OVERVIEW OF ADVERSE CARDIOVASCULAR EVENTS IN THE BRODALUMAB PSORIASIS STUDIES

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1 OVERVIEW OF ADVERSE CARDIOVASCULAR EVENTS IN THE BRODALUMAB PSORIASIS STUDIES Bruce Strober, 1,2 Lawrence F. Eichenfield, 3 April Armstrong, 4 Alice Gottlieb, 5 Kenneth Gordon, 6 Tina Lin, 7 Radhakrishnan Pillai, 8 Robert Israel 7 1 University of Connecticut Health Center, Farmington, CT; 2 Probity Medical Research, Waterloo, ON, Canada; 3 University of California, San Diego, CA; 4 University of Southern California, Los Angeles, CA; 5 New York Medical College, Valhalla, NY; 6 Medical College of Wisconsin, Milwaukee, WI; 7 Valeant Pharmaceuticals North America LLC, Bridgewater, NJ; 8 Dow Pharmaceutical Sciences (a division of Valeant Pharmaceuticals North America LLC), Petaluma, CA This study was sponsored by Valeant Pharmaceuticals North America LLC. Medical writing support was provided by MedThink SciCom and funded by Valeant Pharmaceuticals North America LLC. 75th Annual Meeting of the American Academy of Dermatology; March 3-7, 217; Orlando, FL 4758

2 Introduction and Methods INTRODUCTION Psoriasis is associated with increased risk factors for cardiovascular disease (CVD; eg, smoking, excess alcohol intake, hypertension, hyperlipidemia, obesity, and insulin resistance), although the nature of this relationship is unclear 1,2 The efficacy and safety of brodalumab, an IL-17 receptor A (IL-17RA) antagonist, has previously been demonstrated in patients with moderate-to-severe plaque psoriasis 3,4 OBJECTIVE To assess cardiovascular (CV) events, including major adverse cardiovascular events (MACEs), in a phase 2 and 3 phase 3 large, multicenter, randomized trials of patients with moderate-to-severe plaque psoriasis (AMAGINE-1/-2/-3) METHODS Study Population Patients (N=4464) with a total of 9174 patient-years (PYs) of brodalumab exposure were included in this analysis 92% of patients received 1 dose of brodalumab 21 mg 88% of patients were on brodalumab 21 mg by week 52 METHODS (cont) Event Identification CV events were grouped as ischemic cerebrovascular disease (ICVD) and ischemic heart disease (ISHD) Occurrence of MACE (CV death, myocardial infarction [MI], or stroke) was prospectively evaluated and adjudicated in the phase 2 and 3 studies Follow-up observation time included gaps and interruptions in exposure, and time beyond the exposure period Exposure time included periods when patients were exposed to the investigational products, excluding any gaps or interruptions Statistical Analyses 12-week data (summarized as patient incidence) are presented to allow direct randomized comparisons of brodalumab with placebo and ustekinumab Data from the 52-week and long-term pools are summarized as exposure-adjusted or follow-up adjusted rates CV, cardiovascular; CVD, cardiovascular disease; ICVD, ischemic cerebrovascular disease; IL-17RA, IL-17 receptor A; ISHD, ischemic heart disease; MACE, major adverse cardiovascular event; MI, myocardial infarction; PY, patient-year. 1. Parisi et al. J Invest Dermatol. 213;133: Samarasekera et al. J Invest Dermatol. 213;133: Papp et al. Br J Derm. 216;175: Lebwohl et al. N Engl J Med. 215;373: th Annual Meeting of the American Academy of Dermatology; March 3-7, 217; Orlando, FL

3 Baseline Cardiovascular Risk Factors A total of 83% of patients who received brodalumab had 1 CV risk factor at baseline Parameter, n (%) CV risk factors present 1 Placebo (N=879) 132 (15) 747 (85) Ustekinumab (N=613) 19 (18) 54 (82) Brodalumab a (N=366) 514 (17) 2552 (83) Smoking status (former/current) 493 (56) 361 (59) 168 (55) Overweight/Obese BMI >3 Overweight/Obesity preferred term 397 (45) 387 (44) 66 (8) 285 (47) 282 (46) 57 (9) 1425 (47) 1411 (46) 264 (9) Hypertension 22 (25) 189 (31) 824 (27) Dyslipidemia 244 (28) 111 (18) 76 (23) Glucose intolerance/diabetes 91 (1) 77 (13) 351 (11) At least 1 relevant medical history 32 (4) 6 (.7) 27 (3) 24 (4) 9 (1.5) 16 (3) 14 (3) 21 (.7) 88 (3) BMI, body mass index; CV, cardiovascular; ICVD, ischemic cerebrovascular disease; ISHD, ischemic heart disease; SMQ, Standardised MedDRA Query. a Includes data from patients in clinical studies who received 1 dose of brodalumab. 75th Annual Meeting of the American Academy of Dermatology; March 3-7, 217; Orlando, FL

4 Cardiovascular Events in Psoriasis Studies Few CV events were reported during the 12-week placebo-controlled period Events, n (%) Placebo (N=879) Ustekinumab (N=613) 1 (.1) 1 (.2) 1 (.2) Brodalumab 14 mg Q2W (N=1491) 21 mg Q2W (N=1496) 1 (.1) 4 (.3) Exposure- and follow-up adjusted rates of CV events were comparable between groups 52-week pool 1 (.1) Long-term pool Events, n (rate) Ustekinumab (N=613) All brodalumab (N=419) All brodalumab (N=4464) Exposure-adjusted Follow-up adjusted 495 PY 1 (.2) 5 (1.) 54 PY 1 (.2) 6 (1.2) 3446 PY 7 (.2) 4 (1.2) 3584 PY 11 (.3) 41 (1.2) 8655 PY 21 (.2) 85 (1.) 9174 PY 24 (.3) 93 (1.) CV, cardiovascular; ICVD, ischemic cerebrovascular disease; ISHD, ischemic heart disease; PY, patient-year; Q2W, every 2 weeks; SMQ, Standardised MedDRA Query. 75th Annual Meeting of the American Academy of Dermatology; March 3-7, 217; Orlando, FL

5 MACE Events in Psoriasis Studies Few occurrences of MACE were observed in the 12-week placebo-controlled phase Rates of MACE were constant over time Brodalumab a Events, n (%) Placebo (N=842) Ustekinumab (N=613) 14 mg Q2W (N=1452) 21 mg Q2W (N=1456) All doses (N=298) a All CV death MI Stroke 3 (.2) 2 (.1) 1 (.1) 3 (.1) 2 (.1) 1 (<.1) All patients with reported MACE had 1 major CV risk factor and additional comorbidities (eg, increased body mass index [BMI], glucose intolerance, history of smoking, elevated lipids, or other relevant medical history) Most patients with reported MACE had 3 risk factors BMI, body mass index; CV, cardiovascular; MACE, major adverse cardiac event; MI, myocardial infarction; Q2W, every 2 weeks. a Includes mixed doses and variable doses. 75th Annual Meeting of the American Academy of Dermatology; March 3-7, 217; Orlando, FL

6 MACE Events in Psoriasis Studies (cont) Exposure-adjusted and follow-up adjusted rates of MACE were comparable between groups at week 52 and remained stable with brodalumab in the long-term analysis Events, n (rate) [95% CI] a Exposure-adjusted All MACE events [95% CI] CV death MI Stroke Follow-up adjusted All MACE events CV death MI Stroke Ustekinumab (N=613) 495 PY 2 (.4) [.5, 1.46] 1 (.2) 1 (.2) 54 PY 2 (.4) [.5, 1.43] 1 (.2) 1 (.2) 52-week pool All brodalumab (N=419) 3295 PY 2 (.6) [.37,.94] 2 (.1) 14 (.4) 4 (.1) 3378 PY 24 (.7) [.46, 1.6] 3 (.1) 16 (.5) 5 (.1) Long-term pool All brodalumab (N=4464) 787 PY 4 (.5) [.36,.69] 5 (.1) 25 (.3) 1 (.1) 8365 PY 54 (.6) [.48,.84] 12 (.1) 3 (.4) 12 (.1) CI, confidence interval; CV, cardiovascular; MACE, major adverse cardiac event; MI, myocardial infarction; PY, patient-year. a Multiple occurrences of the same event for a single patient are counted as multiple events. There were 2 patients with multiple MACE events. 75th Annual Meeting of the American Academy of Dermatology; March 3-7, 217; Orlando, FL

7 Conclusions The results did not support a causative relationship between brodalumab treatment and MACE, as the incidence confidence intervals for brodalumab and ustekinumab overlapped Rates of MACE were constant over time and no temporal pattern was observed There was no dose trend associated with MACE between brodalumab 14 and 21 mg Q2W Results from the current analysis suggest that there is no increased CV risk associated with brodalumab treatment beyond the underlying risk associated with psoriasis 75th Annual Meeting of the American Academy of Dermatology; March 3-7, 217; Orlando, FL

(Poster presented on Sunday 05 March, 08:50 08:55; 2017 AAD Meeting, Orlando, Florida, USA)

(Poster presented on Sunday 05 March, 08:50 08:55; 2017 AAD Meeting, Orlando, Florida, USA) Secukinumab in Psoriasis Patients with Concurrent Psoriatic Arthritis: Patient-Reported Outcomes in the Corrona Psoriasis Registry AB Gottlieb, B Strober, 2 AW Armstrong, 3 JD Greenberg, 4,5 C Karki, 4