1. 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

2. 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 ml/min/1.73m2). 2
Ridker ACC 2018

3. 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 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:

4. 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 Canakinumab Canakinumab 300
Ridker PM et al. N Engl J Med. 2017;377:

5. 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
P = 0.007
HR 0.83
95%CI
P =
Cumulative Incidence (%)
Cumulative Incidence (%) 1 2 3 4 5
Follow-up Years
Follow-up Years
% reductions in hsCRP and IL-6
No change in LDLC
Ridker PM et al. N Engl J Med. 2017;377:

6. 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 (referent) (referent)
Canakinumab, hsCRP ≥2mg/L ( ) 0.95
Canakinumab, hsCRP <2mg/L ( )
Placebo (referent) (referent)
Canakinumab, hsCRP ≥2mg/L ( ) 0.56
Canakinumab, hsCRP <2mg/L ( ) <0.0001
% reductions in hsCRP and IL-6
No change in LDLC
Ridker PM. Circulation 2018

7. 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 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

8. 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 <
P <
P <
Incidence Rate / 100 person-years
Moderate CKD
Normal Renal Function
Ridker ACC 2018

9. 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
0.36
6.27
0.79
0.09
6.19
0.07
6.46
0.82
0.05
0.045
Normal Kidney Function
4.55
1.00
4.05
0.90
0.21
3.89
0.85
0.032
3.82
0.84
0.023
3.92
0.86
0.012
0.018
Ridker ACC 2018

10. 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
0.36
6.27
0.79
0.09
6.19
0.07
6.46
0.82
0.05
0.045
Normal Kidney Function
4.55
1.00
4.05
0.90
0.21
3.89
0.85
0.032
3.82
0.84
0.023
3.92
0.86
0.012
0.018
P-heterogeneity NS
Ridker ACC 2018

11. 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
P = 0.05
HR 0.86
95%CI
P = 0.01
Years
Years
Moderate CKD
(N = 1875)
Normal Renal Function
(N = 8184)

12. 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
0.11
0.69
0.0039
Cardiovascular Mortality
0.96
0.66
0.0223
Total Mortality
0.99
0.93
0.76
0.05
*HRs adjusted for age, gender, smoking, HTN, diabetes, BMI, baseline hsCRP, Baseline LDLC

13. 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
0.11
0.69
0.0039
Cardiovascular Mortality
0.96
0.66
0.0223
Total Mortality
0.99
0.93
0.76
0.05
*HRs adjusted for age, gender, smoking, HTN, diabetes, BMI, baseline hsCRP, Baseline LDLC

14. 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 Canakinumab 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

15. 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
0.87
0.91
0.89
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

16. 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 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.

17. 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.

18. “Residual Cholesterol Risk” “Residual Inflammatory Risk”
Addressing the Obverse Side of the Atherosclerosis Prevention Coin
Ridker PM. Eur Heart J 2016;37:
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