Antibody therapy of multiple sclerosis Prof. Alastair Compston Dr. Alasdair Coles

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1 Antibody therapy of multiple sclerosis & Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, U.K. 1 The story of multiple sclerosis: The symptoms of multiple sclerosis Uncoordinated large movements Abnormal eye movements Uncoordinated fine movements Leg weakness 3 The screen versions of these slides have full details of copyright and acknowledgements 1

2 The pathogenesis of multiple sclerosis 4 T T T T 5 Pathological heterogeneity in multiple sclerosis Inflammation Axonopathy Neurodegeneration Type Primary 1.. and Type.. 2 secondary Type 3 progressive Type 4 6 The screen versions of these slides have full details of copyright and acknowledgements 2

3 H emispheres Br ainstem Spi nal cord Impairment of function C l inical course 7 First drug proven to reduce disease activity in multiple sclerosis: interferon-beta-1b 8 IFN beta study group Neurology 1993 Pivotal trials in relapsing-remitting MS: interferons and glatiramer reduce relapse rate Annualised relapse rate β-interferon 0.0 Betaseron Avonex Rebif Glatiramer Pla Betaseron (IFNβ-1b) n= /5 Avonex (IFNβ-1a) n= year data Rebif (IFNβ-1a) n= Copaxone (Copolymer-1) n= The screen versions of these slides have full details of copyright and acknowledgements 3

4 Pivotal trials in relapsing-remitting MS: interferons and glatiramer may reduce disability accumulation % W hose di sability p ro gressed by o n e EDSS p o int N.S p= p< Pl acebo β- i nterferon 0 Y e a r 1 Y e a r 2 Y e a r 3 Y e a r 1 Y e a r 2 B e taseron (IFNβ- 1b) Av o nex (IFNβ- 1a) n = /5 n = Y e a r 1 Y e a r 2 R e bi f (IFNβ- 1a) n = 5 60 PRISMS Cochrane analysis of interferon efficacy Only positive result of interferon trials is a reduction in the relative risk (95% C.I.) of at least one relapse in first year of treatment No significant effect on the accumulation of disability in RR multiple sclerosis Filippini G. Lancet 2003; 361: Monoclonal antibodies trialed in multiple sclerosis T c e ll targets Antibody A First F used Ef ficacy CD3 OKT Ineffective CD4 B-F Ineffective cm-t Ineffective CD6 Anti-T Ineffective α4 integrin Nataluzimab 1999 Some efficacy CD25 Daclizumab 2001 Some efficacy B cell targets CD20 Rituximab 2001? Efficacy T & B ce ll targets CD52 Alemtuzumab 1994 Some efficacy Cytokine targets TNF-α Infliximab 1996 Disease activity Etenercept 1999 Disease activity 12 The screen versions of these slides have full details of copyright and acknowledgements 4

5 Supertotal # of contrast-enhancing lesions In preliminary results, ZENAPAX ( Daclizumab) has robust effect on decreasing contrast-enhancing lesion on brain MRI Zenapax dosing MS-Z1-1 MS-Z1-2 MS-Z1-3 MS-Z1-4 MS-Z1-5 MS-Z1-6 MS-Z1-7 MS-Z2-1 MS-Z2-2 MS-Z2-3 Average Months on trial PNAS 2004:101: Nataluzimab/tysabri reduces relapse rate 1.6 Annualized relapse rate Betaseron Avonex Rebif Glatiramer Avonex & Avonex Betaseron (IFNβ-1b) n= /5 Avonex (IFNβ-1a) n= Rebif (IFNβ-1a) n= Copaxone (Copolymer-1) n= (Natalizumab) n= (Natalizumab) n= year data 1 year data 14 Pivotal trials of natalizumab (tysabri): 2 year results Drug Phase N Reduction in relapse rate versus placebo (AFFIRM) Reduction in probability of acquiring fixed disability III % 42% (17% vs. 29%) Adverse effects & avonex versus avonex alone (SENTINEL) III % (0.34 vs. 0.75) 24% (23% vs. 29%) PML in 2 cases (1 death) NEJM : 911 & :899 The screen versions of these slides have full details of copyright and acknowledgements 5

