Basic Treatment Principles in MS Start Early/Switch Early Bassem I Yamout, MD, FAAN Professor of Clinical Neurology Head, Multiple Sclerosis Center Clinical Research American University of Beirut Medical Center Florian Deisenhammer Dept. of Neurology Innsbruck Medical University, Germany On behalf of the ParadigMS Board Members

What you see clinically is only the tip of the iceberg MRI Pathology Basic Treatment Principles in MS Making connectionS - 05.11.2016

A. Immune Attack leading to Demyelination Activated T cells A. Immune Attack leading to Demyelination Differentiation of Astrocytes and activation of Microglia Myelin specific Ab + Complement Microglia products NO ROS Glutamate MMPs Cytokines

A. Immune Attack leading to Demyelination Activated T cells A. Immune Attack leading to Demyelination Differentiation of Astrocytes and activation of Microglia Myelin specific Ab + Complement Microglia products NO ROS Glutamate MMPs Cytokines B. Loss of Axonal Trophic Support Disturbed axon-glia interaction Mitochondrial dysfunction CD8 + CTL + Perforin

A. Immune Attack leading to Demyelination Differentiation of Astrocytes and activation of Microglia Microglia products Activated T cells NO Myelin specific Ab + Complement ROS Glutamate MMPs Cytokines A. Immune Attack leading to Demyelination B. Loss of Axonal Trophic Support Disturbed axon-glia interaction CD8 + CTL + Perforin Mitochondrial dysfunction C. Axonal Transection and Wallerian Degeneration N-type Ca-channel® Ca++ influx ® Ca overload ® Cytoskeleton disintegration ® Apoptosis

Pathological Events in MS Axonal Transection is irreversible and most abundant in area of inflammation Trapp et al., NEJM 1998

Natural History Study for MS Association of early relapses (almost all for the 1st year) Median time from onset of MS to DSS3 Median time from onset of MS to DSS6 Number of attacks in the first two years Number of attacks in the first two years Weinshenker BG al. Brain 1989, Ebers et al. JNNP (suppl.) 2001 Basic Treatment Principles in MS Making connectionS - 05.11.2016

Relationship between the number of T2 lesions detected at presentation with a CIS and outcome 14 years later Brex t al. NEJM 2002 Basic Treatment Principles in MS Making connectionS - 05.11.2016

Why treat or escalate early? Permanent axonal loss correlates with ongoing inflammation We have to prevent further damage, and this is best done as early as possible if the disease is active “What is lost by delaying treatment cannot be regained at a later stage” Early suppression of active inflammation may help to minimise cumulative axonal loss Basic Treatment Principles in MS Making connectionS - 05.11.2016

Early Treatment of RRMS: The Current Evidence Wait or start? Prognostic markers to help us make this choice? Basic Treatment Principles in MS Making connectionS - 05.11.2016

BENEFIT: Early treatment significantly delayed CDMS onset by 750 days over 5 years Patients at risk n = 176 n = 292 116 223 83 192 67 160 62 147 33 95 CDMS (%) 10 20 30 40 50 60 Delayed treatment Year 1 Year 2 Year 3 Year 5 Year 4 BL + 750 days 40th percentile Early treatment Log rank: P=0.003 Risk reduction* of 37% over 5 years (Hazard ratio= 0.63) 57% 46% *By proportional hazards regression adjusted for age/gender/steroids/onset of disease/T2-lesions/Gd-lesions

Effect of early treatment on cognitive performance Primary analysis* At Year 5: P=0.0045 Sensitivity analysis** At Year 5 LOCF: P<0.001 Improvement Early treatment Delayed treatment p=0.064* *The PASAT is a subtest of the Multiple Sclerosis Functional Composite (MSFC) No significant difference between the two treatment groups for the other Multiple Sclerosis Functional Composite (MSFC) subscales (25-Foot Walk, 9-Hole Peg Test) or the overall MSFC. **Non-parametric analysis covariance adjusted for baseline LOCF = last observation carried forward Early and sustained effect of early vs. delayed treatment in follow-up study Kappos et al Lancet Neurology, 2009 Basic Treatment Principles in MS Making connectionS - 05.11.2016

Preventing SPMS IFNB delays the time from first visit to onset of SPMS Data from an Italian RR-MS cohort (n=1,504) follow for up to 7 years 20.2% 8.0% *Propensity score-adjusted survival curves for end point Kappos et al Lancet Neurology, 2009

