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Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials

Arthritis Advisory Committee

March 4, 2003

Ellis F. Unger, M.D.

Office of Therapeutics Research and Review (OTRR)

Center for Biologics Evaluation and Research (CBER)

U.S. Food and Drug Administration (US FDA)

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Why the Interest in Anti-TNF- Strategies in CHF?

• Clinical observations:

• elevated TNF- levels in patients with CHF, especially cardiac cachexia

• Preclinical data showing:

• TNF--induced LV dysfunction

• deleterious effects on LV remodeling

3

Anti-TNF- Hypotheses in CHF:

• TNF- contributes to the morbidity of CHF

• Anti-TNF- therapies would have salutary effects in patients with CHF

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Randomized Controlled Trials of TNF- Blockers in CHF:

• Etanercept

2 Randomized Controlled Studies:

• “RENAISSANCE”

• “RECOVER”

• Infliximab

1 Randomized Controlled Study:

• “ATTACH”

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Studies of Etanercept in CHF:

“RENAISSANCE”

“RECOVER”

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Etanercept in CHF:

“RENAISSANCE” - conducted by Immunex in North America; ~900 subjects

“RECOVER” - conducted by Wyeth in Europe, Israel, Australia, New Zealand; ~1100 subjects

Both:

• phase 2/3

• randomized

• double-blind

• placebo-controlled

• multicenter

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Inclusion Criteria:

• CHF on ischemic or non-ischemic basis

• ejection fraction < 30%

• symptoms of CHF X 3 months

• NYHA Functional Class 2, 3, or 4

• receiving diuretic and ACE inhibitor

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Randomization - Dosing Regimens:

Randomization 1:1:1 - blocked by study site, NYHA FC, and -blocker use

RENAISSANCE RECOVER

Enbrel 1X per week

25 mg SC 2X per week * 2X per week *

3X per week

Placebo 2X or 3X per week

Treatment duration > 24 weeks

* regimen licensed for RA

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RENAISSANCE & RECOVER: Endpoints

Primary endpoints:

• “Clinical Composite Score” at 24 weeks

(Score improved, worse, unchanged)

• Combined endpoint across both studies:

Mortality or CHF hospitalization

(BIW + TIW) vs. placebo

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Clinical Composite Score “Worse” if:

· subject died

· was hospitalized for CHF

· worsened NYHA FC

· “Global Assessment” (judged by subject) moderately or markedly worse

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Clinical Composite Score “Improved” if:

· the Clinical Composite Score was not worse

AND

· NYHA FC is improved OR

· “Global Assessment” moderately or markedly improved

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Clinical Composite Score “Unchanged” if:

Clinical Composite Score neither better nor worse.

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Results

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March 2001: Studies Stopped for Futility

At a planned interim review, the DSMB recommended that both RENAISSANCE and RECOVER be halted because the pre-specified results indicating futility had been observed.

Median follow-up:

RENAISSANCE - 12.7 months

RECOVER - 5.7 months

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Patient Demographic & Baseline Disease Characteristics: RENAISSANCE

Age: 62.3 years (mean)

Gender: 78% male

Race: 84% Caucasian;

11% African Ancestry

CHF duration: 5.6 years (mean)

Ejection Fraction: 22.3% (mean)

NYHA FC: FC II – 24%

FC IIIa – 47%

FC IIIb – 25%

FC IV – 5%

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Imbalances in Patient Demographics & Disease Characteristics: RENAISSANCE

Treatment groups well balanced with respect to demographic and baseline characteristics

4 notable exceptions. For the placebo group, on average, baseline:

• BP was higher

• 6-minute walk was longer

• antiarrhythmic use was less frequent

• atrial fib/flutter was less frequent

These imbalances were small, but all would be associated with a more favorable prognosis in the placebo group.

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Demographic & Baseline Characteristics: RECOVER

Age: 64.6 years

Gender: 78% male

Caucasian: 99%

CHF duration: 4.6 years

Ejection Fraction: 24.2%

NYHA FC: FC II – 27%

FC IIIa – 45%

FC IIIb – 25%

FC IV – 3%

* Good balance across treatment groups

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Clinical Composite Score at Week 24: RENAISSANCE

placebo Enbrel BIW Enbrel TIW0

20

40

60

80

100

% o

f P

atie

nts

improved same worse

44% 39% 42%

36%32% 31%

20% 29% 27%

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Clinical Composite Score at Week 24: RECOVER

placebo Enbrel QW Enbrel BIW0

20

40

60

80

100

% o

f P

atie

nts

improved same worse

32% 33% 38%

50% 47% 43%

19% 21% 19%

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1° Endpoint: All-Cause Mortality and CHF Hospitalizations Across Both Studies (Enbrel BIW + TIW vs. placebo)

0 8 16 24 32 40 48 56 64 72 80 88 96

time (weeks)

0.5

0.6

0.7

0.8

0.9

1.0

cum

ula

tive

eve

nt-

free

su

rviv

al

placebo (n=682)