6 Progressive multifocal leucoencephalopathy with natalizumab (tysabri) Langer-Gould N Engl J Med 2005; The story of Campath-1H treatment of multiple sclerosis 17 Campath-1H causes prolonged T cell depletion Median time (months) to reach pre-treatment levels: CD3 51 (38-67) CD4 61 (47-78) CD8 30 (19-46) Lymphocyte count (x109/l) Lymphocyte count (x109/l) CD4 T cells Months post Campath- 1H CD8 T cells The screen versions of these slides have full details of copyright and acknowledgements 6

7 The first dose of Campath-1H induces cytokine release and transient exacerbation of symptoms 800 Cytokine concentration (pg/ml) TNF-α IFN-γ IL Hours after Campath-1H administration 19 Inflammation causes conduction block, then axonal damage Intact axons Intact axons Acute axonal Acute axonal loss loss Smith KJ Smith et al., KJ Ann et al., Neurol, Ann 2001; Neurol, 49: 2001; : Campath-1H suppresses relapses in multiple sclerosis Months before and after Campath-1H 91% reduction in relapse rate 21 Coles AJ, J Neurol The screen versions of these slides have full details of copyright and acknowledgements 7

8 The effect of Campath-1H on disability depends upon the stage of the disease Relapsing-remitting cohort Change in EDSS from baseline Secondary progressive cohort Change in EDSS from baseline Worse Better Months after Campath-1H Years after Campath-1H 22 Coles AJ, J Neurol Comparison of interim analyses of trials on Campath-1H and tysabri Drug Phase N Reduction in relapse rate compared to interferon at one year Campath-1H vs. rebif (from Genzyme press release) Reduction in probability of acquiring fixed disability II 334 > 70% > 60% compared to interferon at 1 year Adverse effects ITP in 3 cases (1 death) & avonex vs. avonex (NEJM 2006) III % 24% compared to interferon at 2 years PML in 2 cases (1 death) 23 Infections after Campath-1H 500 patient-years experience Infection Facial zoster & 2 o bacterial infection Listeria meningitis Spirochaetal gingivitis Measles Herpes zoster Chickenpox Time after Campath-1H 3 days 10 days 10 days 11 days 6 & 9 months 3/12 and 2 years 3 cases of patients exposed to chickenpox in first three months: all found to have anti-varicella IgG and did not experience infection 24 The screen versions of these slides have full details of copyright and acknowledgements 8

9 Graves disease after Campath-1H T4 pmmol/l TSH T Months post Campath-1H TSH mu/l Technetium 99 uptake Carbimazole 25 Graves disease after Campath-1H treatment of MS 15% of patients with MS treated using Campath-1H will develop Graves disease 5-24 months after a dose of Campath-1H It can be detected pre-symptomatically It can be ea sily treated, dru gs ± radio-iodine Main concern is Graves eye disease Is the risk of Grave's disease worth the potential benefit on multiple sclerosis disease activity? 26 Immune thrombocytopenia after Campath-1H 4 cases (approx. 1% incidence) One death Three responded to steroids 27 The screen versions of these slides have full details of copyright and acknowledgements 9

10 Autoimmune disease after Campath-1H treatment of MS Cambridge experience of >100 patients: 15 of patients develop Graves disease (autoimmune hyperthyroidism) 5-24 months after a dose of Campath-1H From all patients (c. 500) Four cases of autoimmune thrombocytopenia Single case of Goodpasture s syndrome (awaiting renal Tx) Single case of anti-neutrophil antibody Single cases of transient antibody expression, without disease, to: Gliadin Neutrophils dsdna 28 Other examples of reconstitution autoimmunity HAART treatment of HIV: Graves disease, ITP, ADEM BMT autoimmunity CLL autoimmunity Penhale / Mason animal models of autoimmunity Mechanism (Don Mason): Loss of dominant toelrance Target organ defined by strain & genetics 29 The pathology and course of multiple sclerosis Relapsing-remitting Relapsing-persistent Relapsing-Persistent Secondary progression 30 The screen versions of these slides have full details of copyright and acknowledgements 10

11 The treatment of multiple sclerosis 2006 and beyond R e lapsing-remitting S econdary progression U Azathioprine l tra-early use of C yclophosphamide corticosteroids... i.v regular immunoglobulin pulsed steroids Gl atarimer acetate Ear Interferon-ß ly and aggressive anti-inflammatory R ebif inflammatory therapy Betaseron Avonex N europrotective therapy and growth factors M itoxantrone T ysabri R C emyelination ampath-ih with stem cells The screen versions of these slides have full details of copyright and acknowledgements 11