The 2 Extremes: Benign MS does exist but is a retrospective diagnosis 28 patients with EDSS 0-2 and disease duration>10 years had: 25/27 had an EDSS≤3 10 years later None developed SPMS 2/27 were unemployed All reported satisfactory or better QOL Pittock et al. Ann Neurol; 2004 Basic Treatment Principles in MS Making connectionS - 05.11.2016

The 2 Extremes: Benign MS does exist but is a retrospective diagnosis Is it possible to predict benign multiple sclerosis? Ottawa-Canada, Trieste-Italy A retrospective study of patients with the following inclusion criteria: clinically definite EDSS score ≤2 or ≤1 at 10 years from onset of first symptoms; clinical assessments performed at 10±1 and 20±1 years from onset of MS symptoms. Results: Of 175 patients enrolled, patients with EDSS score ≤2 or ≤1 at 10 years 71.9% and 81.6%, remained benign at 20 years respectively. There were significantly more patients (p=0.033) treated with disease modifying drugs (DMD) in the NLB group. In a logistic regression analysis EDSS ≤1 at 10 years was able to predict a benign course at 20 years with better than 80% specificity. Discussion and conclusions: We found a higher percentage of benign patients at 20 years compared to previous studies, possibly due to a higher percentage of patients treated with DMD in our population. However, EDSS ≤2 at 10 years had a better predictive value than EDSS score ≤3 at 10 years, which was neither sensitive nor specific for predicting continuing to be benign at 20 years. We propose that a better definition of benign use stricter EDSS cut-offs (≤2 or even ≤1) at 10 years, in order to enhance the specificity. A. Sartori, M. Abdoli, M.S. Freedman; ECTRIMS 2015 Basic Treatment Principles in MS Making connectionS - 05.11.2016

Effect of baseline characteristics on the risk of attaining EDSS 3.0 The 2 Extremes: Aggressive MS requires high efficacy DMD early on Time from onset of MS to EDSS 6.0 according to initial relapses: EDMUS Lyon Effect of baseline characteristics on the risk of attaining EDSS 3.0 Variable Median years to EDSS 6.0 95% CI P value Initial course Relapsing-remitting* Progressive** 23.1 7.1 20.1–26.1 6.3–7.9 Reference <0.001 Recovery from the 1st relapse Complete Incomplete 27.1 13.0 23.5–30.7 9.7–16.3 Time from onset of MS to 2nd neurological episode <2 years 2–5 years >5 years 17.1 20.1 27.9 14.2–19.9 15.7–24.5 23.9–31.9 0.02 Number of relapses during 1st 5 years n=1 n=2 n≥3 25.3 21.9 24.7 21.9–28.6 15.3–28.6 16.9–32.4 0.01 Number of relapses during the initial course and incomplete recovery from the first relapse Predict a more aggressive course of the disease Presence of OCB, >10 lesions on MRI, Non-optic neuritis presentation and older age were predictive of an aggressive course and future disability Confavreux et al. Brain 2003 Tintore et al. Brain 2015

Switching Therapy When to switch ? Switch to what? Basic Treatment Principles in MS 19 Making connectionS - 05.11.2016

When to switch? Intolerable side-effects: Neutralizing antibodies: adverse reaction: injection site reaction, infusion reaction, infections persistent symptoms: flu-like symptoms, headache, nausea laboratory abnormalities: increased liver enzymes, severe autoimmune hypothyroidism Neutralizing antibodies: anti-IFN-β (high-titre), anti-natalizumab Risk of life-threatening infection: JC virus (pertinent for natalizumab use) Unacceptable disease activity: definition of suboptimal response: clinical activity: relapse rate, cognitive decline, increased EDSS (transition to progression) ? MRI activity: appearance of 2 or more T2 lesions, persistence of active lesions? a mix of clinical and MRI parameters? Basic Treatment Principles in MS Making connectionS - 05.11.2016

MRI Predicting Treatment Effects N=152, RRMS, observation over 2 years (months 12-36). MRI determined in the first 12 months of treatment Probability of remaining free of progression Rio et al, Mult Scler 2008; Rio et al Nat Rev Neurol et al 2009 Time since treatment onset (months) Basic Treatment Principles in MS Making connectionS - 05.11.2016

