any of the studies • ADAs were considered to be transient if the result of the patients’ final on-study test was negative • Descriptive statistics were used to summarize positive and negative antibody responses in each treatment group RESULTS Patients • Immunogenicity was assessed in a total of 4461 patients across all studies – 564 patients were treated with ustekinumab before they received brodalumab 210 mg Anti-drug antibodies • Steady-state brodalumab serum concentrations were below the drug tolerance threshold in all samples for the immunoassay used to detect ADAs • 122 patients (2.7%) tested positive for ADAs at any time after receiving brodalumab (Table 1) – 15 patients also tested positive for ADAs at baseline – ADAs were transient in 58 patients (1.4%) • No patients had neutralizing ADAs, including those who received brodalumab 210 mg after ustekinumab (Table 1) Effect of anti-drug antibodies Pharmacokinetics • Because anti-brodalumab antibody incidence was <3% of the patient population, anti-brodalumab antibody status was not evaluated in a population pharmacokinetic model; however, based on tabulated pharmacokinetic data (data not shown), no trends were observed to suggest reduction in pharmacokinetics due to the presence of binding ADAs Efficacy • There was no clear initial indication that patients with ADAs developed tolerance to brodalumab with loss of therapeutic effect, based on Static Physician’s Global Assessment (sPGA) responses. Among patients with binding ADAs: – 3/5 (60%) patients treated with brodalumab 210 mg Q2W and 9/14 (64%) patients treated with brodalumab 140 mg Q2W achieved sPGA success (score of 0 or 1) at week 12 – 7/14 (50%) patients in the brodalumab 210 mg Q2W group, 1/12 (8.3%) in the 140 mg Q8W group, 0/8 in the 140 mg Q4W group, and 5/21 (24%) in the 140 mg Q2W group achieved sPGA success at week 52 Hypersensitivity and injection-site reactions • No meaningful differences were observed in the incidence of hypersensitivity or injection-site reactions for brodalumab compared with placebo or ustekinumab within the 12 weeks of the Phase II study or the 12-week induction phases of the Phase III studies (Table 2) – The most frequent (≥0.3% in any group) hypersensitivity reaction was pruritus – The most frequent injection-site reactions were injection-site pain, erythema, bruising, and generalized injection-site reaction • There were no reports of serious hypersensitivity or injection-site reactions in the first 12 weeks of the study, including hypersensitivity within 1 day of treatment administration Table 1. Total Antibody Incidence Brodalumab 140 mg Q2W* (N=279) Brodalumab 210 mg Q2W† (N=1291) Variable brodalumab dosing‡ (N=2327) Brodalumab 210 mg after ustekinumab§ (N=564) All (N=4461) Patients with a positive ADA result prior to the first dose of brodalumab N=255 N=1257 N=2231 N=562 N=4305 Binding 0 4 (0.3) 4 (0.2) 7 (1.2) 15 (0.3) Neutralizing 0 0 0 0 0 Patients with an on-study positive ADA result N=277 N=1287 N=2325 N=564 N=4453 Binding 6 (2.2) 24 (1.9) 78 (3.4) 14 (2.5) 122 (2.7) Neutralizing 0 0 0 0 0 Patients with a positive ADA result after the first active brodalumab dose who had a negative or no result before the first active brodalumab dose N=274 N=1281 N=2316 N=375 N=4246 Binding 6 (2.2)0 20 (1.6) 74 (3.2) 7 (1.9) 107 (2.5) Transient 3 (1.1) 8 (0.6) 44 (1.9) 3 (0.8) 58 (1.4) Neutralizing 0 0 0 0 0 Transient 0 0 0 0 0 All data are n (%) unless otherwise stated. Treatment groups are as treated after the first dose of brodalumab. *≥75% of doses were 140 mg. †≥75% of doses were 210 mg. ‡All other brodalumab-treated patients without ustekinumab exposure. §Includes three patients not randomized to ustekinumab who inadvertently received a dose of ustekinumab. Table 2. Incidence of Hypersensitivity and Injection-Site Reactions Up to Week 12 Placebo (N=879) Ustekinumab (N=613) Brodalumab 140 mg Q2W (N=1491) Brodalumab 210 mg Q2W (N=1496) All brodalumab doses* (N=3066) Hypersensitivity AEs† 27 (3.1) 8 (1.3) 39 (2.6) 26 (1.7) 66 (2.2) Pruritus 14 (1.6) 5 (0.8) 18 (1.2) 10 (0.7) 28 (0.9) Injection-site reaction‡ 11 (1.3) 12 (2.0) 25 (1.7) 23 (1.5) 56 (1.8) Injection-site pain 3 (0.3) 4 (0.7) 7 (0.5) 9 (0.6) 20 (0.7) Injection-site erythema 3 (0.3) 3 (0.5) 6 (0.4) 5 (0.3) 16 (0.5) Injection-site bruising 2 (0.2) 1 (0.2) 4 (0.3) 4 (0.3) 9 (0.3) Injection-site reaction 0 (0.0) 1 (0.2) 5 (0.3) 1 (0.1) 4 (0.1) All data are n (%). *70 mg Q2W (N=38), 140 mg Q2W (N=1491), 210 mg Q2W (N=1496), 280 mg Q4W (N=41). †Standardized Medical Dictionary for Regulatory Activities (MedDRA) query. ‡Amgen-defined medical query. Acknowledgments: The brodalumab clinical study programme was sponsored by Amgen/ AstraZeneca, and this analysis was performed by Amgen/AstraZeneca. This poster was sponsored by LEO Pharma. Medical writing support was provided by Laura Maguire, MChem from Mudskipper Business Ltd, funded by LEO Pharma. Author disclosures: The authors disclose past or current financial relationships with the following companies: Reich – AbbVie, Affibody, Amgen, Biogen, Boehringer Ingelheim, Celgene, Centocor, Covagen, Forward Pharma, GlaxoSmithKline, Janssen-Cilag, LEO Pharma, Lilly, Medac, Merck, Novartis, Ocean Pharma, Pfizer, Regeneron, Sanofi, Takeda, UCB, and Xenoport; Lebwohl – Amgen, Anacor, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen Biotech, Kadmon, LEO Pharma, MedImmune, Novartis, Pfizer, Sun Pharmaceutical Industries, and Valeant Pharmaceuticals North America LLC; Paul – none; Røpke – LEO Pharma; Rosen – LEO Pharma; and Hansen – LEO Pharma. References: 1. Papp KA et al. N Engl J Med. 2012;366:1181-1189. 2. Papp KA et al. J Am Acad Dermatol. 2014;71:1183-1190. 3. Papp KA et al. Br J Dermatol. 2016;175:273-286. 4. Lebwohl M et al. N Engl J Med. 2015;373:1318-1328. 5. Purcell RT & Lockey RF. J Invest Allergol Clin Immunol. 2008;18:335-342. 6. Smith A et al. J Immunol Res. 2016;2016:2342187. 7. Schellekens H. Clin Ther. 2002;24:1720-1740. 8. Lecluse LLA et al. Arch Dermatol. 2010;146:127-132. 9. Liang F & Loré K. Clin Transl Immunology. 2016;5:e74. 10. Martinon F et al. Annu Rev Immunol. 2009;27:229-265. 11. van Schouwenburg PA et al. J Biol Chem. 2014;289:34482-34488. CONCLUSIONS • The overall incidence of brodalumab-specific immunogenicity in patients with moderate- to-severe psoriasis was low, and ADAs were transient in almost half the patients in whom they were detected • Brodalumab-neutralizing ADAs were not detected in any patients, including those who received brodalumab 210 mg after ustekinumab • There was no association between ADAs and reduction of response to brodalumab or increased incidence of hypersensitivity or injection-site reactions © 2017. All Rights Reserved.