Targeting Inflammation in Atherosclerosis: Has CANTOS ... Targeting Inflammation in Atherosclerosis:

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Targeting Inflammation in Atherosclerosis:

Has CANTOS Nailed It? Controversies and Advances in the

Treatment of Cardiovascular Disease

The Seventeenth in the Series

Beverly Hills, November 16, 2017

Sanjay Kaul, MD, FACC, FAHA Division of Cardiology

Cedars-Sinai Medical Center

Los Angeles, California

The Laws of Diminishing Objectivity

in the Interpretation of Evidence

vehemence a evidence-1

Peter McCulloch

The Lancet, 2004;363;9004

vehemence a eminence2

Libby P. JACC (October 31, 2017)

Interleukin-1b as a Target for Atherosclerosis

Biologic Basis for CANTOS and Beyond

Ridker PM. Circ Res 2016;118:145-156.

Modulation of IL-1b for Atheroprotection

Can Inflammation Reduction, in the Absence of Lipid Lowering, Reduce Cardiovascular Event Rates?

Neutralizing Antibody (Ilaris) Long half-life (4-8 weeks) Approved indications:

- Cryopyrin-Associated Period Syndrome

(CAPS)

- Familial Cold Autoinflammatory Syndrome

(FCAS)

- Muckle-Wells Syndrome

- Active systemic juvenile idiopathic arthritis

- Tumor Necrosis Factor Receptor

Associated Periodic Syndrome (TRAPS)

- Hyperimmunoglobulin D Syndrome

(HIDS)/Mevalonate Kinase Deficiency

(MKD)

- Familial Mediterranean Fever (FMF).

Not approved for gouty flare up because of safety concerns (2011)

Cost per dose: $16K ($200K/y)

Canakinumab Anti-inflammatory Thrombosis

Outcomes Study (CANTOS)

Randomized

Canakinumab 150 mg

SC q 3 months

Randomized

Placebo

SC q 3 months

Primary Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE)

Randomized

Canakinumab 300 mg

SC q 3 months

Secondary Endpoint: MACE plus Unstable Angina Requiring Urgent Revascularization (MACE+)

Additional Adjudicated Endpoints: Cancer, Infection

Randomized

Canakinumab 50 mg

SC q 3 months

N = 10,061

39 Countries

April 2011 - June 2017

1490 Primary Events

Ridker PM et al. N Engl J Med. 2017;377:1119-31

Stable CAD (post MI)

Residual Inflammatory Risk

(hsCRP > 2 mg/L)

Characteristic

Placebo

(N=3347)

Canakinumab SC q 3 months

50 mg

(N=2170)

150 mg

(N=2284)

300 mg

(N=2263)

Age (years) 61.1 61.1 61.2 61.1

Female (%) 25.9 24.9 25.2 26.8

Current smoker (%) 22.9 24.5 23.4 23.7

Diabetes (%) 39.9 39.4 41.8 39.2

Lipid lowering therapy (%) 93.7 94.0 92.7 93.5

Renin-angiotensin inhibitors (%) 79.8 79.3 79.8 79.6

Prior Revascularization (%) 79.6 80.9 82.2 80.7

LDL cholesterol (mg/dL) 82.8 81.2 82.4 83.5

HDL cholesterol (mg/dL) 44.5 43.7 43.7 44.0

Triglycerides (mg/dL) 139 139 139 138

hsCRP (mg/L) 4.1 4.1 4.2 4.1

CANTOS - Baseline Clinical Characteristics

Ridker PM et al. N Engl J Med. 2017;377:1119-31

10

0

10

20

30

40

50

60

70

Pe

rcent C

ha

nge fro

m B

ase

line (

me

dia

n)

hs

CR

P

LD

LC

H

DL

C

TG

0 3 6 12 24 36 48

10

0

-10

10

0

-10

10

0

-10

Placebo Canakinumab 50 Canakinumab 150 Canakinumab 300

9

Months

Placebo SC q 3 mth

Canakinumab 50mg SC q 3 m (D = - 26%)

Canakinumab 150mg SC q 3 m (D = - 37%)

Canakinumab 300mg SC q 3 m (D = - 41%)

CANTOS:Effects on Inflammatory Biomarkers & Lipids (48m)

Ridker PM et al. N Engl J Med. 2017;377:1119-31

CANTOS Trial

Primary Cardiovascular Endpoints

Ridker PM et al. N Engl J Med. 2017;377:1119-31

HR 0.85

95%CI 0.76-0.96

P = 0.007

Cu

mu

lati

ve In

cid

ence

(%

)

Follow-up Years

HR 0.83

95%CI 0.74-0.92

P = 0.0006

MACE MACE - Plus

Follow-up Years

0 1 2 3 4 5 C

um

ula

tive

Inci

den

ce (

%) HR 0.83

95%CI 0.74-0.92

P = 0.0006

Placebo SC q 3 months

Canakinumab 150/300 mg SC q 3 months

CANTOS Primary Clinical Outcome Effects Dose Response

Ridker PM et al. N Engl J Med. 2017;377:1119-31

Endpoint

Placebo

(N=3347)

