Safety & Tolerability of Biologics
1 / 39

Overview - PowerPoint PPT Presentation

  • Uploaded on

Safety & Tolerability of Biologics Dubai, United Arab Emirates January 19th, 2009 Prof. Joachim R. Kalden Director emeritus Department of Internal Medicine III Div. of Molecular Immunology Niklolaus-Fiebiger-Center University of Erlangen-Nuremberg. Overview. Monitoring of safety: registries

I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
Download Presentation

PowerPoint Slideshow about ' Overview' - alton

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

Safety & Tolerability of BiologicsDubai, United Arab EmiratesJanuary 19th, 2009Prof. Joachim R. KaldenDirector emeritusDepartment of Internal Medicine IIIDiv. of Molecular ImmunologyNiklolaus-Fiebiger-CenterUniversity of Erlangen-Nuremberg


Monitoring of safety: registries

Safety: Tuberculosis

Safety: Serious infectious events

Safety: Malignancy

Safety: Lymphoma

European registries
European 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 to wyeth
Why are registries important to 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 registries
Original registries


  • 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


  • BSRBR - national registry powered to detect 2 fold increase in lymphoma in comparison to a DMARD treated cohort


  • 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

Monitoring of safety problems
Monitoring of safety: problems

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 disadvantages of registries


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


Non randomised, subject to bias

Confounding by indication

Missing data

Potential for confounding

Channelling bias

Choice of reference group

Advantages and disadvantages of registries

Conditions where mechanism of action differences may affect safety profile
Conditions Where Mechanism of Action Differences May Affect Safety Profile


Serious Infectious Events (SIEs)


Tuberculosis tb

Tuberculosis (TB) Safety Profile

Fda medwatch spontaneous reporting system aers 2001
FDA MedWatch spontaneous reporting system (AERS): 2001 Safety Profile

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



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

Inhibition of ifn gamma
Inhibition of IFN gamma Safety Profile

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 trials t b events despite screening
TB associated with clinical trials: T Safety ProfileB events despite screening

Enbrel and tb portugal
Enbrel and TB: Portugal Safety Profile

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 incidence of tb in spain
BIOBADASER: Risk and incidence of TB in Spain Safety Profile

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 tb
BSRBR: Anti-TNFs and risk of TB Safety Profile

Dixon WG et al. THU0134. EULAR 2008

Ratio factors predictive of tb
RATIO: Factors predictive of TB Safety Profile

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 events Safety ProfilePooled analysis of randomised clinical trials for Enbrel in RA

Serious infectious events

No difference vs. placebo

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

Etanercept and opportunistic infections Safety ProfilePooled analysis of randomised clinical trials for Enbrel in RA

Opportunistic infections

No difference vs. placebo

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

Bsrbr etanercept and mabs vs dmards

SIE rates relative to DMARDS in first 90 days of therapy Safety Profile

BSRBR: Etanercept and mAbs vs. DMARDS




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

Rabbit etanercept and sies herpes virus infections
RABBIT: Etanercept and SIEs - Herpes virus infections Safety Profile

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

Risk of Infection vs. Control

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

Artis hospitalisation risk for infection all anti tnfs

1.5 Safety Profile


Relative risk (9.5% CI)



Year 1

Year 3

Year 2

Time since treatment start

ARTIS: Hospitalisation risk for infection – all anti-TNFs

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

Artis serious infection rate in patients treated with a 2nd tnf antagonist
ARTIS: Serious infection rate in patients treated with a 2nd TNF antagonist







Infections leading to

Infections leading to













First TNF inhibitor

Second TNF inhibitor

First TNF inhibitor

Second TNF inhibitor

Patients hospitalized prior to treatment with TNF inhibitor (n=2,692)

All TNF inhibitor-treated patients


Crude Incidence

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


Malignancies TNF antagonist

Malignancy TNF antagonist

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


Number of Patients

Point Estimate

95% CI




Lymphoma only

All malignancies


1.0 (OR)



1.2 (OR)


Skin cancer

Higher Risk

Lower Risk


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

Artis anti tnf and solid cancers

Swedish national registry ARTIS TNF antagonist

Data compared with Swedish nationwide cancer & census registers

ARTIS: Anti-TNF and solid cancers

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

Artis anti tnf and solid cancers1

Swedish national registry ARTIS TNF antagonist

Data compared with Swedish nationwide cancer & census registers

ARTIS: Anti-TNF and solid cancers

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

Artis 2008 no increase in cancer following anti tnf therapy
ARTIS (2008): No increase in cancer following anti-TNF therapy

No increased cancer risk with anti-TNF therapy

Askling J et al. OP-0013. EULAR 2008

Ra and cancer
RA and cancer therapy

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 therapy

Lymphoma and rheumatic disease
Lymphoma and rheumatic disease therapy

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 disease activity pre biologics
Lymphoma risk and RA disease activity: Pre-biologics therapy

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 therapy

TNFalpha antagonists might improve or prevent important comorbidities

  • Cardiovascular diseases

  • Lymphomas


  • Decreasing inflammation

  • Decreasing activation of endothelial cells

  • Normalizing pathologic lipid profiles

  • Normalizing insulin resistance

Lymphoma risk and rheumatoid arthritis disease activity
Lymphoma risk and rheumatoid arthritis disease activity therapy



Inflammatory Activity

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

No increased risk of l ymphoma in ra patients upon treatment with anti tnf
No therapyincreased risk of lymphoma in RA patients upon treatment with 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
Further safety issues therapy

  • Infections

  • Pregnancies

  • Non-tb pulmonary disease

  • Heart failures

  • Surgical issues

  • Vaccination

  • Haematological chances

  • Demylating diseases

  • Allergic reactions

Summary areas in which data suggest a difference between mabs and etanercept
Summary: Areas in which data suggest a difference between mAbs and Etanercept


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


    Possible 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