Post on 23-Dec-2015
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
OverviewOverview
Monitoring of safety: registries
Safety: Tuberculosis
Safety: Serious infectious events
Safety: Malignancy
Safety: Lymphoma
European registriesEuropean registries
Post approval commitment to EMEA that Wyeth would monitor safety
Professional Societies independently supported establishment of registries to monitor safety
Established 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 competitors
Providing rich stream of data for differentiation
Currently under analysed – registries focusing on limited number of questions
Potential for pooled analyses to give even greater power
Why are registries important Why are registries important to Wyethto Wyeth
Meet post approval commitment
Large cohorts of Enbrel patients treated in clinical practice
Source of comparative data with MAbs
Resource for evaluation of safety and efficacy
Potential 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 cohort
Germany 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 database
These 3 registers meet together annually with companies
Use standard report which is sent companies twice a year for inclusion in safety reports to regulators
Estimates of patient Estimates of patient numbersnumbers
Country StartedDate of
EstimateTotal 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
TB
Serious Infectious Events (SIEs)
Malignancy
FDA MedWatch spontaneous FDA MedWatch spontaneous reporting system (AERS): reporting system (AERS):
20012001
TB associated with infliximab
70 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 3.3
Pooled analysis N. America1 0.8
REACT Trial7 5.0
Infliximab (mAb) Yes
Pooled analysis Not available
START Trial2 13.1
Infliximab vs abatacept trial3 12.1
Certolizumab (mAb) Yes
Pooled analysis Not available
RAPID I Trial4 6.9
RAPID 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
Etanercept
Infliximab
Adalimumab
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
CasesTB 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
8,7174,576
4,170
152
13
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)Undetermined
4,8 (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
Ra
te/1
00
,00
0 y
rs
Etaner
cept
Adalim
umab
Infli
xim
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) 0.006
Etanercept 35
Infliximab 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
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
2
2.53
3.5
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 ri
sk (
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
lead
ing
to
h
osp
ital
isat
ion
/100
p
atie
nt-
year
s
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 inhibitor
Infe
ctio
ns
lead
ing
to
h
osp
ital
isat
ion
/100
p
atie
nt-
year
s
5.4
10.0
Crude Incidence
Adapted from Askling J, et al. Ann Rheum Dis. 2007 66:1339–44
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
nSIR
(95% IC)n
SIR (95% IC)
nSIR
(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
nSIR
(95% IC)n
SIR (95% IC)
nSIR
(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 cancer
National 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
Lymphoma and rheumatic Lymphoma and rheumatic diseasedisease
Several studies suggested an increased lymphoma risk in patients with rheumatic disease
Risk may be tied to degree of disease severity and inflammation
What is the impact of biologics on this?
Lymphoma risk and RA Lymphoma risk and RA disease activity: Pre-disease activity: Pre-
biologicsbiologics
Patients: 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.
Outlook
TNFalpha 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-TNF
Swedish 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 issues
1. Infections
2. Pregnancies
3. Non-tb pulmonary disease
4. Heart failures
5. Surgical issues
6. Vaccination
7. Haematological chances
8. Demylating diseases
9. Allergic reactions
Summary: Areas in which data Summary: Areas in which data suggest a difference between mAbs suggest a difference between mAbs
and Etanerceptand Etanercept
Tuberculosis
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