MRI in Multiple Sclerosis Features of Cerebral Atrophy with special focus on Multiple Sclerosis. E.W. Radue K. Bendfeldt Till Sprenger

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2 MRI in Multiple Sclerosis Features of Cerebral Atrophy with special focus on Multiple Sclerosis E.W. Radue K. Bendfeldt Till Sprenger Medical Image Analysis Center University Hospital Basel www. miac.ch

3 CNS effects of fingolimod in MS: potential for neuroprotection 1 Preclinical evidence Protects against demyelination, 5-8 axonal loss 6,9 and dendritic loss 10 Enhances survival of neurons and increases BDNF levels 6,11-16 Neurodegeneration / demyelination Inflammation MS Failure of repair / gliosis Preclinical evidence Reduction in inflammatory infiltrates and CNS inflammation 2,3 Preserved BBB integrity 2-4 Preclinical evidence Enhances remyelination 9,17,18 Protects against astrogliosis (scarring) 6,19 Potential preclinical effects of fingolimod may explain observed brain volume change in clinical trials Image courtesy of Professor Barkhof, VU University Medical Center, Amsterdam. 1. Groves A et al. J Neurol Sci 2013; 2. Brinkmann V et al. Nat Rev Drug Discov 2010; 3. Atkas O et al. Nat Rev Drug Discov 2010; 4. Foster CA et al. Brain Pathol Anthony DC et al. Poster P814 presented at ECTRIMS 2010; 6. Choi JW et al. PNAS 2011; 7. Kim HJ et al. FASEB J 2011; 8. Sheridan GK, Dev KK. Glia 2012; 9. Slowik A et al. Poster P511 presented at ECTRIMS 2012; 10. Rossi S et al. Br J Pharmacol Deogracias R et al. PNAS 2012; 12. Di Menna L et al. Pharmacol Res 2013; 13. Doi Y et al. PLos ONE 2013; 14. Efstathopoulos P et al. Poster P501 presented at ECTRIMS 2012; 15. Noda H et al. J Neuroimmunol Stessin AM et al. Neuro Sci Lett 2012; 17. Jackson SJ et al. J Neuroinflammation 2011; 18. Miron VE et al. Am J Pathol 2010; 19. Wu C et al. J Neuroinflammation 2013; 20. Cohen JA et al. N Engl J Med 2010; 21. Kappos L et al. N Engl J Med Radue EW et al. Poster P724 presented at ECTRIMS 2012; 23. Bermel R, Bakshi R. Lancet Neurol 2006; 24. Miller D et al. Brain 2002; 25. Simon J. Mult Scler 2006; 26. Zivadinov R et al. Neurology 2008; 27. O Connor P et al. N Engl J Med Arnold DG et al. Poster Dx21 presented at CMSC 2012

4 MRI measures of MS pathology Acute combined activity Gd-enhancing T1 lesions Relapse - Rate New/enlarging T2 lesions BL Year 1

5 MRI outcome measures Inflammatory activity : Number of new/enlarged T2 lesions, Number of Gd-enhancing T1 lesions Proportions of patients free from new/enlarged T2 lesions or Gd-enhancing lesions and relapses Burden of disease: Absolute and per cent change from baseline in total T2 lesion volume Tissue loss or destruction: Absolute and per cent change from baseline in total T1 hypointense lesion volume. Per cent change in brain volume from baseline

6 ARR Sustained reductions in ARR with fingolimod were observed across long-term studies Fingolimod Phase II and III studies Placebo Fingolimod 0.5 mg IFNβ-1a IM Fingolimod 1.25, 5.0 mg * 0.21* 0.18* n = TRANSFORMS FREEDOMS FREEDOMS II FREEDOMS 1 year 1 2 years 2 2 years 3 extension >4 years 4 TRANSFORMS extension ~4.5 years 5,6 Phase II 7 years 7,8 *p<0.001 vs respective control; patients may have received placebo for 6 months in the core study before switching to fingolimod 1.25 mg or 5.0 mg. Patients on fingolimod 5.0 mg were switched to openlabel fingolimod 1.25 mg in s All patients transitioned to fingolimod 0.5 mg after 5 years until study end; Gilenya 0.5 mg / day is the only dose approved for the treatment of MS. 1. Cohen JA et al. N Engl J Med 2010; 2. Kappos L et al. N Engl J Med 2010; 3. Calabresi PA et al. Poster P491 presented at ECTRIMS 2012; 4. Kappos L et al. Oral presentation S at AAN 2012; 5. Khatri B et al. Poster 218 presented at ENS 2012; 6. Montalban X et al. Poster P517 presented at ECTRIMS 2012; 7. Antel J et al. Oral presentation P01.129; at AAN Montalban X et al. Poster P348 presented at ENS 2012

