Accepted Manuscript Dual neutralization of both IL-17A and IL-17F with bimekizumab in patients with psoriasis: results from BE ABLE 1, a 12-week randomized, double-blinded placebocontrolled phase 2b trial Kim A. Papp, MD, Joseph F. Merola, MD, Alice B. Gottlieb, MD, PhD, Professor Christopher E.M. Griffiths, MD, Nancy Cross, MD, Luke Peterson, MS, Christopher Cioffi, PhD, Andrew Blauvelt, MD PII: DOI: S0190-9622(18)30491-2 Reference: YMJD 12426 10.1016/j.jaad.2018.03.037 To appear in: Journal of the American Academy of Dermatology Received Date: 5 January 2018 Revised Date: 19 March 2018 Accepted Date: 21 March 2018 Please cite this article as: Papp KA, Merola JF, Gottlieb AB, Griffiths CEM, Cross N, Peterson L, Cioffi C, Blauvelt A, Dual neutralization of both IL-17A and IL-17F with bimekizumab in patients with psoriasis: results from BE ABLE 1, a 12-week randomized, double-blinded placebo-controlled phase 2b trial, Journal of the American Academy of Dermatology (2018), doi: 10.1016/j.jaad.2018.03.037. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 2 3 Bimekizumab PS0010 manuscript: JAAD Dual neutralization of both IL-17A and IL-17F with bimekizumab in patients with psoriasis: results from BE ABLE 1, a 12-week randomized, double-blinded placebo-controlled phase 2b trial 1 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Kim A Papp MD 1, Joseph F Merola MD 2, Alice B Gottlieb MD, PhD 3, Professor Christopher E M Griffiths MD 4, Nancy Cross MD 5, Luke Peterson MS 5, Christopher Cioffi PhD 6, Andrew Blauvelt MD 7 1 Probity Medical Research and K Papp Clinical Research, Waterloo, ON, Canada 2 Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA 3 New York Medical College, Metropolitan Hospital, New York, NY, USA 4 Dermatology Centre, Salford Royal Hospital, University of Manchester, National Institute for Health Research Biomedical Research Centre, Manchester, UK 5 UCB Biosciences Inc., Raleigh, NC, USA 6 UCB Pharma, Brussels, Belgium 7 Oregon Medical Research Center, Portland, OR, USA Correspondence to: Dr Kim Papp Probity Medical Research and K Papp Clinical Research, 135 Union Street East, Waterloo, Ontario, Canada, N2J 1C4; Tel: +1 519 579 9535; Email: kapapp@probitymedical.com Funding: The study was funded by UCB Pharma. Declaration of interests KAP has received consultant fees from Astellas, AstraZeneca, Baxalta, Baxter, Boehringer 22 23 24 25 Ingelheim, Bristol-Myers Squibb, CanFite, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Forward Pharma, Galderma, Genentech, Janssen, Kyowa Hakko Kirin, LEO Pharma, Meiji, Seika Pharma, MSD, Merck Serono, Mitsubishi Pharma, Novartis, Pfizer, Regeneron, Roche, Sanofi/Genzyme, Takeda, UCB, and Valeant; investigator fees from Astellas,
2 26 27 28 29 Baxalta, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Galderma, Genentech, GSK, Janssen, Kyowa Hakko Kirin, LEO Pharma, MedImmune, MSD, Merck-Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi/Genzyme, Takeda, UCB, and Valeant; speaker fees from Astellas, Celgene, Eli Lilly, Galderma, Kyowa 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 Hakko Kirin, LEO Pharma, MSD, Novartis, Pfizer, and Valeant; has participated in advisory boards for Astellas, Baxter, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dow Pharma, Eli Lilly, Galderma, Janssen, MSD, Novartis, Pfizer, Regeneron, Sanofi/Genzyme, UCB, and Valeant; is a steering committee member for Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, Kyowa Hakko Kirin, MSD, Merck-Serono, Novartis, Pfizer, Regeneron, Sanofi/Genzyme, and Valeant; and is a scientific officer for Kyowa Hakko Kirin. JFM has received honoraria from AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Samumed and UCB. ABG has received consultant fees, advisory board fees or speaker fees from Abbvie, Allergan, Beiersdorf Inc., Bristol-Myers Squibb, Celgene, Dermira, Lilly, Incyte, Janssen, Novartis, Reddy Labs, Sun Pharmaceutical Industries, UCB, and Valeant; and research grants from Allegran, Incyte, Janssen, LEO, Lilly and Novartis. AB has received consultant fees from Eli Lilly and Company, Janssen, Regeneron, and Sanofi Genzyme; and a scientific adviser and/or clinical study investigator for AbbVie, Aclaris, Allergan, Almirall, Amgen, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Inc., Eli Lilly and Company, Genentech/Roche, GlaxoSmithKline, Janssen, Leo, Merck Sharp & Dohme, Novartis, Pfizer, Purdue Pharma, Regeneron, Sandoz, Sanofi Genzyme, Sienna Pharmaceuticals, Sun Pharma, UCB Pharma, Valeant, and Vidac. CEMG has received grants and personal fees from AbbVie, Celgene, LEO, Lilly, Janssen, Novartis, Pfizer, and UCB Pharma; grants from Sandoz; personal fees from Almirall and Galderma. CG has received research grants from AbbVie, Celgene, Novartis, Eli Lilly, Janssen, Sandoz, Pfizer, LEO, and UCB. NC, LP and 50 CC are employees at UCB. LP and CC own stock in UCB.