TNFR biw + tiw (n=991)

log-rank p-value = 0.15

Placebo (n=682)

Enbrel BIW +TIW (n=991)

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0 8 16 24 32 40 48 56 64 72 80 88 96

time (weeks)

0.6

0.7

0.8

0.9

1.0cu

mu

lati

ve s

urv

ival

placebo (n=309)

TNFR biw (n=308)

TNFR tiw (n=308)

All-Cause Mortality: RENAISSANCE

14.2%

17.9%

19.8%

Placebo (n=309)

Enbrel BIW (n=308)

Enbrel TIW (n=308)

1/4 remain at risk

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All-Cause Mortality: RECOVER

0 8 16 24 32 40 48 56 64 72 80 88 96

time (weeks)

0.6

0.7

0.8

0.9

1.0cu

mu

lati

ve s

urv

ival

placebo (n=373)

TNFR qw (n=375)

TNFR biw (n=375)

Placebo (n=373)

Enbrel QW (n=375)

Enbrel BIW (n=375)

5.9%

7.2%

8.8%

1/4 remain at risk

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Comparison of Subject Populations:

RENAISSANCE vs. RECOVER

RENAISSANCE RECOVER

age (years) 62.3 64.6Caucasian (%) 83.6 99.4weight (kg) 84.5 79.0BPs (mm Hg) 108 120BPd (mm Hg) 66 75VT / VF (%) 23 11HTN (%) 55 45hyperlipidemia (%) 61 44use of K+ sparing diuretic (%) 33 91use of digitalis compounds (%) 82 54use of lipid lowering agents (%) 55 37use of nitrates (%) 44 52

exploratory analyses performed

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RENAISSANCE: Mortality by Treatment and NYHA Functional Class

0 8 16 24 32 40 48 56 64 72 80 88 96time (weeks)

0.4

0.5

0.6

0.7

0.8

0.9

1.0

cum

ula

tive

su

rviv

al

placebo (n=77)

TNFR biw (n=75)

TNFR tiw (n=75)

0 8 16 24 32 40 48 56 64 72 80 88 96time (weeks)

0.4

0.5

0.6

0.8

0.9

1.0

cum

ula

tive s

urv

ival

placebo (n=142)

TNFR biw (n=141)

TNFR tiw (n=141)

0 8 16 24 32 40 48 56 64 72 80 88 96time (weeks)

0.4

0.5

0.6

0.8

0.9

1.0

placebo (n=76)

TNFR biw (n=76)

TNFR tiw (n=77)

FC II FC IIIa FC IIIb

Placebo (n=77)

Enbrel BIW (n=75)

Enbrel TIW (n=75)

Placebo (n=142)

Enbrel BIW (n=141)

Enbrel TIW (n=141)

Placebo (n=76)

Enbrel BIW (n=76)

Enbrel TIW (n=77)

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RENAISSANCE: Cardiovascular SAEs

Placebo Etanercept

BIW TIW

n = 307 n = 305 n = 307

increased CHF 67 (22%) 81 (27%) 77 (25%)

cardiac arrest 6 (2%) 12 (4%) 10 (3%)

ventricular tachycardia 10 (3%) 7 (2%) 12 (4%)

angina pectoris 13 (4%) 12 (4%) 6 (2%)

syncope 9 (3%) 10 (3%) 7 (2%)

atrial fibrillation 5 (2%) 6 (2%) 7 (2%)

acute MI 7 (2%) 0 4 (1%)

coronary artery disease 5 (2%) 0 1 (<1%)

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RENAISSANCE: Selected AEs

Placebo Etanercept

BIW TIW

n = 307 n = 305 n = 307

dizziness 52 (17%) 62 (20%) 71 (23%)

pain chest 37 (12%) 42 (14%) 56 (18%)

angina pectoris 20 (7%) 17 (6%) 10 (3%)

hypotension 33 (11%) 32 (10%) 24 (8%)

syncope 18 (6%) 21 (7%) 21 (7%)

atrial fibrillation 14 (5%) 19 (6%) 16 (5%)

ventricular tachycardia 18 (6%) 16 (5%) 18 (6%)

palpitations 16 (5%) 5 (2%) 12 (4%)

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RECOVER: Cardiovascular SAEs

Placebo Etanercept

BIW TIW

n = 373 n = 375 n = 375

increased CHF 9% 13% 12%

angina pectoris 2% 2% 2%

cardiac arrest 2% 2% 2%

V-tach 1% 1% 0%

V-fib <1% <1% 1%

syncope 1% <1% 1%

atrial fibrillation 1% 1% <1%

AMI 1% 1% 1%

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Summary: Etanercept in CHF (1)

• No evidence that Etanercept is beneficial in CHF

• The data suggest harm, though the results are not conclusive.

• The key finding of concern was a trend towards higher mortality in Etanercept-treated subjects in RENAISSANCE; this was heightened by the apparent dose-response relation.

