CSF Axonal Injury Markers

Transcription

1 CSF Axonal Injury Markers Gavin Giovannoni Barts and The London Disclosures Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer Schering Healthcare, Biogen Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck Serono, Novartis, Pfizer, Roche, Sanofi Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals. Regarding res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni. Professor Giovannoni would like to acknowledge and thank many colleagues, Biogen Idec, Genzyme and Novartis for making available slides and data for this presentation. 1

2 Why MS biomarkers? Diagnostic testing Positive & negative predictive testing Pathogenesis Immunology Aetiology Disease progression & recovery Disease heterogeneity Pharmacovigilance Monitor disease processes Prognosis (high vs. low risk patients) Monitoring effect of therapeutic interventions MS Iceberg Relapses Unreported relapses Clinical disease progression Clinical activity Subclinical relapses: focal MRI activity Focal gray and white matter lesions not detected by MRI Brain atrophy Focal MRI activity Hidden focal and diffuse MRI activity Spinal fluid neurofilament levels Biomarkers Microscopic or biochemical pathology 2

3 End organ damage 3

4 ESRF end stage renal failure Control Multiple sclerosis 4

5 Treatment effect on disability predicted by effect on T2 lesion load and brain atrophy Meta-analysis of treatment effect on EDSS worsening (y) vs effects on MRI lesions and brain atrophy, individually or combined, in 13 placebo-controlled RRMS trials (13,500 patients) Sormani MP et al. Ann Neurol. 2014;75: No evident disease activity: NEDA Treat-2-target No evidence of disease activity defined as: 1,2 No relapses No sustained disability progression No MRI activity NEDA-3 No new or enlarging T2 lesions No Gd-enhancing lesions Normalisation of the rate of brain atrophy (NEDA-4) Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8: ; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:

6 AFFIRM Study: natalizumab and brain atrophy 0.0% Years 0-2 Year 0-1* Year 1-2 Mean (SE) percentage change in BPF -0.2% -0.4% -0.6% -0.8% -1.0% -0.80% -0.82% P=0.822 Placebo (N=315) -0.40% -0.56% P= % -0.43% P=0.004 Natalizumab (N=627) Difference between treatments; Change from baseline; Miller DH et al. Neurology 2007;68: Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb 1a IM Change in mean BV from baseline (%) TRANSFORMS, 1 year Time (months) *** 40% vs IFNb 1a IM p<0.001 Fingolimod 0.5 mg (n = 368) IFNb 1a IM (n = 359) Change in mean BV from baseline (%) FREEDOMS, 2 years Time (months) ** 0.4 * 0.8 *** % vs placebo p<0.001 Fingolimod 0.5 mg (n = 356) Placebo (n = 329) ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p values are for comparisons over Months 0 6, Months 0 12, Months 0 24 BV, brain volume; ITT, intent to treat. Gilenya Prescribing Information 19 April Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: , and Cohen JA et al. N Engl J Med 2010; 362: Copyright 2011 Massachusetts Medical Society. All rights reserved 6

7 Reduction in brain atrophy on alemtuzumab Coles et al. AAN 2015L (7.263) Jun yr girl, myelitis Feb-2001 Feb st -yr University L-optic neuritis IFN-beta Jan clumsy left hand Oct-2003 pins & needles in legs Mar-2004 R optic neuritis Dec 2007 Brainstem syndrome; diplopia and ataxia Jan 2008 Cervical cord relapse weak L arm with pain Feb-2008 to May-2014 Bladder dysfunction depression, anxiety and fatigue Reduced mobility Jan-2008 NEDA (no evident disease activity) Natalizumab Mild urinary frequency No depression,anxiety or fatigue Fully mobile Residual deficits: Walking distance >500m Unable to run Exercise induces intermittent sensory symptoms in L arm Mild urinary frequency 6.0 EDSS Jun-2000 IFN-beta Natalizumab May

8 MRI progressive brain atrophy Dec 2007 Jul 2010 Jul 2013 MS is an iceberg? Clinical MRI Pathology 8

9 Pathogenic markers 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

10 Acute axonal transection Acute inflammatory scissors or shredder Trapp et al. NEJM 1998 Delayed secondary neurodegeneration Acute Neuroprotection vs. Chronic Neuroprotection Post inflammatory slow burn Petzold, J Neurol Sci Jun 15;233(1 2):

11 Spinal fluid neurofilament levels Trapp et al. NEJM 1998 Post inflammatory slow burn Petzold et al. J Neurol Neurosurg Psychiatry Feb;76(2):

12 Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis Trapp et al. NEJM 1998 Lyke et al. J Neurol Neurosurg Psychiatry 1998;64: Acute inflammatory scissors or shredder Spinal fluid neurofilament levels Petzold et al. J Neurol Neurosurg Psychiatry Feb;76(2):

