Novel Therapeutics in Multiple Sclerosis Management: Clinical Applications Thomas Leist, M.D. Associate Professor Director, Comprehensive Multiple Sclerosis Center Thomas Jefferson University Philadelphia, PA Clyde Markowitz, M.D. Associate Professor of Neurology Director, Multiple Sclerosis Perelman School of Medicine University of Pennsylvania Philadelphia, PA Daniel Kantor, M.D. President, Florida Society of Neurology Medical Director, Neurologique Ponte Vedra, FL Samuel F. Hunter, M.D., Ph.D. President, Advanced Neurosciences Institute President, NeuroNexus Center for Neurology Education and Research Nashville, TN

State of the Science Thomas Leist, M.D. Associate Professor Director, Comprehensive Multiple Sclerosis Center Thomas Jefferson University Philadelphia, PA

Diagnostic Criteria in RRMS: From Poser to McDonald to Revised-Revised (RR) McDonald Time (years) Clinical Disease Activity/Disability MRI T2 Disease Activity

Diagnostic Criteria in RRMS: From Poser to McDonald to Revised-Revised (RR) McDonald Time (years) Clinical Disease Activity/Disability MRI T2 Disease Activity Poser Criteria >2 relapses

Diagnostic Criteria in RRMS: From Poser to McDonald to Revised-Revised (RR) McDonald Time (years) Clinical Disease Activity/Disability MRI T2 Disease Activity RR McDonald Criteria >1 attack T2+ and Gad+ lesions

Lesions considered as part of McDonald Criteria on conventional MRIs: DiPerri C, et al. Neuroimage ;47(4): Cohen-Adad J, et al. Neuroimage. 2011;57(1) Gd+PeriventricularInfratentorialJuxtacortical Characteristic MS Lesions

Evolving Diagnostic MRI Criteria in MS Dissemination in space McDonald McDonald McDonald ≥ 3 of the following: ≥ 2 of the following: ≥ 9 T2 lesions or ≥ 1 enhancing lesion ≥ 3 periventricular lesions ≥ 1 periventricular lesions ≥ 1 juxtacortical lesion ≥ 1 posterior fossa lesion 1 cord lesion can replace 1 brain lesion Any number of cord lesions can be included ≥ 1 asymptomatic infratentorial lesions McDonald WI, et al. Ann Neurol. 2001;50(1): Polman CH, et al. Ann Neurol. 2005;58(6) Polman CH, et al. Ann Neurol. 2011;69(2)

Evolving Diagnostic MRI Criteria in MS (cont’d) Dissemiantion in Time McDonald McDonald McDonald ≥ 1 enhancing lesion > 3 months after CIS onset (if not related to CIS) Presence of asymptomatic enhancing and nonenhancing lesions at any time ≥ 1 new T2 lesion on a scan obtained ≥ 3 months after CIS ≥ 1 new T2 lesion on a scan obtained ≥ 30 days after CIS ≥ 1 new T2 or enhancing lesion McDonald WI, et al. Ann Neurol. 2001;50(1): Polman CH, et al. Ann Neurol. 2005;58(6) Polman CH, et al. Ann Neurol. 2011;69(2)

MS Current Therapies Daniel Kantor, MD President, Florida Society of Neurology Medical Director, Neurologique Ponte Vedra, FL

MS FDA Approved Medications 1992

MS FDA Approved Medications 2012 NameDoseRouteFreq.Refrigerate Beta interferon 1a30 mcgIMQWY Beta interferon 1b250 mcgSCQODN Beta interferon 1a44 mcgSCTIWY Glatiramer Acetate20 mgSCDailyY Natalizumab300 mgIVMonthlyN/A Fingolimod0.5 mgPODailyN Teriflunomide7 or 14 mgPODailyN MitoxantroneVariableIVVariableN/A

