ACC 2018 Orlando, Florida Interleukin-1b Inhibition with Canakinumab and Cardiovascular Event Reduction Among Patients with Moderate Chronic Kidney Disease Analyses from the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) Paul M Ridker MD, Jean MacFadyen BS, Robert J Glynn, PhD, Wolfgang Koenig, MD, Peter Libby, MD, Brendan Everett MD, Martin Lefkowitz, MD, Tom Thuren MD, and Jan H Cornel, MD on behalf of the worldwide investigators and participants in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) Ridker ACC 2018

Why assess the impact of IL-1b inhibition with canakinumab in patients with moderate chronic kidney disease? Patients with chronic kidney disease (CKD) suffer from accelerated atherosclerosis and enhanced risk of cardiovascular events, yet the mechanism of this risk remains uncertain. As a result, therapies that reduce risk of myocardial infarction and cardiovascular death in the CKD population are limited. Work over the past decade suggests that multiple processes related to renal injury and repair induce unique changes in innate and adaptive immunity, including enhanced NLRP3 inflammasome function resulting in activation of IL-1b, a critical cytokine also involved in multiple aspects of accelerated atherothrombosis, independent of lipid levels. We therefore hypothesized that canakinumab, a human monoclonal antibody targeting IL-1b, might reduce cardiovascular event rates and improve renal function among post-MI patients with moderate CKD (Stage 3, eGFR 30-60 ml/min/1.73m2). 2 Ridker ACC 2018

Residual Inflammatory Risk Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) Stable CAD (post MI) Residual Inflammatory Risk (hsCRP > 2 mg/L) N = 10,061 39 Countries April 2011 - June 2017 1490 Primary Events Randomized Canakinumab 50 mg SC q 3 months Randomized Canakinumab 150 mg SC q 3 months Randomized Canakinumab 300 mg SC q 3 months Randomized Placebo SC q 3 months Primary Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE) Secondary Endpoint: MACE plus Unstable Angina Requiring Urgent Revascularization (MACE+) Patients were excluded from CANTOS if they had nephrotic syndrome or eGFR < 30ml/min/1.73m2. Ridker PM et al. N Engl J Med. 2017;377:1119-31

CANTOS: Dose-Dependent Effects on Inflammatory Biomarkers and Lipids (48 Months) Placebo SC q 3 mth hsCRP Canakinumab 50mg SC q 3 mth Canakinumab 150mg SC q 3 mth Canakinumab 300mg SC q 3 mth Percent Change from Baseline (median) LDLC HDLC TG Months Placebo Canakinumab 50 Canakinumab 150 Canakinumab 300 Ridker PM et al. N Engl J Med. 2017;377:1119-31

CANTOS: Primary Cardiovascular Endpoints Placebo SC q 3 months Canakinumab 150/300 mg SC q 3 months MACE MACE - Plus HR 0.85 95%CI 0.76-0.96 P = 0.007 HR 0.83 95%CI 0.74-0.92 P = 0.0006 Cumulative Incidence (%) Cumulative Incidence (%) 1 2 3 4 5 Follow-up Years Follow-up Years 35 - 40% reductions in hsCRP and IL-6 No change in LDLC Ridker PM et al. N Engl J Med. 2017;377:1119-31

Among Participants with Robust Inhibition of the Inflammatory Response CANTOS : 31% Reduction in Cardiovascular Mortality and All-Cause Mortality Among Participants with Robust Inhibition of the Inflammatory Response CANTOS - Cardiovascular Mortality CANTOS - All Cause Mortality Years Cumulative Incidence 1 2 3 4 5 0.20 0.15 0.10 0.05 0.00 Years Cumulative Incidence 1 2 3 4 5 0.20 0.15 0.10 0.05 0.00 Placebo 1.0 (referent) (referent) Canakinumab, hsCRP ≥2mg/L 0.99 (0.82-1.21) 0.95 Canakinumab, hsCRP <2mg/L 0.69 (0.56-0.85) 0.0004 Placebo 1.0 (referent) (referent) Canakinumab, hsCRP ≥2mg/L 1.05 (0.90-1.22) 0.56 Canakinumab, hsCRP <2mg/L 0.69 (0.58-0.81) <0.0001 35 - 40% reductions in hsCRP and IL-6 No change in LDLC Ridker PM. Circulation 2018