Prediction of Disease Activity from 1 year MRI 370 patients treated with IFNB and followed for 4 years MRI performed at 1 year At 4-year follow-up: Risk of disability worsening in those with increased MRI activity at 1 year : HR=5.31 (P<0.001) N = 370 Relapse Sustained EDSS progression Relapse & sustained EDSS progression CEL=contrast-enhancing lesion. Prosperini L et al. Mult Scler. 2014 Basic Treatment Principles in MS Making connectionS - 05.11.2016

MRI to monitor treatment response to IFN-beta A systematic review Pooled analysis of those with ≥2 new T2 lesions Relapse or sustained EDSS progression Basic Treatment Principles in MS Making connectionS - 05.11.2016

MRI lesions as a surrogate for relapses in MS: a meta-analysis of randomized trials Sormani et al. Lancet Neurol 2013 Basic Treatment Principles in MS Making connectionS - 05.11.2016

MRI lesions as a surrogate for relapses in MS: a meta-analysis of randomized trials 18 901 Patients The effect of a treatment on relapses can be accurately predicted by the effect of that therapy on MRI lesions Sormani et al. Lancet Neurol 2013 Basic Treatment Principles in MS Making connectionS - 05.11.2016

Progression Probability (%) Scoring treatment response in patients with relapsing MS: The Modified Rio Score Modified Rio Score Criterion Relapse=0; New T2 lesions ≤4 1 Relapse=0; New T2 lesions >4 OR Relapse=1; New T2 lesions ≤4 2 Relapse=1; New T2 lesions >4 Relapse ≥2; New T2 lesions ≤4 3 Relapse ≥2; New T2 lesions >4 100 80 60 40 20 Progression Probability (%) Years 1 2 3 Score ≥2 Score=1 Score=0 Modified Rio Score Assessment Window Risk of progression = 65%† P<0.001 vs Score of 0 Risk of progression = 33%† P=0.13 vs Score of 0 Risk of progression = 24% *Data taken from the PRISMS Trial; †compared to modified Rio score of 0 Sormani et al. Lancet Neurol 2013 Basic Treatment Principles in MS Making connectionS - 05.11.2016

Combining clinical and MRI predictors 1280 patients with RRMS on IFNB from 9 MAGNIMS centers were followed for 3 years. MRI and clinical assessment were performed at 1 year Treatment failure defined as EDSS progression or switching of treatment for inefficacy was assessed after a period of at least 3 years 17% 27% 48% Sormani et al. Neurology 2016 Basic Treatment Principles in MS Making connectionS - 05.11.2016

Ideal predictors of treatment response in MS: The future Proteomics Metabolomics .............. A Clinical and radiological characteristics Variables A B C D C Others A1........An B1........Bn C1........Cn D1........Dn 1 2 N % R to treament 1 ……………………………. % R to treament N % R to treament 1 Prediction of response Patients ……………………………. B Transcriptomics % R to treament N % R to treament 1 ……………………………. % R to treament N D Genetic polymorphisms Genes SNP a SNP d “Pharmacogenomics in multiple sclerosis: Getting the right medicine to the patient” Manuel Comabella Therapy 2008; 5(5):623-629 Non- responder SNP f Responder

Basic switch principles and suggestions for switching Switching because of side-effects or poor adherence generally involves changing between first-line agents (IFNβ, GA, Teriflunomide, DMF). Switching from first- to second-line agents is suggested for patients with significant breakthrough activity. There is currently no Class I evidence to support the administration of any monotherapy in patients with breakthrough disease, except for the CARE-MS II study which showed the superiority of Alemtuzumab to INFB in patients with breakthrough disease on INFB or GA Basic Treatment Principles in MS Making connectionS - 05.11.2016

TOP-MSBase study: Escalation to natalizumab vs interferon beta/ glatiramer acetate in active RRMS patients >1 relapse in prior year TOP Natalizumab IFN/ GA 12-week confirmed disability progression over the 4 years after treatment transition GA/IFN 1.00 0.75 0.50 0.25 0.00 10 20 30 40 50 Months Natalizumab IFN/GA 26% risk reduction with switch to natalizumab† HR=0.74; 95% CI: 0.55–0.97; P<0.036 MSBase ARR in the first year after treatment transition Proportion of patients without confirmed disability progression Annualised relapse rate 66% reduction P <0.0001 (n=497) (n=607) Spelman T et al. Ann Clin Transl Neurol. 2015

