Safety & Tolerability of Safety & Tolerability of BiologicsBiologics

Dubai, United Arab EmiratesDubai, United Arab EmiratesJanuary 19th, 2009January 19th, 2009

Prof. Joachim R. KaldenProf. Joachim R. KaldenDirector emeritusDirector emeritus

Department of Internal Medicine IIIDepartment of Internal Medicine IIIDiv. of Molecular ImmunologyDiv. of Molecular Immunology

Niklolaus-Fiebiger-CenterNiklolaus-Fiebiger-CenterUniversity of Erlangen-NurembergUniversity of Erlangen-Nuremberg

OverviewOverviewMonitoring of safety: registriesSafety: TuberculosisSafety: Serious infectious eventsSafety: MalignancySafety: Lymphoma

European registriesEuropean registriesPost approval commitment to EMEA that Wyeth would monitor safetyProfessional Societies independently supported establishment of registries to monitor safetyEstablished in a number of countries independently but with different approaches, with or without Reference groups Efficacy endpoints

Why important?Why important?Only source of comparisons with competitorsProviding rich stream of data for differentiationCurrently under analysed – registries focusing on limited number of questionsPotential for pooled analyses to give even greater power

Why are registries important Why are registries important to Wyethto Wyeth

Meet post approval commitmentLarge cohorts of Enbrel patients treated in clinical practiceSource of comparative data with MAbsResource for evaluation of safety and efficacyPotential to combine data to provide increased power to undertake analyses of rare events

Original registriesOriginal registriesSweden ARTIS – nationwide but organised on a regional basis

– STURE – Stockholm registry– SSAGT – Southern Sweden

Both ARTIS and the regional registries publish results No concurrently recruited controls but use other RA cohorts for reference

UK BSRBR - national registry powered to detect 2 fold increase in lymphoma in

comparison to a DMARD treated cohortGermany RABBIT – national registry to describe the long term effectiveness

– treatment continuation – clinical outcomes – long term hazards– direct and indirect costs

Comparison with conventional DMARD treatment from national databaseThese 3 registers meet together annually with companiesUse standard report which is sent companies twice a year for inclusion in safety reports to regulators

Estimates of patient Estimates of patient numbersnumbers

Country Started Date of Estimate

Total TNFi Controls

Sweden 1999 2008 14000 National DB

UK 2001 2008 12000 3300

Germany 2001 2008 5300 National DB

France

Spain 2000 2007 8320 N/A

Norway 2000 2006 1500 DMARDs

Denmark 2000 2006 1021 None

Czech 2001 2007 1040

Switzerland 2000 2005 1600 SCQM

Total 44781

Monitoring of safety: Monitoring of safety: problemsproblems

Controlled trials Relatively few pts, not the same patient population as

in clinical practice, seldom long-term, randomisation may create well-balanced comparator

Spontaneous reporting Very low reporting rates; only certain adverse drug

reactions (with attribution)Long-term observational studies Difficult to obtain enough compliance, need for

comparator data

Advantages and Advantages and disadvantages of registriesdisadvantages of registries

Advantages Usually much larger than

clinical trials Greater power than RCTs to

detect rare events Enrolment reflects clinical

practice Potential for studying

numerous outcomes Suited to long term follow-up Can examine complex

situations not suited to RCTs Results can usually be

generalised

Disadvantages Non randomised, subject to

bias Confounding by indication Missing data Potential for confounding Channelling bias Choice of reference group

Conditions Where Mechanism of Conditions Where Mechanism of Action Differences May Affect Action Differences May Affect

Safety ProfileSafety Profile

TBSerious Infectious Events (SIEs)Malignancy

Tuberculosis (TB)Tuberculosis (TB)

FDA MedWatch spontaneous FDA MedWatch spontaneous reporting system (AERS): reporting system (AERS):

20012001TB associated with infliximab70 reported cases of TB after treatment with infliximab for a median of 12 weeks 40/70 had extra-

pulmonary disease

Normal

Post-infliximab

Keane J. et al. NEJM 2001;345:1098-1104.

Inhibition of IFN gammaInhibition of IFN gamma

Effect of drugs on IFN production in whole blood cultures stimulated with M tb culture filtrate. Median and interquartile ranges n=15

Saliu et al. J Infect Dis 2006 .

