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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


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%)



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


CANTOS Trial

Primary Cardiovascular Endpoints


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


Endpoint

Placebo

(N=3347)


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


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 <0.001

Stroke 1.00 1.01 0.98 0.80 0.17

Cardiac Arrest 1.00 0.72 0.63 0.46 0.035

CV Death 1.00 0.89 0.90 0.94 0.62

All Cause Mortality 1.00 0.94 0.92 0.94 0.39

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


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

hsCRP > 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


Adverse event

Placebo

(N=3347)


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

Benefit–Risk 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





• Implications


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<0.05 (0.025 x 0.025 = 0.000625 = 0.001)

FDA Evidence

Guidance for Industry,

1998

“A highly reliable and statistically persuasive (p

value <0.001) evidence of an important clinical

benefit in a single trial with some other indication

of the study’s reliability (e.g., multicenter with no

center driving the results)”

FDAMA 115 (1998) “One adequate and well-controlled study and

confirmatory evidence.”

Regulatory criterion Attribute

Pre-specification

• Superiority for MACE (PEP), MACE+ (key SEP #1),

and new-onset T2DM among pre-diabetics (key SEP

#2) prespecified for all 3 doses

• Exploratory analysis for incident & fatal overall

cancer (but not lung cancer) prespecified

Replication • MACE or MACE+ does not meet ‘statistically

persuasive’ criterion for a single trial result, i.e. P<0.001,

thereby ensuring a replication probability of >90%

Preservation of Type 1

error (adjustment for

multiple comparisons)

• P value for MACE & MACE+ not robust enough

(0.02074 & 0.00525; multiplicity-adjusted a threshold

= 0.02115 & 0.00529, respectively)


Robustness of Outcomes from a Regulatory Perspective

MACE or MACE+ does not meet the regulatory criterion for a

superiority claim based on “substantial evidence” of effectiveness

-0.50 -0.25 0.00 0.25 0.50

Moderating Robustness of Results Bayesian Analysis of MACE in CANTOS

Prior NP Post NP

0.50 0.07

0.75 0.19

0.90 0.42

HR 95% CI P (2-tailed)

0.85 0.74, 0.98 0.021

4.5

3.9

Incidence

Rate (100PY)

3344

2284

N

Control

Canakinumab

OUTCOME EVENT Total

+ -

Group

Ept 320 2284 5795

Study

Con 535 3344 4347

Total 855 5628 6483

Harm Benefit Log OR

Prior (skeptical)

1.00 (0.75, 1.33)

Evidence

0.85

(0.74 0.98)

Posterior

0.88 (0.77, 1.00)

Minimum Bayes Factor: 0.0799

Weak to moderate evidence that requires independent substantiation in subsequent studies



• Lack of low or normal hsCRP arm


• Implications


Deep Dive

• CANTOS used an ‘enriched’ population

- High-risk post-MI patients with residual inflammatory risk (hsCRP>2)

• Enrolling low or normal hsCRP arm would inflate the sample size

• FDA-approved claim for Rosuvastatin based on JUPITER

- “Rosuvastatin is indicated in patients with one additional risk factor in

addition to the JUPITER criterion based on age and hsCRP>2”

- JUPITER excluded patients with hsCRP<2

• HOPE-3 trial (rosuvastatin for primary prevention)

- co-PEP #1 (MACE): HR of 0.82 (hsCRP<2) and 0.77 (hsCRP >2)

- co-PEP #2 (MACE, cardiac arrest, CHF, revascularization):

HR of 0.79 (hsCRP<2) and 0.78 (hsCRP >2)


Lack of Low or Normal hsCRP Arm

Without including an arm with low or no inflammation (hsCRP <2), can one

be sure that CANTOS unequivocally validates the inflammatory hypothesis?





• Implications


Deep Dive

Inflammatory Hypothesis for Atherothrombosis Totality of Evidence

Pro Con

Inflammation

• CANTOS

(Canakinumab: anti-IL1b)

• ? LoDoCo

(Colchicine)

• Lp-PLA2 inhibition

(Darapladib; 2 negative trials:

STABILITY, SOLID-TIMI 52)