CANTOS - Baseline Clinical Characteristics Among Those With Moderate CKD (N=1875) as Comapred to Those with Normal Renal Function (N = 8184) Normal Renal Function (eGFR > 60mL/min/1.73m2) Moderate CKD (eGFR 30-60 mL/min/1.73m2) Characteristic Placebo (N=2717) Canakinumab (N=5467) (N=626) (N=1249) Age (years) 60.0 68.0 Female (%) 24.1 23.0 33.7 36.9 Current smoker (%) 25.3 26.0 12.3 14.2 Diabetes (%) 38.4 38.8 46.0 46.1 Hypertension (%) 76.9 78.0 88.3 87.8 LDL cholesterol (mg/dL) 83.1 83.0 80.0 hsCRP (mg/L) 4.0 4.1 4.7 Serum creatinine (umol/L) 78 115 118 eGFR (ml/min/1.73m2) 84 51 50 Urine albumin:creatinine ratio 0.70 1.44 1.40 Urinary protein, >1+ (%) 14.5 15.0 23.4 Ridker ACC 2018

Incidence Rate / 100 person-years CANTOS: Increased Incidence Rates of MACE, Cardiovascular Death, and All-Cause Mortality Among Patients with Moderate CKD as Compared to Those with Normal Renal Function. P < 0.0001 P < 0.0001 P < 0.0001 Incidence Rate / 100 person-years Moderate CKD Normal Renal Function Ridker ACC 2018

Canakinumab SC q 3 months CANTOS: Incidence Rates and Effects of Canakinumab on MACE+ Among Those With Moderate CKD or Normal Renal Function at Study Entry Canakinumab SC q 3 months Placebo 50 mg 150 mg 300 mg All Doses P-trend Moderate CKD IR (per 100 person years) HR 95%CI P 7.89 1.0 (referent) 6.96 0.88 0.68-1.15 0.36 6.27 0.79 0.61-1.03 0.09 6.19 0.61-1.02 0.07 6.46 0.82 0.68-1.00 0.05 0.045 Normal Kidney Function 4.55 1.00 4.05 0.90 0.77-1.06 0.21 3.89 0.85 0.73-0.99 0.032 3.82 0.84 0.72-0.98 0.023 3.92 0.86 0.77-0.97 0.012 0.018 Ridker ACC 2018

Canakinumab SC q 3 months CANTOS: Incidence Rates and Effects of Canakinumab on MACE+ Among Those With and Without CKD at Study Entry Canakinumab SC q 3 months Placebo 50 mg 150 mg 300 mg All Doses P-trend Moderate CKD IR (per 100 person years) HR 95%CI P 7.89 1.0 (referent) 6.96 0.88 0.68-1.15 0.36 6.27 0.79 0.61-1.03 0.09 6.19 0.61-1.02 0.07 6.46 0.82 0.68-1.00 0.05 0.045 Normal Kidney Function 4.55 1.00 4.05 0.90 0.77-1.06 0.21 3.89 0.85 0.73-0.99 0.032 3.82 0.84 0.72-0.98 0.023 3.92 0.86 0.77-0.97 0.012 0.018 P-heterogeneity NS Ridker ACC 2018

CANTOS : Effects of Canakinumab on Major Vascular Events Among Those With and Without Moderate CKD at Study Entry eGFR < 60 mL/min/1.73m2 eGFR > 60 mL/min/1.73m2 HR 0.82 95%CI 0.68-1.00 P = 0.05 HR 0.86 95%CI 0.77-0.97 P = 0.01 Years Years Moderate CKD (N = 1875) Normal Renal Function (N = 8184)

CANTOS : Efficacy of Canakinumab on Cardiovascular Events, Cardiovascular Mortality, and All-Cause Mortality Among Moderate CKD Patients, According to On-treatment hsCRP Levels Achieved at 3 months Placebo Canakinumab On-treatment hsCRP > 2mg/L On-treatment hsCRP < 2 mg/L MACE+ HR (adjusted) 95% CI P 1.0 Referent 0.81 0.64-1.04 0.11 0.69 0.54-0.89 0.0039 Cardiovascular Mortality 0.96 0.68-1.35 0.66 0.46-0.94 0.0223 Total Mortality 0.99 0.76-1.29 0.93 0.76 0.57-1.00 0.05 *HRs adjusted for age, gender, smoking, HTN, diabetes, BMI, baseline hsCRP, Baseline LDLC

