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Efficacy measures of the future:
what to expect and accept?
Professor Gavin Giovannoni
Blizard Institute, Barts and The Lo...
Disclosures
Professor Giovannoni has received personal compensation for participating on Advisory
Boards in relation to cl...
Defining the therapeutic target
No evident disease activity: NEDA
Gd, gadolinium.
1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et...
NEDA is a sensitive outcome
1.87
5.29
2.75
2.92
3.41
1.64
2.29
0 1 2 3 4 5 6
Dimethyl fumarate (DEFINE)
Natalizumab (AFFIR...
The modified Rio score can predict disability
progression and response to IFN-β therapy
*No qualifying relapses or confirm...
*As measured by modified Rio score. EDSS, Expanded Disability Status Scale;
RRMS, relapsing–remitting MS; tiw, three times...
Yes, 72
No, 28
Relapse reporting
• Most common reasons for not reporting their most recent relapse to a specialist MS team...
Pseudo-relapses
• “I think I know what causes pseudo-relapes, but I don’t know how to define
them!”
• Too many patients wi...
Normal
neurological
examination
No
disability
Minimal
disability
Moderate
disability
Relatively
severe
disability
Disabili...
Yes – I do an EDSS whenever I see a patient 14 25%
Yes – I do an EDSS annually 10 18%
Yes – I occasionally do an EDSS 20 3...
Validating a novel web-based method to
capture disease progression outcomes in MS
P-EDSS, physician or actual EDSS.
The mi...
Monitoring your own disease
http://www.patientslikeme.com/
Epstein Bar Virus
Genetics
Vitamin D
Smoking
Risks
Adverse events
Differential
Diagnosis
MRI
Evoked
Potentials
Lumbar
punc...
No evident disease activity: NEDA
Gd, gadolinium.
1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et...
Treating-2-target
Choosing therapy
X Y Z
Define the
Individual’s MS
No
Treatment failure?Yes
• Patient’s preferences?
• Yo...
Relapses
Unreported relapses
Clinical disease progression
Subclinical relapses: focal MRI activity
Focal gray and white ma...
Control Multiple sclerosis
Brainatrophyoccursacrossallstagesofthedisease
De Stefano, et al. Neurology 2010
n= 963 MSers
Treatment-effect on atrophy correlates with treatment-effect on disability
Sormani et al. Ann Neurol 2014;75:43–49.
Treatment effect on disability predicted by effect on
T2-lesion load and brain atrophy
Meta-analysis of treatment effect o...
-1.0%
-0.8%
-0.6%
-0.4%
-0.2%
0.0%
Years 0-2
-0.82%
-0.80%
P=0.822†
Placebo (N=315) Natalizumab (N=627)
Year 0-1* Year 1-2...
Fingolimod has an early and sustained effect on the rate
of brain atrophy compared with placebo and IFNb-1a IM
FREEDOMS, 2...
Reduction in brain atrophy on alemtuzumab
Alemtuzumab Improves Brain MRI Outcomes
in Patients With Active Relapsing-Remitting
Multiple Sclerosis: Three-Year Follow-...
CARE-MS I & II Three-Year MRI Outcomes
Change in Brain Parenchymal Fraction (BPF)
 Alemtuzumab slowed brain volume loss o...
CARE-MS I & II Three-Year MRI Outcomes
Proportion of Patients Free of Gd Lesions, T2 Lesions, and MRI Activity
 The major...
Rheumatoid arthritis
End-stage joint disease
No evident disease activity: NEDA
Gd, gadolinium.
1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et...
Natalizumaband FunctionalBenefit– Double-blind,
Placebo-controlledStudy (AFFIRM)
1. Phillips JT et al., Mult Scler 2011;17...
Alemtuzumabimproved pre-existing disability
CARE-MS II
aSecondary endpoint; defined as decrease of ≥1 EDSS point lasting a...
No evident disease activity: NEDA
Gd, gadolinium.
1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et...
Re-defining the therapeutic window
Coles et al. J Neurol. 2006 Jan;253(1):98-108..
