Review of Available Therapies Mark S. Freedman MSc MD FANA FAAN FRCPC Professor of Medicine (Neurology) University of Ottawa Sr. Scientist The Ottawa Hospital Research Institute Disclosures Receipt of research or educational grants: Genzyme Receipt of honoraria or consultation fees: Actelion, BayerHealthcare, BiogenIdec, Chugai, EMD Canada, Genzyme, Hoffman La-Roche, Novartis, Sanofi-Aventis, Teva Canada Innovation Member of a company advisory board, board of directors or other similar group: Actelion, BiogenIdec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, Teva Canada Innovation Participation in a company sponsored speaker’s bureau: Genzyme Existing & Emerging MS therapies Other Phase I Lymphocyte CS-0777 BIIB033 trafficking Phase II Idebenone Phase III Firategrast Interferons ONO-4641 ELND-002 Marketed Siponimod Ponesimod AZD5904 Peg IFNβ 1a IFNβ-1b Fingolimod GRC4039 IFNβ-1a im Natlizumab IFNβ-1a sc CCX-140 Azathioprine Laquinimod Novantrone AIN457 Immune BG12 regulation Teriflunomide GA Daclizumab Antiproliferative Secukinumab agents Cladribine THC:CBD NI-0801 GA generics X2 4-AP PiXantrone GA 40 tiw AlemtuzumabIPX-056 RPI-78M Ocrelizumab ATX-MS-1467 Ofatumumab Nerispirdine PI2301 LY-2127399 Vaccine, RTL1000 Symptomatic Tx tolerization Belimumab = Oral administration Cytolytic mAbs = Injectable mAb, monoclonal antibody; Tx, treatment Evolving Treatment Landscape in MS RRMS Progressive MS (SPMS/PPMS) Generic/Biosimilar RRMS mAb Cladribine Firategrast Fingolimod MD1003 Orals Teriflunomide NeXt Gen Fingolimod Laquinimod S1pRA Dimethyl NeXt Gen Fumarate Masitinib Siponimod Fumarates Approved 2013 2014 2015 2016 2017 2018+ GA GA 3TW Tcelna Injectables Peg IFNβ1a (non Mab) IFNβ1a IFNβ1b Biosimilar Generic GA? Interferon-β MitoXantrone Natalizumab Alemtuzumab Daclizumab Ocrelizumab Ofatumumab mAbs Natalizumab Secukinumab Anti-LINGO1 Remyelination rHIgM22 GSK239512 MS: Pathological vs. Clinical Course of Disease RIS CIS Relapsing – Remitting Transitional Secondary Progressive First Clinical Attack Treatment depends on Are you dealing with new diseaseWHEREOr advanced in the ( silent)window disease you presenting early? think thepresenting patient is late?when you Time (Years) Axonal Loss Time Window for are initiating treatment Early Treatment 12,000 11,236 Clinical Threshold 10,000 8,000 6,000 4,000 3,138 Disease parameter Demyelination2,000 875 17 0.7 0 Active Chronic Chronic NAWM Control active active white edge core Inflammation What is the Imminent Risk for Disease Progression for the Patient? DISEASE PROGRESSION Prognostic Features in Early MS Better prognosis Poorer prognosis l Caucasian l Afro-American or non-white l Monofocal onset l Smoking or obesity l Onset with optic neuritis or l +OCB in CSF with high WBC isolated sensory symptoms l Multifocal onset l Low relapse rate first 2–5 years l Onset with motor, cerebellar, or l Long interval to second relapse bladder/bowel symptoms l No or low disability at 5 years l High relapse rate first 2–5 years l Abnormal MRI low lesion load l Short inter-attack latency l Early response to DMT l Disability at 5 years l Abnormal MRI - high lesion load ≥2 contrast lesions, ≥9 T2 lesions l Poor response to DMT Miller DH, et al. J Manag Care Pharm. 2004;10:S4–S11; Kantarci O, et al. Prognostic Factors in Multiple Sclerosis. In: Handbook of Multiple Sclerosis (3rd ed). Cook SD, editor. New York: Marcel Dekker. 2001. pp 449–463. How Can We Prevent Progression? What are the contributing factors? ¡ Attacks o Are all attacks the same? ¡ Progression o How well do patients “heal” and recover function? o How quickly have patients shown progression? ¡ Burden of silent disease on MRI o How much has accumulated prior to clinical expression? Attacks Why do we get them? ¡ Strategic hit? Vs. ¡ “Straw that broke the camel’s back”? Attacks What qualities about attacks help to characterize their seriousness? ¡ Rate? ¡ Severity? ¡ Repair capability? Progression What qualities about “progression” help to characterize the seriousness? ¡ EDSS change? ¡ Presence of motor incapability? ¡ Cognitive involvement? ¡ Speed of change over time (i.e. MSSS)? MS Severity Score (MSSS) MRI What qualities about MRI change help to characterize the seriousness? ¡ T2 burden of disease? ¡ Presence or quantity of Gd+ lesions? ¡ Presence or quantity of black holes? ¡ Presence of atrophy? What Features tell us the disease is behaving more “aggressive”? Clinical ¡ Attack number & severity ¡ Progression (EDSS, T25FW, change/time) ¡ MSSS MRI Poor response to 1st line DMT Responders vs. Non-Responders These can easily be defined as they are having the events (relapse, MRI or progression) True How do you responders distinguish • No or reduced activity these? due to treatment effect Non- responders False • Continued disease activity despite responders treatment • No or reduced activity due to natural history Where is NEDA in These Groups? NEDA would be a subgroup of the true and false responders True responders • No or reduced activity due to treatment effect Non- responders False • Continued disease activity despite responders treatment • No or reduced activity due to natural history How Predictable is NEDA? Does NEDA early on predict disability progression? Large actively treated cohort (n= 517) followed for 10 years at UCSF 17.9% of patients met NEDA criteria at year 2 NEDA at year 2 was NOT associated with significant EDSS progression after 10 years (trending actually to worsening EDSS!) No identified significant effect of new or enlarging T2 lesions at year 2 on disability progression at 10 years ¡ As measured by EDSS, T25FW, 9HPT, PASAT-3 ¡ Increase in EDSS by year 2 paradoxically associated with lower risk of subsequent worsening Cree BA, et al. Ann Neurol. 