future efficacy measures for multiple sclerosis

Efficacy measures of the future: what to expect and accept?

Professor Gavin Giovannoni

Blizard Institute, Barts and The London School of Medicine and Dentistry

Disclosures

Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni.

Professor Giovannoni would like to acknowledge and thank Biogen-Idec, Genzyme and Novartis for making available data slides on natalizumab, alemtuzumab and fingolimod for this presentation.

http://www.ms-res.org/







Defining the therapeutic target

No evident disease activity: NEDA

Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.

Treat-2-target What is NEDA?

× No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions

DAF1,2

NEDA is a sensitive outcome

1.87

5.29

2.75

2.92

3.41

1.64

2.29

0 1 2 3 4 5 6

Dimethyl fumarate (DEFINE)

Natalizumab (AFFIRM)

Cladribine (CLARITY)

Fingolimod (FREEDOMS)

sc IFN β-1a (DoF)

Teriflunomide (TEMSO)

Alemtuzumab (CARE MS II)

Increase in proportion of NEDA patients relative to comparator

Patients with RRMS over 2 years. Increase in proportion of patients with NEDA versus placebo (except CARE MS II)

All data from post hoc analyses of randomized controlled trials in patients with RRMS. Table adapted from Bevan CJ and Cree BA. JAMA Neurol 2014;71:269-70, with the exception of: TEMSO. Freedman et al. Neurology 2012;78 [Meeting

Abstract s 1]: PD5.007; sc IFN b1-a sc. Data on file; CARE MS II. Coles AJ et al. Lancet 2012;380:1829-39

versus sc IFN b-1a

Slide courtesy Prof. Mark Freedman, EFNS-ENS Istanbul 2014

The modified Rio score can predict disability progression and response to IFN-β therapy

*No qualifying relapses or confirmed EDSS progression; †Percentage calculated using total number of patients with a particular modified Rio score at Week 48; ‡No clinical activity, gadolinium-enhancing lesions, or new/enlarging T2 lesions. EDSS, Expanded Disability Status Scale

Outcomes after 1 year of IFN-β treatment Modified Rio score

≤5 new T2 lesions and 0 relapses 0

≤5 new T2 lesions and 1 relapse, or >5 new T2 lesions and 0 relapses 1

≤5 new T2 lesions and ≥2 relapses, or >5 new T2 lesions and 1 relapse 2

>5 new T2 lesions and ≥2 relapses 3

Higher modified Rio score predicts greater risk of progression1

Modified Rio score at Week 48 (REGARD)

Clinical activity-free* at Week 96 n (%)†2

Disease activity-free at Week 96 n (%)‡2

Yes No Yes No

0 (n=156) 121 (77.6) 35 (22.4) 53 (34.0) 103 (66.0)

1 (n=42) 3 (7.1) 39 (92.9) 0 42 (100)

2 (n=5) 0 5 (100) 0 5 (100)

Total (N=203) 124 79 53 150

Wo

rse

nin

g d

ise

ase

1. Sormani MP et al. Mult Scler J 2013;19:605-12 2. Freedman M et al. Mult Scler J 2013;19(Suppl. 1):262 [P610]


*As measured by modified Rio score. EDSS, Expanded Disability Status Scale; RRMS, relapsing–remitting MS; tiw, three times weekly

Faster disability progression seen in patients with worse Rio-defined disease activity*

Kaplan–Meier cumulative incidence curves of time to confirmed EDSS progression by modified Rio score in patients with RRMS receiving sc IFN β-1a 44 µg tiw

156 42

155 41

151 39

144 33

138 27

No. of patients at risk: Rio score 0 Rio score 1

Baseline Week 24 0.0

0.1

0.2

Cu

mu

lati

ve in

cid

en

ce

0.3

0.4

0.5

Week 48 Week 72 Week 96

O (n=156) 1 (n=42)

Rio score group

Time to 3-month EDSS confirmed progression

Freedman M et al. Mult Scler J 2013;19(Suppl. 1):262 [P610]


Yes, 72

No, 28

Relapse reporting

• Most common reasons for not reporting their most recent relapse to a specialist MS team were: – ‘Mild relapse so not felt necessary’ 5/28 (18%) – ‘Saw or spoke to their GP’ 4/28 (14%)

• Most common reasons for not seeking healthcare support were: – ‘Felt I could manage’/mild relapse 18/42 (43%) – ‘Nothing that they can do to help’ 8/42 (19%)

Duddy M, et al. ECTRIMS 2013. P590.