3 51 52 53 Prior presentation: An abstract reporting the primary and secondary results of this clinical trial was presented at the American Academy of Dermatology annual meeting (16 20 February 2018, San Diego, CA, USA). 54 55 56 57 58 59 60 61 62 63 64 65 Capsule Summary: 50 words (in 3 bullet points) Abstract: 200 words Main text: 2496 words References: 34 Number of figures and tables: 5 IRB statement: The study protocol, amendments, and subject informed consent were reviewed by a national, regional, or Independent Ethics Committee (IEC) or Institutional Review Board (IRB). This study is registered with ClinicalTrials.gov (NCT02905006) and EudraCT (#2016-001891-31), first entered on 5 Jul 2016 (Hungary). List of attachments: Supplementary material (including 2 tables and 4 figures), CONSORT checklist, trial protocol, SAP
66 Bimekizumab PS0010 manuscript: JAAD Abstract 4 67 68 Background: Neutralizing interleukin (IL)-17F in addition to IL-17A may provide a more complete and specific approach to inhibiting inflammation. 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 Objective: Assess the efficacy and safety of bimekizumab, a monoclonal antibody that potently and selectively neutralizes IL-17A and IL-17F, in patients with moderate-to-severe plaque psoriasis. Methods: Double-blinded, placebo-controlled phase 2b study (NCT02905006). Patients (randomized 1:1:1:1:1:1) received subcutaneous bimekizumab every four weeks at doses of 64mg, 160mg, 160mg with 320mg loading dose, 320mg, 480mg, or placebo. Primary endpoint was 90% reduction in Psoriasis Area Severity Index (PASI90) at Week 12. Results: There was a significant (P<0.0001) dose-response for PASI90 (Week 12); more patients achieved PASI90 than placebo (46.2 79.1% versus 0%, P<0.0001 all doses). Across all doses, there were significant improvements from baseline for all secondary endpoints (PASI90 [Week 8], PASI75 and PASI100 [Week 12], Investigators Global Assessment clear / almost clear [Weeks 8&12]; P 0.0003 versus placebo). More bimekizumab-treated patients achieved PASI100 (Week 12) than placebo (27.9 60.0% versus 0%; P 0.0002 all doses). TEAEs were reported by 126/208 (61%) bimekizumabtreated patients and 15/42 (36%) placebo-treated patients. Limitations: No active comparator. Conclusion: Dual neutralization of IL-17A and IL-17F with bimekizumab provided rapid and 87 88 substantial clinical improvements in patients with psoriasis, with no unexpected or dose- related safety findings. 89
5 90 Introduction 91 92 Psoriasis is a chronic, immune-mediated inflammatory skin disease that affects up to 3% of the population and is associated with significant comorbidities including chronic pulmonary 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 disease, diabetes, liver disease, cardiovascular disease, chronic kidney disease, and rheumatologic disease. 1,2 The disease burden extends beyond physical manifestations with significant social and psychologic factors leading to a negative impact on quality of life. 3,4 Basic immunologic advances augment our understanding of psoriasis pathogenesis and have led to the development of therapies targeted against key proinflammatory cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-17A, and IL-23. 5,6 While targeting TNF-dependent pathways has demonstrated positive responses in patients with psoriasis, 7-10 greater efficacy has been achieved with more recently developed drugs that target the IL-23/T-helper 17 immunologic pathway, a key driver of psoriasis. 11-17 Despite these advances, achieving completely clear skin, and maintaining this level of clearance, remains challenging; additionally, several safety considerations have been noted with these therapies, including injection-site reactions, fungal infections (particularly candida infections), and exacerbations of, and new onset, inflammatory bowel disease (IBD). 12-14,18 Therefore, treatments that demonstrate greater efficacy and fewer safety issues could provide additional patient benefit. Within the IL-17 cytokine family (IL-17A, IL-17B, IL-17C, IL-17D, IL-17E [also known as IL-25], and IL-17F), the most extensive research has focused on IL-17A. 16,19-24 Consequently, of the currently available therapies targeting the IL-17 pathway, two specifically inhibit IL-17A (secukinumab and ixekizumab), while a third (brodalumab) targets IL-17RA, a receptor subunit utilized by IL-17A, IL-17C, IL-25, and IL-17F. Although IL-17A 113 114 115 116 and IL-17F are the closest relatives within the IL-17 family, historically, the role of IL-17F has not been widely investigated. IL-17F shares an approximate 50% structural homology and overlapping biologic proinflammatory function with IL-17A, 20,25,26 suggesting it may also play an important role in psoriasis. Indeed, evidence from preclinical studies has demonstrated
6 117 118 119 120 that both IL-17A and IL-17F are expressed in lesional skin and inflamed synovium from patients with psoriatic arthritis (PsA). 27-29 Moreover, in preclinical models, both IL-17A and IL-17F have been shown to cooperate with TNF to stimulate production of key proinflammatory cytokines and amplify tissue inflammation. 28,30 When compared with IL-17A 121 122 123 124 125 126 127 128 129 130 131 132 133 blockade alone, dual neutralization of IL-17A and IL-17F resulted in lower levels of expression of inflammation-linked genes and cytokines as well as a greater suppression of disease-relevant immune cell migration. 27,28,30 These data support the rationale for targeting both IL-17A and IL-17F. To that end, bimekizumab, a humanized monoclonal immunoglobulin G1 (IgG1) antibody, was designed to potently and selectively neutralize the biologic functions of both IL-17A and IL-17F. Here, we report the efficacy and safety results of a phase 2b dose-ranging study (BE ABLE 1) evaluating bimekizumab (64 480 mg) and placebo in patients with moderate to severe plaque psoriasis. The primary objective was to evaluate the dose response of bimekizumab, administered subcutaneously every four weeks (Q4W) for 12 weeks, using the Psoriasis Area and Severity Index (PASI)90 response at Week 12; secondary objectives were to evaluate the efficacy, safety, and tolerability of bimekizumab compared with placebo.