Window of therapeutic efficacy
Theoretical model: treat early and effectively
Natural course
of disease
Later
intervention
Later
treatment
Treatment
at d...
Coles et al. J Neurol. 2006 Jan;253(1):98-108..
Window of therapeutic efficacy
Tur et al. Arch Neurol. 2011 Nov;68(11):1421-7.
Motor system to legs
Cerebellar or balance systems
BladderTherapeutic window 1
Therapeutic window 2
Therapeutic window 3
U...
Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive
multiple sclerosis (MS-STAT): a r...
Normal
neurological
examination
No
disability
Minimal
disability
Moderate
disability
Relatively
severe
disability
Disabili...
Ceiling and floor effects
Effect of dronabinol on progression in progressive multiple
sclerosis (CUPID): a randomised, placebo-controlled trial
Zaji...
0 200 400 600 800 1000 1200
0.0
0.2
0.4
0.6
0.8
1.0
Time to EDSS progression (days)
P(EDSSprogression)
Treatment group
Act...
0 200 400 600 800 1000 1200
0.0
0.2
0.4
0.6
0.8
1.0
Time to EDSS progression (days)
P(EDSSprogression)
Baseline EDSS score...
0 200 400 600 800 1000 1200
0.0
0.2
0.4
0.6
0.8
1.0
Time to EDSS progression (days)
P(EDSSprogression)
Treatment group
Act...
Long-term effect of early treatment with IFNB-1b after CIS:
5-yr active extension of the phase 3 BENEFIT trial
Kappos et a...
Therapeutic strategies
Proof of concept Trials
Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
Spinal fluid neurofilament levels
Gunnarsson et al. Ann Neurol 2010; Epub.
CSF NFL
Phase 2A study of natalizumab in progressive MS:
CSF markers of axonal damage and demyelination (2° endpoint)
Slide courte...
Fingolimod and CSF neurofilament light chain levels in
relapsing-remitting multiple sclerosis
Kuhle et al. submitted for p...
No evident disease activity: NEDA
Gd, gadolinium.
1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et...
38 year old woman with left optic neuritis
sTE fFLAIR images
Baseline 52 weeks
Hickman et al. Neuroradiology 2001;43:123-8...
Acute neuroprotection
No evident disease activity: NEDA
Gd, gadolinium.
1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et...
Remyelination
Nogo, MAG, OMgP
Lingo-1-NgR-p75NTR
GAP-43
NCAM
Neuregulin
Slide courtesy of Klaus Schmierer.
Agents in trial...
No evident disease activity: NEDA
Gd, gadolinium.
1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et...
Therapeutic hierarchy
Neuro-restoration
Remyelination
Neuroprotection
Anti-inflammatory
Therapeutic pyramid
Anti-ageing
Br...
Conclusions
• Therapeutic target is moving
– NEDA
– PROMS/PROS/Smart Devices
– End-organ damage
– Sustained improvement in...
Future efficacy measures for Multiple Sclerosis
Future efficacy measures for Multiple Sclerosis
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Future efficacy measures for Multiple Sclerosis

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Presentation at a MS meeting in Copenhagen held on the 26th August 2014.

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Transcript of "Future efficacy measures for Multiple Sclerosis"

  1. 1. Efficacy measures of the future: what to expect and accept? Professor Gavin Giovannoni Blizard Institute, Barts and The London School of Medicine and Dentistry
  2. 2. 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 www.ms-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 Biogen-Idec, Genzyme and Novartis for making available data slides on natalizumab, alemtuzumab and fingolimod for this presentation.
