A CME-certified Neurology Exchange Activity

Jointly provided by Potomac Center for Medical Education and RockpointeThis program is supported by an educational grant from EMD Serono

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CME Information

Educational Objectives

• Incorporate the latest MRI criteria and other prognostic measures to improve diagnosis and initiate DMD therapy earlier in the course of MS

• Assess the mechanisms of action and efficacy and safety profiles of current and emerging DMD therapies to develop individualized MS therapies that optimize adherence and improve patient outcomes

• Utilize evidence from recent diagnostic and prognostic biomarker studies to improve monitoring of disease activity and response to DMD therapy in MS

Polling QuestionActivity Survey

Please rate your level of confidence in the diagnosis and management of MS:

A. Not confident

B. Slightly confident

C. Confident

D. Very confident

E. Expert

Polling QuestionActivity Survey

Which of the following clinical features is NOT associated with a worse prognosis in MS?

A. African American ethnicity

B. Female gender

C. Smoking

D. Obesity

E. Vitamin D deficiency

MS

Immune Dysregulation

Genetic Predisposition

-Twins studies

-HLA-DR2 (DRß1*1501)(antigen presentation)

-IL-2Ra(regulatory T-cells)

-IL-7Ra(memory T-cells)

GWAS (>100 alleles)

Environmental Factors Demographics/Epidemics

Microbial Agents

EBV

Vit. D

Smoking

Salt

BMI

Microbiome

Multiple Sclerosis An Immuno-genetic Disease

Images courtesy of Dhib-Jalbut S; 2013.

Additional Disease Modifiers

• Poly unsaturated fatty acids diet (PUFAs)1

• Body mass index and role of adipokines2

• Melatonin3

1. Bjornevik et al. Presented at: ECTRIMS 2015, abstract #1054.2. Hagman et al. Presented at: ECTRIMS 2015, P725.3. Farez et al. Presented at: ECTRIMS 2015, abstract #46.

2. Adhesion

4. Reactivation

Tissue damage

Periphery

BBB CNS

3. Invasion

MMPs

1. Activation

Th1/17

T helper 1/17

A View of MS Immunopathogenesis

Courtesy of Amit Bar-Or.

Pathology of MRI Gd-enhancing Lesion

Gd-enhancing Lesions

Images courtesy of Dhib-Jalbut S.

Perivascular inflammationand demyelination

Inflammation

Regeneration

Inflammatory Processes Occurring Early in MS Lead to Demyelination and Axonal Loss

TimeOnset of Disease

Demyelination Axonal loss

Compston A et al. Lancet. 2008;372:1502-1517. Kuhlmann T et al. Brain. 2002;125:2202-2212.Paolillo A et al. J Neurol. 2004;251:432-439. Trapp BD et al. Curr Opin Neurol. 1999;12:295-302.

Immunopathogenesis of MS

Inflammation

Case Presentation

• 27-year-old man previously healthy develops weakness and tingling in both legs, imbalance and impaired bladder emptying two weeks after upper respiratory infection and possible fever

• PMH positive for Lyme disease (erythema chronicum migrans) at age 12, treated with antibiotics

• FH positive for MS in paternal grandmother

Case Presentation (continued)

• Brain MRI shows multiple T2H, including periventricular ovoid lesions, juxtacortical lesions, and cerebellar lesion; also, multiple very small gadolinium-enhancing lesions

• Cervical spine MRI shows multiple T2H

• CSF positive for oligoclonal bands, not present in serum, and elevated IgG index

Polling QuestionActivity Survey

The likeliest diagnosis for this patient is:

A. Acute disseminated encephalomyelitis

B. Clinically isolated syndrome

C. Definite multiple sclerosis

D. Lyme encephalomyelitis (neuroborreliosis)

E. Possible multiple sclerosis

1996 vs 2013 MS Phenotype Descriptions Relapsing-Remitting Disease

1996 MS Clinical Description

Subtypes

2013 MS Disease Modifiers

Phenotypes

Relapsing-RemittingDisease(RRMS)

With full recoveryfrom relapses

With sequelae / residual deficit after incompleterecovery

Relapsing-RemittingDisease(RRMS)

ClinicallyIsolated

Syndrome(CIS)

not active*

active*

not active*

active*

*activity = clinical relapses and/or MRI (Gd-enhancing MRI lesions; new/enlarging T2 lesions)

International Advisory Committee on Clinical Trials in MS. National Multiple Sclerosis Society (NMSS) and European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); 2013.

