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. Rio J, et al. Nat Rev Neurol. 2009;5:553–560. Data from Barcelona cohort MRI Criteria Predicting Treatment Effects free of of free progression Probability of Probability remaining

Time since treatment onset (months) n=152, RRMS, observation 2 years. MRI determined in the first 12 month of treatment Rio J, et al. Nat Rev Neurol. 2009;5:553–560. Treatment Optimization: Switching Therapies

1st line treatment IFNβ, GA, Teriflunomide, Dimethyl fumarate, Fingolimod* Perceived risk LOW level for disease HIGH

progression nd Another 2 line: Fingolimod, Switch Therapy 1st line Natalizumab, Alemtuzumab

Type of escalation Temporary Prolonged Monitor Tx Response Assess for Sub-Optimal Response ≤ 1 year

Switch Therapy 3rd line agent: Mitoxantrone or Cladribine (sc, iv) Monitor Tx Response ≤ 1 year Further Sub-Optimal Tx Response

Switch Therapy ≥ 4th line agent *Only in some countries such as USA

Modified from: Freedman MS, et al. Can J Neurol Sci. 2013;40: 307-323. What is the Imminent Risk for Disease Progression for the Patient?

Induction?

Escalation?

DISEASE PROGRESSION Rationale for Starting MS Therapy With a 1st Line Agent (Escalation Approach)

— Rationale • Long-term and real-life clinical and safety data lacking for many DMT • Patients may still respond well to 1st line agents • MS is a disease of years and decades • ‘Induction’ remains a concept but may be required for certain patients • Target populations warranting early and aggressive treatment are yet to be well defined — The principle • “Start safe and effective, reassess early, and escalate if necessary”

Fingolimod, Mitoxantrone, Platform/Basic Natalizumab, or Cladribine, or Therapy Alemtuzumab Cyclophosphamide

Naismith RT, et al. Neurol Clin Pract. 2011:1;69-71. Disease Modifying Medications: Mechanism of Action

Blood Brain Barrier

Optic Nerves, Brain & Spinal Cord

Disease causing immune cells Disease Modifying Medications: Mechanism of Action

Blood Brain Barrier

Immunomodulators

(IFNβ, GA, DMF) Optic Nerves, Brain & Spinal Cord

Disease causing immune cells Rationale for Starting MS Therapy With a ≥ 2nd Line Agent (Induction Approach)

— Reserved for patients with aggressive disease onset — Rationale • Start with an agent with a rapid onset of action • Ideal treatment has the following goals ÷ Damage control to prevent or limit further damage ÷ To protect injured axons and neurons from further injury ÷ To encourage repair of reversible damaged tissue • Once a patient enters the progressive phase of MS, it may be too late to attain any stated goals of treatment

Alemtuzumab

Natalizumab But are these types of agents appropriate for Fingolimod these types of patients?

Freedman MS, Neurol Clin Pract. 2011:1;66-69. Disease Modifying Medications: Mechanism of Action

Blood Brain Barrier

Natalizumab Optic Nerves, Brain & Spinal Cord

Disease causing immune cells Why Not Natalizumab?

A B F E T F E O R R E

Rigau V, et al. Neurology. 2012;79:2214-2216. Lethal Rebound Post-Natalizumab

Brain MRI & Neuropathology — Brain MRI: ¡ Numerous disseminated demyelinating lesions 4 months after natalizumab withdrawal in A: FLAIR; B T1 + Gd cf previous C, D — Neuropathology: ¡ Typical MS pattern I lesion with a mean perivascular CD4/CD8 T lymphocyte ratio of 1.78 (p = 0.03) ¡ C’ staining argues against complement activation compared to a control from patient with NMO (C9neo NMO)

Rigau V, et al. Neurology. 2012;79:2214-2216. Disease Modifying Medications: Mechanism of Action

Blood Brain Barrier

Fingolimod

Optic Nerves, Brain & Spinal Cord

Disease causing immune cells Rebound Post-Fingolimod: TDL

— 44-year-old Caucasian woman with MS for 6 yrs treated with IFN but poorly tolerated. — Switched to Fingolimod after 4 years but severe lymphopenia so switched to DMF, admitted 2/12 later with TDL

Faissner S, et al. Ther Adv Neurol Disord. 2015;8:233–238. Rebound Post-Fingolimod: TDL

—36-year-old female with MS x 13 years —Started with IFN-β1b, but because of ongoing relapses was switched to IFN- β1a sc, then GA & eventually Nz —Nz d/c’ed due to severe bronchitis 2 years later so it was d/c’ed —After a therapy-free interval of 6 months, started Fingolimod —Developed AP so Fingolimod d/c’ed and 7 weeks later DMF started —1/52 later: cognitive decline, ataxia, disturbed balance and difficulties with writing and coordination

