CANTOS: The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study CANTOS results show that inhibiting inflammation reduces CV events and possibly lung cancer rates Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. NEJM 2017 Ridker PM, MacFadyen JG, Thuren T, et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. The Lancet 2017

CANTOS: Background and Objective Inflammation is associated with a higher CV risk, independently of cholesterol levels. It is not clear whether reducing inflammation, without affecting lipid levels, lowers the CV risk. Study objective The CANTOS study was designed to assess, whether reducing inflammation in stable patients with a history of MI and a persistent pro-inflammatory response, leads to a lower risk of recurrent CV events.

CANTOS: Study design Inclusion criteria: Stable patients with a history of MI on SOC therapies and hs-CRP ≥ 2 mg/L (N=10,061) Canakinumab 50 mg SC once every 3 months N=2,170 Canakinumab 150 mg SC once every 3 months N=2,284 Canakinumab 300 mg SC once every 3 months N=2,263 Placebo N=3,344 Median follow-up: 3.7 years Primary endpoint: composite of non-fatal MI, non-fatal stroke, and CV death The randomized, double-blind, placebo-controlled CANTOS trial aimed to test whether reducing inflammation in 10061 patients (in 39 countries) with stable coronary artery disease (CAD, with prior MI) can lower the risk of recurrent CV events. Patients were randomized to canakinumab (50 mg or 150 mg or 300 mg subcutaneously (SC) once every 3 months) or placebo (SC once every 3 months). Canakinumab is a fully human monoclonal antibody with anti-inflammatory effects that has been approved for clinical use in rheumatologic disorders, and reduces plasma levels of interleukin-6 and high-sensitivity C-reactive protein, without lowering LDL-c. Inclusion criteria: history of MI hsCRP ≥ 2 mg/L Exclusion criteria: history of chronic or recurrent infection previous cancer other than basal-cell skin carcinoma history or high risk of tuberculosis disease related to the human immunodeficiency virus ongoing use of other systemic anti-inflammatory treatments The primary endpoint was the composite of non-fatal MI, non-fatal stroke, and CV death (MACE). The key secondary endpoints were: MACE plus unstable angina requiring unplanned revascularization incidence of new-onset type 2 diabetes among patients with prediabetes at randomization (not reported in this publication) Other secondary endpoints were: - all-cause death - non-fatal MI, non-fatal stroke, or all-cause death The critical non-CV endpoints were cancer and cancer mortality, infection and infection mortality. Canakinumab is a fully human monoclonal antibody that reduces plasma levels of interleukin-6 and high-sensitivity C-reactive protein, without lowering LDL-c. It has been approved for clinical use in rheumatologic disorders. MI: myocardial infarction; hs-CRP: high sensitivity C-reactive protein; SC: subcoutaneous; CV: cardiovascular; SOC: standard of care Ridker PM, et al. NEJM 2017; Ridker PM, et al. The Lancet 2017

CANTOS: Main CV efficacy results: primary endpoint Canakinumab 150/300 led to a significant reduction in hs-CRP and the primary endpoint (non-fatal MI, non-fatal stroke, CV death) compared with placebo, without affecting LDL-c levels. N IR/100 P-Y (N) HR; 95%CI; P value Placebo N=3,344 4.50 (535) 1.00 Canakinumab 50 mg N=2,170 4.11 (313) 0.93; 0.80-1.07; 0.30 Canakinumab 150 mg N=2,284 3.86 (320) 0.85; 0.74-0.98; 0.021 Canakinumab 300 mg N=2,263 3.90 (322) 0.86; 0.75-0.99; 0.031 Canakinumab all doses N=6,717 3.95 (955) 0.88; 0.79-0.97; 0.02 The benefit was greatest in patients achieving hs-CRP of 1.8 mg/L after 3 months, with a 27% RRR for MACE (HR: 0.73; 95%CI: 0.63-0.83; P=0.0001). P value for trend across canakinumab doses vs. placebo: 0.02 IR: incidence rate; P-Y: persons-years; HR: hazard ratio; CI: confidence interval; RRR: relative risk reduction; MACE: major adverse clinical events; hs-CRP: high sensitivity C-reactive protein; MI: myocardial infarction; CV: cardiovascular; Ridker PM, et al. NEJM 2017; Ridker PM, et al. The Lancet 2017