1996 MS Clinical Description Subtypes

2013 MS Disease Modifiers Phenotypes

1996 vs 2013 MS Phenotype Descriptions Progressive Disease

*activity = clinical relapses and/or MRI (Gd-enhancing MRI lesions; new/enlarging T2 lesions)#progression measured by clinical evaluation at least annually

International Advisory Committee on Clinical Trials in MS. National Multiple Sclerosis Society (NMSS) and European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); 2013.

Progressive accumulationof disability from onsetwith or without temporaryplateaus, minor remissions, and improvements

PP

SPProgressive accumulationof disability after initialrelapsing course, with orwithout occasional relapsesand minor remissions

Progressive accumulationof disability from onset,but clear acute clinical attacks with or without full recovery

PR

(PP)

(SP)

active* and with progression#

active but without progression

not active but with progression

not active and without progression (stable disease)

Progressiveaccumulation of disability from onset

Progressive accumulation of disability after initial relapsing course

ProgressiveDisease

ProgressiveDisease

Incr

easi

ng d

isab

ility

Gd = gadolinium

Level of disability

Accumulated MRI lesion burden

Acute (new and Gd+) MRI activity

Brain volumeRelapses

Cognitive dysfunction

T1 BH lesion load

-5-2 yrs 0 yrs +2-5 yrs +10-15 yrs +20 yrs +25-30 yrs

CISRIS McDonald MS

Clinically Definite MS

SecondaryProgressive MS

Adapted from Goodkin, DE. UCSF MS Curriculum. January 1999.

Existing and Emerging MS Therapies

*In March 2011, the FDA did not approve cladribine and requested Merck KGaA provide an improved understanding of its safety risks and overall benefit-risk profile.

2009 2010 201120051995 2000

Gilenya® (fingolimod)

Extavia®

(IFNβ-1b)

Tysabri® (natalizumab)

Betaseron®

(IFNβ-1b)

Copaxone®

(glatiramer acetate)

Avonex® (IFNβ-1a)

Rebif® (IFNβ-1a)

Novantrone® (mitoxantrone)

Approval date

Cladribine*

2012

Ocrelizumab

Ofatumumab

Mastinib

Ampyra® (dalfampridine)

Nuedexta® (Dextromethorph

anquinidine)

2013

Lemtrada®

(alemtuzumab)

Tecfidera® (dimethyl fumarate)

Plegridy®

(IFNβ-1a)

2014

Aubagio®

(teriflunomide)

Laquinimod

Daclizumab

Approved Therapy Phase III completed In Phase III Other Approved Treatment

2015 2016

Predicting the Course of MS

• Clinical features of onset bout

– Motor worse than sensory

– Polyregional worse than monosymptomatic

– Early bladder involvement poor prognosis

• Incomplete recovery from initial attack

• Short interval between attacks

Prognosis

Initial MRI

• T2 lesion numbers

• Median EDSS at 20 years = 6 for ≥10 T2 lesions

• 3 or 4 Barkhof criteria moderate correlation with EDSS at 5 years

Fisniku LK. Brain. 2008;131:808-817.

0 1-3 4-9 ≥100

10

20

30

40

50

60

70

EDSS > 3EDSS ≥ 6

# of brain lesions

% p

atie

nts

“The future ain’t what it used to be.”

— Lawrence Peter “Yogi” Berra

Making Treatment DecisionsConsidering the Benefits and Risks

Evidence- based

approach

MOA

Response

Physician experience

Patient preference Cost

Pregnancy issues

Monitoring

Convenience

Tolerability

Safety

Treatmentdecisions

Polling QuestionActivity Survey

In comparing glatiramer acetate to interferon beta, which of the following statements is true:

A. Extensive focal lipoatrophy may develop with either GA or IFNB

B. Head-to-head trials show no difference in clinical or MRI activity between GA and IFNB

C. Head-to-head trials show greater MRI activity in patients treated with GA compared to those treated with IFNB

D. Immediate post-injection systemic reactions may occur with either GA or IFNB

E. Three-times weekly GA has been shown to have equivalent clinical efficacy to IFNB

BEYOND: IFNβ-1b 250 or 500 µg vs Glatiramer Acetate

O’Connor P et al. Lancet Neurol. 2009;8:889-897.

Glatiramer acetate IFNβ-1b 500 mcg IFNβ-1b 250 mcg n = 2,244; Randomized 2:2:1; 2 to 3.5 years

P = NS

22

0

20

40

60

80

100

21 20

0.33

0

0.1

0.2

0.3

0.4

0.5

0.360.34

EDSS Progression (%)

ARR

P = NS

3.3

0

1

2

3

4

5

3.3

4.6

12

0

5

10

15

20

25

10

17

P = 0.0009

New T2(Mean #)

Change in T2 Vol.(%)

P = 0.0008

Interferon Beta

INTERFERON ADVERSE EVENTS ROUTE AND FREQUENCY COMMENTS

IFNB-1b (Betaseron) Flu-like sx; depression, ISRs

SC every other day No pre-filled syringe

IFNB-1a (Avonex) Same but no ISRs IM weekly Flu-like sx may persist

IFNB-1a (Rebif) Same as IFNB-1b SC 3 times weekly

IFNB-1a pegylated (Plegridy)

Same as IFNB-1b SC every other week Flu-like sx may persist and possibly be more intense

Outcome GA vs. Placebo P-value

Cumulative no. of gd-enhancing lesions 44.8% ↓ <0.0001

Cumulative no. of new or enlarging T2 lesions 34.7% ↓ <0.0001

↓34.4% vs. placebo(P <0.0001)

GA (40 mgSC TIW)

ARR

0

0.1

0.2

0.3

0.4

0.5

0.6 0.505

0.331

Glatiramer Acetate

GA PREPARATION DOSAGE AEs COMMENTSCopaxone 20 mg daily ISRs; Post-injection

systemic reaction, lipoatrophy

1st available prep; ~30% ARR reduction

Copaxone 40 mg tiw Same ~34% ARR reductionGlatopa 20 mg daily ?Same Pharmcologically equivalent;

no human studies

Kahn O et al. Presented at: European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2012; Lyon, France. Abstract 166.

Placebo

S1P receptor

FTY720 results in internalization of the S1P1 receptor

This blocks lymphocyte egress from lymph nodes while sparing

immune surveillance by circulating memory T cells

LN

Prevents T cell invasion of CNS

FTY720 traps circulating

lymphocytes in peripheral lymph

nodes

Fingolimod (FTY720): Mode of Action

Cohen JA, Chun J. Ann Neurol. 2011;69:759-777.

T cellFTY720-P

Managing Patients on Fingolimod

• Before Initiation of Treatment–Baseline CBC and liver panel

–Cardiac status and ECG

–Baseline ophthalmological exam

–Baseline dermatological exam

–Varicella immune status

• Baseline 6-hour monitoring because of potential bradycardia

• On Treatment Monitoring– Follow CBC, liver panel– Ophthalmological f/u at 3-4

months and annually– Annual dermatological exam– Check BP

• Infections– 5 reported cases of PML– Rare cases of cryptococcal

meningitis– Increased risk of shingles

or VZV

Teriflunomide: A Selective Dihydroorotate Dehydrogenase Inhibitor

• A newly approved oral disease-modifier for relapsing forms of MS (RMS)

• Blocks de novo pyrimidine synthesis, reducing T- and B-cell proliferation and function in response to autoantigens

• Preserves replication and function of cells (e.g. hemopoietic cells, memory T-cells) living on the existing pyrimidine pool (salvage pathway)

DHO-DH, dihydroorotate dehydrogenase;

Blasting lymphocyte

De novo pathway

DHO-DH

Pyrimidine pools Salvagepathway

CTP-, UTP-sugars Nucleotides CDP lipids

Glycoproteins, Glycolipids RNA, DNA Phospholipids

Cell-cell contactAdhesion and

diapedesis

ProliferationIg

secretion

Cell membranesSecond

messengers

Non-lymphoid

cells

Resting lymphocyte

Teriflunomide

Miller A et al. Presented at: American Academy of Neurology (AAN) 2011, April 9-16; Honolulu, HI.