TB associated with clinical TB associated with clinical trials: Ttrials: TB events despite B events despite

screeningscreeningAnti-TNF Agent Required

Screening for TBTB Event Rate(per 1000 pt-yr)

Etanercept (soluble receptor) Not mandated

Pooled analysis of all clinical trials across indications (Europe / N. America)4 (N=11,390; 2 cases TB)

0.11

Adalimumab (mAb) Yes

Pooled analysis Europe1 3.3Pooled analysis N. America1 0.8REACT Trial7 5.0

Infliximab (mAb) Yes

Pooled analysis Not availableSTART Trial2 13.1Infliximab vs abatacept trial3 12.1

Certolizumab (mAb) Yes

Pooled analysis Not availableRAPID I Trial4 6.9RAPID II Trial5 12.5

Enbrel and TB: PortugalEnbrel and TB: Portugal

0

0.5

1

1.5

2

2.5

% TB

Infliximab Adalimumab Etanercept

Percentage of Treated Patients Developing TB

EtanerceptInfliximabAdalimumab

2.3%(4/171)

1.5%(8/456)

0.3%(1/333)

TB events associated with anti-TNF agents were compared for 960 pts treated between 1999 – 2005 in Portugal*:

* 13 events total: 9 RA (n=639); 3 AS (n=200); 1 PsA (n=101).

Fonseca JE et al. Acta Reumatol Port. 2006;31:247-53.

BIOBADASER: Risk and BIOBADASER: Risk and incidence of TB in Spainincidence of TB in Spain

Treatments starts

Patient-years of exposure

to TNF antagonists

Cases TB rate per 100,000 p/y

RR vs. general population

(IC 95%)

RR vs. EMECAR (IC 95%)

<March 2002 8,671 41 472 (384–642) 19 (11–32) 5,8 (2,5–15,4)

>March 2002100% compliance<100% compliance

8,7174,5764,170

15213

172 (103–285)43 (11–175)

311 (181–636)

7 (3–13)1,8 (0,28–7,1)

13 (6–25)

2,4 (0,8–7,2)Undetermined4,8 (1,04–44,3)

Annual incidence rate / 100,000 p. y. General population 25; EMECAR (RA pre-biologic era)

Carmona et al. Arthritis Rheum 2005; 52(6):1766-72; Gómez-Reino et al. Arthritis Care & Research 2007.

BSRBR: Anti-TNFs and risk of BSRBR: Anti-TNFs and risk of TBTB

50

191

136

0

20

40

60

80

100

120

140

160

180

200

Rat

e/10

0,00

0 yr

s

Etanerc

ept

Adalimumab

Inflixim

ab

Dixon WG et al. THU0134. EULAR 2008

RATIO: Factors predictive of RATIO: Factors predictive of TBTB

Last anti-TNF received

No. of cases HR (95% CI) vs etanercept

P-value

Adalimumab 27 10.05 (1.92-52.61) 0.006Etanercept 35Infliximab 5 8.63 (1.38-53.78) 0.02

Use of specific biologics is predictive of TB in anti-TNF-treated patients (n=67)

• Incidence TBC 39.2/100,000 pt/year • ETA: 6.0/100,000 pt/year • INF or ADA: 71.5/100,000 • General Population: 8.7/100,000 pt/year• Two thirds (30/45) of the patients who developed TB had negative skin tests

Tubach F et al. OP-0014. EULAR 2008

Serious Infectious Serious Infectious Events (SIEs)Events (SIEs)

Etanercept and serious infectious Etanercept and serious infectious eventsevents

PooledPooled analysis of randomised clinical trials for analysis of randomised clinical trials for Enbrel in RAEnbrel in RA

00.5

11.5

22.5

33.5

Events per 100 pt-yr

Placebo/control

Etanercept

Etanercept open labelextensions

Serious infectious events

No difference vs. placebo

Hamza S et al. EULAR 2007 ARD 2007;66(2): THU0153 Abstract

Etanercept and opportunistic Etanercept and opportunistic infectionsinfections

PooledPooled analysis of randomised clinical trials for analysis of randomised clinical trials for Enbrel in RAEnbrel in RA