Faissner S, et al. Ther Adv Neurol Disord. 2015;8:233–238. Rebound Post-Fingolimod

— Case 1: 30ish woman with 18 yr RRMS d/c’ed due to brainstem relapse & given RTX 6 wks post fingolimod cessation — Case 2: 30ish woman with 4 yr RRMS d/c’ed for pregnancy & severe attack 6/52 later — Case 3: Late 20’s woman with 12 yr RRMS d/c’ed for pregnancy, severe relapse 4/52 later — Case 4: 40ish woman with 17 yr RRMS d/c’ed due to s/e, started DMF 12d later & severe relapse 12/52 later — Case 5: 30ish woman with 15 yr RRMS d/c’ed on own and 12/52 later severe attack with >30 Gd+ lesions

Hatcher SE, et al. JAMA Neurol. 2016; 73:790-4. Rebound Post-Fingolimod

Hatcher SE, et al. JAMA Neurol. 2016; 73:790-4. Disease Modifying Medications: Mechanism of Action

Blood Brain Barrier

Immune cell depleting agents (e.g. Teriflunomide, Alemtuzumab)

Optic Nerves, Brain & Spinal Cord

Disease causing immune cells Goals of MS Therapy

Treatments. http://www.nationalmssociety.org. Accessed May 16, 2013 Comparison of Main Outcome Measures in Established Treatments:

Glatiramer IFNβ-1b 250µg IFNβ-1a 30µg IFNβ1a 44µg sc Study Agent Acetate 20mg sc eod1 im qw2 tiw3 sc od4 Relative Reduction in ARR 34% 18% 32% 29% Absolute Reduction in ARR 0.43 0.15 0.41 0.4

Relative Reduction in new T2 & Gd+ MRI 83% 52% 78% 30% Activity

Relative Reduction in EDSS Progression 39%* 37% 30% 12%*

Absolute Reduction in Proportion 8%* 13% 11% 3%* Progressing

1 2 3 *p= ns IFNB Study Group .Neurol.1993; 43(4):655–61.; Jacobs L, et al. Ann Neurol.1996;39(3):285–9.; PRISMS Study Group.Lancet.1998;352(9139):1498–504.; 4Johnson KP, et al. Neurology. 1995;45(7):1268–76. Evidence Highlights How the MS Population is Changing

2.0

1.5 1.3 1.3

0.9 1.0 0.8

Annualized relapse rate Annualizedrelapse 0.7

0.5 0.4 0.3

0.0 Pivotal MSCRG* Pivotal GA PRISMS† AFFIRM CLARITY FREEDOMS IFN β-1b study (1990) study (1994) (2001) (2005) (2006) (1988) (1991)

Median time to first relapse ~153 ~270 198 135 ~365 – – (days) Relapse free at 15 26 27 16 41 61 46 2 years (%)

*Patients who completed 104 weeks of the study (inclusion criteria in MSCRG required two relapses in 3 years); †Unconfirmed relapses GA, glatiramer acetate; IFN, interferon; MSCRG, Multiple Sclerosis Collaborative Research Group Uitdehaag BMJ, et al. Curr Med Res Opin. 2011;27:1529–37. Comparison of Main Outcome Measures in Recent Treatments:

Study Agent Natalizumab1 Fingolimod2 Teriflunomide3 DMF4

Relative Reduction in ARR 68% 54% 31% 53% Absolute Reduction in ARR 0.5 0.22 0.17 0.19

Relative Reduction in 83%6 74% 85%7 new T2 & Gd+ MRI 67% Activity 92% 82% 90%

Relative Reduction in EDSS Progression 42% 30% 30% 38%

Absolute Reduction in Proportion 12% 6.4% 7.1% 10.7% Progressing

1. Polman, et al. N Engl J Med. 2006;354:899–910.; 2. Kappos, et al. N Engl J Med. 2010;362:387–401.; 3. O’ Connor, et al. N Engl J Med. 2011;365:1293-1303.; 4. Data from bid dosing; 5. Comi AAN 2011 Presentation. 6. Yearly scan only. 7. ~43% of pts scanned, scans; only 3 scans performed Comparing Clinical Trial Data

— Gold standard is “head to head” studies ¡ TRANSFORMS: IFNβ1a im vs. finolimod ¡ COMBI Rx: IFNβ1a im vs. GA vs. combination ¡ CARE MS I & II: IFNβ1a sc vs. alemtuzumab ¡ OPERA I & II: IFNβ1a sc vs. ocrelizumab ¡ DECIDE: daclizumab vs. IFNβ1a im — Next level would be “active comparator” studies ¡ CONFIRM: DMF vs. GA ¡ BRAVO: Laquinimod vs. IFNβ1a im — Next level observational “switch me” studies — Next level “big data” (e.g. MS Base registries) Comparison of Main Outcome Measures in Recent and Emerging Treatments: Active Comparator Trials