• Steroids ↑ atherogenesis

• NSAIDs ↑ CVD risk

• Anti-TNF-a agents ↑ mortality

Validation of the inflammatory hypothesis implies that targeting of

molecules involved in inflammation reduces CV risk





• Implications


Deep Dive

0 1 2 3 4 5

0.0

00.0

50.1

00.1

50.2

00.2

5

Cu

mu

lative

Incid

ence

Placebo

On Treatment hsCRP: >=2.0 mg/L

On Treatment hsCRP: <2.0 mg/L

Confirmed MACE by 3 Month hsCRP

HR (95% CI) P__________________________________________________________

1.0 (ref) (ref)

0.95 (0.84,1.09) 0.48

0.75 (0.66,0.85) <0.0001

Follow-up (years)No. at risk:

Placebo 3182 3014 2853 2525 1215 200

Canakinumab:hsCRP >= 2.0 mg/L 2868 2724 2574 2258 1087 195

hsCRP < 2.0 mg/L 3484 3353 3214 2890 1411 243

CANTOS: Responder Analysis (On-Rx hsCRP < vs >2)

Confirmed MACE by 3 Month hsCRP

Ridker PM et al. Lancet 2017; AHA 2017

hsCRP >2mg/L

hsCRP <2mg/L

On-treatment hsCRP Threshold

Placebo

Canakinumab

On-treatment hsCRP

above threshold

Canakinumab

On-treatment hsCRP

below threshold

hsCRP < or >

clinical cutpoint

(2 mg/L)

HR (adjusted)

95% CI

P

1.0

Referent

Referent

0.90

0.79-1.02

0.11

0.75

0.66-0.85

<0.0001

hsCRP < or >

median

(1.8 mg/L)

HR (adjusted)

95% CI

P

1.0

Referent

Referent

0.90

0.79-1.02

0.10

0.73

0.64-0.84

<0.0001

hsCRP > or <

50% reduction

HR (adjusted)

95% CI

P

1.0

Referent

Referent

0.87

0.76-1.00

0.05

0.81

0.71-0.91

0.0008

hsCRP > or <

Median % (58%)

reduction

HR (adjusted)

95% CI

P

1.0

Referent

Referent

0.86

0.75-0.98

0.02

0.80

0.70-0.92

0.001

HRs adjusted for age, gender, smoking, HTN, diabetes, BMI, baseline hsCRP, Baseline LDLC

CANTOS Sensitivity Analysis (MACE) Alternative Thresholds for On-treatment hsCRP


Binary response according to clinical cutpoint or median change, but not 50% or median % ↓

Clinical Outcome

Placebo

Canakinumab

hsCRP > 2mg/L

(N = 2868)

Canakinumab

hsCRP < 2 mg/L

(N = 3484)

MACE HR (adjusted)

95% CI

P

1.0

Referent

Referent

0.90

0.79-1.02

0.11

0.75

0.66-0.85

<0.0001

MACE+ HR (adjusted)

95% CI

P

1.0

Referent

Referent

0.91

0.81-1.03

0.14

0.74

0.66-0.83

<0.0001

CV death HR (adjusted)

95% CI

P

1.0

Referent

Referent

0.99

0.82-1.21

0.95

0.69

0.56-0.85

0.0004

All-cause

mortality

HR (adjusted)

95% CI

P

1.0

Referent

Referent

1.05

0.90-1.22

0.56

0.69

0.58-0.81

<0.0001


CANTOS Responder Analysis (hsCRP < 2 vs >2)

Impact on CV Outcomes


Binary response according to clinical cutpoint for all outcomes

Canakinumab dose

Placebo

Canakinumab

hsCRP > 2mg/L

(N = 2868)

Canakinumab

hsCRP < 2 mg/L

(N = 3484)

50 mg SC

q 3 months

HR (adjusted)

95% CI

P

1.0

Referent

Referent

0.96

0.80-1.14

0.63

0.78

0.63-0.96

0.02

150 mg SC

q 3 months

HR (adjusted)

95% CI

P

1.0

Referent

Referent

0.86

0.71-1.04

0.11

0.75

0.62-0.91

0.003

300 mg SC

q 3 months

HR (adjusted)

95% CI

P

1.0

Referent

Referent

0.87

0.71-1.07

0.18

0.74

0.62-0.88

0.0009



Binary response according to clinical cutpoint for all 3 doses


Impact of Canakinumab Dose on MACE

The proportions of those treated who achieved hsCRP levels < 2 mg/L were

44%, 55%, and 65% in the 50mg, 150mg, and 300mg canakinumab groups, respectively

Clinical Outcome

Placebo

Canakinumab

hsCRP > 2mg/L

(N = 2868)

Canakinumab

hsCRP < 2 mg/L

(N = 3484)

Fatal Infection

Incidence rate

(per 100 person years)

0.18

0.35

0.27


How does one explain lack of increase in incident fatal infection while

observing greater CV risk reduction with greater IL-1b blockade?


Impact on Fatal Infection

---------------FDA WARNINGS AND PRECAUTIONS------------

“Interleukin-1 blockade may interfere with immune response to infections.

Treatment with medications that work through inhibition of IL-1 has been

associated with an increased risk of serious infections”

CANTOS Responder Analysis Limitations that Challenge Interpretation

hsCRP 1.8 mg/L

(3 month)

Known Cardiovascular Disease

LDL 150 mg/dL

hsCRP 7.0 mg/L

hsCRP 2.8 mg/L

(3 month)

High Intensity Statin

LDL 70 mg/dL

hsCRP 6.0 mg/L

LDL 70 mg/dL

hsCRP 3.0 mg/L

“Residual Inflammatory Risk” “Residual Inflammatory Risk”

D = 1.2mg/L or <50% D = 3.2mg/L or >50% Canakinumab 150mg SC

Which patient is a “responder” and should be a candidate for treatment?

• Patients not randomized to treat-to-target strategy

• Observational dataset, vulnerable to residual confounding that cannot be

overcome by multivariable adjustment

• Individuals most likely to achieve targets are those who started out

with lower baseline values

• Patients achieving > median (58%) percentage reduction in hsCRP

versus not (a definition less influenced by baseline hsCRP), both groups

benefited with substantial overlap in 95% Cis (20% vs 14% RRR)

• Post-randomization variable (“improper” subgroup)

• Not reliable for regulatory or clinical-decision making

CANTOS Responder Analysis (hsCRP <2 @ 3m)

Limitations that Challenge Interpretation

Does CANTOS Provide the Elusive Validation of the Inflammatory Hypothesis?

The Verdict is in. No!

• Modest effect size which barely met multiplicity-adjusted P value for significance

• PEP driven by nonfatal outcomes (MI, revascularization)

• Vulnerable to missing data (1 or 2 excess events would overturn significance)

• Not consistent with the FDA statutory criterion of “substantial evidence”

• Evidence not strong enough to overcome reasonable degree of skepticism

• Reverse dose response for CV death (HR 0.80, 0.88 & 0.93 for 50, 150 & 300 mg)

• Lack of low/normal hsCRP arm precludes drawing firm conclusions

Does CANTOS Provide the Elusive Validation of the Inflammatory Hypothesis?

The Verdict is in. No! • Cancer outcomes exploratory and susceptible to ‘false positive’ error

• Blockade of innate immunity would be expected to impair tumor surveillance,

thereby potentially ↑ cancer risk (anti-TNF-a ↑ lymphoma; rilonacept ↑ malignancy)

• No affect on COPD incidence, a known risk factor for lung cancer, with

canakinumab or MEDI8968, a human anti-interleukin-1 receptor MAb

• Is reduced cancer risk related to anti-inflammatory effect or inhibition of tumor

invasiveness & metastasis mediated by MMP-2 or to a play of chance?

• Totality of evidence not consistent with the inflammatory hypothesis

• Prohibitive cost-effectiveness

CANTOS did move the needle forward for the inflammatory hypothesis,

but not beyond a reasonable doubt!

CVOTs Addressing the Inflammatory Hypothesis of Atherothrombosis

Trial Type Blind Power

(1-b) MDD (d) Cohort

Time

period

CIRT

(N=7,000)

Methotrexate

vs Placebo

Superiority DB 90%-95%

(514 events) HR 0.75

Post-MI + T2DM

or metabolic

syndrome

2013-

2019

LoDoCo2

(N=4,230)

Colchicine

vs Placebo

Superiority DB 90%

(331 events) HR 0.70 Stable CAD

2014-

2019

COLCOT

(N=4,500)

Colchicine

vs Placebo

Superiority DB 90%

(301 events) NR Post-MI <30d

2015-

2019

These trials are likely have a greater impact on the inflammatory hypothesis

given the safety, tolerability, & affordability of methotrexate and colchicine

“Extraordinary claims require extraordinary proof”

Marcello Truzzi

Documents

Targeting Inflammation in Atherosclerosis: Has CANTOS ... · Targeting Inflammation in Atherosclerosis: Has CANTOS Nailed It? Controversies and Advances in the ... SC q 3 months Secondary