  3. 3. Defining the therapeutic target
  4. 4. No evident disease activity: NEDA Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337. Treat-2-target What is NEDA? × No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions DAF1,2
  5. 5. NEDA is a sensitive outcome 1.87 5.29 2.75 2.92 3.41 1.64 2.29 0 1 2 3 4 5 6 Dimethyl fumarate (DEFINE) Natalizumab (AFFIRM) Cladribine (CLARITY) Fingolimod (FREEDOMS) sc IFN β-1a (DoF) Teriflunomide (TEMSO) Alemtuzumab (CARE MS II) Increase in proportion of NEDA patients relative to comparator Patients with RRMS over 2 years. Increase in proportion of patients with NEDA versus placebo (except CARE MS II) All data from post hoc analyses of randomized controlled trials in patients with RRMS. Table adapted from Bevan CJ and Cree BA. JAMA Neurol 2014;71:269-70, with the exception of: TEMSO. Freedman et al. Neurology 2012;78 [Meeting Abstract s 1]: PD5.007; sc IFN b1-a sc. Data on file; CARE MS II. Coles AJ et al. Lancet 2012;380:1829-39 versus sc IFN b-1a Slide courtesy Prof. Mark Freedman, EFNS-ENS Istanbul 2014
  6. 6. The modified Rio score can predict disability progression and response to IFN-β therapy *No qualifying relapses or confirmed EDSS progression; †Percentage calculated using total number of patients with a particular modified Rio score at Week 48; ‡No clinical activity, gadolinium-enhancing lesions, or new/enlarging T2 lesions. EDSS, Expanded Disability Status Scale Outcomes after 1 year of IFN-β treatment Modified Rio score ≤5 new T2 lesions and 0 relapses 0 ≤5 new T2 lesions and 1 relapse, or >5 new T2 lesions and 0 relapses 1 ≤5 new T2 lesions and ≥2 relapses, or >5 new T2 lesions and 1 relapse 2 >5 new T2 lesions and ≥2 relapses 3 Higher modified Rio score predicts greater risk of progression1 Modified Rio score at Week 48 (REGARD) Clinical activity-free* at Week 96 n (%)†2 Disease activity-free at Week 96 n (%)‡2 Yes No Yes No 0 (n=156) 121 (77.6) 35 (22.4) 53 (34.0) 103 (66.0) 1 (n=42) 3 (7.1) 39 (92.9) 0 42 (100) 2 (n=5) 0 5 (100) 0 5 (100) Total (N=203) 124 79 53 150 Worseningdisease 1. Sormani MP et al. Mult Scler J 2013;19:605-12 2. Freedman M et al. Mult Scler J 2013;19(Suppl. 1):262 [P610] Slide courtesy Prof. Mark Freedman, EFNS-ENS Istanbul 2014
  7. 7. *As measured by modified Rio score. EDSS, Expanded Disability Status Scale; RRMS, relapsing–remitting MS; tiw, three times weekly Faster disability progression seen in patients with worse Rio-defined disease activity* Kaplan–Meier cumulative incidence curves of time to confirmed EDSS progression by modified Rio score in patients with RRMS receiving sc IFN β-1a 44 µg tiw 156 42 155 41 151 39 144 33 138 27 No. of patients at risk: Rio score 0 Rio score 1 Baseline Week 24 0.0 0.1 0.2 Cumulativeincidence 0.3 0.4 0.5 Week 48 Week 72 Week 96 O (n=156) 1 (n=42) Rio score group Time to 3-month EDSS confirmed progression Freedman M et al. Mult Scler J 2013;19(Suppl. 1):262 [P610] Slide courtesy Prof. Mark Freedman, EFNS-ENS Istanbul 2014
  8. 8. Yes, 72 No, 28 Relapse reporting • Most common reasons for not reporting their most recent relapse to a specialist MS team were: – ‘Mild relapse so not felt necessary’ 5/28 (18%) – ‘Saw or spoke to their GP’ 4/28 (14%) • Most common reasons for not seeking healthcare support were: – ‘Felt I could manage’/mild relapse 18/42 (43%) – ‘Nothing that they can do to help’ 8/42 (19%) Duddy M, et al. ECTRIMS 2013. P590. N = 101 Yes, 46 No, 54 N = 102 Patients who have ever experienced an MS relapse and not contacted a healthcare professional Patients reporting most recent relapse to a specialist MS team
  9. 9. Pseudo-relapses • “I think I know what causes pseudo-relapes, but I don’t know how to define them!” • Too many patients with transient, or intermittent, symptoms have active MRI scans (Gd+ lesions) • What about non-classical symptoms? – Cognitive relapse – Fatigue – Narcolepsy – Well described transient syndromes, e.g. Lhermitte’s, flexor spasms • NOT ("the appearance of new symptoms, or the return of old symptoms, for a period of 24 hours or more – in the absence of a change in core body temperature or infection“) – Trial protocols are more restrictive and require patients to move on the EDSS and/or FS (one FS by at least 2 points or two FS by at 1 point) – The above creates protocol and non-protocol defined relapses.
  10. 10. Normal neurological examination No disability Minimal disability Moderate disability Relatively severe disability Disability precludes full daily activities Assistance required to walk Restricted to a wheelchair Restricted to bed or chair Confined to bed Death 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 EDSS Adapted from http://www.msdecisions.org.uk/. Accessed 15 April 2014. Previously adapted from Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33:1444–1452.
  11. 11. Yes – I do an EDSS whenever I see a patient 14 25% Yes – I do an EDSS annually 10 18% Yes – I occasionally do an EDSS 20 36% No – I never do an EDSS 3 5% Other 9 16%Yes – I do an EDSS whenever I see a patient [14] Yes – I do an EDSS annually [10] Yes – I occasionally do an EDSS [20] No – I never do an EDSS [3] Other [9] Survey of UK MSologists Schmierer K, et al. ABN 2014; Unpublished. Clinical – In your routine MS clinical practice, do you use the EDSS? Clinical – If you do an EDSS in your routine clinical practice, do you walk the patients to assess their walking distance? Yes [9] No [20] Sometimes [22] Other [5] Yes 9 16% No 20 36% Sometimes 22 39% Other 5 9%
  12. 12. Validating a novel web-based method to capture disease progression outcomes in MS P-EDSS, physician or actual EDSS. The midpoint of the diamonds is the mean difference between the two EDSS scores, the upper and lower lines within the diamonds are the 95% CI. The width of the diamond indicates the sample size, the dots the actual values. The horizontal line at 0.46 indicates the mean difference between the two scores. The graph indicates the greater variation at lower EDSS scores, with greater agreement at scores > 5. Leddy S, et al. J Neurol 2013; 260:2505–2510. ORIGINAL COMMUNICATION web-EDSS–P-EDSSscore P-EDSS score –4 –3 –2 –1 0 1 2 3 4 0 1 1.5 2 2.5 3 3.5 4 4.5 5.5 6 6.5 7 8
  13. 13. Monitoring your own disease http://www.patientslikeme.com/
  14. 14. Epstein Bar Virus Genetics Vitamin D Smoking Risks Adverse events Differential Diagnosis MRI Evoked Potentials Lumbar puncture Blood Tests Diagnostic Criteria Cognition Depression Fatigue Bladder Bowel Sexual dysfunction Tremor Pain Swallowing SpasticityFalls Balance problems Insomnia Restless legsFertility Clinical trials Gait Pressure sores Oscillopsia Emotional lability Seizures Gastrostomy Rehab Suprapubic catheter Intrathecal baclofen Physio- therapy Speech therapy Occupational Therapy Functional neurosurgery Colostomy Tendonotomy Studying Employment Relationships Travel Vaccination Anxiety Driving Nurse specialists Family counselling Relapses 1st line 2nd line Maintenance Escalation Induction Monitoring Disease-free Disease progression DMTs Side Effects Advanced Directive Exercise Diet Alternative Medicine Pregnancy Breast Feeding Research Insurance Visual loss Palliative Care Assisted suicide Social services Legal aid Genetic counselling Prevention Diagnosis DMT Symptomatic Therapist Terminal CounsellingAn holistic approach to MS Intrathecal phenol Fractures Movement disorders Osteopaenia Brain atrophy Hearing loss Tinnitus Photophobia Hiccoughs DVLA Neuroprotection Psychosis Depersonaliation Brain Health Cognitive Reserve Sudden death Suicide OCD Narcolepsy Apnoea Carers Respite Hospice Respite Dignitas Advanced Directive Rhiztomy Rhiztomy Wheelchair Walking aids Blood/Organ donation Brain donation Exercise therapy NABs Autoimmunity Infections Outcome measures Web Resources Pathogenesis Double vision What is MS? NEDA T2T OCT Neurofilaments JCV status Pharma Anaesthesia
