1. Adverse Drug Reactions to Biopharmaceuticals A New Challenge Sheila C Noble Senior Pharmacist Yellow Card Centre, Scotland (Centre for Adverse Reactions to Drugs, Scotland)

2. CARDS ADRs and Biopharmaceuticals Types of reactions to biological agents - the new challenge Overview of significant ADRs and how to reduce the risk Reporting ADRs to biopharmaceuticals

3. CARDS Standard drugs vs Biopharmaceuticals Penicillin (MW 350)Trastuzumab (MW 145,000)

4. CARDS Types of Adverse Reactions to Biopharmaceuticals ADRs to regular xenobiotics Types ABCDE Augmented, Bizarre, Chronic, Delayed, End of treatment Suggested classification of ADR to biopharmaceuticals Types α β    (Pichler WJ, 2006*) *Pichler WJ. Adverse Side Effects to Biological Agents. Allergy;61:912-920 (2006)

5. CARDS Pichler classification of biopharmaceuticals ADRs(1) Alpha ( α) High cytokine administration cytokine release syndrome

6. CARDS Pichler classification of biopharmaceuticals ADRs(2) Beta ( β ) Hypersensitivity – three forms of allergy Immediate IgE Delayed IgG mediated reactions Delayed T-cell mediated reactions

7. CARDS Risk of allergy with MABs Chimeric – mixed mouse/human DNA- ximab Humanised – 95% human - zumab Human – fully human - mumab High Low

8. CARDS Pichler classification of biopharmaceuticals ADRs(3) Gamma (  ) Immune (cytokine) imbalance syndromes – immunological features but not due to high cytokines or hypersensitivity. Immunodeficiency e.g. recurrence of latent infection Autoimmunity e.g. Lupus with infliximab Autoinflammatory e.g.psoraisis with TNF α blockers or IFN α Varied and rare – individual predisposition such as atopy or co-morbidity

9. CARDS Pichler classification of biopharmaceuticals ADRs(4) Delta (  ) Cross reactivity. Antibodies generated to an antigen over- expressed on tumour cells might cross react with normal cells which express this antigen to a lower degree. Cetuximab blocks EGFR - acneform lesions Traztuzumab and CCF

10. CARDS Pichler classification of biopharmaceutical ADRs (5) Epsilon (  ) Non-immunological side effects due to unknown functions of the biological agent given or targeted Psychiatric ADRs with Interferon α

11. CARDS TGN1412 at Northwick Park To treat B-cell Chronic Lymphocytic Leukemia (CD28) Aimed to stimulate T-cell production Resulted in cytokine storm (TNFα, IFN  IL-10 ) (Type α reaction) and T lymphopenia Animal model varied from human CD28 T surface receptor Lab Animals not previously exposed to infection

12. CARDS How to avoid future clinical trial disasters Regulation of first-in-human trials Access to info on unpublished studies Share safety info on Phase I trials Consult with outside experts Cautious calculation of initial doses Cautious rate of admin Give new agents sequentially with adequate gaps Consider using patients rather than healthy volunteers Highly qualified principal investigator Appropriate facilities, equipment and staff

13. CARDS Cardiac Side Effects with Trastuzumab Trastuzumab (Herceptin) assoc with asymptomatic reversible reduced LV function or CCF Trastuzumab my interfere with HER2 signalling and function in myocytes (  cross reactivity reaction) Trastuzumab can increase cardiotoxicity with anthracyclines Assess cardiac function before treatment, monitor during and following treatment, treat with ACEIs, beta blockers diuretics as appropriate. Avoid anthracyclines in combination with Herceptin.

14. CARDS Cardiac Side Effects with anti-TNFα agents TNF α serum levels elevated in CHF ATTACH trial - infliximab for CCF Infliximab worsened CCF TNF α increases NO production -> vasodilation to maintain blood flow ?? Anti TNF α drugs also assoc with de novo CCF Monitor closely if mild CCF & stop prn Submit a Yellow Card

15. CARDS Infections with TNFα antagonists TNF α stimulates macrophage function to control intracellular infections Anti-TNF α therapy allows underlying disease to multiply & spread Do not give if active disease TB, sepsis, opportunistic infection. Screen for latent TB (treat) Avoid infection and be alert for signs of infection (atypical as fever masked)

16. CARDS Progressive Multifocal Leucoencephalopathy (PML) PML – demyelinating, fatal, from JC virus Identified with efalizumab, rituximab, natalizumab (  immune imbalance) Efalizumab (Raptiva) for psoraisis Marketing Authorisation withdrawn June 09 due to unfavourable risk/benefit Photograph courtesy of Pharmaceutical Journal

17. CARDS PML (2) - Natalizumab Symptoms of PML may mimic MS Patients with anti-JC virus antibodies >44 times more likely to develop PML 1 Inc risk if previously treated with immunosupressants +/or > 2yr treatment At least 212 cases of PML with monotherapy Tx Plasma exchange,Mirtazapine, Mefloquine Recovery complicated by IRIS Patients to carry PML alert cards – regular MRI 1. NEJM 366:1870-80 2012

18. CARDS Leukemias with anti-TNFα FDA reported increased incidence of malignancies in adolescents & children treated with TNF α blockers (  immune imbalance) Confounding factors – RA and Crohn’s have independent cancer risk Warn patients/parents to be alert to signs/symptoms (wt loss, swollen lymph nodes, bruising/bleeding) Monitor

19. CARDS Infusion reactions to biopharmaceuticals Any biopharmaceutical could cause IgE infusion reaction ( β ) – Anaphylaxis kit ready Rituximab cetuximab and infliximab – pre- treat with antihistamines/paracetamol/ glucocorticoid Initial low and slow regimen In RA concomitant use of methotrexate as appropriate reduced production of antibodies

20. CARDS Reporting ADRs Submit Yellow Cards for all ADRs to Black Triangle Biopharmaceuticals including Biosimilars State specific Brands & Batch Numbers Report Serious ADRs only if well established drug for well-established licensed indication Report via www.mhra.gov.uk/yellowcard or on paper Yellow Cardswww.m