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 vehemence a eminence 2 Peter McCulloch The Lancet, 2004;363;9004
Interleukin-1b as a Target for Atherosclerosis Biologic Basis for CANTOS and Beyond Libby P. JACC (October 31, 2017)
Modulation of IL-1b for Atheroprotection 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) Can Inflammation Reduction, in the Absence of Lipid Lowering, Reduce Cardiovascular Event Rates? Ridker PM. Circ Res 2016;118:145-156.
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+) Additional Adjudicated Endpoints: Cancer, Infection Ridker PM et al. N Engl J Med. 2017;377:1119-31
CANTOS - Baseline Clinical Characteristics Canakinumab SC q 3 months Characteristic 50 mg 150 mg 300 mg Placebo (N=2170) (N=2284) (N=2263) (N=3347) 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 Ridker PM et al. N Engl J Med. 2017;377:1119-31
TG Percent Change from Baseline (median) HDLC LDLC hscrp CANTOS:Effects on Inflammatory Biomarkers & Lipids (48m) 10 0 10 20 30 40 50 60 70 10 0-10 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%) 10 0-10 10 0-10 0 3 6 9 12 24 36 48 Months Placebo Canakinumab 50 Canakinumab 150 Canakinumab 300 Ridker PM et al. N Engl J Med. 2017;377:1119-31
Cumulative Incidence (%) Cumulative Incidence (%) CANTOS Trial Primary Cardiovascular Endpoints MACE Placebo SC q 3 months Canakinumab 150/300 mg SC q 3 months 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 Follow-up Years 0 1 2 3 4 5 Follow-up Years Ridker PM et al. N Engl J Med. 2017;377:1119-31
CANTOS Primary Clinical Outcome Effects Dose Response Endpoint Primary Endpoint IR (per 100 PY) HR 95%CI P value Secondary Endpoint IR (per 100PY) HR 95%CI P value Placebo (N=3347) 4.5 1.0 (referent) (referent) 5.1 1.00 (referent) (referent) *Statistically significant adjusted for multiplicity Canakinumab SC q 3 months 50 mg (N=2170) 4.1 0.93 (0.80-1.07) 0.30 4.6 0.90 (0.78-1.03) 0.11 150 mg (N=2284) 3.9 0.85 (0.74-0.98) 0.021* 4.3 0.83 (0.73-0.95) 0.005* Ridker PM et al. N Engl J Med. 2017;377:1119-31 300 mg (N=2263) 3.9 0.86 (0.75-0.99) 0.031 4.3 0.83 (0.72-0.94) 0.004 Only 150 mg dose met multiplicity-adjusted PEP & SEP P-trend 0.020 0.003
CANTOS Components of PEP Canakinumab SC q 3 months(hr) Endpoint Placebo 50 mg 150 mg 300 mg P-trend (N=3347) (N=2170) (N=2284) (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 Any Coronary Revascularization 1.00 0.70 0.64 0.58 0.005 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 Ridker PM et al. N Engl J Med. 2017;377:1119-31
CANTOS Subgroup Analysis: Consistency of Treatment 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 0.5 Canakinumab Superior 1.0 Canakinumab Inferior Ridker PM et al. N Engl J Med. 2017;377:1119-31 0.5 Canakinumab Superior 1.0 Canakinumab Inferior
CANTOS Safety Outcomes Canakinumab SC q 3 months Adverse event Placebo 50 mg 150 mg 300 mg P-trend (N=3347) (N=2170) (N=2284) (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 * P-value for combined canakinumab doses vs placebo risk of leukopenia, thrombocytopenia, and fatal infection risk of fatal cancer, osteoarthritis and gout Ridker PM et al. N Engl J Med. 2017;377:1119-31
Evaluation of CANTOS Trial Deep Dive Benefit-risk balance of Canakinumab Robustness of outcomes Lack of low or normal hscrp group Totality of evidence Implications
Benefit Risk Balance of Canakinumab (CANTOS) 1000 Patients Treated with Canagliflozin for 3.7 years Benefit 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 Canakinumab 150 mg Risk 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
Evaluation of CANTOS Trial Deep Dive Benefit-risk balance of Canakinumab Robustness of outcomes Lack of low or normal hscrp group Totality of evidence Implications
Quantity of Evidence Necessary to Support Effectiveness of Drugs and Biologics: FDA CFR FDC Act 1962 FDA Evidence Guidance for Industry, 1998 FDAMA 115 (1998) Statutory criterion 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) 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) One adequate and well-controlled study and confirmatory evidence.