Intersecting Spheres of Treatment Self InjectableIntravenous Oral Immunosuppressant MitoxantroneNatalizumab TeriflunomideFingolimod Glatiramer Acetate (GA) Selective Immunosuppressant Monoclonal Antibody (Mab) Glatiramer Sphingosine-1-Phosphate Modulator Interferon-β IMSC 1a 1b

Different Targets Immunomodulation – Shift from Th1 to Th2 (proinflammatory to antiinflammatory) Interferon-β – 1a » Intramuscular (IM) weekly » Subcutaneous (SC) three times a week – 1b » Subcutaneous (SC) every other day Glatiramer Acetate (GA) subcutaneous daily

Different Targets – Interfere with production of certain immune cells Teriflunomide oral daily Immunosequestration Natalizumab intravenous q 4 weeks Fingolimod oral daily Immunosuppression Mitoxantrone intravenous variable frequency

Therapeutic Principles Prior to 1993 there were no FDA approved disease modifying drug for MS Medications approved for MS: – Reduce the number of relapses (annualized relapse rate or ARR) ± – Delay the progression of disability (EDSS or Kurtzke Expanded Disability Status Scale) MS DMDs are not approved to reduce day-to-day MS symptoms MS is treated earlier (after 1 clinical event = CIS or clinically isolated syndrome) MS is diagnosed earlier (fueled mostly by MRI0 – latest criteria McDonald 2010

Therapeutic Principles Need to differentiate efficacy from safety from tolerability Self injectables have long-term safety (and efficacy) data Self injectables offer moderate efficacy with tolerability concerns and excellent safety Lack of consensus guidelines Overall monotherapy preferred over combination Usually placebo controlled, but some active comparator trials Switch trials not well designed

Decision Making Physician-guided joint decision with patient and care partner Issues to consider – Efficacy in clinical trials – Effectiveness in real life clinical practice – Common safety concerns – Burden of safety monitoring

Decision Making – Serious adverse events – Special populations – Tolerability – Route of administration – Frequency of administration – Patient risk averseness – Insurance coverage (formulary, prior authorization, copay tiering, step edits)

Specific Characteristics Site reactions: –Interferons –Glatiramer Acetate Immediate post- injection reaction – Glatiramer Acetate Flu-like symptoms: – Interferons Infusion reactions: – Natalizumab – Mitoxantrone Liver : –Interferons –Mitoxantrone –Natalizumab –Fingolimod –Teriflunomid Infectious: – Mitoxantrone – Natalizumab – Fingolimod – Teriflunomide

Specific Characteristics –Hematologic: –Interferons –Mitoxantrone –Natalizumab –Fingolimod –Teriflunomide Cardiovascular: – Mitoxantrone – Fingolimod Malignancy: – Mitoxantrone – Fingolimod (basal cell carcinoma) Macular edema – Fingolimod Thyroid: – Interferons Depression: – Interferons Pulomonary: – Fingolimod –Teriflunomide

Emerging Treatments in Clinical Trials for MS Clyde Markowitz, M.D. Associate Professor of Neurology Director, Multiple Sclerosis Perelman School of Medicine University of Pennsylvania Philadelphia, PA

Disease-Modifying Therapies in Late Stages of Clinical Development Oral AgentsMonoclonal Antibodies Dimethyl fumarate (BG-12) Laquinimod Alemtuzumab CD20-Targeting mAbs - Ocrelizumab - Ofatumumab Daclizumab

Proposed Mechanisms: BG12 An oral formulation of dimethyl fumarate Inhibits the expression of adhesion molecules and proinflammatory cytokines Induces a T H 1 to T H 2 shift Decreases circulating T cells Activates the Nrf2 pathway > 30 years of use of fumaric acids in the treatment of psoriasis (both topical and oral) Kappos L, et al. Lancet. 2008;372: Gold R, et al. Presented at WCTRIMS, Montréal, Canada, September 17-20, [P50] Gasperini C, et al. Expert Opin Emerg Drugs. 2008;13:

BG-12 DEFINE Trial Results 240 mg of BG-12 BID significantly reduced the proportion of patients who relapsed by 49% at 2 yrs compared with placebo (p <.0001) BG-12 BID reduced the ARR by 53% and reduced the risk of disability progression by 38% (both p <.0001) BG-12 BID reduced the mean number of new or newly enlarging T2 hyperintense lesions by 85% (p <.0001), the mean number of Gd+ lesions by 90% (p <.0001), and the mean number of new T1 hypointense lesions by 72% (p <.0001) Safety signals mild including flushing, GI Gold et al, 2011b.

BG-12 CONFIRM Trial Results 240 mg of BG-12 PO BID significantly reduced the ARR by 44% at 2 yrs compared with placebo (p <.0001). GA reduced the ARR by 29% (p =.0128). BG-12 BID reduced the proportion of patients who relapsed over 2 yrs by 34% (p <.0020). GA = 29% reduction (p =.0097). BG-12 BID had significant reductions of MRI activity, as did GA over 2 yrs on new T2 lesions by 71% (p <.0001). GA = 54% reduction (p =.0001). A nonsignificant reduction in rate of sustained accumulation of disability sustained over 12 wks occurred with BG-12 (21%, p =.2536) and GA (7%, p =.7036) compared to placebo Fox et al, 2012a.

Laquinimod Proposed MOA Novel oral immunomodulatory agent (quinoline-3-carboxamide) Structurally related to linomide - Does not have MI, serositis, pericarditis - Modulates T H 1/T H 2 activity by: Inhibiting proinflammatory pathways Enhancing anti-inflammatory pathways - Suppresses pathways involved in antigen presentation to naïve T cells - Increased levels of transcripts encoding: Insulin-like growth factor-1 by > 20-fold Brain-derived neurotrophic factor (BDNF) by 3-fold Gurevich M, et al. J Neuroimmunol. 2010;221:87–94. Silva C, et al. Presented at ECTRIMS 2010; October 13-16, 2010; Gothenburg, Sweden. [Poster 882]

ALLEGRO/BRAVO ALLEGRO (Phase III) - Relapsing MS mg laquinimod vs placebo (N=1106) - 24 months Significant effects reported for ARR, brain atrophy, and sustained disability (EDSS) - ARR ↓23%; 0.39 vs 0.30 (P=0.002) - Sustained disability ↓36%; 16% vs 115 (P=0.01) - Brain atrophy ↓33% Bravo similar results on disability and MRI - IFN had no effect on disability progression No major safety signals, mild LFT elevations

Alemtuzumab- Proposed Mechanisms Humanized mAb directed against CD52 (expressed on leukocyte surface) Rapidly and profoundly depletes T cells, B cells, and monocytes through: - Antibody-dependent cell-mediated cytotoxicity (ADCC) -Complement-mediated cytotoxicity (CDC) CD4+ cells may take ~5 years to fully recover Reconstituted lymphocytes appear to have regulatory properties Jones JL, Coles AJ. Int MS J. 2009;16:77-81.

Alemtuzumab—Trials CAMMS 223 – N=334 with 3 arms (12, 24 mg alemtuzumab; IFNβ- 1a SC 44 μg) for 3 years – Relapse rate  74%; sustained disability  71%; EDSS change  0.39 vs +0.38; ARR 0.10 vs 0.35 CARE-MS 1 – N ≅ 525 treatment-naive with 2 arms (12 mg; IFNβ- 1a SC 44 μg) for 2 years CARE MS 2 – Previously treated RRMS

Alemtuzumab Trial Results Substantial alemtuzumab treatment effect on relapse rate vs. active comparator (SC IFNB-1a 44 mcg) in both phase III trials – CARE-MS I = 55% reduction in relapse rate compared to IFNβ-1a over the 2 yrs of the study (p <.0001) – CARE-MS II ARR = 0.52 with IFN vs with alemtuzumab, a 49% reduction that was highly statistically significant (p <.0001) No significant treatment differences on EDSS-based end points in CARE-MS I – Unexpected low rate of sustained disability in the comparator group. However, CARE-MS II trial showed clear superiority of alemtuzumab over active comparator in disability measures. No new safety signals identified – Proactive risk minimization procedures allowed early detection and management of secondary immunity with good outcomes Coles et al, 2011; Cohen et al, 2012.

Alemtuzumab—Adverse Events Thyroid dysfunction 30% ITP 3% Goodpasture’s syndrome 0.3% Mild or moderate infections (respiratory tract, UTIs, herpes, influenza)

Comparison of Alemtuzumab and Interferon Beta- 1a SC Efficacy in Multiple Sclerosis II (CARE-MS II): A Phase 3 Trial in Previously Treated Patients Comparison of Alemtuzumab and Interferon Beta- 1a SC Efficacy in Multiple Sclerosis II (CARE-MS II): A Phase 3 Trial in Previously Treated Patients SAFETY Serious infection1.5%3.7% Autoimmune thyroid-related adverse event 5.0%15.9% Immune thrombocytopeniaNR0.9% Coles A, et al. AAN Abstract S01.004;

Anti-CD20s—Role of B Cells Antigen-presenting cells Immune regulation -By expression of accessory molecules, cytokine production Antibody secretion - Through plasma cells

Rituximab in Relapsing MS Phase 2 48-week study (N=104) – 1000 mg IV on days 1 and 15 (N=69) – Placebo (N=35) 1°outcome number of contrast lesions on MRI scans (wks 12, 16, 20, 24) – Mean 0.5 vs 5.5 (91% relative reduction; P<0.001)

Ocrelizumab Phase 2 Trial Relapsing MS (N=220) – 1000 mg or 300 mg ocrelizumab days 0, 15 vs placebo vs IFNβ-1a IM 1  outcome – Total number of contrast MRI lesions at 9, 12, 16, 20, and 24 weeks – 5.5 placebo vs 6.9 (IFNβ-1a IM), 0.6 ocrelizumab 600 mg, ↓89%, 0.2 ocrelizumab 2000 mg, ↓96% – AAR vs 0.354, (↓80%), (↓73%) – IRR ↓ by 2 nd infusion; one death involved DIC, contaminated contrast material (?)

Ocrelizumab Phase II Safety No participants dropped out of study due to adverse events during weeks 48–96 No opportunistic infections reported among all groups during entire trial Serious infection rates were similar for OCR 600 mg and OCR 2000 mg groups -Rates did not increase over time Infusion-related reactions occurred after initial infusion and decreased on subsequent infusions

Other Approaches More selective S-1-P molecules at different doses- ONO, BAF312, T-Cell Vaccination (Tcellna) Stem cells Neuroprotection/repair- Lingo

Emerging Concepts New MS therapies are on the horizon - Will add to treatment complexity Novel MOAs will raise concern about unknown, rare, or long-term safety issues - Risk-benefit ratio analysis Personalized medicine Future focus - Optimal drug selection, induction/combination strategies, when/how to switch, CNS repair strategies

Differences Between Physicians in Diagnosis and Management of MS: Evolving Practices Samuel F. Hunter, M.D., Ph.D. President, Advanced Neurosciences Institute President, NeuroNexus Center for Neurology Education and Research

Overview Practice of MS is highly idiosyncratic Evolving concepts of relapsing MS – Data is replacing dogma – New outcomes are being sought Principals of therapy – Relapse – MRI – Disability

Progression of Disability Expanded Disability Status Scale (EDSS) Kurtzke JF. Neurology. 1983;33(11): Normal No disability (few signs) Minimal disability Mild disability Reduced ambulation Unilateral assistance required Bilateral assistance required Wheelchair, some steps Bedbound Dead Wheelchair, no steps