7 134 Methods 135 Study design and participants 136 This randomized, double-blinded, placebo-controlled, parallel-group, dose-ranging study 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 (NCT02905006) recruited patients between 25 August 2016 and 1 March 2017 in six countries (Canada, Czech Republic, Hungary, Japan, Poland, USA). All patients who discontinued or who did not enroll in the extension study (NCT03010527) were required to complete a 20-week safety follow-up visit after administration of the final dose of study drug. The study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Guidance for Good Clinical Practice. Independent institutional review board approvals were obtained. Eligible patients were 18 years of age, with a confirmed diagnosis of moderate to severe plaque psoriasis for 6 months with a PASI of 12, psoriasis affecting 10% of body surface area, an Investigator s Global Assessment (IGA) score of 3on a 5-point scale, and who were candidates for systemic psoriasis therapy and/or phototherapy. Patients were excluded if they had prior treatment with an anti-il-17 therapy or prior exposure to >1 other biologic therapy for psoriasis or PsA, presence of significant uncontrolled neuropsychiatric disorder, history of suicide attempt, or suicide ideation within 6 months (assessed using the electronic Columbia Suicide Severity Rating Scale [ec-ssrs]). Other inclusion and exclusion criteria are detailed in supplementary material. All patients provided written informed consent in accordance with local requirements. Patients were randomized (1:1:1:1:1:1) to receive bimekizumab Q4W at doses of 64 mg, 160 mg, 160 mg (with 320 mg loading dose at baseline), 320 mg, 480 mg, or placebo. An 156 157 158 159 interactive voice or web response system was used for assigning eligible patients to a treatment regimen according to a randomization schedule produced by an independent biostatistician who was not associated with the design or analysis of the study. Treatment assignment was stratified by geographic region and prior biologic exposure.
8 160 161 162 163 Bimekizumab was provided in single-use vials containing 160 mg/ml. Due to differences in presentation and to ensure study blinding, bimekizumab and placebo injections were prepared and administered at the investigational sites by unblinded, dedicated study personnel (see supplementary material). 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 Procedures Treatment was administered at baseline, Week 4, and Week 8, for a total of three subcutaneous injections (see supplementary material). Efficacy and safety were assessed at baseline and Weeks 1, 2, 4, 6, 8, and 12. Safety was monitored by an external data monitoring committee. Outcomes The primary efficacy endpoint was 90% reduction from baseline in PASI (PASI90) at Week 12. Secondary efficacy endpoints were: PASI90 at Week 8; PASI75 and PASI100 at Week 12; and IGA response (defined as clear or almost clear with 2 categories of improvement from baseline) at Weeks 8 and 12. Safety monitoring during the study included: adverse events (AEs) (frequency and severity, by Common Terminology Criteria for Adverse Events), serious AEs, suicide ideation and behavior (ec-ssrs), depression and anxiety (Hospital Anxiety and Depression Scale), electrocardiogram data, vital signs, physical examination, and laboratory assessments. Statistical analysis Analyses of demographics, baseline disease characteristics, and safety included all patients who received study treatment (safety set). Efficacy analyses included patients who received 181 182 183 184 1 dose of study treatment and had a valid measurement of the primary efficacy variable at baseline (full analysis set [FAS]). Sample size calculations were performed based on evaluating a linear dose-response relationship for the proportion of PASI90 responders across ascending doses (placebo up through bimekizumab 480 mg). With 40 patients in
9 185 186 each treatment group and a two-sided significance level of 0.05, the test for detecting a linear dose response was powered at >99%. 187 The primary analysis evaluated the dose-response relationship between treatment and 188 189 190 191 192 193 194 195 196 197 198 199 PASI90 response using a logistic regression model where treatment was included as a linear variable with fixed effects for region and prior biologic exposure (see supplementary material). Patients with missing efficacy data were imputed as non-responders. Pairwise comparisons of each bimekizumab dose versus placebo for PASI90 at Week 12 accounted for multiplicity using a fixed-sequence testing procedure with each bimekizumab dose being tested versus placebo (Fisher s exact test) sequentially from the highest dose to the lowest dose. Subsequent tests were only conducted if the previous test reached significance at a two-sided significance level of α=0.05, thereby controlling the overall type I error rate. For secondary endpoints, p-values were based on Fisher s exact test (if there were no placebo responders) or the odds ratio from a logistic regression model (if there were placebo responders). All p-values for secondary endpoints were considered nominal. Safety data were described using summary statistics.