CANTOS: Main non-CV results (1/2) Canakinumab 300 mg led to a 51% RRR in death from any cancer, compared with placebo. N IR (N) HR; 95%CI; P value ANY CANCER (P-value for trend across doses: 0.31) Placebo N=3,344 1.88 (231) 1.00 Canakinumab 50 mg N=2,170 1.85 (144) 0.99; 0.80-1.22; 0.91 Canakinumab 150 mg N=2,284 1.69 (143) 0.90; 0.73-1.11; 0.31 Canakinumab 300 mg N=2,263 1.72 (144) 0.91; 0-74-1.12; 0.38 Canakinumab all doses N=6,717 1.75 (431) 0.93; 0.79-1.09; 0.38 N IR (N) HR; 95%CI; P value ANY FATAL CANCER (P-value for trend across doses: 0.0007) Placebo N=3,344 0.64 (81) 1.00 Canakinumab 50 mg N=2,170 0.55 (44) 0.86; 0.59-1.24; 0.42 Canakinumab 150 mg N=2,284 0.50 (44) 0.78; 0.54-1.13; 0.19 Canakinumab 300 mg N=2,263 0.31 (27) 0.49; 0.31-0.75; 0.0009 Canakinumab all doses N=6,717 0.45 (115) 0.71; 0.53-0.94; 0.0158 IR: incidence rate; HR: hazard ratio; CI: confidence interval; RRR: relative risk reduction; CV: cardiovascular Ridker PM, et al. NEJM 2017; Ridker PM, et al. The Lancet 2017

CANTOS: Main non-CV results (2/2) Canakinumab 300 mg led to a 67% RRR in incident lung cancer and to a 77% RRR in fatal lung cancer, compared with placebo. N IR (N) HR; 95%CI; P value LUNG CANCER (P-value for trend across doses <0.0001) Placebo N=3,344 0.49 (61) 1.00 Canakinumab 50 mg N=2,170 0.35 (28) 0.74; 0.47-1.17; 0.20 Canakinumab 150 mg N=2,284 0.30 (26) 0.61; 0.39-0.97; 0.0337 Canakinumab 300 mg N=2,263 0.16 (14) 0.33; 0.18-0.59; <0.0001 Canakinumab all doses N=6,717 0.27 (68) 0.55; 0.39-0.78; 0.0007 N IR (N) HR; 95%CI; P value FATAL LUNG CANCER (P-value for trend across doses 0.0002) Placebo N=3,344 0.30 (38) 1.00 Canakinumab 50 mg N=2,170 0.20 (16) 0.67; 0.37-1.20; 0.18 Canakinumab 150 mg N=2,284 0.19 (17) 0.64; 0.36-1.14; 0.13 Canakinumab 300 mg N=2,263 0.07 (6) 0.23; 0.10-0.54; 0.0002 Canakinumab all doses N=6,717 0.15 (39) 0.51; 0.33-0.80; 0.0026 IR: incidence rate; HR: hazard ratio; CI: confidence interval; RRR: relative risk reduction; CV: cardiovascular Ridker PM, et al. NEJM 2017; Ridker PM, et al. The Lancet 2017

CANTOS: Main safety results More leukopenia was seen with canakinumab (0.30, 0.37 and 0.52 per 100 person years (PY) of exposure for 50, 150 and 300 mg respectively) as compared with placebo (0.24 per 100 PY, P for trend=0.002). Fatal infections were seen more often with canakinumab versus placebo (0.27 for 50 mg, 0.28 for 150 mg, and 0.30 for 300 mg vs. 0.18 per 100 PY, P for trend=0.09, P=0.02 for combined doses vs. placebo). Ridker PM, et al. NEJM 2017; Ridker PM, et al. The Lancet 2017

CANTOS: Conclusions Canakinumab significantly reduced high-sensitivity C-reactive protein levels from baseline, as compared with placebo, without reducing the LDL-c levels, and the 150/300 mg doses resulted in a significantly lower incidence of recurrent CV events compared with placebo. The benefit was greatest in patients achieving hs-CRP of 1.8 mg/L after 3 months, with a 27% RRR for MACE. The main adverse events were neutropenia and an increase in the risk of fatal infections. Additionally, canakinumab 300 mg led to a 51% RRR in death from any cancer, a 67% RRR in incident lung cancer, and a 77% RRR in fatal lung cancer, compared with placebo. Ridker PM, et al. NEJM 2017; Ridker PM, et al. The Lancet 2017