TRANSFORMS DECIDE Care MS I OPERA I/II Study Agent Fingolimod1 Daclizumab2 Alemtuzumab3 Ocrelizumab4

Relative Reduction in ARR 52% 45% 55% 47% Absolute Reduction in ARR 0.17 0.18 0.21 0.14

Relative Reduction in 29% 54% 77/83% new T2 & Gd+ MRI 67% Activity 56% 65% 94/95%

Relative Reduction in 16%* 25%* 30%* 43/37% EDSS Progression (27%)

Absolute Reduction in Proportion 2% 4% 3.1% 4.7/6.4% Progressing

Active comparator IFNβ1a 30 µg im qw or IFNβ1a 44 µg sc tiw; *=ns

1Cohen J, et al. NEJM. 2010 362:402.; 2Kappos L, et al. NEJM. 2015 373:1418.; 3Cohen J, et al. Lancet. 2012;380:1819.; 4Hauser S, et al. N Engl J Med. 2017;19;376:221-234. What is Most Important in MS Therapy?

— NEUROLOGISTS: ¡ “….The goal of immunomodulatory therapy for RRMS is to avoid disease progression”1

— MS PATIENTS: ¡ Reduction in disability progression favored over decreased relapses2 ¡ Rating treatment attributes importance (e.g. efficacy): o Years to progression (how long until their MS got worse) rated highest overall o Frequency of relapses had the lowest rating.3

1Carrol W, Mult Scler. 2009;15:951-958.; 2Giovanni G, and Rhoades R, et al. Curr Opin Neurol. 2012;S20-S27. 3Johnson FR, et al. J Neurol. 2009; 256: 554-662. Effect of BP Lowering Agents

— ACE inhibitor trial of BP reduction — Mean BP change between treated & placebo groups = 3 mm Hg — This has little clinical meaning Kaplan–Meier Estimates of the Composite in and of itself Outcome of Myocardial Infarction, Stroke, or Death from Cardiovascular Causes in the ACE treated Group and the Placebo Group

N Engl J Med. 2000;342:145-53. Results For EDSS Progression In Pivotal Trials Assessing MS Therapies

Statistically Agent Study Control Significant p values Benefit?

GA COP-1 Placebo NO p=0.11 sc IFNβ-1a PRISMS Placebo YES p<0.05 im IFNβ-1a MSCRG Placebo YES p=0.02 IFNβ-1b IFNB-1b Placebo NO p=0.161 DEFINE Placebo YES p=0.005 DMF CONFIRM Placebo NO p=0.25 FREEDOMS I Placebo YES p=0.02 Fingolimod FREEDOMS II Placebo NO p=0.25

Natalizumab AFFIRM Placebo YES p<0.001

TEMSO Placebo YES p=0.03 (14 mg) Teriflunomide TOWER Placebo YES P=0.04 Results For EDSS Progression In Pivotal Comparative Trials Assessing MS Therapies

Statistically Agent Study Control Significant p values Benefit?

IFN-β1a 30 µg Fingolimod TRANSFORMS NO p = ns im qw IFN-β1a 44 µg CARE MS-I NO p = ns sc tiw Alemtuzumab IFN-β1a 44 µg CARE MS-II YES p = 0.008 sc tiw IFN-β1a 30 µg p = ns Daclizumab DECIDE NO im qw IFN-β1a 44 µg OPERA I YES p = 0.014 sc tiw Ocrelizumab IFN-β1a 44 µg OPERA II YES p = 0.017 sc tiw Modern RMS Trials Reporting Confirmed Disability Progression Over 2 Years

50 AFFIRM

CARE-MS I 40 CARE-MS II

30 DEFINE FREEDOMS

20 TEMSO

CONFIRM 10 OPERA I Confirmed progression at 2 years (%) Confirmed progression at 2 years OPERA II 0 1a - Placebo acetate Dimethyl 20 mg qd fumarate fumarate 44 µg tiw Glatiramer 0.5qd mg Fingolimod 240 mg bid sc IFN β 14 mg qd Natalizumab Ocrelizumab 300 mg q4w 600 mg q6m Teriflunomide Alemtuzumab* — 3-month confirmed disability progression, unless otherwise stated. Data cannot be directly compared between trials because of different populations and lengths of treatment — 6-month confirmed disability progression; *Administered in 2 treatment courses (12 mg/d for 5 days followed 12 months later by 12 mg/d for 3 days) Observational Comparator Studies “Big Data” – MS Base Switching to IFNβ/GA vs. Fingolimod

• Patients propensity score matched at baseline (time of new therapy) • Retrospective analysis of RMS patients on IFNβ/GA with relapse/progression in previous 1 year How do you decide if someone truly has aggressive disease warranting induction?