2016;80:499-510. Responders vs. Non-Responders When do events occur relative to the Treatment? Treatment becomes Only events occurring after a treatment is effective deemed effective should count towards non-responsiveness Time Do events occurring before treatments are deemed effective count towards non- responsiveness? Start of Need to re-Baseline at Treatment time when Treatment is deemed to be effective The Canadian Treatment Optimization Model Assessing Concern Whether to Modify a Treatment Regimen Each gauge represents a continuum from 0 no concern Low concern Medium concern High concern Relapse Progression MRI Freedman MS, et al. Can J Neurol Sci. 2013;40: 307-323. The Canadian Treatment Optimization Model: Assessing Concern Whether to Modify a Treatment Regimen Each gauge represents a continuum from 0 no concern Low concern Medium concern High concern Relapse Progression Sub-optimal response: Consider treatment change if: 3 X low low low 2 X med med 1 X high MRI Freedman MS, et al. Can J Neurol Sci. 2013;40: 307-323. Determining the Level of Concern to Consider Treatment Modification Based on Relapse Outcomes Low Medium High Rate* High reduction Moderate reduction Minimal reduction <35% 75%–100% 35–75% (~not better than results in clinical trials) 1 attack in 2nd yr TX 1 attack in 1st yr TX > 1 attack in 1st year of TX Severity Mild Moderate Severe l No Steroids l Steroids required l Steroids/hospital l Min effect on ADL l Mod effect on ADL l Severe effect on ADL l 1 FS involved l >1 FS involved l >1 FS involved l No l Moderate l Severe motor/cerebellar motor/cerebellar motor/cerebellar involvement involvement involvement Recovery Prompt Incomplete at 3 mths Incomplete at 6 mths *Rate of change is relative to baseline. Reference time frame for baseline ≥2 years prior to treatment initiation. Ideally, prospective and objective relapse data should be obtained during the reference period (minimum 6 mths); Probably not applicable to CIS or early MS FS, functional system; ADL, activities of daily living; mths, months Freedman MS, et al. Can J Neurol Sci. 2013;40: 307-323. Determining the Level of Concern to Consider Treatment Modification Based on Progression Outcomes Baseline EDSS Low Medium High ≤3.5 • <2 points • 2 points • >2 points confirmed at 6 mths confirmed at 6 mths • 2 points confirmed at 1 year 4–5 • <1 point • 1 point • >1 point confirmed at 6 mths confirmed at 6 mths • 1 point confirmed at 1 year ≥5.5 • 0.5 points • >.5 points confirmed at 6 confirmed at 6 mths mths Clinically • No motor • Some motor, • Pronounced motor, documented Minor cerebellar or cognitive cerebellar, or cognitive progression sensory • Multiple domains • Multiple domains affected affected T25FW* • ≤ 20% • > 20% and < 100% • ≥ 100% increase confirmed 6 increase confirmed 6 confirmed 6 mths mths mths *T25FW tested at baseline with aid if required Freedman MS, et al. Can J Neurol Sci. 2013;40: 307-323. Determining the Level of Concern to Consider Treatment Modification Based on MRI Outcomes Change in MRI Categories Low Medium High Gd-enhancing lesions 1 lesion 2 lesions ≥ 3 lesions New T2 lesions (per year)* 1 lesion 2 lesions ≥ 3 lesions Note: 1. Routine follow-up MRI is recommended 6-12 months after initiating therapy (or in CIS if therapy is not initiated) 2. New T2 lesions that are also enhancing on the same scan are only counted once as unique active lesions *There must be confidence that lesions are truly “new” compared to previous scans Freedman MS, et al. Can J Neurol Sci. 2013;40: 307-323. Data from Barcelona cohort Proportion of Non-Responders Varies According to the Definition Applied Non-responder definitions % non-responders A An increase of ≥ 1 EDSS step confirmed after 6 months 18 B Presence of any relapses 45 C Presence of ≥ 2 relapses 20 D A decrease in relapse rate < 30% compared with 2 years 16 before therapy E A decrease in relapse rate < 50% compared with 2 years 20 before therapy F No decrease or identical relapse rate compared with 2 years 15 before therapy G Definition A or B 49 H Definition A or E 30 ICriteriaDefinition based A on and disability B progression had higher sensitivity, specificity and 13accuracy and were considered as clinically more relevant than those based on relapse rate J Definition A and E 7 Results from a study that evaluated various criteria for treatment response in 393 patients with RRMS who had been treated with IFNB for at least 2 years.