  15. 15. No evident disease activity: NEDA Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337. Treat-2-target What is NEDA? × No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions  Patient-related outcomes (PRO or PROMS / Smart Devices) DAF1,2
  16. 16. Treating-2-target Choosing therapy X Y Z Define the Individual’s MS No Treatment failure?Yes • Patient’s preferences? • Your choice? Individual measures: • Evidence of disease activity? • Tolerability/safety? • Adherence? • Drug or inhibitory markers? Monitoring • MS prognosis • Life style and goals • Shared goals for therapy Rebaseline Rebaseline: • IFNβ, natalizumab, fingolimod, teriflunomide, DMF=3-6 months • Glatiramer acetate=9 months • Alemtuzumab=24 months DMF=dimethyl fumarate.
  17. 17. Relapses Unreported relapses Clinical disease progression Subclinical relapses: focal MRI activity Focal gray and white matter lesions not detected by MRI Brain atrophy Spinal fluid neurofilament levels MS Iceberg Clinical activity Focal MRI activity Hidden focal and diffuse MRI activity Microscopic or biochemical pathology Biomarkers
  18. 18. Control Multiple sclerosis
  19. 19. Brainatrophyoccursacrossallstagesofthedisease De Stefano, et al. Neurology 2010 n= 963 MSers
  20. 20. Treatment-effect on atrophy correlates with treatment-effect on disability Sormani et al. Ann Neurol 2014;75:43–49.
  21. 21. 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;75:43-49.
  22. 22. -1.0% -0.8% -0.6% -0.4% -0.2% 0.0% Years 0-2 -0.82% -0.80% P=0.822† Placebo (N=315) Natalizumab (N=627) Year 0-1* Year 1-2 -0.40% -0.56% -0.43% -0.24% P=0.004† P=0.002† †Difference between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401. AFFIRM Study: natalizumab and brain atrophy Mean(SE)percentagechangeinBPF
  23. 23. Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM FREEDOMS, 2 years Fingolimod 0.5 mg (n = 356) Placebo (n = 329) *** * ** 60 12 24 Time (months) 0 -0.4 -0.8 -1.2 -1.6 -2.0 −38% vs placebo p<0.001 ChangeinmeanBVfrom baseline(%) TRANSFORMS, 1 year 0 12 Time (months) 0.0 -0.4 -0.6 -1.0 IFNb-1a IM (n = 359) Fingolimod 0.5 mg (n = 368) −40% vs IFNb-1a IM p<0.001 ***-0.2 -0.8 ChangeinmeanBVfrom baseline(%) 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 2012. Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: 387-401, and Cohen JA et al. N Engl J Med 2010; 362: 402-415. Copyright © 2011 Massachusetts Medical Society. All rights reserved
  24. 24. Reduction in brain atrophy on alemtuzumab
  25. 25. Alemtuzumab Improves Brain MRI Outcomes in Patients With Active Relapsing-Remitting Multiple Sclerosis: Three-Year Follow-up of the CARE-MS Studies Douglas L Arnold,1,2 Elizabeth Fisher,3 Jeffrey A Cohen,4 Frederik Barkhof,5 Krzysztof W Selmaj,6 David H Margolin,7 Jeffrey Palmer,7 Edward J Fox8 AAN 2014 Blitz S65-008 1NeuroRx Research, Montréal, Québec, Canada, and 2Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada; 3Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH, USA; 4Cleveland Clinic, Cleveland, OH, USA; 5VU University Medical Centre, Amsterdam, Netherlands; 6Department of Neurology, Medical University of Łódź, Łódź, Poland; 7Genzyme, a Sanofi company, Cambridge, MA, USA; 8University of Texas Medical Branch, Round Rock, TX, USA