Induction?

DISEASE PROGRESSION Determining the Risk of Imminent Disease Progression

— Relapse severity • >1 moderate or severe attack • Steroids/hospitalization required • Severe effect on activities of daily living • >1 functional system affected • Severe motor/cerebellar/brainstem involvement — Relapse recovery • Incomplete — MRI • >2 Gd+/new T2 lesions or >2 T1 hypointense lesions • >2 spinal cord lesions • Brain atrophy — Older age — Male sex — African-American ethnicity

Freedman MS, et al. Can J Neurol Sci. 2013;40: 307-323. How Common is Aggressive MS?

— Retrospective analysis of 5891 patients in UBC cohort followed 1980-2009 — 3 Definitions of aggressive MS (AMS) ¡ AMS 1: EDSS ≥6 within 5 years of onset o 5.5% of all patients: 59.6% female; 74.5% RRMS ¡ AMS 2: EDSS ≥6 by age 40 o 14.0% of all patients: 65.2% female; 92.8% RRMS ¡ AMS 3: SPMS within 3 years of RRMS onset o 4.0% of all patients : 61.0% female

Menon S, et al. J Neurol Neurosurg Psychiatry. 2013;84:1192–1198. Predicting Response to Intensive Therapy

Patients Most Likely to Respond Patients Least Likely to Respond Age <40 Age >50 Active progression, or frequent/severe Long-standing stable disability or motor relapses, in past several months deficits Still mobile Long-standing immobility RRMS or early SPMS Profound or only cerebellar symptoms Frequent relapses, resulting in disability Substantial spinal cord atrophy Incomplete recovery from relapse(s) Multiple persistent enhancing lesions

Boster A , et al. Lancet Neurol. 2008;7:173-183. Earlier Introduction of Immunosuppressive induction

Severe active Active RRMS on Active SPMS CIS or RRMS IFNβ on IFNβ No. 20 30 20 Treatment Induction with Mx Mx/IFNβ Add-on/ Rescue with Mx Maintenance- IFNβ Combination Reduction in RR 3.0 → 0.4 2.0 → 0.4 1.3 → 0.3 P value 0.024 0.0007 EDSS 3.0 → 1.0 2.5 → 2.0 4.8 → 6.5 P value 0.00025 0.0002 Efficacy Very effective Very effective Not effective

Zaffaroni M, et al. Neurol Sci. 2008;29:S230–S232. Failure of 1st / 2nd Line Treatment (or Treatment Naïve with poor prognostic profile)

Maintenance Therapy Interferon-β or GA Cy (Teriflunomide?)

Az Immunosuppression Mx

Cd

Monitor closely for 1 year and If IMMUNOSUPPRESSNATS Further Further breakthrough Re-Treatment Re-Treatment disease, consider breakthrough Regimen breakthrough in year 3+ Regimen in year 3+ re-treatment or escalation

Az, alemtuzumab; Cy, cyclophosphamide; Mx, mitoxantrone; Cd, cladribine Continued breakthrough Aggressive MS Treatment Immunoablation Algorithm

& aHSCT Rush, et al. Nat Rev Neurol. 2015;11:379-89. Immunosuppression: Induction vs. Chronic/Intermittent

Secondary RIS CIS Relapsing Remitting Transitional Progressive

Disease Activity Regeneration/Repair

ChronicChronic Therapy Therapy

Time (Years) Immunosuppression: Induction vs. Chronic/Intermittent

Secondary RIS CIS Relapsing Remitting Transitional Progressive Disease Activity Regeneration/Repair

Induction/Re-induction Therapy

Alemtuzumab Cyclophosphamide Cladribine BMT + ASCT

Time (Years) Ottawa, CANADA Interactive Panel Discussion

§ Please submit questions to the faculty panel using the provided iPad.

MSCURRICULUM.COM/ORLANDO2017 Audience Response Questions

Which of the following monoclonal antibodies showed positive results on the primary endpoint in the phase 3 trial in PPMS patients?

a. Ocrelizumab b. Natalizumab c. Alemtuzumab d. Secukinumab

MSCURRICULUM.COM/ORLANDO2017 Audience Response Questions

When applying intensive therapeutics to MS patients, physicians should look for the following predictors to optimize likelihood of positive response.

a. Frequent relapses, resulting in disability b. Substantial spinal cord atrophy c. Multiple persistent enhancing lesions d. Profound or only cerebellar symptoms e. A and C f. B and D

MSCURRICULUM.COM/ORLANDO2017