Progression of Disability Expanded Disability Status Scale (EDSS) Kurtzke JF. Neurology. 1983;33(11): Normal No disability (few signs) Minimal disability Mild disability Reduced ambulation Unilateral assistance required Bilateral assistance required Wheelchair, some steps Bedbound Dead Wheelchair, no steps Slow

Progression of Disability Expanded Disability Status Scale (EDSS) Kurtzke JF. Neurology. 1983;33(11): Normal No disability (few signs) Minimal disability Mild disability Reduced ambulation Unilateral assistance required Bilateral assistance required Wheelchair, some steps Bedbound Dead Wheelchair, no steps Slow Fast

Progression of Disability Expanded Disability Status Scale (EDSS) Kurtzke JF. Neurology. 1983;33(11): Normal No disability (few signs) Minimal disability Mild disability Reduced ambulation Unilateral assistance required Bilateral assistance required Wheelchair, some steps Bedbound Dead Wheelchair, no steps Slow Fast Very slow

MS Concepts are Changing Relapsing MS (not only remitting) – Broader classification – includes those with progression – Almost all patients experience fluctuations which would meet criteria for a relapse – MRI activity and relapses are easy targets – Most trials now demonstrate disability effects Progressive MS (primary, secondary, relapsing) – In practice this is lower extremity function – EDSS has not proved a satisfactory outcome – Many trials fail to demonstrate benefit, although positive on other outcomes

Less Effective Suppression of Disease More effective 30% 40% 50% 60% 70% 80% 90+% Therapeutic Effect vs. Safety Risk of major complication More safe <1:1000 1:200 1% 5-10% More risky Fluoxetine Vitamin D Laquinimod Mitoxantrone Alemtuzumab Natalizumab Anti-CD20 Fingolimod IFN b-1a IM HD IFN Glatiramer Teriflunomide Dimethyl- fumarate

Less Effective Suppression of Disease More effective 30% 40% 50% 60% 70% 80% 90+% Therapeutic Effect vs. Safety Risk of major complication More safe <1:1000 1:200 1% 5-10% More risky Fluoxetine Vitamin D Laquinimod Mitoxantrone Alemtuzumab Natalizumab Anti-CD20 Fingolimod IFN b-1a IM HD IFN Glatiramer Teriflunomide Dimethyl- fumarate Adjuncts Standard Efficacy Enhanced effect Highly effective

Less Effective Suppression of Disease More effective 30% 40% 50% 60% 70% 80% 90+% Therapeutic Effect vs. Safety Risk of major complication More safe <1:1000 1:200 1% 5-10% More risky Fluoxetine Vitamin D Laquinimod Mitoxantrone Alemtuzumab Natalizumab Anti-CD20 Fingolimod IFN b-1a IM HD IFN Glatiramer Teriflunomide Dimethyl- fumarate Low risk High risk

Escalation of Therapy Model Watchful waiting – delay therapy in absence of proven disease activity First line treatment – low risk – low oversight, until evidence of MRI, unacceptable relapses, or disability Second line treatment – more effective, more risk, until progressive disability or unacceptable relapses or MRI activity Third line treatment – high risk, highly effective

Early Triage to Effective Therapy Highly Effective with Risks Enhancing lesion volume Cerebral or cord volume Intolerable disability Risk tolerant Mitoxantrone (very high risk) Natalizumab Alemtuzumab Anti-CD20 Interferon-beta with immunosuppressive Highly Effective Lower risk Enhancement Cerebral volume or cord lesion Low to moderate disability Not risk tolerant Fingolimod Dimethylfumarate PEG-IFN?

Principles of Appropriate Therapy We are preventing, not treating disability Gait dysfunction is a slippery slope Replace rather than combine Worse prognosis: more effective therapy Map out response to therapy – Relapses, gait disability, MRI response Re-evaluate periodically – after disease activity – More effective agent for disease activity Avoid high liability in fertile women