N = 101

Yes, 46

No, 54

N = 102

Patients who have ever experienced an MS relapse and

not contacted a healthcare professional

Patients reporting most recent relapse to a specialist MS team

Pseudo-relapses • “I think I know what causes pseudo-relapes, but I don’t know how to define

them!”

• Too many patients with transient, or intermittent, symptoms have active MRI scans (Gd+ lesions)

• What about non-classical symptoms?

– Cognitive relapse

– Fatigue

– Narcolepsy

– Well described transient syndromes, e.g. Lhermitte’s, flexor spasms

• NOT ("the appearance of new symptoms, or the return of old symptoms, for a period of 24 hours or more – in the absence of a change in core body temperature or infection“)

– Trial protocols are more restrictive and require patients to move on the EDSS and/or FS (one FS by at least 2 points or two FS by at 1 point)

– The above creates protocol and non-protocol defined relapses.

Normal neurological examination

No disability

Minimal disability

Moderate disability

Relatively severe disability

Disability precludes full daily activities

Assistance required to walk Restricted

to a wheelchair

Restricted to bed or chair Confined

to bed

Death

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0

EDSS

Adapted from http://www.msdecisions.org.uk/. Accessed 15 April 2014. Previously adapted from Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).

Neurology 1983; 33:1444–1452.

http://www.msdecisions.org.uk/

Yes – I do an EDSS whenever I see a patient 14 25%

Yes – I do an EDSS annually 10 18%

Yes – I occasionally do an EDSS 20 36%

No – I never do an EDSS 3 5%

Other 9 16% Yes – I do an EDSS whenever I see a

patient [14] Yes – I do an EDSS

annually [10]

Yes – I occasionally do an EDSS [20]

No – I never do an EDSS [3]

Other [9]

Survey of UK MSologists

Schmierer K, et al. ABN 2014; Unpublished.

Clinical – In your routine MS clinical practice, do you use the EDSS?

Clinical – If you do an EDSS in your routine clinical practice, do you walk the patients to assess their walking distance?

Yes [9]

No [20]

Sometimes [22]

Other [5] Yes 9 16%

No 20 36%

Sometimes 22 39%

Other 5 9%

Validating a novel web-based method to capture disease progression outcomes in MS

P-EDSS, physician or actual EDSS. The midpoint of the diamonds is the mean difference between the two EDSS scores, the upper and lower lines within the diamonds are the 95% CI. The width of the diamond indicates the sample size, the dots the actual values. The horizontal line at 0.46 indicates the mean difference between the two scores. The graph indicates the greater variation at lower EDSS scores, with greater agreement at scores > 5. Leddy S, et al. J Neurol 2013; 260:2505–2510.