Teriflunomide for RRMS (Phase III TEMSO Study): Key Clinical Outcomes

RRR: 31.2%P = 0.0002

RRR: 31.5%P = 0.0005

Annualized Relapse Rate

TeriflunomideTeriflunomide

27.3

Placebo (n = 363) 7 mg (n = 365) 14 mg (n = 358)0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.539

0.370 0.369

Placebo (n = 363) 7 mg (n = 365) 14 mg (n = 358)0.0

5.0

10.0

15.0

20.0

25.0

30.0

21.7 20.2

27.3 23.7%P = 0.0835

29.8%P = 0.0279

EDSS 12 Week Sustained Change

RRR = relative risk reduction

O’Connor P et al. N Engl J Med. 2011;365:1293-1303.

Tolerability Issues with Teriflunomide

• Low incidence of GI symptoms, particularly diarrhea

• Mild hair thinning

• Monthly liver panel x 6 months

• Occasional neutropenia – check CBC periodically

• Check BP

• Category X pregnancy rating

– Accelerated elimination procedure

DMF Has Shown Nrf2 Pathway Activation

DMF = dimethyl fumarate; MMF = monomethyl fumarateScannevin R et al. Poster presented at ECTRIMS, October 13-16, 2010. Gothenburg, Sweden. P887. Feinstein D et al. Poster presented at ECTRIMS, October 13-16, 2010. Gothenburg, Sweden. P879.

Keap1

MafJunATF4

Nucleus

- Detoxification enzymes- Antioxidant enzymes- NADPH generating enzymes- GSH biosynthesis enzymes- Chaperones- Ubiquitination/proteasome

- Detoxification- Normalization of energy metabolism- Repair/degradation of damaged proteins

Nrf2

Cytoplasm

OO

O

O DMF (BG-12)O

O

OH

O MMFOR

ARE

DMF: Integrated Efficacy Analysisof DEFINE and CONFIRM

Endpoint (at 2 years) Placebo(n = 771)

DMF BID(n = 769)

Annualized relapse rate (ARR)Reduction vs placebo

0.37 0.19*49%

Proportion of patients relapsedHR vs placebo 0.57*

Time to 12-week confirmed disability progressionHR vs placebo 0.68*

Time to 24-week confirmed disability progressionHR vs placebo 0.71*

* Statistically significant vs placebo Fox RJ et al. Presented at: American Academy of Neurology (AAN) 2013, March 16-23; San Diego, CA. Abstract P07.097.

Safety and Tolerability Issues with Dimethyl Fumarate• Gastrointestinal symptoms• Flushing• Occasional lymphopenia – follow CBC

– 4 cases of PML reported*• Infrequent liver enzyme elevations (follow LFTs)• Adherence to twice-a-day regimen• Category C pregnancy rating

*All PML cases reported in patients with severe and prolonged lymphopenia (lymphocyte counts <500/µl and >6 months)

Tecfidera SPC; EU: www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002601/human_med_001657. jsp&mid=WC0b01ac058001d124.

Tecfidera SPC; US: http://google2.fda.gov/search?q=Tecfidera&client=FDAgov&site=FDAgov&lr=&proxystylesheet=FDAgov&requiredfields=-archive%3AYes&output=xml_no_dtd&getfields=*. Real-life data.

Natalizumab Mechanism of Action

O’Connor P. Expert Opin Biol Ther. 2007;7:123-136.

Reduced Leukocyte Infiltration and Brain Inflammation

Leukocyte Infiltration and Brain Inflammation

Leukocyte

Chemoattractant signal

a4b1 (VLA-4)

Blood Vessel Lumen

Endothelial Cells

Tissue VCAM-1

LeukocyteChemoattractant Signal

a4b1 (VLA-4)Blood Vessel Lumen

Endothelial Cells

Tissue VCAM-1

Natalizumab vs Placebo Affirm Study (1801)

Polman C et al. N Engl J Med. 2006;354:899-910.