10 200 Results 201 202 In this study, 355 patients were screened, with 250 randomized to treatment (supplementary material). Of these, 224 patients completed the study; 26 patients discontinued participation 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 (five AEs; one lack of efficacy; two protocol violations; two lost to follow-up; three withdrew consent; and 13 other reasons). Patient demographics and baseline disease characteristics (Table I) were similar among treatment groups. All randomized patients were included in the FAS. Efficacy Efficacy increased with dose from placebo to bimekizumab 320 mg (Figs 1 and 2). A statistically significant dose response was observed for the primary endpoint, PASI90 response at Week 12 (P<0.0001). PASI90 response at Week 12 was achieved by significantly more patients in all bimekizumab-treatment groups compared with placebo (46.2 79.1% versus 0%; P<0.0001, all comparisons) (Fig 3). The percentage of patients achieving a PASI90 response at Week 8 was also significantly greater for each bimekizumab dose compared with placebo (41.0 86.0% versus 0%; P<0.0001, all comparisons) (supplementary material). A significantly greater percentage of bimekizumab-treated patients achieved PASI75 (61.5 93.0% versus 4.8%; P<0.0001, all comparisons) and PASI100 (27.9 60.0% versus 0%; P 0.0002, all comparisons) at Week 12 compared with placebo (Fig 3 and supplementary material). When viewed at the individual patient level, there were improvements in absolute PASI over time for patients receiving bimekizumab. By Week 12, in the three highest dose groups almost all patients had an absolute PASI less than 5 with the majority at or near 0 (Fig 2). 222 223 224 225 Treatment with bimekizumab was associated with significant improvement from baseline in psoriasis severity compared with placebo, as measured by IGA responders at Week 8 (46.2 86.0% versus 4.8%; P 0.0003, all comparisons) and Week 12 (51.3 86.0% versus 4.8%; P 0.0001, all comparisons) (Fig 3 and supplementary material). The clinical response
11 226 227 was rapid, with clinically meaningful improvements relative to placebo observed in all bimekizumab groups as early as Week 4 across all measures of disease activity (Fig 1). 228 Safety 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 The safety set consisted of the 250 patients. Treatment with bimekizumab was not associated with any unexpected safety signals and no dose-related safety risks were observed. Treatment-emergent adverse events (TEAEs) were reported by 126 of 208 (61%) bimekizumab-treated patients and 15 of 42 (36%) placebo-treated patients. The most commonly reported TEAEs ( 5% patients in any group) at Week 12 are reported in Table II. AEs led to treatment discontinuation in 10 of 208 (4.8%) bimekizumab-treated patients and 1 of 42 (2.4%) in the placebo group. There was no apparent dose relationship with the incidence of TEAEs leading to discontinuation. Two patients reported three serious AEs: meningitis viral was reported by one patient on placebo while large intestinal polyp and colon cancer were reported 15 days after the first dose for a patient receiving bimekizumab 480 mg; both patients were withdrawn from the study. The AE of viral meningitis resolved. None of the serious AEs were considered related to the study treatment by the investigator. No deaths were reported during the study. Fungal infections (oral candidiasis, oral fungal infection, vulvovaginal mycotic infection, and tinea pedis) were reported in nine (4.3%) bimekizumab-treated patients; no cases were reported in the placebo group. No cases of anaphylactic reactions, IBD, major cardiovascular events, neuropsychiatric events, serious hematopoietic cytopenias, or systemic opportunistic infections were reported during the treatment period (supplementary material). Five patients receiving bimekizumab had grade 2 non-serious neutropenia 248 reported, all of which were transient and resolved without interruption of study treatment.
12 249 Discussion 250 251 In this phase 2b study, bimekizumab treatment of moderate to severe psoriasis was associated with superior efficacy versus placebo in all primary and secondary endpoints. 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 The highest responses were generally observed in the 320 mg dose group, with approximately 80% of patients achieving high levels of skin clearance (PASI90 or IGA clear or almost clear ) at Week 12. Of note, around 50 60% of patients in the three highest dose groups achieved complete skin clearance (PASI100) at Week 12. The rapid onset of clinically meaningful skin clearance was notable, with PASI75 response rates of 70 80%, occurring in the bimekizumab 160 mg with 320 mg loading dose, 320 mg, and 480 mg groups as early as Week 4, after a single dose of bimekizumab. Although it appears that the dose response peaked at bimekizumab 320 mg, with numerically lower responses seen in the 480 mg dose group, the small patient numbers and short duration of the study do not enable us to determine from these data alone whether this observation illustrates saturation of the dose-response curve, variability in disease biology among patients, or variability in assessments. In a first-in-human single-dose study in patients with mild psoriasis (NCT02529956), bimekizumab treatment was associated with rapid onset of clinically meaningful efficacy and sustained reductions in disease activity measures, with no unexpected safety signals. 