13 Axonal damage in R MS is markedly reduced by Natalizumab Gunnarsson et al. Ann Neurol 2010; Epub. AFFIRM Study: natalizumab and brain atrophy 0.0% Years 0-2 Year 0-1* Year 1-2 Mean (SE) percentage change in BPF -0.2% -0.4% -0.6% -0.8% -1.0% -0.80% -0.82% P=0.822 Placebo (N=315) -0.40% -0.56% P= % -0.43% P=0.004 Natalizumab (N=627) Difference between treatments; Change from baseline; Miller DH et al. Neurology 2007;68:

14 Natalizumab treatment of progressive MS reduces inflammation and tissue damage: CSF markers of axonal damage R MS Gunnarsson et al. Ann Neurol Romme Christensen et al. Neurology Apr 29;82(17): Natalizumab SPMS (ASCEND STUDY) ClinicalTrials.gov ID: NCT Fingolimod and CSF neurofilament light chain levels in relapsing remitting multiple sclerosis Khule et al. Neurology Apr 21;84(16): Fingolimod PPMS (INFORMS STUDY) ClinicalTrials.gov ID:NCT Siponimod SPMS (EXPAND STUDY) ClinicalTrials.gov ID: NCT

15 Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb 1a IM Change in mean BV from baseline (%) TRANSFORMS, 1 year Time (months) *** 40% vs IFNb 1a IM p<0.001 Fingolimod 0.5 mg (n = 368) IFNb 1a IM (n = 359) Change in mean BV from baseline (%) FREEDOMS, 2 years Time (months) ** 0.4 * 0.8 *** % vs placebo p<0.001 Fingolimod 0.5 mg (n = 356) Placebo (n = 329) ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p values are for comparisons over Months 0 6, Months 0 12, Months 0 24 BV, brain volume; ITT, intent to treat. Gilenya Prescribing Information 19 April Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: , and Cohen JA et al. N Engl J Med 2010; 362: Copyright 2011 Massachusetts Medical Society. All rights reserved Post inflammatory neurodegeneration Coles et al. J Neurol Jan;253(1):

16 Axonal damage in R MS is markedly reduced by Natalizumab Gunnarsson et al. Ann Neurol 2010; Epub. CSF NFL Gunnarsson et al. Ann Neurol 2010; Epub. 16

17 300 MSers Placebo tablet 600 MSers Year 1 Year 2 Year MSers Active tablet 30 MSers placebo tablet 6 months 60 MSers 6 months 6 months 6 months 30 MSers active tablet LP1 LP2 LP3 Recruitment Trial Data analysis 2 years 17

18 600 MSers for 7 years 60 MSers for 2 years 3 LPs = 10x as many trials in a ⅓ of the time 18

19 66% n = % 13% PPMS RIS CIS RRMS R SPMS SPMS Inflammation Disease Severity Subclinical disease 1 st clinical attack Brain volume loss Neuroaxonal loss Relapses 1 st MRI lesion MRI Events Time (Years) PPMS: Fingolimod, Ocrelizumab, Laquinimod SPMS: Natalizumab, Siponimod CIS: PHENYTOIN RRMS:? DE FLAMES STUDY Early SPMS: PROXIMUS oxcarbazepine Late SPMS: SMART STUDY ibudilast, amiloride, riluzole RIS = radiologically isolated syndrome; CIS = clinically isolated syndrome, RRMS = relapsing remitting MS; R SPMS = relapsing secondary progressive MS; SPMS = secondary progressive MS; PPMS = primary progressive MS 19

20 Brain atrophy occurs across all stages of the disease n= 963 MSers De Stefano, et al. Neurology 2010 Acute neuroprotection 20

21 Pre Treatment (Day 27) Period of Daily Treatment ROTAROD ACTIVITY Measure of Motor Co ordination Post Relapse (Day 48) Vehicle CFMA D33 D48 6/29/2015 Primary outcome: RNFL RNFL average m baseline UNaffected eye Placebo Phenytoin Placebo 6m affected eye Phenytoin Active placebo adjusted difference 7.15 m (95% CI 1.08, p=0.02) 30% reduction of atrophy in active group PP comparison: Active placebo adjusted difference 7.40 m (95% CI 0.76, p=0.03) Bars are standard errors around the unadjusted group means Kapoor et al. AAN 2015 Ischaemic penumbra Immunologic penumbra Trapp et al. NEJM 1998 CFMA Induces Neuroprotection in EAE 4.0 Hindlimb Paralysis No Immunosuppression Evident 3.5 Mean Neurological Score ±SEM Hindlimb 3.0 Paresis 2.5 Impaired 2.0 Right Reflex 1.5 Tail 1.0 Paralysis Time of on Accelerating RotaRod (s) Neuroprotection *** Neuroprotection 0.5 Tail Paresis Time Post Disease Induction (days). Al Izki et al. Brain Jan;137(Pt 1):