Annu

alize

d Re

laps

e Ra

te (9

5% C

I)

68%

P<0.0001

Placebon=315

0.81

Natalizumabn=627

0.26

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Natalizumab-associated PML Overall Incidence by Treatment Epoch

430 (428 MS, 2 CD) confirmed PML cases as of January 6, 2014; (141 US, 252 EEA, 37 ROW).

JCV antibody status

Negative Positive<1/1,000Calculation based

on 2 cases of JCV antibody–negative PML in patients exposed for at least 1 month of

therapy as of September 3, 2013

Natalizumabexposure

PML risk estimate per 1000 pts (No prior IS use)Prior IS

useIndex Result ≤0.9

Index Result

≤1.1

Index Result

≤1.3

Index Result

≤1.5

Index Result

>1.5

1-24 months

0.1(0-0.41)

0.1(0-0.34)

0.1(0.01-0.39)

0.1(0.03-0.42)

1.0(0.64-1.41) 1/1,000

25-48 months

0.3(0.04-1.13)

0.7(0.21-1.53)

1.0(0.48-1.98)

1.2(0.64-2.15)

8.1(6.64-9.8) 13/1,000

49-72 months

0.4(0-0.41)

0.7(0.08-2.34)

1.2(0.31-2.94)

1.3(0.41-2.96)

8.5(6.22-11.38) 9/1,000

JCV Antibody Status and Risk for PML

IS = immunosuppressantTysabri (natalizumab) Prescribing Information. www.tysabri.com/en_US/tysb/site/pdfs/TYSABRI-pi.pdf. Accessed: April 7, 2014.

PML Risk Stratification Using Anti-JCV Antibody Index and L-selectin

• Low CD62L in natalizumab-treated patients was prospectively validated as a biomarker for increasing a patient's relative risk 55-fold.

• 86% sensitivity / 91% specificity for CD62L and 100% sensitivity / 59% specificity for JCV index as predictors of PML.

• CD62L values inversely correlated with JCV seropositivity, so the lower the CD62L value of a patient was, the higher the probability that they were JCV+, culminating in the finding that 26/27 (96%) of CD62L low patients were JCV+.

• CD62L values negatively correlated with JCV index values.

Schwab et al. Mult Scler. 2015;1352458515607651.

L-Selectin and Risk of PML

Schwab et al. Mult Scler. 2015;1352458515607651.

Patients with high PML risk

Choosing Therapy

Aggressive Disease?

Yes No

JCV Ab+ JCV Ab-Safest Pregnancy Non-

injectable

NatalizumabAlemtuzumab

FingolimodDMF Natalizumab

IFNGA GA Teriflunomide

DMFFingolimodNatalizumab

Image courtesy of Aaron Miller.

Are Stable MS Patients Who Stop DMT at Risk for Increased Relapses and Disability

• 36% of stoppers experienced relapses within 5 years

• More likely in young, less-disabled patients

• Relapse rate for stoppers and stayers was similar but stoppers showed more disability progression

• Stopping DMT in patients with no relapses for 5 years does not appear to put them at risk for relapse

Kister et al. Presented at: ECTRIMS 2015; poster #261.

Ocrelizumab: Results of Opera 1 and Opera 2 Phase III Trials in Relapsing-remitting MS

• Ocrelizumab 600 mg q 6 months vs subcutaneous IFNB-1a 3X weekly

• Primary endpoint: 46% and 47% reduction in ARR compared to INFB

• Secondary endpoints:– 43% and 37% reduction in confirmed disability progression (12 weeks) vs IFNB

– 43% and 37% reduction in confirmed disability progression (24 weeks) vs IFNB

– 94% and 95% reduction in total no. of T1 gadolinium enhancing lesions vs IFNB

– 77% and 83% reduction in total no. of new and/or enlarging T2H lesions vs IFNB

• Adverse events: Most common was infusion reactions (34.3% vs 9.7%)

– SAEs, including infection, similar in both groups (6.9% vs 8.7%)

Case Presentation (continued)

• The patient began subcutaneous interferon beta-1a three times weekly

• Examination 8 months later is normal and the patient feels well

• About one year after beginning IFNB, patient is doing fine

• Repeat MRI shows two tiny new T2 hyperintense lesions compared to his initial MRI

Modified Rio Score

Score=0

Score=1

Score=2-3

100%

80%

60%

40%

20%

0%

Prog

ress

ion

Prob

abili

ty*

Years0 1 2 3 4

Modified Rio Score:

After 1 Year on Treatment

New T2 Lesions Relapses

0 ≤4 0

1≤4 1

>4 0

2≤4 ≥2

>4 1

3 >4 ≥2

* Probability of disability progression from the first year since treatment started and over the follow-up period (4 years), according to application of the modified Rio score on the “validation set” (observational cohort study, n=222).Figure adapted from Sormani MP et al. Mult Scler. 2013;19:605-612.