31 A subsequent phase 1b proof-of-concept study in patients with PsA (NCT02141763) did not identify any new safety signals, and met both predefined efficacy criteria, demonstrating superiority of bimekizumab over both placebo and a predefined clinically relevant threshold (based on results from a TNF inhibitor clinical study) as assessed by American College of Rheumatology response rates at Week 8. 32 Moreover, in patients with skin involvement 272 273 274 (BSA 3%), Week 8 response rates for PASI75 and PASI100 were 100% and 87%, respectively, compared with 0% for placebo. Overall, the results from the current study in patients with moderate to severe psoriasis further build on the encouraging outcomes
13 275 276 277 278 observed in the early clinical trials of bimekizumab and support the preclinical evidence that IL-17F plays a meaningful role in chronic tissue inflammation, beyond that of IL-17A. Although it is not possible to draw conclusions from comparisons across clinical studies in the absence of direct head-to-head data, the magnitude and particularly the speed at which 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 high levels of skin clearance were achieved in the current trial appear to compare favorably to therapies targeting IL-17A alone 11,12, the IL-17RA subunit 13,14, or IL-23. 15-17 Future analyses and phase 3 clinical trials with active comparators with different mechanisms of action will help characterize the net contribution of IL-17F neutralization to potentially improve outcomes across different disease manifestations. Overall, TEAEs occurred with greater frequency in patients treated with bimekizumab than those receiving placebo. Although the study was 12 weeks in duration, the safety profile was consistent with previous reports 31,32 and there were no unexpected clinically relevant safety findings. Reported AEs were generally mild to moderate in intensity and resolved; there was no relationship between increased dose and AEs (type or frequency). The non-serious neutropenia cases reported were transient and resolved without interruption of the study treatment. Trials of longer duration are required to fully establish the safety profile of bimekizumab. Consistent with the association between therapies targeting the IL-17 pathway and increased susceptibility to mucocutaneous fungal infections, 33,34 nine fungal infections (four of which were oral candidiasis) were reported during the treatment period across bimekizumab dose groups, with no association between events and dose. All cases were localized, superficial infections of mild or moderate intensity and none led to discontinuation. In the context of previous reports with anti-il-17a and anti-il-17ra antibodies, 12-14,18 the 298 299 300 301 absence of anaphylactic reactions, IBD, neuropsychiatric events or systemic opportunistic infections is promising, although it must be noted that the present study was only 12 weeks in duration and evaluated 250 patients. Indeed, the interpretation of the results is limited by small sample size and short treatment duration, which are both inherent to phase 2 studies.
14 302 303 Larger studies of longer duration are needed to fully evaluate the efficacy and safety of bimekizumab in this population. 304 In conclusion, these 12-week phase 2b data provide encouraging evidence that dual 305 306 307 308 neutralization of IL-17A and IL-17F with bimekizumab can provide both rapid and complete skin clearance in a majority of patients with moderate to severe plaque psoriasis and suggest it may be a new therapeutic approach in this population.
15 309 310 311 312 ACKNOWLEDGMENTS The authors would like to acknowledge Katie Alexander, PhD, of imed Comms, an Ashfield Company, part of UDG Healthcare plc, for medical writing support that was funded by UCB Pharma in accordance with Good Publication Practice (GPP3) guidelines. The authors 313 314 315 316 317 acknowledge Alvaro Arjona, PhD of UCB Pharma for publication and editorial support and Cynthia Madden, MD, MPH of UCB Pharma for her critical review of the manuscript. The authors thank the patients and their caregivers, in addition to the investigators, their teams, and the UCB Pharma PS0010 clinical team, who contributed to this study. CEMG is a National Institute for Health Research Senior Investigator.