22 PPMS RIS CIS RRMS R SPMS SPMS Inflammation Disease Severity Subclinical disease 1 st clinical attack Brain volume loss Neuroaxonal loss Relapses 1 st MRI lesion MRI Events Time (Years) PPMS: Fingolimod, Ocrelizumab, Laquinimod SPMS: Natalizumab, Siponimod CIS: PHENYTOIN RRMS:? DE FLAMES STUDY Early SPMS: PROXIMUS oxcarbazepine Late SPMS: SMART STUDY ibudilast, amiloride, riluzole RIS = radiologically isolated syndrome; CIS = clinically isolated syndrome, RRMS = relapsing remitting MS; R SPMS = relapsing secondary progressive MS; SPMS = secondary progressive MS; PPMS = primary progressive MS Therapeutic Lag Therapeutic lag Delayed effect on disability progression from IFN beta treatment in years 1 & 2 9HPT, cognition, brain atrophy Progression from inflammation in years 2 and 1 Progression from inflammation in years +1 and +2 Progression from inflammation in years +3 to +5 Note the slopes are now parallel because IFN beta was stopped after year +2 Yr 1 Yr 2 Yr +1 Yr +2 Yr +3 Yr +4 Yr +5 Yr +6 Yr +7 No treatment IFN beta 1b Placebo No treatment Tur et al. Arch Neurol Nov;68(11): Time 22

23 Asynchronous progressive MS hypothesis Diagnosis of clinically apparent progressive MS Therapeutic window 1 Bladder Therapeutic window 2 Therapeutic window 4 Therapeutic window 5 Therapeutic window 6 Therapeutic window 7 Therapeutic window 8 Therapeutic window 9 Therapeutic window 10, etc. Motor system to legs Lower limb sensory Cerebellar or balance systems Upper limb motor Upper limb sensory Cognition Vision Etc. Effective DMTs could still target the remaining windows of therapeutic opportunity for individual neurological systems despite some systems have entered the clinically apparent progressive phase of the disease End organ damage Control Multiple sclerosis 23

24 No evident disease activity: NEDA Treat-2-target No evidence of disease activity defined as: 1,2 No relapses No sustained disability progression No MRI activity NEDA-3 No new or enlarging T2 lesions No Gd-enhancing lesions Normalisation of the rate of brain atrophy (NEDA-4) Normalisation of CSF neurofilament levels (NEDA-5) Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8: ; 2. Giovannoni G, et al. Lancet Neurol 2011; 10: Fingolimod and CSF neurofilament light chain levels in relapsing remitting multiple sclerosis Khule et al. Neurology Apr 21;84(16): Fingolimod PPMS (INFORMS STUDY) ClinicalTrials.gov ID:NCT Siponimod SPMS (EXPAND STUDY) ClinicalTrials.gov ID: NCT

25 Remyelination Nogo, MAG, OMgP Lingo-1-NgR-p75 NTR GAP-43 NCAM Neuregulin Agents in trial Slide courtesy of Klaus Schmierer. 1. GSK239512: histamine H(3) receptor antagonist 2. BIIB033: anti-lingo-1 3. Clemastine: anti-histamine 4. IRX4204 & Bexarotene: RXRagonists 5. Etc. Conclusions MS is an iceberg we need to measure markers of subclinical damage Early highly effective therapy is a realistic option of preventing end organ damage Treat 2 target of NEDA (DAF) is gradually being adopted Zero tolerance or ZeTo Markers of end organ damage Brain atrophy OCT CSF neurofilament levels Neuroprotection Acute neuroprotection, e.g. phenytoin in acute optic neuritis Delayed neuroprotection,? Remyelination Several trials underway Therapeutic pyramid Neuro restoration Remyelination Neuroprotection Anti inflammatory 25

26 Acknowledgements Giovannoni Sharmilee Gnanapavan David Baker Gareth Pryce Sarah Al Izki Sam Jackson Katie Lidster Yuti Chernajovsky Alex Annenkov Anne Rigby Michelle Sclanders Larry Steinman Peggy Ho Charles ffrench Constant Robin Franklin Siddharthan Chandran David Hampton Ian Duncan Sam Jackson Peter Calabresi Avi Nath Raj Kapoor John Zajicek Doug Brown UK MS Clinical Trial Network BioMS Co investigators NABINMS Affirm study Care MS 1 & 2 studies Select trial 26