ORIGINAL COMMUNICATION

we

b-

EDSS

– P

-ED

SS s

core

P-EDSS score

–4

–3

–2

–1

0

1

2

3

4

0 1 1.5 2 2.5 3 3.5 4 4.5 5.5 6 6.5 7 8

Monitoring your own disease

http://www.patientslikeme.com/

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events

Differential Diagnosis

MRI

Evoked Potentials

Lumbar puncture

Blood Tests

Diagnostic Criteria

Cognition

Depression

Fatigue

Bladder

Bowel

Sexual dysfunction Tremor

Pain Swallowing

Spasticity Falls

Balance problems Insomnia

Restless legs Fertility

Clinical trials

Gait

Pressure sores

Oscillopsia

Emotional lability

Seizures

Gastrostomy

Rehab

Suprapubic catheter Intrathecal

baclofen

Physio- therapy

Speech therapy

Occupational Therapy

Functional neurosurgery

Colostomy

Tendonotomy

Studying

Employment Relationships

Travel

Vaccination

Anxiety

Driving

Nurse specialists

Family counselling

Relapses

1st line

2nd line

Maintenance Escalation Induction

Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet

Alternative Medicine

Pregnancy Breast Feeding

Research

Insurance

Visual loss

Palliative Care

Assisted suicide

Social services

Legal aid

Genetic counselling

Prevention

Diagnosis

DMT Symptomatic

Therapist

Terminal

Counselling An holistic approach to MS

Intrathecal phenol

Fractures

Movement disorders

Osteopaenia

Brain atrophy

Hearing loss

Tinnitus

Photophobia

Hiccoughs

DVLA

Neuroprotection

Psychosis

Depersonaliation

Brain Health

Cognitive Reserve

Sudden death

Suicide

OCD

Narcolepsy

Apnoea Carers

Respite

Hospice

Respite

Dignitas

Advanced Directive

Rhiztomy

Rhiztomy

Wheelchair

Walking aids

Blood/Organ donation

Brain donation

Exercise therapy

NABs

Autoimmunity

Infections

Outcome measures

Web Resources

Pathogenesis

Double vision

What is MS?

NEDA

T2T OCT

Neurofilaments

JCV status Pharma

Anaesthesia




× No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions Patient-related outcomes (PRO or PROMS / Smart Devices)

DAF1,2

Treating-2-target

Choosing therapy

X Y Z

Define the Individual’s MS

No

Treatment failure? Yes

• Patient’s preferences?

• Your choice?

Individual measures:

• Evidence of disease activity?

• Tolerability/safety?

• Adherence?

• Drug or inhibitory markers?

Monitoring

• MS prognosis

• Life style and goals

• Shared goals for therapy

Rebaseline

Rebaseline:

• IFNβ, natalizumab, fingolimod,

teriflunomide, DMF=3-6 months

• Glatiramer acetate=9 months

• Alemtuzumab=24 months

DMF=dimethyl fumarate.

Relapses

Unreported relapses

Clinical disease progression

Subclinical relapses: focal MRI activity

Focal gray and white matter lesions not detected by MRI

Brain atrophy

Spinal fluid neurofilament levels

MS Iceberg

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

Control Multiple sclerosis

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

Treatment-effect on atrophy correlates with treatment-effect on disability

Sormani et al. Ann Neurol 2014;75:43–49.

Treatment effect on disability predicted by effect on T2-lesion load and brain atrophy

Meta-analysis of treatment effect on EDSS worsening (y) vs effects on MRI lesions

and brain atrophy, individually or combined, in 13 placebo-controlled RRMS trials

(13,500 patients)

Sormani MP et al. Ann Neurol. 2014;75:43-49.

-1.0%

-0.8%

-0.6%

-0.4%

-0.2%

0.0% Years 0-2

-0.82%

-0.80%

P=0.822†

Placebo (N=315) Natalizumab (N=627)

Year 0-1* Year 1-2

-0.40%

-0.56%

-0.43%

-0.24%

P=0.004†

P=0.002†

†Difference between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401.

AFFIRM Study: natalizumab and brain atrophy

Mean

(S

E)

perc

en

tag

e c

han

ge i

n B

PF

Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM

FREEDOMS, 2 years

Fingolimod 0.5 mg (n = 356)

Placebo (n = 329)

***

*

**

6 0 12 24

Time (months)

0

-0.4

-0.8

-1.2

-1.6

-2.0

−38%

vs placebo p<0.001

Ch

ange

in m

ean

BV

fro

m

bas

elin

e (%

)

TRANSFORMS, 1 year

0 12

Time (months)

0.0

-0.4

-0.6

-1.0

IFNb-1a IM (n = 359)

Fingolimod 0.5 mg (n = 368)

−40%

vs IFNb-1a IM p<0.001

*** -0.2

-0.8

Ch

ange

in m

ean

BV

fro

m

bas

elin

e (%

)

ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24 BV, brain volume; ITT, intent-to-treat. Gilenya™ Prescribing Information 19 April 2012. Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: 387-401, and Cohen JA et al. N Engl J Med 2010; 362: 402-415. Copyright © 2011 Massachusetts Medical Society. All rights reserved

Reduction in brain atrophy on alemtuzumab

Alemtuzumab Improves Brain MRI Outcomes in Patients With Active Relapsing-Remitting

