MultipleSclerosis:Current&Emerging Treatments Personalized Strategies

Dr. Suhail Al-ShammriAssociate Professor& Head Division of Neurology, Mubark Al Kabir Hospital

Overview

• The diagnostic criteria of multiple sclerosis( MS)

• Classification of idiopathic inflammatory demyelinating disorders

• Clinical course of MS• Current and emerging MS therapies

Idiopathic CNS Demyelinating Diseases

• Typical CNS demyelinating Diseases:– Radiologically isolated syndrome (RIS)– Clinically isolated syndrome (CIS)– Relapsing –remitting multiple sclerosis (RRMS)– Secondary progressive MS (SPMS)– Primary progressive MS (PPMS)

Atypical CNS Demyelinating Diseases

• Acute disseminated encephalomyelitis (ADEM)

• Acute hemorrhagic leukoencephalitis (AHLE)• Tumefactive MS• Balo’s concentric sclerosis• Marburg

Radiologically Isolated Syndrome (RIS)

– No typical symptoms of CNS demyelination– No formally accepted diagnostic criteria– MRI : Typical MS lesions– CSF abnormalities– Clinical MS Attack:– 35% over 5 years– MRI progression:

• 59-83% in 2 years– DMT is initiated only in case of clinical/MRI progression

Okuda DT et al, Neurology2011:76()8, 686-692

Diagnostic Criteria for MS

• An effort to make the diagnostic process more objective• Formal criteria were devised to codify the typical MS

features into indisputable diagnostic criteria• The primary driving force is identification of patients for

research trials. ”a consensus on which patient has MS”• Criteria are designed to be specific• There are patients with MS who do not meet those

criteria• “A patient has MS when an an experienced neurologist

says he or she has MS”

Schumacher Criteria- 1965

• Onset of symptoms between 10 and 50 years• Objective abnormalities on neurologic examination• The signs and symptoms indicate CNS white

matter damage• The lesions are disseminated in space ( 2 or more

separate lesions)• The lesions are disseminated in time (2 attacks at

least 1 month apart)• No better explanation

The Mc Donald Criteria

• ‘the world consists of three types of person: those who have multiple sclerosis; those who do not; and those who might’. Polman CH et al,Ann Neurology, 2001

Episodes from history

Objective clinical signs Additional data needed from MRI or clinical follow up

2 attacks2 attacks1 attack1 attack

Progressive course over 1 year

2 lesions1 lesion2 lesions1 lesion

NoneDISDITBoth DIS&DIT

DIS demonstrated by 2 :1- MRI brain2. MRI cord3. CSF oligoclonal bands

Dissemination in Space

Polman CH et al, Ann Neurol 2011; 69:292–302

Dissemination in Time

Polman CH et al, Ann Neurol 2011; 69:292–302

MRI Brain DIS

MRI Cervical spine: DIS

MRI Brain T2WI

MRI Brain Enhanced T1WI:DIT

CASE

• On 18/3/08 patient complained of ocular pain on moving the left eye with blurred vision.

• 2 days later she developed left frontal headache. • Seen by the ophthalmologist who diagnosed her as

optic neuritis and advised to be on neurobion.• She had several attacks of Rt. Upper limb heaviness

in the last 2 years, each was lasting for a week. • Her cousin has MS .

CASE : Examination

• Her vision was 20/200 in the left eye and 20/40 in the right eye. There was a central scotoma, and red and blue colors were less intense in the left eye.

• RAPD on the left• Left fundus: disc is congested and swollen.• Central Scotoma• Treated with pulse IV methylprednisolone for 3 days

and improved followed by short prednisolone taper

Case 1: Fundoscopy

Case : MRI Brain

Case 2: MRI Spine

Case : CSF Oligoclonal bands

Clinically Isolated Syndrome (CIS)

• Single characteristic clinical attack of CNS demyelination:– Optic neuritis– Acute partial myelitis– Brain stem syndrome– Cortical

•

Clinically Isolated Syndrome (CIS)

• MRI:– Low risk: 1 or no other asymptomatic brain lesion– High risk: 2 or > asymptomatic lesions

• Treatment approved for high risk patients– IFN-B, GA reduces second attack: ARR 15%

Baseline MRI and Risk of CDMS for Monofocal onset CIS (BENEFIT Placebo N=93)

CHAMPS CHAMPS2 ETOMS BENEFIT25

Unifocal/multifocal/No pt

Unifocal/383

Unifocal Unifocal+multifocal/309

Unifocal/487

IFN-B Avonex+Pulse MP

Avonex Rebif Betasron

Dose/ 30µg/im/weekly 30µg/IM/weekly

22µg/SC/Weekly

250µg/SC/EOD

Duration/years 3 5 2 2

Pre-MRI T2 load 2or> 4 or > 2 OR>

%CDMS,P value 35 VS50, p=0.002

36 VS 49,P=0.03

34 VS 45P=0.047

28 VS 45 (69%/85%

+MRI effect Yes Yes, P=0.001

Yes,P=0.001

TOPIC

Primary end point:Conversion to CDMS (as defined by the occurrence of a relapse)

Key inclusion criteria:• Patients 18 to 55 years of age with a first acute/subacute neurologic event consistent with demyelination.• MS symptom onset within 90 days of randomization.• Screening MRI scan with 2 T2 lesions 3 mM diameter that are characteristic of MS.

Screened(N=846)

Placebo(n=197)

Teriflunomide 7 mg (n=205)R Long-Term Extension

Teriflunomide 14 mg(n=216)

108-Week Treatment Phase

Randomizedn=618

Miller A. Plattform presentation ECTRIMS 2013

Primary / Key Secondary Endpoint

Primary Endpoint: Time to Clinically Definite MS

(CDMS)

43%

Safety / Tolerability:Adverse events observed in the trial were consistent with previous clinical trials with Aubagio.

Miller A. Plattform presentation ECTRIMS 2013

21%p=0.43

66

59%p=0.000

8

Gd-enhancing T1 Lesions)

CIS: When To Initiate Therapy?

• Patients with normal MRI or with fewer than 2 – Low risk of developing early clinical attacks– Clinical and MRI monitoring – Without immediately commencing immunotherapy (DMT)

• Those with abnormal MRI with2or> lesions consistent with MS or with evidence of intrathecal synthesis of antibodies should be considered for DMT,

• Patients with atypical clinical or MRI presentation require further diagnostic evaluation.

Relapsing-Remitting MS

• Subacute repeated onset of CNS dysfunction with resolution ( sometimes incomplete , over days to weeks)

• Revised McDonald criteria• MRI: Periventricular, brainstem, juxtacortical

prominent T2, often Gad enhancing lesions, T1 hypointense (black holes)

• Treatment: Interferon-B, Glatiramer acetate, natalizumab, mitoxantrone

Features Consistent With MS

• Relapses and remissions• Age Onset between ages 15 and 50 • Optic neuritis • Lhermitte's sign• Internuclear ophthalmoplegia • Fatigue• Uhthoff's phenomenon

Features Inconsistent With MS

• Steady progression • Onset before age 10 or after age 50 • Cortical deficits such as aphasia, apraxia, alexia,

neglect • Rigidity, sustained dystonia • Convulsions • Early dementia • Deficit developing within minutes

Secondary Progressive MS

• Majority of RRMS many years following onset• Progressive impairment (spastic gait disturbance)

between or in absence of attacks• No clear effect of DMT without ongoing attacks

or inflammation• Role of DMTs in SPMS patients:

– with ongoing relapses – Substantial ongoing accrual on new MRI

inflammatory lesions

Primary Progressive MS

• Presents with progressive myelopathic gait, cerebellar ataxia or cognitive impairment without clear history of any clinical attacks

• Clinical progression must be for at least 1 year and accompanied by a combinstion of brain&spinal abnormalities and/or CSF anormalities consistent with MS

• Lack of clinical attacks/ relative paucity of MRI lesions• No approved DMTs

Multiple Sclerosis (MS)

• Multiple Sclerosis is the commonest disabling neurological condition to afflict young adults

• MS is an autoimmune disease triggered by environmental agents acting in a genetically susceptible people

• Auto-aggresive autoimmune attack on the myelin sheath and other components of CNS

• Current&emerging DMTs are based in the above paradigm

• Is MS a primary neurodegenerative disease

MS: Pathology

MS: Pathology

Demographic Characteristics of Multiple

Sclerosis in Kuwait

Mean Curre

nt age

Mean ag

e at pre

sentati

on

Mean duration of D

isease

0

5

10

15

20

25

30

35

Years

SD±5.4

SD±9.3

Total recruited patients in study: 195

Gender Distribution N(M/F): 195(76/119)

Cross sectional or retrospectively included patients:134

Newly diagnosed drug naïve patient:65

SD±10.3

Clinical Characteristics of Multiple Sclerosis in Kuwaiti Population

0.00%

5.00%

10.00%

15.00%

20.00%

25.00%20.50%

11.70%9.40% 8.60% 7.30%

2.10% 1.50% 1.20% 0.60%

Presenting symptoms

PRESENTING SYMPTOMS IN MS Total %

SENSORY LOSS IN LIMBS 30.7

VISUAL LOSS 15.9

MOTOR WEAKNESS 14.2

DIPLOPIA 6.8

GAIT DISTURBANCE 4.8

INCOORDINATION 2.9

SENSORY LOSS-FACE 2.8

LHERMITTE’S 1.8

VERTIGO 1.7

BLADDER SYMPTOMS 1

AUTE TRANSVERSE MYELOPATHY 0.7

PAIN 0.5

OTHERS 2.5

POLYSYMPTOMATIC 13.7

Medication details in studied Kuwaiti MS patients

Rebif(n=94)

Avonex(n

=30)

Betaferon(n=6)

Copaxone(n=17)

Tysabry(

n=19)

Mitozan

trome(n=1)

Rituxim

ab(n=1)

Iv Ig

G(n=2)

Plasma E

xchan

ge(n=1)

Geliniya

(n=5)0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%48.90%

15.40%

3.10%8.70% 9.70%

0.50% 0.50% 1.00% 0.50% 2.60%

MS Therapy: Deciding on which Medication

• Determine Therapeutic Goals– To reduce clinical relapse– To reduce accumulation of new MRI lesions– new T2 lesions– Gadolinium-enhancing lesions– black holes– Brain and spinal cord atrophy

• Reduce short-term relapse related disability

How To Determine of The Goals are Met?

• Compare with baseline relapse rate– Recall bias– Regression to the mean

• Assessment of improvement or stability in neurological impairment– Assess functional ambulatory limitation

• May indicate progression

• MRI ongoing/new inflammatory activity– Serial MRI to assess radiologic stability, worsening or

improvement- q12-24 month except

How To Determine of The Goals are Met?

• If goals of DMT or symptomatic treatment are being met no change in DMT unless problems with medication tolerability

• A detailed evaluation of common and idiopathic side effects will be required– Switching of medication based on adherence and

tolerability ma be needed

What if Goals are not being Met

• If pre-therapy relapse rate is not improved– A therapeutic switch may be indicated

• Relapse rate is incomplete indicator of ongoing inflammatory disease activity

– Cranial and spinal MRI• May show therapy resistant inflammatory disease• Guide switch to a more potent anti-inflammatory

medication• Clinical attack or definitive worsening disability is may

lacking

Case 2• Mr. A.M.J is a 33 years old Kuwaiti male, diagnosed to have

MS in 2008.• In Jan 2008, he developed diplopia, followed by paresthesia

in feet, ascending to abdomen, chest and forearms.• These symptoms persisted • By June 2008, he was ataxic and on a wheel chair, when he

sought medical advice• MRI was consistent with MS• Marked imrovement was noted in sensory symptoms after

pulse steroids.

Case 2

• His symptoms showed a rapid progression, by Sept 2008, he had optic neuritis, sphincteric disturbance, and positive Lhermitte’s sign.

• In Oct 2008, he started to take Rebif.• His disease remained stable, with no new

relapses and no new lesions on MRI till 2011.• In April 2011, he went for CCSVI treatment and

discontinued Rebif without our knowledge or advice.

CASE 1

• Lhermitte’s sign was positive• Cranial nerves were normal• No motor weakness• Mild sensory deficit for light touch and vibration

on left side• Plantars were flexor bilaterally• Romberg’s sign was mildly positive• Moderate left sided dysmetria, with tandem ataxia• EDSS :2; AI :1.

Case 1: MRI Cervical spineTWI

Case 2• In August 2011 he reported dizziness, ataxia and diplopia • He was treated with pulse steroids with marked recovery.• He was clinically stable, and was advised to restart Rebif.• In Jan 2012, EDSS:1, AI:0.• MRI in June 2012 showed new cerebellar lesions, with no

enhancement. • In Oct 2012, he came in with a mild relapse and was treated with

pulse steroids.• An MRI in Dec 2012 showed worsening lesion load, and he was

advised to start Tysabri after JCV serology.• He started Tysabri in Dec 2012, and till 5 months post Tysabri ,

there were no active lesions.

Case 2

• In Sept 2013, patient came with another severe relapse , with homonymous hemianopia, sphincteric problems, gait ataxia, and sensory disturbance.

• Treated with pulse steroids with partial improvement in urinary symptoms and ataxia, but not in visual symptoms.

Case 2: MRI Brain 2

Case 2: MRI Cervical spine 2

Case 2

• MRI showed marked worsening, with tumefactive enhancing lesions

• A CSF study was done, which was normal, negative for JCV.

• Considering this as a failure of Tysabri, it is planned to treat him with Rituximab

Is Clinical Worsening due to Attack related Disease or Progression?

• If it is due to non-inflammatory MS progressive disease– Neurodegenerative MS– ?subclinical ( and sub-radiologic) inflammation

unresponsive to current DMTs– Switching to alternative MS therapy is futile

• Escalating therapy If clinical impairment is strongly associated with ongoing relapses or marked new inflammatory MRI activity

Existing & Emerging MS therapies

Modified from P. Vermersch

Phase I

Phase II

Phase III

MarketedInterferons

Antiproliferativeagents

Cytolytic mAbs

Symptomatic TxVaccine, tolerization

Lymphocyte trafficking

Immune regulation

Other

Idebenone

BIIB033

Fingolimod

Firategrast

SiponimodONO-4641

CS-0777

ELND-002

Tysabri

Daclizumab

LaquinimodBG12

NI-0801

AZD5904

GRC4039

CCX-140

AIN457

Cladribine

Nerispirdine Ofatumumab

Belimumab

Ampyra

Ocrelizumab

Sativex

Alemtuzumab

Copaxone

IPX-056 RPI-78M

LY-2127399

Novantrone

Rebif Betaferon

Pixantrone

Peg IFNb(BIIB017)

ATX-MS-1467PI2301RTL1000

Copaxone generics x2

Azathioprine

Teriflunomide

LV Copaxone

Avonex

= Oral administration= Injectable

ExtaviaPonesimod

IFNβ-1b SC qod

GA SC qd

IFNβ-1a IM qwk

MitoxIV q 90 d

wks

IFNβ-1a SC tiw

NatalizumabIV q 4 wks

Fingolimod 0.5 mg gd

TeriflunPO qd

LaquinPO

DaclizumabSC

BG-12PO bid

Alemtuz IV

The Changing Landscape of MS Disease Modifying Treatment Of Approved and Emerging Therapies

19901992

19941996

19982000

20022004

20062008

20102012

2014

How are MS medication is selected?

• Injectable interferon-β and glatiramer acetate remain the first line DMT for many clinicians– Their side effects are manageable with minimum

of serious side effects• First line DMTs are effective in reducing clinical

attacks and new MRI lesions

Injectable therapiesOral therapies

Consider side effectsBG 12

FingolimodTerflunomide

Natalizumab

GlatiramerInterferon β

Relapsing inflammatory MS clinical course

First lineFirst line?

Severe relapsing inflammatory MS/JCV negative

Inadequate response/inj intolerance

Inadequate response/oral intolerance

Parallel switch

Inadequate response/JCV negative

Drawback of injectable Medication

• Interferon-β– “Flue-like illness” often transient– Liver enzyme monitoring– Rarely depression

• Glatiramer acetate– Flushing, eosinophilia, rare allergic reaction,

injection-site reactions (skin liopatrophy)– Conbination therapy+interferon-β1a IM/weekly and

glatiramer acetate does not appear to be significantly more efficacious than monotherapy

Lublin FD et al, Ann Neurology 2013

BG-12Phase III trials

BG-12 Integrated analysis• Compared with PBO, BG-12 240 mg BID and TID

significantly reduced ARR, risk of relapse, adjusted ARR requiring steroids, disability progression, and MRI outcomes.

• Demonstrated consistent benefits on clinical efficacy across prespecified subgroups of RRMS pts with varied baseline demographics and disease characteristics

• Overall incidence of AEs, SAEs, and discontinuations due to AES similar across tx groups; flushing and GI events most common AEs

Nrf2

- Detox Enzymes- Antioxidant Enzymes- NADPH Generating Enzymes- GSH Biosynthesis Enzymes- Chaperones- Ubiquitination/Proteasome

Cell and Tissue Protection

NFkB

- Proinflammatory cytokines- Leukocyte adhesion molecules

- Lymphocyte activation

Inflammation, Tissue Damage

Nrf2 Pathway May Induce a Cytoprotective Response and Inhibit NFkB Mediated Inflammation

BG-12

DEFINE Trial BG12 240mg bid vs tid: Primary endpoint - Relapses

p<0.0001

p<0.000141.3%

52.7%

DEFINE: MRI

p<0.000185%

p<0.000190%

PlaceboBG12 bidBG12 tid

BG-12 (dimethyl fumarate, DMF): CONFIRM — Annualized Relapse Rate

Daclizumab• Anti-CD25 mAb

Daclizumab

• Effects similar in patients with highly active MS compared with pts with less aggressive disease prior to tx initiation

• Treatment resulted in significant increase in number of pts who were disease- activity free following 1 year of tx in SELECT trial

• Patients had reductions in % change in volume of T1-hypointense and T2-hyperintense lesions over 52 wks of treatment vs increases in PBO group

S1P receptor modulators/ agonists• In phase 2b study, ponesimod significantly reduced inflammatory MRI

activity at all doses tested, with a significant dose response; lower ARR also observed with ponesimod compared with PBO, and was generally well tolerated

• Primary endpoint met in phase 2 DreaMS trial: ONO-4641 demonstrated significant efficacy on all key MRI measures of disease activity at all 3 doses compared with PBO, and was generally

• well tolerated Compared with PBO, reduction in mean CUAL observed as early as

• month 1 for siponimod 0.25 mg/day and 2.0 mg/day, and in all doses at month 2 in phase 2 BOLD trial; effect maintained at each month up to month 6; similar pattern for new/enlarging T2 lesions for all siponimod doses at month 2 and maintained at each month up to month 613

Glatiramer acetate

• Compared with PBO, GA 40 mg SC TIW significantly reduced:

• ARR by 34.4.% (P < .0001) Cumulative # GdE lesions by 44.8% (P < .0001) Cumulative # new/enlarging T2 lesions by 34.7%

• (P < .0001) Safety profile consistent with GA 20 mg/day SC

Teriflunomide

Pyrimidine Synthesis Inhibitor (anti-

metabolite)

Teriflunomide• Compared with PBO, 7 mg/day and 14 mg/day teriflunomide

significantly reduced ARR by 22.3% and 36.3%, respectively (P = .0183 and P = .0001, respectively)

• Compared with PBO, 14 mg/day teriflunomide significantly reduced 12-wk CDP (HR = .685; P = .0442)

• Both teriflunomide doses generally well tolerated; safety profile consistent with prior studies

• Update from TEMSO trial Mean reductions in lymphocyte and neutrophil observed in TEMSO were small in magnitude and were reversible after treatment discontinuation or on treatment in some cases; no other clinically significant complications to blood cytopenias reported

a)Adjusted for Expanded Disability Status Scale (EDSS) score strata at baseline and takes duration of treatment into account .ARR, annualised relapse rate; RRR, relative risk reduction

0.369

0.370

0.539

0 0.1 0.2 0.3 0.4 0.5 0.6

14 mg

7 mg

Placebo

Terif

luno

mid

e

Adjusteda annualized relapse rate

RRR: 31.2% p=0.0002

RRR: 31.5% p=0.0005

TEMSO: Relapse Rate

279290285

363365358

306309302

Number at riskPlacebo7 mg teriflunomide14 mg teriflunomide

242252251

211234227

200224217

160178175

336343329

258266262

40

00 36 72 84 96 10848 60

Disa

bilit

y pr

ogre

ssio

n (%

)