00.050.1

0.150.2

0.250.3

0.35

Events per 100 pt-yr

Placebo/control

Etanercept

Etanercept open labelextensions

Opportunistic infections

No difference vs. placebo

Hamza S et al. EULAR 2007 ARD 2007;66(2): THU0153 Abstract

BSRBR: Etanercept and BSRBR: Etanercept and mAbs vs. DMARDSmAbs vs. DMARDS

0

1

2

3

4

5

6

Adjusted Incidence Rate Ratio

SIE rates relative to DMARDS in first 90 days of therapy

ETN INFLIX ADAL

Dixon WG et al. A&R 2007;56(9):2896-904

RABBIT: Etanercept and SIEs RABBIT: Etanercept and SIEs - Herpes virus infections- Herpes virus infections

RABBIT Registry (Germany)*

Evaluated RA patients for reactivation or first infection of Herpes virus infections (Varicella Zoster Virus, Herpes simplex Virus) “Our data suggest a different mode of action of TNF antibodies and the soluble TNF receptor fusion protein etanercept in respect to the reactivation of a latent herpes infection.”Reactivation of Herpes virus infections suggest a loss of cell-mediated immunity

Hazard Ratio P value

Etanercept 1.2 0.53

Infliximab 2.1 0.01

Adalimumab 2.0 0.01

Risk of Infection vs. Control

*Strangfeld A. et al. Oral Presentation Abstract OP0214 Friday June 15, 2007 EULAR 2007

ARTIS: Hospitalisation risk ARTIS: Hospitalisation risk for infection – all anti-TNFs for infection – all anti-TNFs

0

0.5

1

1.5

Time since treatment start

Year 2 Year 3Year 1

Rel

ativ

e ris

k (9

.5%

CI)

Askling J, et al. Ann Rheum Dis. 2007 66:1339–44

ARTIS: Serious infection rate in ARTIS: Serious infection rate in patients treated with a 2nd TNF patients treated with a 2nd TNF

antagonistantagonist

0

4

8

12

16

First TNF inhibitor Second TNF inhibitor

Infe

ctio

ns le

adin

g to

ho

spita

lisat

ion/

100

patie

nt-y

ears

4.5

7.0

All TNF inhibitor-treated patients

(n=4,167)

Patients hospitalized prior to treatment with TNF inhibitor

(n=2,692)

0

4

8

12

16

First TNF inhibitor Second TNF inhibitorIn

fect

ions

lead

ing

to

hosp

italis

atio

n/10

0 pa

tient

-yea

rs

5.4

10.0

Crude Incidence

Adapted from Askling J, et al. Ann Rheum Dis. 2007 66:1339–44

MalignanciesMalignancies

MalignancyMalignancy

Lower Risk Higher Risk

Lymphoma only

All malignancies

Skin cancer

1.0

0.7(OR) 0.3-1.6

1.0 (OR) 0.8-1.3

1.2 (OR) 1.0-1.5

13001

19591

13001

Point Estimate 95% CIAnalyses Number of Patients

Malignancy Risk: ENBREL vs. control, derived from a large patient database*

*Wolfe F and Michaud K. A&R 2007;56:1433-1439; 2886-2895.

Swedish national registry ARTIS Data compared with Swedish nationwide cancer & census

registers

ARTIS: Anti-TNF and solid ARTIS: Anti-TNF and solid cancerscancers

Prevalent RA n = 53067

Incident RAn = 3703

RA on anti-TNFn = 4160

n SIR (95% IC) n SIR

(95% IC) n SIR (95% IC)

All cancers 3379 1.05 (1.01-1.08) 138 1.1 (0.9-1.3) 67 0.9 (0.7-1.2)Melanoma 120 1.19 (0.99-1.42) 4 0.9 (0.2-2.2) 1 0.3 (0.0-1.8)

Askling et al. Ann Rheum Dis 2005;64:1414–1420

Swedish national registry ARTIS Data compared with Swedish nationwide cancer & census

registers

ARTIS: Anti-TNF and solid ARTIS: Anti-TNF and solid cancerscancers

Prevalent RA n = 53067

Incident RAn = 3703

RA on anti-TNFn = 4160

n SIR (95% IC) n SIR

(95% IC) n SIR (95% IC)

All cancers 3379 1.05 (1.01-1.08) 138 1.1 (0.9-1.3) 67 0.9 (0.7-1.2)

Melanoma 120 1.19 (0.99-1.42) 4 0.9 (0.2-2.2) 1 0.3 (0.0-1.8)