CANTOS : Efficacy of Canakinumab on Cardiovascular Events, Cardiovascular Mortality, and All-Cause Mortality Among Moderate CKD Patients, According to On-treatment hsCRP Levels Achieved at 3 months Placebo Canakinumab On-treatment hsCRP > 2mg/L On-treatment hsCRP < 2 mg/L MACE+ HR (adjusted) 95% CI P 1.0 Referent 0.81 0.64-1.04 0.11 0.69 0.54-0.89 0.0039 Cardiovascular Mortality 0.96 0.68-1.35 0.66 0.46-0.94 0.0223 Total Mortality 0.99 0.76-1.29 0.93 0.76 0.57-1.00 0.05 *HRs adjusted for age, gender, smoking, HTN, diabetes, BMI, baseline hsCRP, Baseline LDLC

CANTOS : Effects of Canakinumab on eGFR and Creatinine Over Time Among Those With Moderate CKD at Study Entry (ml/min/SA) eGFR * * Creatinine (umol/L) * 3 6 9 12 24 36 48 Months Placebo Canakinumab 50 Canakinumab 150 Canakinumab 300 * P < 0.05 for canakinumab 150mg and 300 mg at 48 months for eGFR and for canakinumab 300mg at 48 months for creatinine

Canakinumab SC q 3 months CANTOS: Effects of Canakinumab on Indices of Renal Function Over Time Canakinumab SC q 3 months Placebo 50 mg 150 mg 300 mg All Doses uACR > 3 mg/mmol (HR) 1.0 (referent) 0.80 0.62-1.04 0.87 0.68-1.11 0.91 0.71-1.16 0.89 0.72-1.09 Most Severe eGFR Grade (ml/min/1.73m2) Stage 3, % (30-60) Stage 4, %(15-29) Stage 5, % (<15) 37.5 4.4 0.4 41.0 3.5 0.5 40.5 3.8 0.6 40.0 4.7 0.3 4.0 Post-randomization Progression to dialysis (%) 0.2 Ridker ACC 2018

Conclusions: CANTOS CKD The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS ) Interleukin-1b inhibition with canakinumab reduces major adverse cardiovascular event rates among high-risk atherosclerosis patients with moderate to severe chronic kidney disease (eGFR 30-60 mg/min/1.73m2). Among CANTOS CKD patients, the largest benefits of canakinumab accrued among those who had the most robust anti-inflammatory response; those who achieved on-treatment hsCRP levels < 2 mg/L after the first dose of canakinumab had a 31% reduction in major cardiovascular events (P=0.004, a 34% reduction in cardiovascular mortality (P=0.02), and a 24% reduction in all-cause mortality (P=0.05). Canakinumab had neither clinically meaningful benefits nor substantive harms with respect to adverse clinical renal events inclusive microalbuminuria progression, decline in eGFR, or need for dialysis. However, CANTOS did not enroll patients with eGFR between 15 and 30 mg/min/1.73m2.

Conclusions: CANTOS CKD The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS ) Canakinumab, and IL-1b inhibitor, represents a new class of therapy for atherosclerotic disease that lowers hsCRP and IL-6 with no effect on lipid levels and no hemodynamic effects. The current data demonstrate that anti-inflammatory therapy – at least with canakinumab – has considerable cardiovascular efficacy in high risk patients with moderate to sever CKD. Moving forward, it will be important to extend these data and test the efficacy of canakinumab in patients with end-stage renal failure and/or those undergoing dialysis. In that setting, hsCRP and IL-6 are powerful predictors of risk while LDL-C is not, and dialysis is one of the few settings where LDL reduction with statins has not been highly effective. Thus, a new clinical trial of canakinumab in patients with severe renal failure recently initiating hemodialysis – a group with very high vascular risk and considerable unmet need - is warranted.

“Residual Cholesterol Risk” “Residual Inflammatory Risk” Addressing the Obverse Side of the Atherosclerosis Prevention Coin Ridker PM. Eur Heart J 2016;37:1720-22 Known Cardiovascular Disease LDL 150 mg/dL hsCRP 4.5mg/L High Intensity Statin “Residual Cholesterol Risk” “Residual Inflammatory Risk” LDL 110 mg/dL hsCRP 1.8 mg/L LDL 80 mg/dL hsCRP 3.8 mg/L Additional LDL Reduction IMPROVE-IT : Ezetimibe 6% RRR FOURIER/SPIRE: PCSK9 Inhibition q2 weeks 15% RRR Additional Inflammation Reduction CANTOS Canakinumab 150mg SC q 3 months 15%RRR 18