UK clinical perspective on treatment reviews of multiple

UK clinical perspective on treatment reviews of multiple sclerosis therapies Alasdair Coles Neurologist, Cambridge, UK Disclaimer Investigator on many Genzyme studies of alemtuzumab treatment of multiple sclerosis. Received honoraria and travel assistance for

speaking on alemtuzumab from Genzyme. Received grant support from Genzyme. My institution (University of Cambridge) has received gifts from Genzyme. A marathon runner 19 year old female law student and marathon runner History

18 months: ataxia, diplopia and headache 10 months: numb right big toe, tripping 4 months: burning sensation on right shoulder 1 month: diplopia, vertigo, numb right leg for 2 weeks EDSS 1.0 A marathon runner A marathon runner 19 year old law student Treatment Started on interferon beta-1a SC. 2 months later: ascending numbness, weak

legs then arms, then difficulty breathing, admitted to intensive care with quadraparesis. Steroids and plasma exchange. Good improvement over 6 weeks. EDSS 2.5 A marathon runner What category of multiple sclerosis does she have according to NICE? RES: rapidly evolving severe multiple sclerosis 2 disabling relapses in the previous year AND

1 gadolinium-enhancing lesions on brain MRI Licensed indication for natalizumab in many regions HAD: high disease activity despite interferon-beta 1 relapse in the previous year on interferonbeta What evidence can guide switching from interferon to another drug ? No RCT has compared switching to fingolimod versus natalizumab. Sources of other evidence may be: real-life databases

Indirect treatment comparison Real-life databases: MSBase Proportion of patients whose disability improves after switching Natalizumab Fingolimod Kalincik Ann Neurol. 2015 Mar;77(3):425-35 Indirect treatment comparison: relapse-free outcome

Genzyme, Manufacturers Indirect treatment comparison of treatments of high disease activity despite interferon-beta A comparison of alemtuzumab, interferon beta-1a SC, teriflunomide and fingolimod in HAD Genzyme,

Manufacturers Sketch of disease-modifying therapies in 2015/6 Modified from Hauser S, ANN NEUROL 2013;74:317327 Increasing efficacy Alemtuzumab Natalizum ab JC neg Rituximab / ocrelizumab Dimethyl fumarate

Autologous stem cell transplantation Mitoxantrone Natalizuma b JC+ Fingolimo d Daclizumab Laquinimod Glatiramer Azathioprin

e Teriflunomide Interferon-beta Increasing burden of treatment (worse safety, more difficult administration) Escalation Strategy Disease active Treatment A Mildly effective, mildly toxic Disease suppressed Disease still active Treatment B More effective, more toxic Disease suppressed Disease still active

Treatment C Most effective, most toxic First, second and third line therapies Increasing efficacy Alemtuzumab Natalizuma b JC neg Rituximab / ocrelizumab Dimethyl fumarate

Autologous stem cell transplantation Mitoxantrone Natalizuma b JC+ Fingolimo d Daclizumab Laquinimod Glatiramer Teriflunomide

Interferon-beta Third line Second line First line Increasing burden of treatment (worse safety, more difficult administration) Induction Strategy Disease active Treatment C Most effective, most toxic Disease suppressed Disease still active Treatment C again or..A

Mildly effective, mildly toxic Disease suppressed Disease still active Increasing efficacy High and low risk treatments Alemtuzumab Natalizumab JC neg Rituxmab / ocrelizumab Dimethyl fumarate

Laquinimod Fingolimo d Daclizumab Glatiramer Teriflunomide Interferon-beta Autologous stem cell transplantation Mitoxantrone Natalizuma b JC+

Dangerous Aggressive Safe Increasing burden of treatment (worse safety, more difficult administration) Back to our case 19 year old female law student and marathon runner Attitude to illness: Very concerned to maintain intellectual level and run good marathon times. Attitude to risk: I am a high risk, high gain person

Elected to receive alemtuzumab (in the UK) Received two cycles in 2003 and 2004. Since then has had one relapse and this triggered a further cycle of alemtuzumab. Continues to run marathons. UK approved use of alemtuzumab Alemtuzumab is recommended as a possible treatment for people with active relapsingremitting multiple sclerosis. European Medicines Agency, 2013 We are very pleased to be able to recommend alemtuzumab for adults with relapsing-remitting multiple sclerosis. Evidence has shown that alemtuzumab is more effective and less expensive

than current similar treatments for those with severe relapsing-remitting MS National Institute for Health and Care Excellence Chief Executive, Sir Andrew Dillon , 2014 Conclusion Rigid derivation of treatment guidelines from randomised controlled trials leads to unforeseen consequences. Indirect treatment comparisons and real-lef database studies answer questions not resolvable by RCTs Safety- conscious investigators and pharma tend to promote an escalation approach, which misses the opportunities of induction

treatment. Detailed guidelines fail reduce the opportunity for physicians to adapt advice for individual patient factors, such as approach to risk.

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