Skin (non-melanoma) 374 1.66 (1.50-1.84) 5 0.7 (0.2-1.6) 11 3.6 (1.8-6.5)

Lung 330 1.48 (1.33-1.65) 23 2.4 (1.5-3.6) 10 1.8 (0.9-3.3)

Askling et al. Ann Rheum Dis 2005;64:1414–1420

ARTIS (2008): No increase in ARTIS (2008): No increase in cancer following anti-TNF cancer following anti-TNF

therapytherapy

No. primary cancers

Relative risk (95% CI)

Compared to national RA cohort

Compared to general population

Anti-TNF treatment

169 0.94 (0.80-1.12) 1.04 (0.89-1.21)

No increased cancer risk with anti-TNF therapy

Askling J et al. OP-0013. EULAR 2008

RA and cancerRA and cancerNational Data Base for Rheumatic Diseases (NDBRD) 13,001 RA patients (49,000 p/y) of observation (1998/2005)

– At least 1 year of follow-up– 49% of whom exposed to biological therapy

Cancer rates compared with population rates US National Cancer Institute database

Incidence of new cancers in patients with anti-TNF/ without anti-TNF

ORs as estimates RR adjusted for 6 confounders: age, sex, education level, smoking history, RA severity and prednisone use

Wolfe , ACR 2006 and Arthritis and Rheum 2007

LymphomaLymphoma

Lymphoma and rheumatic Lymphoma and rheumatic diseasedisease

Several studies suggested an increased lymphoma risk in patients with rheumatic diseaseRisk may be tied to degree of disease severity and inflammationWhat is the impact of biologics on this?

Lymphoma risk and RA Lymphoma risk and RA disease activity: Pre-disease activity: Pre-

biologicsbiologicsPatients: Swedish in-patient registry with RA 1964–1995, who developed lymphoma > 1 year after discharge (RA and lymphoma diagnosis validated)Controls: Individually matched RA patients without lymphoma from same source (378 cases and controls)All records retrospectively reviewed to assess disease activity and DMARD therapy

Baecklund E, et al. Arthritis Rheum. 2006;54:692-701.

OutlookTNFalpha antagonists might improve or prevent important comorbidities

Cardiovascular diseases Lymphomas

By:

Decreasing inflammation Decreasing activation of endothelial cells Normalizing pathologic lipid profiles Normalizing insulin resistance

0.1 1 10 100

Low

Medium

High

Unadjusted Odds Ratio (95% CI)

Lymphoma risk and Lymphoma risk and rheumatoid arthritis rheumatoid arthritis

disease activitydisease activity

7.7

71.3

Infla

mm

ator

y A

ctiv

ity

Baecklund E, et al. Arthritis Rheum. 2006;54:692-701.

No increased risk of lymphoma No increased risk of lymphoma in RA patients upon treatment in RA patients upon treatment

with anti-TNFwith anti-TNFSwedish population-based cohort study of RA pts:

one prevalent cohort (n = 53067) one incident cohort (n = 3703) one TNFi -treated cohort 1999 through 2003 (n = 4160)

Prevalent and incident RA pts have an increased risk of lymphoma (SIR = 1.9 and 2.0, respectively) and leukaemia (SIR = 2.1 and 2.2, respectively)

RA pts treated with TNF antagonists had a tripled lymphoma risk (SIR = 2.9)

However, after adjustment (sex, age, and disease duration) the risk was not higher than in the other RA cohorts

.

Askling et al. Ann Rheum Dis 2005;64:1414–1420

Further safety issues1. Infections2. Pregnancies3. Non-tb pulmonary disease4. Heart failures5. Surgical issues6. Vaccination7. Haematological chances8. Demylating diseases9. Allergic reactions

Summary: Areas in which data Summary: Areas in which data suggest a difference between mAbs suggest a difference between mAbs

and Etanerceptand EtanerceptTuberculosis Risk of developing TB appears to be greater with mAbs than with Etanercept based upon: Pooled analyses of randomized controlled trials Multiple national registries MOA

MalignancyPossible risk for development of lymphomas or other malignancies in patients treated with a TNF-antagonist, including Etanercept, cannot be excluded Further analyses pending

Serious Infections Differences in risk for infections may exist between Etanercept and mAbs; however, data are inconclusive RCTs suggest a difference Registries suggest no difference