Current and near-term impact of biomarkers for multiple sclerosis Gavin Giovannoni

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1 Current and near-term impact of biomarkers for multiple sclerosis Gavin Giovannoni Institute of Cell and Molecular Science Queen Mary's School of Medicine and Dentistry Barts and The London NHS Trust The Royal London Hospital, Whitechapel

2 Topics to be covered - key issues A flawed gold-standards EDSS Incorporating biomarkers research into clinical trials Creating incentives for the pharmaceutical industry The scientific process Biobanking (collection, processing & storage of samples) Standardising biomarker studies (oncology networks) Reporting biomarker studies (REMARK guidelines) Biomarkers Predictive testing Diagnostic sensitivity & specificity positive and negative predictive value Prognostic (trial enrichment) Therapeutic efficacy Monitoring therapies Adverse events Responders vs. non-responders

3 Flawed gold-standards Surrogate Endpoint A biomarker intended to substitute for a clinical endpoint. A surrogate endpoint is expected to predict clinical benefit (or harm, or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence. NIH Biomarker Definitions Working Group Compston & Coles, Lancet 2002.

4 Incorporating biomarkers into clinical trials 1.00 Simvastatin 0.95 LDL-C reduced 38% Survival and events Proportion Alive Placebo 30% decreased death rate 34% decreased CHD events 0.80 Log rank: p= Years Since Randomization Reprinted from The Lancet, Vol. 344, Scandinavian Simvastatin Survival Study Group, , copyright 1994, with permission from Elsevier.

5 The Scientific Process Hypothesis Biobanking Assay-Development phase 0 Reliable & Reproducible Low CVs automated Sample collection Reporting External Validation Animal models & crosssectional study proof of concept Independent Longitudinal studies Phase III Longitudinal study Phase II Longitudinal study Phase III FDA licensed surrogate endpoint Phase IV

6 BioMS (Biomarkers in MS)

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8 Key pathological processes in MS Inflammation Inflammation Gliosis Axonal Toxicity (conduction block) Axonal & Neuronal Loss Oligodendrocyte Toxicity & Demyelination Remyelination & Axonal Recovery Central Adaptation & Plasticity

9 Petzold, J Neurol Sci Jun 15;233(1-2):

10 Neuroaxonal loss - neurofilament light (NF-L) Lycke JN, et al. J Neurol Neurosurg Psychiatry 1998; 64:402-4.

11 CSF NfH-SMI35 levels vs. EDSS at 3 year follow up Petzold et al. J Neurol NeurosurgPsychiatry Feb;76(2):

12 CSF NfH-SMI35 levels vs. AI at 3 year follow up Petzold et al. J Neurol NeurosurgPsychiatry Feb;76(2):

13 CSF NfH-SMI35 levels vs. 9HPT at 3 year follow up Petzold et al. J Neurol NeurosurgPsychiatry Feb;76(2):

14 CSF GFAP levels vs. ambulation index (AI) R=0.57, p<0.01 Petzold et al. Brain Jul;125(Pt 7):

15 NFH-SMI35 vs. MSSS CSF NFH levels will be used to enrich neuroprotective trials CSF NFH levels will be used as surrogate endpoints Lamotrigine Neuroprotecton study Petzold et al., JNNP 2006.

16 AzD: : At risk subject - serial scans registered to 1993 baseline /97 11/97 Courtesy Prof. N. Fox, IoN-UCL

17 AzD: : At risk subject - serial scans registered to 1993 baseline /97 11/97 Courtesy Prof. N. Fox, IoN-UCL

18 Clinical Course of CREAE in Biozzi ABH Mice

19 Nerve Damage Loss correlates with Inflammatory Attack Control Pre-Acute Acute 1 st remission 2 nd relapse 3 rd relapse

20 CREAE in Biozzi-ABH mice a model of SPMS NhH GFAP Petzold et al. J Neuroimmunol2003; 138:45-48.

21 CREAE in Biozzi-ABH mice a model of SPMS Petzold et al. J Neuroimmunol2003; 138:45-48.

22 Prevention of Relapsing CREAE after Three Paralytic Episodes Does Not Inhibit Secondary Progression and Deterioration of Mobility Pryce et al. J Neuroimmunol2005.

23 Secondary progressive EAE 4.0 * ** Mean Clinical or disability Score Treatment Placebo or dummy drug CB1 agonist Time (Days) Pryce et al. Brain2003;126:

24 Neuroprotective potential of cannabinoids 1000 Daily CB 1 agonism Distance travelled (cm/5 min) Treatment Period * Disability 0 Post-Acute Remission 1 Post-Relapse 1/ Remission 2 Post-Relapse 2/ Remission 3

25 Neuroprotective potential of cannabinoids Cannabinoids slow nerve damage or loss Neurofilament Levels (µg/mg totl Protein) ± SEM Normal * Vehicle Remission 3 CB 1 Agonist Remission 3

26 Acute spinal cord injury C-02 C-02 NfH ng/ml NCAM ng/l Pre-drug Pre-drug Time Time C-08 C-08 N fh ng/m l NCAM ng/l Time Time Courtesy Wee Yong, Calgary

27 Acute axonal degeneration following chemotherapy Petzold et al., 2007; submitted.

28 CSF NCAM, S-100 and MBP post MS relapse n=26 20 S100 & MBP ng/ml ng.ml 1010 ng/ml 1140 ng/ml 1475 ng/ml 1761ng/mL MBP S-100 NCAM Weeks after onset of exacerbation Massaro AR. Multiple Sclerosis 1998;4:

29 27 year old woman with incomplete recovery from right optic neuritis (A) fflair intraorbital optic nerve image demonstrating atrophy of the affected right optic nerve (arrow) relative to the unaffected left nerve (B) OCT RNFL thickness (y-axis) along a circle imaged around the optic disc demonstrating relative thinning at all optic disc positions (x-axis) in the affected right eye (C) OCT macular volume/thickness map centred on the fovea demonstrating relative macula volume loss in the affected right eye (depicted by loss of the normal green signal)

30 Conclusions Lobbying New clinical outcome measures (EDSS fails on simple metrics) Incorporating biomarkers into clinical trials Standardise the scientific process Publish negative results (biomarker study register) Biomarkers Prognostic (trial enrichment) & therapeutic efficacy CSF (& serum) neurofilament levels Promising candidate biomarkers GFAP, MBP, S100, NCAM, NOGO, GAP43, etc. Other diseases (ALS, acute spinal cord injury, head injury, stroke, etc.) Monitoring therapies (responders vs. non-responders) Industry Neutralizing antibodies (NABs) to biologics Miniaturisation nanotechnology Longitudinal animal experiments Multiplexing assays Online (neuro ITU)

31 Acknowledgements ICMS, Queen Mary University London and the Institute of Neurology, UCL S.Gnanapavan,, A Petzold & E T Lim Research Fellows D Grant Laboratory Technician D Altmann Statistician D Baker & G Pryce EAE DH Miller & AJ Thompson Clinical International Collaborators J Eikenlenboom / B Uitdehaag / C Polman / F Barkhof Amsterdam M Soderstrom & M Pashenkov - Stockholm F Sellebjerg & CV Jensen Copenhagen R Rudick & C Pelfrey Cleveland Clinic R Hintzen & T Mondria - Rotterdam Funding NMSS MS Society of Great Britain and Northern Ireland AIMS2CURE