  26. 26. CARE-MS I & II Three-Year MRI Outcomes Change in Brain Parenchymal Fraction (BPF)  Alemtuzumab slowed brain volume loss over 3 years, as assessed by change in BPF  For both patient populations, the median percentage reduction in BPF observed in in Year 3 (0.19% and 0.10%, respectively) was smaller than that observed in Year 1 (0.59% and 0.48%) and Year 2 (0.25% and 0.22%) Percentage Change in BPF in Formerly Treatment-Naive Patients (CARE-MS I) Percentage Change in BPF in Patients Who Relapsed on Prior Therapy (CARE-MS II) MedianChangeFrom Baseline,%(95%CI) Year No. of Patients 371 367 351 323 % Change from Previous Year – –0.59% –0.25% –0.19% MedianChangeFrom Baseline,%(95%CI) Year 428 414 405 359 – –0.48% –0.22% –0.10% No. of Patients % Change from Previous Year 0 1 2 3 -1 .5 0 -1 .2 5 -1 .0 0 -0 .7 5 -0 .5 0 -0 .2 5 0 .0 0 0 1 2 3 -1 .5 0 -1 .2 5 -1 .0 0 -0 .7 5 -0 .5 0 -0 .2 5 0 .0 0 AAN 2014 Blitz S65-008
  27. 27. CARE-MS I & II Three-Year MRI Outcomes Proportion of Patients Free of Gd Lesions, T2 Lesions, and MRI Activity  The majority of alemtuzumab-treated patients were free of MRI activity (absence of Gd- enhancing lesions and new/enlarging T2 hyperintense lesions) at Year 2 and Year 3 MRI activity-free: absence of both Gd-enhancing and new or enlarging T2 hyperintense lesions; CARE-MS=Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; CI=confidence interval; DMT=disease-modifying therapy; Gd=gadolinium; MRI=magnetic resonance imaging; Y=year No. of Patients 359370 336 356370 325 354369 326 Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3 ProportionofPatients, %(95%CI) 0 20 40 60 80 100 Gd-enhancing lesion-free New/enlarging T2 lesion-free MRI activity-free % MRI Activity Free in Treatment-Naive Patients (CARE-MS I) % MRI Activity Free in Patients Who Relapsed on Prior Therapy (CARE-MS II) No. of Patients 412421 364 405423 361 Gd-enhancing lesion-free New/enlarging MRI activity-free 402414 361 ProportionofPatients, %(95%CI) 0 20 40 60 80 100 Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3 T2 lesion-free  Patients were treated with alemtuzumab 12 mg at baseline and 12 months later  Re-treatment in Year 3 was administered upon recurrence of disease activity  18% of CARE-MS I patients and 20% of CARE-MS II patients were re-treated with alemtuzumab in Year 3; <3% were treated with another DMT in Year 3 AAN 2014 Blitz S65-008
  28. 28. Rheumatoid arthritis End-stage joint disease
  29. 29. No evident disease activity: NEDA Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337. Treat-2-target What is NEDA? × No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions  Patient-related outcomes (PRO or PROMS / Smart Devices)  Normalisation of brain atrophy rates DAF1,2