Multiple Sclerosis: Three-Year Follow-up of the CARE-MS Studies

Douglas L Arnold,1,2 Elizabeth Fisher,3 Jeffrey A Cohen,4 Frederik Barkhof,5

Krzysztof W Selmaj,6 David H Margolin,7 Jeffrey Palmer,7 Edward J Fox8

AAN 2014

Blitz S65-008

1NeuroRx Research, Montréal, Québec, Canada, and 2Department of Neurology and Neurosurgery, Montreal

Neurological Institute, McGill University, Montreal, Québec, Canada; 3Department of Biomedical Engineering,

Cleveland Clinic, Cleveland, OH, USA; 4Cleveland Clinic, Cleveland, OH, USA; 5VU University Medical Centre,

Amsterdam, Netherlands; 6Department of Neurology, Medical University of Łódź, Łódź, Poland; 7Genzyme, a

Sanofi company, Cambridge, MA, USA; 8University of Texas Medical Branch, Round Rock, TX, USA

CARE-MS I & II Three-Year MRI Outcomes Change in Brain Parenchymal Fraction (BPF)

Alemtuzumab slowed brain volume loss over 3 years, as assessed by change in BPF

For both patient populations, the median percentage reduction in BPF observed in in Year 3 (0.19% and 0.10%, respectively) was smaller than that observed in Year 1 (0.59% and 0.48%) and Year 2 (0.25% and 0.22%)

Percentage Change in BPF in Formerly Treatment-Naive Patients (CARE-MS I)

Percentage Change in BPF in Patients Who Relapsed on Prior Therapy (CARE-MS II)

Me

dia

n C

ha

ng

e F

rom

Ba

se

lin

e, %

(9

5%

CI)

Year No. of Patients 371 367 351 323

% Change from Previous Year – –0.59% –0.25% –0.19%

Me

dia

n C

ha

ng

e F

rom

Ba

se

lin

e, %

(9

5%

CI)

Year 428 414 405 359

– –0.48% –0.22% –0.10%

No. of Patients

% Change from Previous Year

0 1 2 3

-1 .5 0

-1 .2 5

-1 .0 0

-0 .7 5

-0 .5 0

-0 .2 5

0 .0 0

0 1 2 3

-1 .5 0

-1 .2 5

-1 .0 0

-0 .7 5

-0 .5 0

-0 .2 5

0 .0 0

AAN 2014

Blitz S65-008

CARE-MS I & II Three-Year MRI Outcomes Proportion of Patients Free of Gd Lesions, T2 Lesions, and MRI Activity

The majority of alemtuzumab-treated patients were free of MRI activity (absence of Gd-enhancing lesions and new/enlarging T2 hyperintense lesions) at Year 2 and Year 3

MRI activity-free: absence of both Gd-enhancing and new or enlarging T2 hyperintense lesions; CARE-MS=Comparison of

Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; CI=confidence interval; DMT=disease-modifying therapy; Gd=gadolinium;

MRI=magnetic resonance imaging; Y=year

No. of Patients 359 370 336 356 370 325 354 369 326

Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3

Pro

po

rtio

n o

f P

ati

en

ts,

% (

95

% C

I)

0

20

40

60

80

100

Gd-enhancing

lesion-free

New/enlarging

T2 lesion-free

MRI

activity-free

% MRI Activity Free in Treatment-Naive

Patients (CARE-MS I)

% MRI Activity Free in Patients Who

Relapsed on Prior Therapy (CARE-MS II)

No. of Patients 412 421 364 405 423 361

Gd-enhancing

lesion-free

New/enlarging MRI

activity-free

402 414 361

Pro

po

rtio

n o

f P

ati

en

ts,

% (

95

% C

I)

0

20

40

60

80

100

Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3

T2 lesion-free

Patients were treated with alemtuzumab 12 mg at baseline and 12 months later

Re-treatment in Year 3 was administered upon recurrence of disease activity

18% of CARE-MS I patients and 20% of CARE-MS II patients were re-treated with

alemtuzumab in Year 3; <3% were treated with another DMT in Year 3

AAN 2014

Blitz S65-008

Rheumatoid arthritis End-stage joint disease




× No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions Patient-related outcomes (PRO or PROMS / Smart Devices) Normalisation of brain atrophy rates

DAF1,2

Natalizumab and Functional Benefit – Double-blind, Placebo-controlled Study (AFFIRM)

1. Phillips JT et al., Mult Scler 2011;17:970-979; 2. Munschauer F et al., ECTRIMS Meeting September 9–12, 2009, Dusseldorf, Germany,

P434; 3. Balcer LJ et al., J Neurol Sci 2012;318:119-24; 4. Weinstock-Guttmanen B et al., J Neurol 2012;259:898–905.

Compared with placebo, Natalizumab showed sustained improvement in

• EDSS1

• Upper limb2

• Walking2

• Vision3

and reduced the risk of progression of cognitive deficit4

-0.30.20.71.21.72.22.73.23.74.2

0.5 5

Hazard Ratio (95% Confidence Interval)

0.5 1.0 1.5 2.0 3.0 4.0 5.0

Favours placebo Favours natalizumab

Cognitive deficit – PASAT-3 (P=0.013)

Vision – 1.25% low contrast acuity (P=0.014)

Vision - 2.5% low contrast acuity (P=0.012)

Timed 25-foot walk (P=0.028)

9-hole peg test (P=0.044)

EDSS (P=0.006)

Favours natalizumab Favours placebo

Alemtuzumab improved pre-existing disability

CARE-MS II

aSecondary endpoint; defined as decrease of ≥1 EDSS point lasting at least 6 months, assessed in patients

with baseline EDSS ≥2.0. bTertiary endpoint. cMeasured by SRD score in relapsing patients.

Coles AJ, et al. Lancet. 2012;380:1829-1839.

IFNB-1a 44 μg Alemtuzumab12 mg

‒0.17

P<0.0001

+0.24

ED

SS

Sco

re, m

ea

n

3.25

3.00

2.75

2.50

2.25

Follow-Up Month

0 3 6 9 12 15 18 21 24

40

30

20

10

0

Pa

tie

nts

With

6-M

on

th S

RD

(%

)

29%

13%

P=0.0002

Mean EDSS Change From Baselinea SRDb‎

Follow-Up Month

0 3 6 9 12 15 18 21 24




× No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions Patient-related outcomes (PRO or PROMS / Smart Devices) Normalisation of brain atrophy rates Sustained improvement in disability (PROM / Smart Device)

DAF1,2

Re-defining the therapeutic window

Coles et al. J Neurol. 2006 Jan;253(1):98-108..

Window of therapeutic efficacy

Theoretical model: treat early and effectively

Natural course of disease

Later intervention

Later treatment

Treatment at diagnosis Intervention

at diagnosis

Time Disease Onset

Dis

abili

ty

Time is brain

Coles et al. J Neurol. 2006 Jan;253(1):98-108..

Window of therapeutic efficacy

Tur et al. Arch Neurol. 2011 Nov;68(11):1421-7.

Motor system to legs

Cerebellar or balance systems

Bladder Therapeutic window 1

Therapeutic window 2


Upper limbs

Sensory

Cognition

Vision

Etc.





Therapeutic window 8, etc….

Diagnosis of Progressive MS

Effective DMTs could still target the remaining windows of therapeutic opportunity for individual

neurological systems

The Asynchronous Progressive MS hypothesis

Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial

Chataway Lancet 2014; 383: 2213–21.

Normal neurological examination

No disability

Minimal disability

Moderate disability

Relatively severe disability

Disability precludes full daily activities

Assistance required to walk Restricted

to a wheelchair

Restricted to bed or chair Confined

to bed

Death

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0

EDSS

Adapted from http://www.msdecisions.org.uk/. Accessed 15 April 2014. Previously adapted from Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).

Neurology 1983; 33:1444–1452.

http://www.msdecisions.org.uk/

Ceiling and floor effects

Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial

Zajicek et al. Lancet Neurol 2013; 12: 857–65.

0 200 400 600 800 1000 1200

0.0

0.2

0.4

0.6

0.8

1.0

Time to EDSS progression (days)

P(E

DS

S p

rog

ressio

n)

Treatment group

Active

Placebo

Slides courtesy of John Zajicek.


0 200 400 600 800 1000 1200

0.0

0.2

0.4

0.6

0.8

1.0


P(E

DS

S p

rog

ressio

n)

Baseline EDSS score

4

4.5

5

5.5

6

6.5



0 200 400 600 800 1000 1200

0.0

0.2

0.4

0.6

0.8

1.0


P(E

DS

S p

rog

ressio

n)

Treatment group

Active

Placebo

Log rank test P = 0.01



Long-term effect of early treatment with IFNB-1b after CIS: 5-yr active extension of the phase 3 BENEFIT trial

Kappos et al. Lancet Neurol 2009; 8: 987–97.

3 6 9 12 24

EDSS

0

TIME

Active (no progression)

Placebo (confirmed progression)

Delayed Recovery

Equal exit EDSS

Therapeutic strategies

Proof of concept Trials

Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.

Spinal fluid neurofilament levels

Gunnarsson et al. Ann Neurol 2010; Epub.

CSF NFL

Phase 2A study of natalizumab in progressive MS: CSF markers of axonal damage and demyelination (2° endpoint)

Slide courtesy of Romme Christensen, ECTRIMS 2012. Oral presentation 170.

NIND Mean +/- 95% CI

p=0.03

CSF

Ne

uro

fila

men

t lli

ght

ng/

L

p=0.048

CSF

MB

P n

g/m

l

NIND Mean +/- 95% CI

Natalizumab → SPMS (ASCEND STUDY) ClinicalTrials.gov ID: NCT01416181

Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis

Kuhle et al. submitted for publication Fingolimod → PPMS (INFORMS STUDY)

ClinicalTrials.gov ID:NCT00731692

Siponimod → SPMS (EXPAND STUDY)

ClinicalTrials.gov ID: NCT01665144




× No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions Patient-related outcomes (PRO or PROMS / Smart Devices) Normalisation of brain atrophy rates Sustained improvement in disability (PROM / Smart Device) Normalisation of CSF neurofilament levels

DAF1,2

38 year old woman with left optic neuritis

sTE fFLAIR images

Baseline 52 weeks

Hickman et al. Neuroradiology 2001;43:123-8.

Trapp et al. N Engl J Med 1998.

Acute mono-focal lesion

Acute neuroprotection




× No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions Patient-related outcomes (PRO or PROMS / Smart Devices) Normalisation of brain atrophy rates Sustained improvement in disability (PROM / Smart Device) Normalisation of CSF neurofilament levels Normalisation of retinal nerve fibre layer thinning (OCT)

DAF1,2

Remyelination

Nogo, MAG, OMgP

Lingo-1-NgR-p75NTR

GAP-43

NCAM

Neuregulin

Slide courtesy of Klaus Schmierer.

Agents in trial

1. GSK239512: histamine H(3)

receptor antagonist

2. BIIB033: anti-LINGO-1

3. Clemastine: anti-histamine

4. IRX4204 & Bexarotene: RXR-

agonists

5. Etc.




× No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions Patient-related outcomes (PRO or PROMS / Smart Devices) Normalisation of brain atrophy rates Sustained improvement in disability (PROM / Smart Device) Normalisation of CSF neurofilament levels Normalisation of retinal nerve fibre layer thinning (OCT) Improvement in central conduction times (VEPs)

Etc.

DAF1,2

Therapeutic hierarchy

Neuro-restoration

Remyelination

Neuroprotection

Anti-inflammatory

Therapeutic pyramid

Anti-ageing

Brain

Health

Initiative

• Smoking

• Exercise

• Diet

• Sleep

• Co-morbidities

• Infections

• Concomitant

medications

Conclusions • Therapeutic target is moving

– NEDA

– PROMS/PROS/Smart Devices

– End-organ damage

– Sustained improvement in disability

– Remyelination

– Neurorestoration

• Therapeutic time window

– Early or late

• Redefining progressive MS

– Asynchronous disease course

– Therapeutic lag

• Novel PoC trials

– OCT in acute optic neuritis

– CSF NF levels in SPMS

– VEPs and MTR in remyelination trials

future efficacy measures for multiple sclerosis

Health & Medicine

slide courtesy

modified rio

care ms ii

sustained

enlarging

evident disease

confirmed

brain atrophy