• The results of RECOVER do not substantiate the findings of Renaissance with respect to Etanercept-induced mortality in CHF.

• The greatest concern is for an Enbrel dose higher than that currently licensed for RA in the US.

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Summary: Etanercept in CHF (2)

• The data do not suggest a specific mechanism of action leading to Etanercept-related adverse outcomes in the CHF patient population.

• Exploratory analyses failed to identify specific factors associated with increased risk of adverse events. In particular, patients in Renaissance with milder CHF (NYHA FC II) did not appear to be at a lower risk of adverse outcomes.

In labeling, there is no basis to provide:

• a measure of reassurance for patients with mild forms of CHF;

• a listing of factors that appear to predispose to worsening CHF

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Study of Infliximab in CHF:

“ATTACH”

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ATTACH:

• phase 2 pilot trial

• randomized

• double-blind

• placebo-controlled

• multicenter (32 centers in USA)

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Randomization - Dosing Regimens:

150 subjects randomized 1:1:1 to:

infliximab 5 mg/kg at 0, 2 and 6 weeks

infliximab 10 mg/kg at 0, 2 and 6 weeks

placebo at 0, 2 and 6 weeks

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ATTACH: Inclusion Criteria

• symptoms of CHF X 3 months

• NYHA functional class 3, or 4

• LV ejection fraction 35%

• receiving diuretic and ACE inhibitor

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ATTACH: Primary Endpoint

“Clinical Status” at 14 weeks:

improved, worse, or unchanged

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ATTACH: Clinical Status at Week 14

placebo 5 mg/kg 10 mg/kg0

20

40

60

80

100

% o

f P

atie

nts

improved same worse

8% 10%22%

59% 52%39%

33% 38% 39%

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ATTACH: Clinical Status at Week 28

placebo 5 mg/kg 10 mg/kg0

20

40

60

80

100

% o

f P

atie

nts

improved same worse

14% 16%31%

49%43%

31%

37%35%43%

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ATTACH: All-Cause Mortality Through One Year

InfliximabPlacebo 5 mg/kg 10 mg/kg(n = 48) (n = 50) (n = 51)

Deaths 4 (8.2%) 4 (8.0%) 8 (15.7%)

worsening heart failure 2 2 3

arrhythmia 0 1 0

acute MI 0 1 1

other cardiac 2 0 2

non-cardiovascular 0 0 2

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Infliximab:

Dear Healthcare Professional letter issued October 18, 2001

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ATTACH: Selected AEs

InfliximabPlacebo 5 mg/kg 10 mg/kg(n = 48) (n = 51) (n = 50)

Dizziness 2 (4.2%) 16 (31.4%) 10 (20.0%)

Dyspnea 6 (12.5%) 10 (19.6%) 12 (24.0%)

Cardiac failure 12 (25.0%) 6 (11.8%) 11 (22.0%)

Chest pain 4 (8.3%) 4 (7.8%) 5 (10.0%)

Angina pectoris 1 (2.1%) 3 (5.9%) 4 (8.0%)

Hypotension 0 (0.0%) 3 (5.9%) 4 (8.0%)

Pulmonary edema 3 (6.3%) 1 (2.0%) 4 (8.0%)

Ventricular tachycardia 4 (8.3%) 2 (3.9%) 3 (6.0%)

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Summary: Infliximab in CHF

• No evidence that Infliximab is beneficial in patients with CHF.

• Although the numbers of subjects treated are small, there is a strong trend suggesting increased mortality in CHF patients treated with Infliximab.

• The data do not show an increase in mortality with the 5 mg/kg dose; however, adverse event data suggest that the 5 mg/kg dose is deleterious.

• The mechanism underlying this apparent effect is unclear.

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Post-Marketing Reports of CHF:

51 cases reported as of February, 2002:

30 received Etanercept; 21 received Infliximab

• 42 reports of new onset CHF - - half with no identifiable risk factors

• 9 reports of CHF exacerbation

Median age = 64 yrs (range 19 to 87 years)

Median time to onset 3.5 months (range: 24 hours to 24 months)

20% were < 50 years old

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• 10 cases:– 6 received infliximab & 4 received

etanercept – Median ejection fraction = 20%

(range 10 to 45%, n=9)– 3 with underlying risk factors for CHF– After discontinuation of TNF antagonists

and HF treatment:• 3 reported complete resolution of CHF• 6 reported improvement• 1 reported death

CHF Cases in Patients Under 50 Years Old

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• Significant overlap between CHF and RA in the general population, to a lesser extent CHF & Crohn’s Disease

• Data from RCT’s in the CHF population raise concerns about the safety of Infliximab and Etanercept.

• Post-marketing data raise concern regarding new-onset CHF.

• CBER plans comprehensive analyses of the RCT databases of all 3 TNF-blockers.

• Specific language for labeling is under discussion.

Summary: TNF Blockers and CHF: