1. UK clinical perspective on treatment reviews of multiple sclerosis therapies Alasdair Coles Neurologist, Cambridge, UK

2. 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.

3. 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

5. 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

7. 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 interferon-beta ≥ 1 gadolinium-enhancing MRI lesions or at least nine T2-hyperintensive lesions on cranial MRI  Approved indication for fingolimod in many regions What category of multiple sclerosis does she have according to NICE?

8. 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

9. “Real-life” databases: MSBase Proportion of patients whose disability improves after switching Kalincik Ann Neurol. 2015 Mar;77(3):425-35 Natalizumab Fingolimod

10. Indirect treatment comparison: relapse-free outcome Genzyme, Manufacturer’s submission to NICE 2014

11. A comparison of alemtuzumab, interferon beta-1a SC, teriflunomide and fingolimod in HAD Genzyme, Manufacturer’s submission to NICE 2014 Indirect treatment comparison of treatments of high disease activity despite interferon-beta

12. Increasing efficacy Increasing burden of treatment (worse safety, more difficult administration) Interferon-beta Natalizumab JC+ Mitoxantrone Fingolimod Dimethyl fumarate Autologous stem cell transplantation Glatiramer Sketch of disease-modifying therapies in 2015/6 Daclizumab Modified from Hauser S, ANN NEUROL 2013;74:317–327 Laquinimod Alemtuzumab Natalizumab JC neg Rituximab / ocrelizumab Teriflunomide Azathioprine

13. Treatment A Mildly effective, mildly toxic Disease active Escalation Strategy Disease suppressedDisease still active Treatment B More effective, more toxic Disease suppressedDisease still active Treatment C Most effective, most toxic

14. Increasing efficacy Increasing burden of treatment (worse safety, more difficult administration) Interferon-beta Natalizumab JC+ Mitoxantrone Fingolimod Dimethyl fumarate Autologous stem cell transplantation Glatiramer First, second and third line therapies Laquinimod Alemtuzumab Natalizumab JC neg Rituximab / ocrelizumab Teriflunomide Third line Second line First line Daclizumab

15. Treatment C Most effective, most toxic Disease active Induction Strategy Disease suppressedDisease still active Treatment C again or…..A Mildly effective, mildly toxic Disease suppressedDisease still active

16. Increasing efficacy Increasing burden of treatment (worse safety, more difficult administration) Interferon-beta Natalizumab JC+ Mitoxantrone Fingolimod Dimethyl fumarate Autologous stem cell transplantation Glatiramer High and low risk treatments Daclizumab Laquinimod Alemtuzumab Natalizumab JC neg Rituxmab / ocrelizumab Teriflunomide “Dangerous” “Aggressive” “Safe”

17. 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. Back to our case

18. “Alemtuzumab is recommended as a possible treatment for people with active relapsing–remitting 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 UK approved use of alemtuzumab

19. 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.