The modified Rio score, after 1 year of treatment, was able to predict the probability of disability progression at 4 years in RRMS patients with 69% accuracy

Algorithm for Identifying Nonresponders Based on the Modified Rio Score

Responders

Nonresponders

Modified Rio score=11 relapse or no relapses and substantial new T2 activity*

Modified Rio score=0No relapses and no

substantial new T2 activity*

Modified Rio score=2–31 relapse or 1 relapse and ˃

substantial new T2 activity*

Treatment Start

Modified Rio Score

No relapses and 2 ˂new T2 lesions

≥1 relapse or ≥2 new T2 lesions

Reassessment If Modified Rio

Score=1

* Substantial new T2 activity is defined as >4–5 new T2 lesions in 1 year of treatment, or >1–2 new T2 lesions if the reference MRI scan to assess new T2 lesion formation is obtained at least 6 months after initiating therapy.

Figure adapted from Sormani MP et al. Nat Rev Neurol. 2013;9:504-512.

Follow-up1.5 years1 year

Case Presentation (continued)

• Patient returns 6 months later with double vision and facial numbness.

• Brain MRI shows a new Gd-enhancing pontine lesion.

• He was treated with a 5-day course of steroids with significant improvement in his vision.

• Would you switch therapy at this point? And what are reasonable alternative therapies?

Case Presentation

• A 25-year-old white female was diagnosed with MS 2 years earlier when she presented with optic neuritis and numbness below the mid-thoracic area. She was placed on interferon-beta 1a IM weekly injections.

• She continues to have relapses and worsening symptoms.

Polling QuestionActivity Survey

Which diagnostic test is least useful in making a decision about changing therapy in this patient?

A. Anti-interferon beta Ab titer (NAB)

B. NMO antibody titer

C. JCV Ab titer

D. CSF oligoclonal banding

Case Presentation (continued)

• NAB Ab titer was low

• Is this treatment failure?

• Would you place the patient on a higher dose of IFN-B or would you switch therapy?

Defining Interferon ß Response Status in MS

• 15-year follow-up of pivotal MSCRG trial for weekly interferon

• 172 patients in placebo-controlled IFN-ß1a trial x 2 years

• In IFNb-1a group, disease activity predicted EDSS worsening:

– Gadolinium-enhancing lesions (OR, 8.96; P<0.001)

– Relapses (OR, 4.44; P=0.01)

– New T2 lesions (OR, 2.90; P=0.08)

– Conclusion: new MRI activity during IFN-ß1a treatment correlates with suboptimal response

Rudick RA et al. Ann Neurol. 2004;56:546-555.Bermel RA et al. Ann Neurol. 2013;73:95-103.

MRI as a Surrogate of Future Disease Activity

• 370 patients underwent MRI at baseline and 1 year after beginning IFN

• Followed for relapse or disability progression in years 1-4

• At year 1: ≥1 Gd-enhancing lesion or ≥2 T2 lesions had same risk for worsening disease in years 1-4 and for a clinical relapse within the first year

• MRI activity after starting IFN has similar implication as a relapse

Prosperini L et al. Mult Scler. 2013;PMID:23999607.

Case Presentation (continued)

• Follow-up MRI showed 2 non-enhancing brain T2 lesions and a new enhancing spinal cord lesion between T1 and T4.

• Serum NMO Ab test was positive.

Neuromyelitis Optica

• Inflammatory demyelination of the optic nerves and spinal cord

• Characterized by a specific IgG antibody marker (NMO antibody)

• Target antigen is aquaporin-4, a water channel abundant in the CNS

• Role of NMO-Ab in pathogenesis remains uncertain

Pittock SJ. Semin Neurol. 2008;28:95-104.Lennon VA et al. Lancet. 2004;364:2106-2112.