Evaluation of CANTOS Trial Robustness of Outcomes from a Regulatory Perspective 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 Preservation of Type 1 error (adjustment for multiple comparisons) 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% P value for MACE & MACE+ not robust enough (0.02074 & 0.00525; multiplicity-adjusted a threshold = 0.02115 & 0.00529, respectively) MACE or MACE+ does not meet the regulatory criterion for a superiority claim based on substantial evidence of effectiveness
Study Group Moderating Robustness of Results Bayesian Analysis of MACE in CANTOS OUTCOME EVENT Total + - Ept 320 2284 5795 Evidence 0.85 (0.74 0.98) Posterior 0.88 (0.77, 1.00) Con 535 3344 4347 Prior (skeptical) 1.00 (0.75, 1.33) Total 855 5628 6483 Canakinumab Control 2284 3344 Incidence Rate (100PY) 3.9 4.5 HR 95% CI P (2-tailed) 0.85 0.74, 0.98 0.021 Minimum Bayes Factor: 0.0799 N -0.50-0.25 0.00 0.25 0.50 Benefit Log OR Harm Prior NP Post NP 0.50 0.07 0.75 0.19 0.90 0.42 Weak to moderate evidence that requires independent substantiation in subsequent studies
Evaluation of CANTOS Trial Deep Dive Benefit-risk balance of Canakinumab Robustness of outcomes Lack of low or normal hscrp arm Totality of evidence Implications
Evaluation of CANTOS Trial Lack of Low or Normal hscrp Arm 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) Without including an arm with low or no inflammation (hscrp <2), can one be sure that CANTOS unequivocally validates the inflammatory hypothesis?
Evaluation of CANTOS Trial Deep Dive Benefit-risk balance of Canakinumab Robustness of outcomes Lack of low or normal hscrp group Totality of evidence Implications
Inflammatory Hypothesis for Atherothrombosis Totality of Evidence Inflammation CANTOS Pro (Canakinumab: anti-il1b)? LoDoCo (Colchicine) Con 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
Evaluation of CANTOS Trial Deep Dive Benefit-risk balance of Canakinumab Robustness of outcomes Lack of low or normal hscrp group Totality of evidence Implications
CANTOS: Responder Analysis (On-Rx hscrp < vs >2) Confirmed MACE by 3 Month hscrp Cumulative Incidence 0.00 0.05 0.10 0.15 0.20 0.25 Confirmed MACE by 3 Month hscrp HR (95% CI) P Placebo On Treatment hscrp: >=2.0 mg/l On Treatment hscrp: <2.0 mg/l 1.0 (ref) (ref) 0.95 (0.84,1.09) 0.48 0.75 (0.66,0.85) <0.0001 hscrp >2mg/L hscrp <2mg/L No. at risk: 0 1 2 3 4 5 Follow-up (years) 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 Ridker PM et al. Lancet 2017; AHA 2017