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20 413 414 415 Abbreviations AE, adverse event FAS, full analysis set 416 417 418 419 420 421 422 423 424 425 IBD, inflammatory bowel disease IGA, Investigator s Global Assessment IgG1, immunogloblin G1 IL, interleukin IL-17RA, interleukin-17 receptor A PASI, Psoriais Area Severity Index PsA, psoriatic arthiritis Q4W, every 4 weeks TEAE, treatment-emergent adverse event TNF, tumor necrosis factor
Bimekizumab PS0010 manuscript: JAAD 21 TABLE I. Baseline demographics and disease characteristics. Placebo Q4W N=42 BKZ 64 mg Q4W N=39 BKZ 160 mg Q4W N=43 BKZ 160 mg Q4W (320 mg LD at baseline) N=40 BKZ 320 mg Q4W N=43 BKZ 480 mg Q4W N=43 All patients N=250 Age, years, mean (±SD) 46.7 (12.3) 44.2 (13.8) 43.4 (12.4) 46.5 (15.2) 42.6 (13.6) 42.9 (15.2) 44.3 (13.7) Sex, n (%) Male 25 (59.5) 20 (51.3) 32 (74.4) 29 (72.5) 28 (65.1) 29 (67.4) 163 (65.2) Weight, kg, mean (±SD) 88.8 (21.2) 86.6 (19.2) 91.6 (24.6) 88.4 (15.4) 86.9 (21.7) 86.4 (20.7) 88.1 (20.6) Racial cohort, n (%) Caucasian 39 (92.9) 35 (89.7) 39 (90.7) 33 (82.5) 39 (90.7) 38 (88.4) 223 (89.2) Prior systemic therapy, n (%) 32 (76.2) 28 (71.8) 25 (58.1) 27 (67.5) 35 (81.4) 30 (69.8) 177 (70.8) Prior non-biologic systemic therapy 14 (33.3) 12 (30.8) 13 (30.2) 12 (30.0) 23 (53.5) 16 (37.2) 90 (36.0) Prior biologic therapy* 10 (23.8) 10 (25.6) 8 (18.6) 10 (25.0) 10 (23.3) 10 (23.3) 58 (23.2) Prior systemic phototherapy 23 (54.8) 22 (56.4) 17 (39.5) 18 (45.0) 23 (53.5) 19 (44.2) 122 (48.8) Prior anti-tnf therapy, n (%) 6 (14.3) 5 (12.8) 6 (14.0) 3 (7.5) 7 (16.3) 6 (14.0) 33 (13.2) Disease duration, years, median (range) 15.0 (0.8 48.0) 15.0 (0 53.4) 15.9 (0.6 58.7) 14.5 (0 50.0) 15.9 (0.7 39.0) 13.9 (0.7 45.0) 15.0 (0 58.7)
Bimekizumab PS0010 manuscript: JAAD 22 PASI, mean (±SD) 18.9 (5.8) 18.6 (5.9) 20.6 (6.8) 18.9 (8.4) 19.4 (6.4) 18.4 (5.1) 19.1 (6.5) IGA score, n (%) 3 (Moderate) 30 (71.4) 29 (74.4) 32 (74.4) 32 (80.0) 32 (74.4) 36 (83.7) 191 (76.4) 4 (Severe) 12 (28.6) 10 (25.6) 11 (25.6) 8 (20.0) 11 (25.6) 7 (16.3) 59 (23.6) Percentage BSA involvement, median (range) 25.5 (11 58) 22.0 (11 47) 24.0 (10 80) 20.5 (10 74) 24.0 (10 51) 21.0 (10 64) 22.0 (10 80) *Patients were excluded if they had prior treatment with an anti-il-17 therapy for either psoriasis or psoriatic arthritis; no patients were enrolled in the study who had previously received anti-il-17 therapy for any other condition. BKZ, bimekizumab; BSA, body surface area; IGA, Investigator s Global Assessment, LD, loading dose; PASI, Psoriasis Area and Severity Index; Q4W, every four weeks; TNF, tumor necrosis factor
Bimekizumab PS0010 manuscript: JAAD 23 TABLE II. Treatment-emergent adverse events. Variable, n (%)* Placebo Q4W n=42 BKZ 64 mg Q4W n=39 BKZ 160 mg Q4W n=43 BKZ 160 mg Q4W (320 mg LD at baseline) n=40 BKZ 320 mg Q4W n=43 BKZ 480 mg Q4W n=43 Any TEAE 15 (35.7) 27 (69.2) 24 (55.8) 24 (60.0) 26 (60.5) 25 (58.1) Serious TEAEs 1 (2.4) 0 0 0 0 1 (2.3) Discontinuation due to TEAEs 1 (2.4) 1 (2.6) 3 (7.0) 3 (7.5) 1 (2.3) 2 (4.7) Treatment-related TEAEs 3 (7.1) 6 (15.4) 3 (7.0) 6 (15.0) 10 (23.3) 5 (11.6) Severe TEAEs 0 1 (2.6) 0 1 (2.5) 0 2 (4.7) Death 0 0 0 0 0 0 Most common treatment-emergent adverse events ( 5% of patients in any group) Nasopharyngitis 2 (4.8) 5 (12.8) 3 (7.0) 3 (7.5) 6 (14.0) 4 (9.3) Upper respiratory tract 1 (2.4) 5 (12.8) 2 (4.7) 3 (7.5) 2 (4.7) 0 infection Arthralgia 0 2 (5.1) 0 1 (2.5) 1 (2.3) 3 (7.0)
Bimekizumab PS0010 manuscript: JAAD 24 γ-glutamyltransferase increased 1 (2.4) 0 3 (7.0) 2 (5.0) 1 (2.3) 0 Hypertension 3 (7.1) 1 (2.6) 1 (2.3) 1 (2.5) 0 1 (2.3) Respiratory tract infection 1 (2.4) 2 (5.1) 1 (2.3) 1 (2.5) 1 (2.3) 0 Neutropenia 0 2 (5.1) 0 1 (2.5) 2 (4.7) 0 Rhinitis 1 (2.4) 2 (5.1) 1 (2.3) 0 0 1 (2.3) Tonsillitis 0 2 (5.1) 2 (4.7) 0 0 0 Oral candidiasis 0 0 0 1 (2.5) 3 (7.0) 0 Headache 0 2 (5.1) 0 0 0 1 (2.3) Leukopenia 0 2 (5.1) 0 0 0 1 (2.3) Vomiting 0 2 (5.1) 0 0 0 0 *Number (%) of patients reporting 1 TEAE within System Organ Class/Preferred Term according to version 19.0 of the Medical Dictionary for Regulatory Activities. BKZ, bimekizumab; LD, loading dose; Q4W, every four weeks; TEAE, treatment-emergent adverse event.
25 Fig 1. Bimekizumab. PASI and IGA responses over time (full analysis set) *Missing data were imputed as non-responders. PASI75, PASI90 and PASI100 responses were defined as reductions from baseline of 75% or more, 90% or more, or 100%, respectively at each time point. IGA response defined as 0 ( clear ) or 1 ( almost clear ) with 2 categories of improvement from baseline. BKZ, bimekizumab; IGA, Investigator s Global Assessment; LD, loading dose; PASI, Psoriasis Area and Severity Index.
26 Fig 2. Bimekizumab. Absolute PASI over time (patient-level data) * Box plots are first quartile, median, and third quartile. Whiskers extend to ±1.5 times the interquartile range. Where the whisker value exceeded the data range, the maximum or minimum value was used, as appropriate. BKZ, bimekizumab; IGA, Investigator s Global Assessment; LD, loading dose; PASI, Psoriasis Area and Severity Index.