TRUST: The German experience TRUST is an ongoing prospective multicenter cohort study in 200 German centers The study enrolls patients with ongoing natalizumab therapy for at least 12 months 427 patients have been enrolled as of August 2015 92% 92% of patients were on BRACE before switch Ziemssen et al. Presented at the AAN 2016 Basic Treatment Principles in MS Making connectionS - 05.11.2016

TOP: Multinational real world evidence The Tysabri Observational Program (TOP) is a 10 year multinational prospective observational study that provides real world data on patients initiating Tysabri This analysis was conducted on patients switching to natalizumab. Butzkueven et al. Presented at the AAN 2016 Basic Treatment Principles in MS Making connectionS - 05.11.2016

TRANSFORMS Trial -61% vs IFNβ-1a IM ARR p<0.001 ARR (n = 149) (n = 160) IFNβ-1a IM Fingolimod Retrospective review of the US administrative claims data from the PharmMetrics Plus database. 264 patients switching from BIFN to GA or fingolimod were identified and matched using propensity scoring Baseline ARR were similar in both groups ( GA: 0.49, Fingolimod: 0.46) In a subgroup analysis of patients with highly active disease despite IFNβ treatment in the year preceding enrollment, fingolimod reduced ARR by 61% relative to IFNβ-1a Cohen et al. J Neurol, 2013

Alemtuzumab: CARE-MS II 2 year study of interferon beta 1a 44 μg vs intravenous alemtuzumab 12 mg/d x5d at baseline and x3d at 12 m 667 RRMS patients with at least one relapse on IFNB or GA Coles et al. Lancet,2012

Lateral Switching between first line treatments 2 year study of interferon beta 1a 44 μg vs intravenous alemtuzumab 12 mg/d x5d at baseline and x3d at 12 m 667 RRMS patients with at least one relapse on IFNB or GA IFN-β/IFN-β IFN-β/GA GA/IFN-β IFN-β or GA/ MTX IFN-β or GA/ NTZ Pre-treatment mARR 1.1 ± 0.6 1.2 ± 0.7 1.1 ± 0.7 1.6 ± 0.7 1.3 ± 0.5 Treatment 1 mARR 0.9 ± 0.8 0.82 ± 0.6 1.3 ± 0.8 0.94 ± 0.4 Treatment 1 pFFR 13% 7% 18% 0% Treatment 2 mARR 0.27 ± 0.4 0.25 ± 0.4 0.16± 0.3 0.34± 0.4 0.04± 0.1 Treatment 2 pFFR 61% 64% 73% 42% 81% Conclusion: In patients with RRMS who have a poor response, switching to another first line DMD may reduce the clinical activity of the disease Basic Treatment Principles in MS Making connectionS - 05.11.2016

Non-aggressive RRMS patients Aggressive RRMS patients MENACTRIMS Algorithm for MS treatment Non-aggressive RRMS patients Aggressive RRMS patients IFN B GA* Ter DMF Patients with contraindications or AE to IFN-B, GA, TER, DMF ≥ 2 disabling relapses in past year AND active MRI Low Concern Fingolimod, Natalizumab Alemtuzumab (Based on risk stratification) Fingolimod Suboptimal Response: Consider Therapy Escalation Fingolimod, Natalizumab Alemtuzumab (Based on risk stratification) Fingolimod, Natalizumab Alemtuzumab (Based on risk stratification) Natalizumab Alemtuzumab (Based on risk stratification) Suboptimal Response: Consider Therapy Escalation Rescue Therapy: Rituximab – Cyclophosphamide – Mitoxantrone – Autologous hematopoietic stem cell transplantation Yamout et al. CMRO, 2015

Conclusion: 2 windows of opportunity Basic Treatment Principles in MS Making connectionS - 05.11.2016

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Prognostic Factors help predicting course CLINICAL Gender, age at onset, multifocal presentation, pyramidal and cerebellar systems involved, partial recovery from relapses, high relapse rate during the first two years from onset MRI T1 lesion load, persistence of ‘activity’ (increased T2 LV, Gd+), brain and GM atrophy, spinal cord lesions CSF MARKERS IgG OB, increased lymphocyte count, markers of neurodegeneration (14-3-3 proteins, tau, NFL [high/low]), IL-1β Basic Treatment Principles in MS Making connectionS - 05.11.2016