  30. 30. Natalizumaband FunctionalBenefit– Double-blind, Placebo-controlledStudy (AFFIRM) 1. Phillips JT et al., Mult Scler 2011;17:970-979; 2. Munschauer F et al., ECTRIMS Meeting September 9–12, 2009, Dusseldorf, Germany, P434; 3. Balcer LJ et al., J Neurol Sci 2012;318:119-24; 4. Weinstock-Guttmanen B et al., J Neurol 2012;259:898–905. Compared with placebo, Natalizumab showed sustained improvement in • EDSS1 • Upper limb2 • Walking2 • Vision3 and reduced the risk of progression of cognitive deficit4 -0.3 0.2 0.7 1.2 1.7 2.2 2.7 3.2 3.7 4.2 0.5 5 Hazard Ratio (95% Confidence Interval) 0.5 1.0 1.5 2.0 3.0 4.0 5.0 Favours placebo Favours natalizumab Cognitive deficit – PASAT-3 (P=0.013) Vision – 1.25% low contrast acuity (P=0.014) Vision - 2.5% low contrast acuity (P=0.012) Timed 25-foot walk (P=0.028) 9-hole peg test (P=0.044) EDSS (P=0.006) Favours natalizumab Favours placebo
  31. 31. Alemtuzumabimproved pre-existing disability CARE-MS II aSecondary endpoint; defined as decrease of ≥1 EDSS point lasting at least 6 months, assessed in patients with baseline EDSS ≥2.0. bTertiary endpoint. cMeasured by SRD score in relapsing patients. Coles AJ, et al. Lancet. 2012;380:1829-1839. IFNB-1a 44 μg Alemtuzumab12 mg ‒0.17 P<0.0001 +0.24 EDSSScore,mean 3.25 3.00 2.75 2.50 2.25 Follow-Up Month 0 3 6 9 12 15 18 21 24 40 30 20 10 0 PatientsWith6-MonthSRD(%) 29% 13% P=0.0002 Mean EDSS Change From Baselinea SRDb‎ Follow-Up Month 0 3 6 9 12 15 18 21 24
  32. 32. No evident disease activity: NEDA Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337. Treat-2-target What is NEDA? × No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions  Patient-related outcomes (PRO or PROMS / Smart Devices)  Normalisation of brain atrophy rates  Sustained improvement in disability (PROM / Smart Device) DAF1,2
  33. 33. Re-defining the therapeutic window
  34. 34. Coles et al. J Neurol. 2006 Jan;253(1):98-108.. Window of therapeutic efficacy
  35. 35. Theoretical model: treat early and effectively Natural course of disease Later intervention Later treatment Treatment at diagnosis Intervention at diagnosis Time Disease Onset Disability Time is brain
  36. 36. Coles et al. J Neurol. 2006 Jan;253(1):98-108.. Window of therapeutic efficacy
  37. 37. Tur et al. Arch Neurol. 2011 Nov;68(11):1421-7.
  38. 38. Motor system to legs Cerebellar or balance systems BladderTherapeutic window 1 Therapeutic window 2 Therapeutic window 3 Upper limbs Sensory Cognition Vision Etc. Therapeutic window 4 Therapeutic window 5 Therapeutic window 6 Therapeutic window 7 Therapeutic window 8, etc…. Diagnosis of Progressive MS Effective DMTs could still target the remaining windows of therapeutic opportunity for individual neurological systems The Asynchronous Progressive MS hypothesis
  39. 39. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial Chataway Lancet 2014; 383: 2213–21.
  40. 40. Normal neurological examination No disability Minimal disability Moderate disability Relatively severe disability Disability precludes full daily activities Assistance required to walk Restricted to a wheelchair Restricted to bed or chair Confined to bed Death 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 EDSS Adapted from http://www.msdecisions.org.uk/. Accessed 15 April 2014. Previously adapted from Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33:1444–1452.
  41. 41. Ceiling and floor effects
  42. 42. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial Zajicek et al. Lancet Neurol 2013; 12: 857–65.
