Adverse Drug Reactions to Biopharmaceuticals A New Challenge

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

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

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

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 αβ (Pichler WJ, 2006*) *Pichler WJ. Adverse Side Effects to Biological Agents. Allergy;61:912-920 (2006)

Pichler classification of biopharmaceuticals ADRs(1) • Alpha (α) • High cytokine administration • cytokine release syndrome

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

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

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 TNFα blockers or IFN α • Varied and rare – individual predisposition such as atopy or co-morbidity

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

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

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

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

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.

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

Infections with TNFα antagonists • TNFα stimulates macrophage function to control intracellular infections • Anti-TNFα 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)

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

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

Leukemias with anti-TNFα • FDA reported increased incidence of malignancies in adolescents & children treated with TNFα 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

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

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 Cards

Adverse Drug Reactions to Biopharmaceuticals A New Challenge