CANTOS Sensitivity Analysis (MACE) Alternative Thresholds for On-treatment hscrp On-treatment hscrp Threshold hscrp < or > clinical cutpoint (2 mg/l) hscrp < or > median (1.8 mg/l) hscrp > or < 50% reduction hscrp > or < Median % (58%) reduction HR (adjusted) 95% CI P HR (adjusted) 95% CI P HR (adjusted) 95% CI P HR (adjusted) 95% CI P Placebo 1.0 1.0 1.0 1.0 Canakinumab On-treatment hscrp above threshold 0.90 0.79-1.02 0.11 0.90 0.79-1.02 0.10 0.87 0.76-1.00 0.05 0.86 0.75-0.98 0.02 Canakinumab On-treatment hscrp below threshold 0.75 0.66-0.85 <0.0001 0.73 0.64-0.84 <0.0001 0.81 0.71-0.91 0.0008 0.80 0.70-0.92 0.001 HRs adjusted for age, gender, smoking, HTN, diabetes, BMI, baseline hscrp, Baseline LDLC Binary response according to clinical cutpoint or median change, but not 50% or median % Ridker PM et al. Lancet 2017; AHA 2017
CANTOS Responder Analysis (hscrp < 2 vs >2) Impact on CV Outcomes Clinical Outcome MACE MACE+ CV death All-cause mortality HR (adjusted) 95% CI P HR (adjusted) 95% CI P HR (adjusted) 95% CI P HR (adjusted) 95% CI P Placebo 1.0 1.0 1.0 1.0 Canakinumab hscrp > 2mg/L (N = 2868) 0.90 0.79-1.02 0.11 0.91 0.81-1.03 0.14 0.99 0.82-1.21 0.95 1.05 0.90-1.22 0.56 Canakinumab hscrp < 2 mg/l (N = 3484) 0.75 0.66-0.85 <0.0001 0.74 0.66-0.83 <0.0001 0.69 0.56-0.85 0.0004 0.69 0.58-0.81 <0.0001 HRs adjusted for age, gender, smoking, HTN, diabetes, BMI, baseline hscrp, Baseline LDLC Binary response according to clinical cutpoint for all outcomes Ridker PM et al. Lancet 2017; AHA 2017
CANTOS Responder Analysis (hscrp < 2 vs >2) Impact of Canakinumab Dose on MACE Canakinumab dose 50 mg SC q 3 months 150 mg SC q 3 months 300 mg SC q 3 months HR (adjusted) 95% CI P HR (adjusted) 95% CI P HR (adjusted) 95% CI P Placebo 1.0 1.0 1.0 Canakinumab hscrp > 2mg/L (N = 2868) 0.96 0.80-1.14 0.63 0.86 0.71-1.04 0.11 0.87 0.71-1.07 0.18 Canakinumab hscrp < 2 mg/l (N = 3484) 0.78 0.63-0.96 0.02 0.75 0.62-0.91 0.003 0.74 0.62-0.88 0.0009 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 HRs adjusted for age, gender, smoking, HTN, diabetes, BMI, baseline hscrp, Baseline LDLC Binary response according to clinical cutpoint for all 3 doses Ridker PM et al. Lancet 2017; AHA 2017
CANTOS Responder Analysis (hscrp < 2 vs >2) Impact on Fatal Infection Clinical Outcome Fatal Infection Incidence rate (per 100 person years) Placebo Canakinumab hscrp > 2mg/L (N = 2868) Canakinumab hscrp < 2 mg/l (N = 3484) 0.18 0.35 0.27 ---------------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 How does one explain lack of increase in incident fatal infection while observing greater CV risk reduction with greater IL-1b blockade? Ridker PM et al. Lancet 2017; AHA 2017
CANTOS Responder Analysis Limitations that Challenge Interpretation Known Cardiovascular Disease LDL 150 mg/dl hscrp 7.0 mg/l High Intensity Statin Residual Inflammatory Risk LDL 70 mg/dl hscrp 3.0 mg/l Residual Inflammatory Risk LDL 70 mg/dl hscrp 6.0 mg/l Canakinumab 150mg SC hscrp 1.8 mg/l (3 month) D = 1.2mg/L or <50% hscrp 2.8 mg/l (3 month) D = 3.2mg/L or >50% Which patient is a responder and should be a candidate for treatment?
CANTOS Responder Analysis (hscrp <2 @ 3m) Limitations that Challenge Interpretation 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
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