Canakinumab SC q 3 months

50 mg

(N=2170)

150 mg

(N=2284)

300 mg

(N=2263)

P-trend

Primary Endpoint

IR (per 100 PY)

HR 95%CI

P value

4.5

1.0

(referent)

(referent)

4.1

0.93

(0.80-1.07)

0.30

3.9

0.85

(0.74-0.98)

0.021*

3.9

0.86

(0.75-0.99)

0.031

0.020

Secondary Endpoint

IR (per 100PY)

HR

95%CI

P value

5.1

1.00

(referent)

(referent)

4.6

0.90

(0.78-1.03)

0.11

4.3

0.83

(0.73-0.95)

0.005*

4.3

0.83

(0.72-0.94)

0.004

0.003

*Statistically significant adjusted for multiplicity

Only 150 mg dose met multiplicity-adjusted PEP & SEP

CANTOS Components of PEP

Ridker PM et al. N Engl J Med. 2017;377:1119-31

Endpoint

Placebo

(N=3347)

Canakinumab SC q 3 months(HR)

P-trend 50 mg

(N=2170)

150 mg

(N=2284)

300 mg

(N=2263)

Primary 1.00 0.93 0.85 0.86 0.020

Secondary 1.00 0.90 0.83 0.83 0.002

Myocardial Infarction 1.00 0.94 0.76 0.84 0.028

Urgent

Revascularization 1.00 0.70 0.64 0.58 0.005

Any Coronary

Revascularization 1.00 0.72 0.68 0.70

Ridker PM et al. N Engl J Med. 2017;377:1119-31

0.5 Canakinumab

Superior

Canakinumab

Inferior

0.5 Canakinumab

Superior

Canakinumab

Inferior

1.0

Group

Women

Men

Age < 60 yrs

Age > 60 yrs

Diabetes

No diabetes

Non Smoker

Smoker

BMI < 30 kg/m2

BMI > 30 kg/m2

LDLC < 80 mg/dL

LDLC > 80 mg/dL

hsCRP > 2 to 4 mg/L

HDLC > 45 mg/dL

HDLC < 45 mg/dL

TG < 150 mg/dL

TG > 150 mg/dL

Overall

MACE MACE Plus

1.0

CANTOS Subgroup Analysis: Consistency of Treatment

CANTOS Safety Outcomes

Ridker PM et al. N Engl J Med. 2017;377:1119-31

Adverse event

Placebo

(N=3347)

Canakinumab SC q 3 months P-trend 50 mg

(N=2170)

150 mg

(N=2284)

300 mg

(N=2263)

Any SAE 12.0 11.4 11.7 12.3 0.43

Leukopenia 0.24 0.30 0.37 0.52 0.002

Any infection 2.86 3.03 3.13 3.25 0.12

Fatal infection 0.18 0.31 0.28 0.34 0.09/0.02*

Injection site reaction 0.23 0.27 0.28 0.30 0.49

Any Malignancy 1.88 1.85 1.69 1.72 0.31

Fatal Malignancy 0.64 0.55 0.50 0.31 0.0007

Arthritis 3.32 2.15 2.17 2.47 0.002

Osteoarthritis 1.67 1.21 1.12 1.30 0.04

Gout 0.80 0.43 0.35 0.37 0.0001

ALT > 3x normal 1.4 1.9 1.9 2.0 0.19

risk of leukopenia, thrombocytopenia, and fatal infection risk of fatal cancer, osteoarthritis and gout

* P-value for combined canakinumab doses vs placebo

Benefit-risk balance of Canakinumab

Robustness of outcomes

Lack of low or normal hsCRP group

Totality of evidence

Implications

Evaluation of CANTOS Trial

Deep Dive

BenefitRisk Balance of Canakinumab (CANTOS)

1000 Patients Treated with Canagliflozin for 3.7 years

Benefit Risk

Canakinumab 150 mg

6 MACE events prevented - 5 MIs prevented

11 fewer coronary PCI/CABG - 2 fewer hosp. UA UR

1 fewer fatal cancer 11 fewer arthritis - 4 fewer gouty arthritis

1 excess fatal infection 1 excess leukopenia 1 excess thrombocytopenia No excess liver toxicity No excess injection site reactions No excess hemorrhage

No effect on stroke, CV death or all-cause mortality

Benefit-risk balance of Canakinumab

Robustness of outcomes

Lack of low or normal hsCRP group

Totality of evidence

Implications

Evaluation of CANTOS Trial

Deep Dive

Quantity of Evidence Necessary to Support

Effectiveness of Drugs and Biologics: FDA

CFR Statutory criterion

FDC Act 1962

Substantial evidence of effectiveness

consisting of adequate and well-controlled

investigations, i.e., two separate trials each with

p

Regulatory criterion Attribute

Pre-specification

Su