27 Fig 3. Efficacy response rates at Week 12 (full analysis set). *p<0.0001 for the comparison with placebo. p=0.0002 for the comparison with placebo. p=0.0001 for the comparison with placebo. PASI75, PASI90 and PASI100 responses were defined as reductions from baseline of 75% or more, 90% or more, or 100%, respectively at each time point. ǁ IGA response defined as 0 ( clear ) or 1 ( almost clear ) with 2 categories of improvement from baseline. Missing data were imputed as non-responders. BKZ, bimekizumab; IGA, Investigator s Global Assessment; LD, loading dose; PASI, Psoriasis Area and Severity Index.
SUPPLEMENTARY MATERIAL Supplement to: Papp K A, Merola J F, Gottlieb A B, et al, Dual neutralization of both IL-17A and IL-17F with bimekizumab in patients with psoriasis: results from BE ABLE 1, a 12-week randomized, double-blinded placebo-controlled phase 2b trial Inclusion Criteria Patients were eligible to participate in this study if all the following criteria were met at screening and reconfirmed at the baseline visit: Male or female of at least 18 years of age. Chronic plaque psoriasis for at least 6 months prior to screening. PASI 12 and BSA 10%, and IGA score 3 on a 5-point scale. Candidates for systemic psoriasis therapy and/or phototherapy and/or chemophototherapy. Female patients were postmenopausal, permanently sterilized or, if of childbearing potential, were willing to use a highly effective method of contraception until 20 weeks after last administration of study medication, and had a negative pregnancy test at visit 1 (screening) and immediately prior to first dose. Male patients with a partner of childbearing potential used a condom when sexually active, until 20 weeks after the last administration of study medication (anticipated 5 half-lives). Patients agreed to not increase their usual sun exposure during the study and to use ultraviolet A/ultraviolet B (UVA/UVB) sunscreens. Exclusion Criteria Patients were not permitted to enroll in the study if any of the following criteria were met: Female patients who were breastfeeding, pregnant or planned to become pregnant during the study or within 20 weeks following last dose of study drug. Male patients who were planning a partner pregnancy during the study or within 20 weeks following the last dose. Prior participation in a bimekizumab clinical trial, or participation in another study of a medication or a medical device under investigation within the last 3 months or at least 5 halflives, whichever was greater, or were currently participating in another study of a medication or medical device under investigation. Known hypersensitivity to any excipients of bimekizumab. Erythrodermic, guttate, pustular form of psoriasis or drug-induced psoriasis. History of chronic or recurrent infections, or a serious or life-threatening infection within the 6 months prior to the baseline visit (including herpes zoster). High risk of infection in the investigator s opinion, any current sign or symptom that may have indicated an active infection (except for common cold), or an infection requiring systemic antibiotics within 2 weeks of baseline. Concurrent acute or chronic viral hepatitis B or C or human immunodeficiency virus (HIV) infection. Known history of or current clinically active infection with Histoplasma, Coccidiodes, Paracoccidioides, Pneumocystis, nontuberculous mycobacteria, Blastomyces or Aspergillus, or current active Candidiasis (local or systemic). Live (including attenuated) vaccination within the 8 weeks prior to baseline, or Bacillus Calmette-Guerin (BCG) vaccinations within 1 year prior to study drug administration. Live vaccines were not allowed during the study or for 20 weeks after the last dose of study drug. History of a lymphoproliferative disorder, including lymphoma or current signs and symptoms suggestive of lymphoproliferative disease. Primary immunosuppressive conditions, including immunosuppressive therapy following an organ transplant. Known tuberculosis (TB) infection, at high risk of acquiring TB infection, with latent TB infection (LTBI), or current or history of nontuberculous mycobacterial (NTMB) infection. Splenectomy. Concurrent malignancy or history of malignancy (including surgically resected uterine/cervical carcinoma-in-situ) during the past 5 years, were excluded, with the exception of: 3 excised or ablated, basal cell carcinomas of the skin; one squamous cell carcinoma of the skin (stage 1
T1 maximum) successfully excised, or ablated only, with no signs of recurrence or metastases for more than 2 years prior to screening; actinic keratosis(-es); and squamous cell carcinoma-in-situ of the skin successfully excised, or ablated, more than 6 months prior to screening, which may have been included. Major surgery (including joint surgery) within the 6 months prior to screening, or planned surgery within 6 month after entering the study. Current or recent history, as determined by the investigator, of severe, progressive and/or uncontrolled renal, hepatic, hematologic, endocrine, pulmonary, cardiac, gastrointestinal, or neurological disease. Greater than two times upper limit of normal (ULN) of any of the following: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or >ULN total bilirubin ( 1.5xULN total bilirubin if known Gilbert s syndrome). Clinically significant laboratory abnormalities (e.g., creatinine >1.5xULN, neutropenia <1.5x10 9 /L, hemoglobin <8.5g/dL, lymphocytes <1.0 x10 9 /L, platelets <100 x10 9 /L). Any other condition which, in the investigator's judgement, made the patient unsuitable for inclusion in the study. Exposure to more than one biological response modifier (limited to anti-tnf or IL-12/-23) for psoriatic arthritis (PsA) or psoriasis prior to the baseline visit. Previous treatment with any anti-il-17 therapy for the treatment of psoriasis or PsA. Diagnosis of inflammatory conditions other than psoriasis or PsA, including but not limited to rheumatoid arthritis, sarcoidosis, or systemic lupus erythematosus. Patients with a diagnosis of Crohn s disease or ulcerative colitis were allowed if they had no active symptomatic disease at screening or baseline. Patients taking PsA medications other than nonsteroidal anti-inflammatory drugs (NSAIDs) or analgesics were excluded. Patients could take stable doses of NSAIDs to treat their PsA symptoms during the study. Patients could use acetaminophen/paracetamol and mild opioids, as needed. History of chronic alcohol or drug abuse within the previous 6 months. Twelve-lead ECG with changes considered to be clinically significant upon medical review. Presence of significant uncontrolled neuropsychiatric disorder, active suicidal ideation, or positive suicide behavior using the baseline version of the electronic Columbia Suicide Severity Rating Scale (ec-ssrs) and the Hospital Anxiety and Depression Scale (HADS) with either of the following criteria: o Lifetime history of suicide attempt (including an actual attempt, interrupted attempt or aborted attempt), or had suicidal ideation in the past 6 months as indicated by a positive response ( Yes ) to either Question 4 or Question 5 of the screening/baseline version of the ec-ssrs at screening. o HADS Depression score >10 or Anxiety score 15. Investigator site personnel directly affiliated with this study and/or their immediate families. Employees of the sponsor, or employees of third-party organizations involved in the study. Additional details of blinding Bimekizumab was provided in single-use vials containing 160 mg/ml. Placebo was supplied as 0.9% saline solution. Treatments were administered as three subcutaneous injections (lateral abdominal wall and upper outer thigh). During each dosing visit, each of the three injections was administered at a separate injection site, and sites were rotated. Due to differences in presentation and to ensure study blinding, bimekizumab and placebo injections were prepared and administered at the investigational sites by unblinded, dedicated study personnel. The unblinded personnel were not involved in the study in any way other than assuring the medication was taken from the correct kit and administered to patients. All other study personnel remained blinded and did not have access to medication-related information. To preserve the blind of treatment doses, each administration consisted of three subcutaneous injections: Dose BKZ 64 mg BKZ 160 mg BKZ 320 mg BKZ 480 mg Placebo Volume of bimekizumab 160 mg/ml and placebo 0.4 ml (1 x 0.4 ml filled syringe with bimekizumab + 2 x 0.4 ml filled syringe with placebo) 1.0 ml (1 x 1.0 ml filled syringe with bimekizumab + 2 x 1.0 ml filled syringe with placebo) 2.0 ml (2 x 1.0 ml filled syringes with bimekizumab + 1 x 1.0 ml filled syringe with placebo) 3.0 ml (3 x 1.0 ml filled syringes with bimekizumab) 3.0 ml (3 x 1.0 ml filled syringe with placebo) 2
Additional details of primary analysis The pre-specified logistic regression model for the primary analysis of evaluating a linear dose response defined fixed effects for treatment group, region, and prior biologic exposure. However, because there were no PASI90 responders in the placebo group, this model did not converge. Therefore, the model was modified such that treatment was specified as a linear predictor (rather than a class variable) where placebo, bimekizumab 64 mg, 160 mg, 320 mg, and 480 mg Q4W were assigned numeric values of -2, -1, 0, 1, and 2, respectively. The 160 mg (with 320 mg loading dose at baseline) dose was not included in the primary logistic regression model to evaluate dose response. Pairwise comparisons between each dose of bimekizumab and placebo were planned to be based on a logistic regression model including fixed effects for treatment, region, and prior biologic exposure. However, due to the lack of PASI90 or PASI100 responders in the placebo group, all pairwise comparisons for these variables were based on Fisher s exact test, instead of logistic regression. For IGA at Weeks 8 and 12, as well as PASI75 at Week 12, p-values for the pairwise comparisons were based on the odds ratios from the logistic regression model as originally planned. The model estimates for the primary logistic regression model that were used to evaluate the dose response are provided below. Effect Degrees of Freedom Wald Chi-square statistic P-value Treatment (linear) 1 44.3842 <0.0001 Region 1 0.0519 0.8197 Prior biologic exposure 1 1.0837 0.2979 3
TABLE 1. Efficacy response rates at Week 8 (full analysis set). Variable, n (%) Responders at Week 8 Placebo Q4W n=42 BKZ 64 mg Q4W n=39 BKZ 160 mg Q4W n=43 BKZ 160 mg Q4W (320 mg LD at baseline) n=40 BKZ 320 mg Q4W n=43 BKZ 480 mg Q4W PASI90 0 16 (41.0)* 25 (58.1)* 27 (67.5)* 37 (86.0)* 30 (69.8)* IGA 2 (4.8) 18 (46.2) 27 (62.8)* 31 (77.5)* 37 (86.0)* 31 (72.1)* In the statistical analyses, missing data were imputed as non-responders. *p<0.0001 for the comparison with placebo. p=0.0003 for the comparison with placebo. PASI90 responses were defined as reductions from baseline of 90% or more at each time point. IGA response defined as 0 ( clear ) or 1 ( almost clear ) with at least two categories of improvement from baseline. BKZ, bimekizumab; IGA, Investigator s Global Assessment; LD, loading dose; PASI, Psoriasis Area and Severity Index; Q4W, every 4 weeks. n=43 4