30

24Week

10

20

12

224238234

Placebo vs 7 mg: HRR 23.7% p=0.0835

Placebo vs 14 mg: HRR 29.8% p=0.0279

27.3%

21.7%20.2%

Placebo7 mg teriflunomide14 mg teriflunomide

TEMSO: EDSS progression (3 month confirmed)

TENERE: Annualized relapse rate

• The ARR in the 14 mg teriflunomide group was not statistically different from the ARR in the Rebif® group

• The estimated ARR was higher in the 7mg treatment group

0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 0.45

Annualized Relapse Rate

Teriflunomide14 mgN=109

Teriflunomide 7 mgN=111

0.216Rebif®N=104

0.259

0.410

Genzyme, Press release, Cambridge, MA – December 20, 2011

FINGOLIMOD

Sphingosine-1-Phosphate (S1P) Receptor Agonist

Fingolimod• Treatment with fingolimod 0.5 mg:

– Significant benefits on relapse-related outcomes within first 3 months and on volume loss over 6 months compared with PBO in FREEDOMS and FREEDOMS II studies; concordant results from 2 large phase 3 trials, along with phase 2 data, allow better definition of expectations regarding time lag between initiation and effects of fingolimod treatment

• Fingolimod treatment initiation effects in pooled population from FREEDOMS, FREEDOMS II (vs PBO), and TRANSFORMS (vs IM IFN à-1a) a transient, mostly asymptomatic decrease in heart rate; symptomatic bradycardia and Mobitz I and 2:1 AVBs were dose-dependent; AVB first occurrences most common <6 h post-dose5

• Analysis of TRANSFORMS trial demonstrated advantage of switching to fingolimod over remaining on IFN à-1a IM with regard to time to relapse in RRMS6

LN

T-cell FTY720-P

Prevents T-cell invasion of central nervous system

S1P receptor

Sphingosine-1-phosphate (S1P) receptor modulator

Internalises S1P1, blocks lymphocyte egress from lymph node (LN) while sparing immune surveillance by peripheral memory T-cells

FTY720 traps circulating lymphocytes in peripheral lymph nodes

Multiple sclerosis

FTY720

Fingolimod: Mechanism of Action

FREEDOMS (Fingolimod) Annualized Relapse Rate

0.160.18

0.40

0.0

0.1

0.2

0.3

0.4

Annu

alise

d re

laps

e ra

te

Placebo (n = 418)

Fingolimod 0.5 mg(n = 425)

Fingolimod 1.25 mg(n = 429)

-54% vs placebop < 0.001

-60% vs placebop < 0.001

ITT population; negative binomial regression model adjusted for treatment group, country, number of relapses in previous 2 years and baseline Expanded Disability Status Scale (EDSS) as covariates

*Analysis performed using a negative binomial regression model adjusted for treatment group and country**Analysis performed using rank ANCOVA adjusted for treatment group, country and number of lesions at baselineGd+, gadolinium-enhancing; MRI, magnetic resonance imaging

Fingolimod 0.5 mg

(n = 370)

Fingolimod 1.25 mg

(n = 337 )

0

2

4

6

8

10

12

9.8(13.2)

2.5 (7.2)

2.5(5.5)

Placebo (n = 339)

# new/enlarging T2 lesions at month 24 from baseline*

Fingolimod 1.25 mg

(n = 343 )

0

0.2

0.4

0.6

0.8

1

1.2

Mea

n (S

D) l

esio

n nu

mbe

r

Placebo (n = 332)

Fingolimod 0.5 mg

(n = 369)

0.2 (1.1)

1.1(2.4)

0.2(0.8)

# T1 Gd+ lesions at month 24**

p < 0.001

p < 0.001

p < 0.001p < 0.001

FREEDOMS (Fingolimod) MRI Lesion Activity

FREEDOMS (Fingolimod) Disability (Disability) Progression

Placebo

Fingolimod 0.5 mg

Fingolimod 1.25 mg

Patie

nts w

ith 3

-mon

th co

nfirm

ed E

DSS

prog

ress

ion

(%)

Days on study

Fingolimod 1.25 mg vs placebo, HR = 0.68, p = 0.012

Fingolimod 0.5 mg vs placebo, HR = 0.70, p = 0.026

0

5

10

15

20

25

30

0 90 180 270 360 450 540 630 720

HR, hazard ratio