  43. 43. 0 200 400 600 800 1000 1200 0.0 0.2 0.4 0.6 0.8 1.0 Time to EDSS progression (days) P(EDSSprogression) Treatment group Active Placebo Slides courtesy of John Zajicek. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial
  44. 44. 0 200 400 600 800 1000 1200 0.0 0.2 0.4 0.6 0.8 1.0 Time to EDSS progression (days) P(EDSSprogression) Baseline EDSS score 4 4.5 5 5.5 6 6.5 Slides courtesy of John Zajicek. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial
  45. 45. 0 200 400 600 800 1000 1200 0.0 0.2 0.4 0.6 0.8 1.0 Time to EDSS progression (days) P(EDSSprogression) Treatment group Active Placebo Log rank test P = 0.01 Slides courtesy of John Zajicek. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial
  46. 46. Long-term effect of early treatment with IFNB-1b after CIS: 5-yr active extension of the phase 3 BENEFIT trial Kappos et al. Lancet Neurol 2009; 8: 987–97. 3 6 9 12 24 EDSS 0 TIME Active (no progression) Placebo (confirmed progression) Delayed Recovery Equal exit EDSS
  47. 47. Therapeutic strategies Proof of concept Trials
  48. 48. Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11. Spinal fluid neurofilament levels
  49. 49. Gunnarsson et al. Ann Neurol 2010; Epub. CSF NFL
  50. 50. Phase 2A study of natalizumab in progressive MS: CSF markers of axonal damage and demyelination (2° endpoint) Slide courtesy of Romme Christensen, ECTRIMS 2012. Oral presentation 170. NIND Mean +/- 95% CI p=0.03 CSFNeurofilamentllightng/L p=0.048 CSFMBPng/ml NIND Mean +/- 95% CI Natalizumab → SPMS (ASCEND STUDY) ClinicalTrials.gov ID: NCT01416181
  51. 51. Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis Kuhle et al. submitted for publication Fingolimod → PPMS (INFORMS STUDY) ClinicalTrials.gov ID:NCT00731692 Siponimod → SPMS (EXPAND STUDY) ClinicalTrials.gov ID: NCT01665144
  52. 52. No evident disease activity: NEDA Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337. Treat-2-target What is NEDA? × No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions  Patient-related outcomes (PRO or PROMS / Smart Devices)  Normalisation of brain atrophy rates  Sustained improvement in disability (PROM / Smart Device)  Normalisation of CSF neurofilament levels DAF1,2
  53. 53. 38 year old woman with left optic neuritis sTE fFLAIR images Baseline 52 weeks Hickman et al. Neuroradiology 2001;43:123-8. Trapp et al. N Engl J Med 1998. Acute mono-focal lesion
  54. 54. Acute neuroprotection
  55. 55. No evident disease activity: NEDA Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337. Treat-2-target What is NEDA? × No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions  Patient-related outcomes (PRO or PROMS / Smart Devices)  Normalisation of brain atrophy rates  Sustained improvement in disability (PROM / Smart Device)  Normalisation of CSF neurofilament levels  Normalisation of retinal nerve fibre layer thinning (OCT) DAF1,2
  56. 56. Remyelination Nogo, MAG, OMgP Lingo-1-NgR-p75NTR GAP-43 NCAM Neuregulin Slide courtesy of Klaus Schmierer. Agents in trial 1. GSK239512: histamine H(3) receptor antagonist 2. BIIB033: anti-LINGO-1 3. Clemastine: anti-histamine 4. IRX4204 & Bexarotene: RXR- agonists 5. Etc.
  57. 57. No evident disease activity: NEDA Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337. Treat-2-target What is NEDA? × No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions  Patient-related outcomes (PRO or PROMS / Smart Devices)  Normalisation of brain atrophy rates  Sustained improvement in disability (PROM / Smart Device)  Normalisation of CSF neurofilament levels  Normalisation of retinal nerve fibre layer thinning (OCT)  Improvement in central conduction times (VEPs)  Etc. DAF1,2
  58. 58. Therapeutic hierarchy Neuro-restoration Remyelination Neuroprotection Anti-inflammatory Therapeutic pyramid Anti-ageing BrainHealthInitiative • Smoking • Exercise • Diet • Sleep • Co-morbidities • Infections • Concomitant medications
  59. 59. Conclusions • Therapeutic target is moving – NEDA – PROMS/PROS/Smart Devices – End-organ damage – Sustained improvement in disability – Remyelination – Neurorestoration • Therapeutic time window – Early or late • Redefining progressive MS – Asynchronous disease course – Therapeutic lag • Novel PoC trials – OCT in acute optic neuritis – CSF NF levels in SPMS – VEPs and MTR in remyelination trials
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