7 TRANSFORMS extension study: inflammatory disease activity (Gd + T 1 lesions) Mean number of Gd + T 1 lesions Core BL n = n = n = n = 35 Core BL n = n = n = n = 34 IFNb-1a IM / fingolimod a Continuous fingolimod 0.5 mg Core ITT population. Gilenya 0.5 mg / day is the only dose approved for the treatment of MS. Sub analyses for which no formal statistical analysis was performed. *Patients switched to fingolimod at 12; includes patients who received both fingolimod 0.5 mg and 1.25 mg. Khatri B et al. Oral 218 presented at ENS 2012

8 Patients free from lesions (%) Patients free from MRI lesion activity up to 4 years Patients free from lesions (%) FREEDOMS extension: 4-year results Patients free from new or newly enlarged T 2 lesions p<0.001 p< Patients free from Gd + T 1 lesions p< p= Placebo ( 0 24) switched to fingolimod 0.5 mg ( 24 48) (n = 69) Continuous fingolimod 0.5 mg (n = 163) Placebo ( 0 24) switched to fingolimod 0.5 mg ( 24 48) (n = 75) Continuous fingolimod 0.5 mg (n = 171) Within group comparison extension ITT population Kappos L et al. Oral presentation S at AAN 2012; Kappos L et al. Poster P979 presented at ECTRIMS 2012

9 Change in mean BV from baseline (%) Mean change (%) Rate of brain volume loss lower for fingolimod vs placebo and IFNb-1a IM FREEDOMS, 2 years TRANSFORMS, 1 year 0 Time (months) Time (months) ** * *** *** Fingolimod 0.5 mg (n = 425) 38% vs placebo p< Placebo (n = 418) as early as 6, and sustained until study end independent of inflammation status Fingolimod 0.5 mg (n = 368) IFNb-1a IM (n = 359) 40% vs IFNb-1a IM p<0.001 *p<0.05, **p<0.01, ***p<0.001 vs comparator; p values are for comparisons over months 0-6, s 0-12, s 0-24 Barkhof et al. ECTRIMS 2011; poster P907; Radue E et al. AAN 2011; poster P05.064; Gilenya (fingolimod) Summary of Product Characteristics, 4 April 2011

10 Phase III brain volume data: FREEDOMS overall and divided by Gd-activity at baseline Fingolimod 0.5 mg Placebo Change in mean BV from baseline (%) Overall study population Time (months) ** Rate of BV loss lower for fingolimod vs placebo at all time points for all groups independent of inflammation status * **p<0.05, **p<0.01, ***p<0.001 vs placebo; p=0.061 vs placebo; BV, brain volume; Gd, gadolinium, IFN, interferon 1. Radue E et al. AAN 2011, Poster P *** Gd-enhancing lesions at baseline Time (months) * *** ** No Gd-enhancing lesions at baseline

11 Mean change in brain volume (%)* FREEDOMS extension study: fingolimod treatment resulted in a sustained reduction in brain volume loss over 4 years Year 1 Year 2 Year 3 Year 4 n = Placebo ( 0 24) Placebo ( 0 24) switched to fingolimod Continuous fingolimod 0.5 mg Core ITT population. *Reduction in brain volume was calculated using SIENA. At baseline, a single-time-point SIENA method, SIENAX, was used to estimate the normalised brain volume. SIENAX uses brain extraction and tissue-type segmentation to calculate brain volume, followed by normalisation (for head size) to standard space; In the extension, these patients were initially re-randomised to fingolimod 0.5 or 1.25 mg, and then all transitioned to open-label fingolimod 0.5 mg. Gilenya 0.5 mg / day is the only dose approved for the treatment of MS. No statistical analysis was performed n, number of patients with non-missing values. Radue EW et al. Oral O219 presented at ENS 2012

12 Meta-analysis of RCTs in RRMS: brain atrophy and T2 lesions as predictors of disability RR disability Brain atrophy + MRI lesions versus disability Analysis of published RCTs in RRMS, lasting 2 years If number of T2 lesions and atrophy are used in combination they predict the treatment effect on disability more strongly R 2 = 0.7, p< RR combined score RR, relative reduction Sormani MP et al. Poster P presented at AAN 2013

13 Semiautomatic segmentation of the cerebellum in MS patients using ECCET Good feasibility, excellent test-retest and interobserver reliability Calculation of total cerebellar volume Segmentation of grey and white matter

14 Semiautomatic segmentation of the cerebellum MS patients using ECCET in Sept. 09 MIAC, Basel 14

15 Pezold, Amann et al. Spinal atrophy

16 volume volume Spinal cord volume and disease characteristics Volume vs Disease Duration Volume vs Brain T2 Lesion Volume 5000 R² = R² = Volume vs EDSS R² = Model R^2=0.398 EDSS Age Gender Disease Duration Cervical Cord Volume T2 Brain Lesion Volume GM Volume WM Volume p-value < < < beta

17 Relation between EDSS and thalamic volume Left Anterior Left Thalamus Thalamus FDR=0.01 Anterior T-map 3 6 Magon et al., in revision

18 MRI in Multiple Sclerosis Features of Cerebral Atrophy with special focus on Multiple Sclerosis E.W. Radue K. Bendfeldt Till Sprenger Medical Image Analysis Center University Hospital Basel www. miac.ch

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