Torres J et al. J Neurol Sci. 2015;351:31-35.

NMO Pre- and Post-treatment Median Annualized Relapse Rates

Pre- and Post-Tx Relapse Rates Change in EDSS with Treatment

Fig. 1 Pre- and post-treatment median annualized relapse rates (ARR). The median ARR decreased from 1.17 to 0.25 on rituximab (P<0.01), 0.92 to 0.56 on azathioprine (P=0.475), 1.06 to 0.39 on mycophenolate (P<0.05), and 1.30 to 0.92 on cyclophosphamide (P=0.021).

Promising Future Biomarkers

Th0GAHL

A-Cl

ass

II

T-ce

ll Re

cept

or

APC/type-2Dendritic cells

IL-4

Th2

Treg

Weber MS et al. Nat Med. 2007;13:935-943.

IL-10TGFBIL-12TNF

Glatiramer Acetate Binds to HLA Class II on Antigen Presenting Cells and induces Type-2 APCs

DR and DQ Haplotypes Predictors of Clinical Response to GA

PROGNOSTIC PROFILE HAPLOTYPES NR / R (%R)

Poor prognostic profile DR15 - DQ6 absentDR17 - DQ2 present 10 / 2 (16.7%)

Neutral prognostic profile

DR15 – DQ6 present &DR17 – DQ2 present

DR15 – DQ6 absent &DR17 – DQ2 absent

17 / 11 (39.5%)

Good prognostic profile DR15 – DQ6 presentDR17 - DQ2 absent 7 / 17 (70.8%)

Dhib-Jalbut S et al. MSARD. 2013;2:340-348.

Potential IFN-β Serum Biomarkers

Responders Non-respondersIncrease in IL-10IL-7 high/Il-17 low T cells

Decrease in IL-10IL-17F levels >200pg/mL

Reduction in Th1 cytokines High baseline IFN-β levels

Increased in neurotrophic factorsMicroRNA 26a-5pIncreased monocytes IFN-I secretion in response to TLR

NABSNPs (IRF8, IRF5)Increase PSTAT1 and IFNR1 on monocytes at baseline

Dhib-Jalbut S et al. J Neuroimmunology. 2013;254:131-140. Comabella M et al. Brain. 2009;132:3353-3365.

Axonal Damage Markedly Reduced by Natalizumab

Gunnarsson M et al. Ann Neurol. 2011;69:83-89.

Exploratory Biomarkers of Newer MS Therapies

Treatment Tissue BiomarkerNatalizumab PB

CSFVLA-4, CD34 cellsNFL, Fetuin-A, Osteopontin, CHI3L1

Fingolimod PB

CSF

Decreased Naïve and Tcm, Decreased CD4:CD8 ratio, Decreased Th17, Decreased B-cellsDecreased T-cells and CD4:CD8 ratio

Rituximab CSF Decreased T and B cells, CXCL13Daclizumab PB/CSF Increased NKreg cells, CD56 bright cells

BMT PB Decreased TH17

PB = peripheral blood; BMT = bone marrow transplant; CSF = cerebrospinal fluid

Safety Biomarkers

Treatment Complication Biomarker

Natalizumab PML JCV assay, L-Selectin, mir320b

Alemtuzumab Autoimmune thyroiditis IL-21

Plavina T et al. Ann Neurol. 2014;76:802-812.Schwab N et al. Neurology. 2013;81:865-871.Munoz-Culla M et al. Mult Scler. 2014;20:1851-1859.Azzopardi L et al. J Neurol Neurosurg Psychiatry. 2014;85:795-798.

CME Credit• Post-activity Survey

– Now that the program has completed, please take a moment to answer the Post-activity Survey questions on your form

– Your answers are important and will help us identify remaining educational gaps and shape future CME activities

• CME Evaluation– If you’re seeking credit, ensure you’ve filled in your name

and demographic information on page 1 and complete the CME Evaluation on your form (after the Post-activity Survey)

– Return all forms to on-site CME staff

Thank you for joining us today!