beyond neda as a treatment target in ms targeting end-organ damage

Beyond NEDA as a treatment target in MS and the role of biomarkers in achieving this.

Gavin GiovannoniBarts and The London

Disclosures

Over the last 15 years 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, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

Professor Giovannoni would also like to thank numerous colleagues for providing him with data and/or slides for this presentation.

This presentation has been designed and prepared by Professor Giovannoni with no input from any other parties.

Pathogenesis of MS

immune activationinnate and adaptive responses

focal inflammation

BBB breakdown

oligodendrocyte toxicity & demyelination

Acute axonal transection and loss

“autoimmune endophenotype”

axonal plasticity & remyelination

delayed neuroaxonal loss and gliosis

Gd-enhancement

T2 & T1 lesions

brain & spinal cord atrophy

release of soluble markers

Clinical Attack

Disease Progression

Clinical Recovery

- biology

- clinical outcomes

- biomarkers

Pathological substrate for brain atrophy: 11,000 to 1

Trapp, et al. NEJM 1998;338:278-85

DEFINING THE TREATMENT 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

EVIDENCE

Predictors of long-term outcome in MSers treated with interferon beta-1a

Bermel RA, et al. Ann Neurol 2013;73:95-103.

Predictors of long-term outcome in MSers treated with interferon beta-1a

Treatment vs. Natural HistoryBermel RA, et al. Ann Neurol 2013;73:95-103.

TREATMENT GOALS

BARTS-MS T2T-NEDA ALGORITHM T2T = treating-to-target; NEDA = no evident disease activity

Choose therapy

A B C

Define the individual’s MS

Treatment failure?

• Patient’s preferences?• Your choice?

Individual measures:• Evidence of disease activity?• Tolerability/safety?• Adherence?• Drug or inhibitory markers,

e.g. NABs?

Monitoring

• MS prognosis based on clinical and MRI indices

• Life style and goals • Shared goals for therapy

Rebaseline

Rebaselining:• IFNβ, natalizumab, fingolimod,

teriflunomide, Dimethyl-Fumarate=3-6 months

• Glatiramer acetate=9 months• Alemtuzumab=24 months

Choose a therapeutic strategy

Maintenance-escalation Pulsed immune reconstitution therapy

Choose therapy

X Z

Rebaseline

Monitoring

Initiate or Switch or Escalate Rx Complete course / Re-treat

Breakthrough disease

Y

• Patient’s preferences?• Your choice?

NoYes Yes

• Only one licensed induction therapy at present

IFNβ = interferon-beta; NABs = neutralizing antibodies; Rx = treatment

Maintenance Therapies vs. Pulsed Immune Reconstitution Therapies (PIRTs)

Maintenance Therapies• Continuous treatment• Low to very high efficacy• Reversible• Perceived to be lower risk

• Cumulative, or increased, risk with time

• Examples• Laquinimod, GA, IFNβ, teriflunomide, BG12,

fingolimod, natalizumab, daclizumab

• Breakthrough disease• Suboptimal or failure to respond• NEDA reliable metric for efficacy

• Rebound activity• Highly likely• Can be life-threatening

• Pregnancy• No potential for a cure

• Rebound• SPMS and progressive brain atrophy

PIRTs• Short-courses or pulsed therapy• High to very high efficacy• Irreversible• Perceived to be higher risk

• Frontloading of risk or reduced risk with time

• Examples• Mitoxantrone, cladribine, alemtuzumab,

anti-CD20 (?), HSCT- BMT

• Breakthrough disease• Marker for retreatment• NEDA unreliable to assess efficacy

• Rebound activity• Less likely• Unlikely to be life-threatening

• Pregnancy• Potentially ‘curative’?

• 15–20-year experiment

The following are not licensed for MS in the UK: laquinimod, daclizumab mitoxantrone, cladribine, anti-CD20 therapies, and BMTPIRTs = pulsed immune reconstitution therapies

A

D

C

B

Treatment Ladder

B

E

F G

Escalation to Alemtuzumab Is More Effective Than Switching from IFN/GA to IFNβ-1a 3×/Week

OR=odds ratio; SC=subcutaneous; SAD=sustained accumulation of disability.Hartung HP et al. Presented at AAN; March 16–23, 2013; San Diego, CA. P07.093.

% o

f Pat

ient

s

CARE-MS II: Disease-Free Status over 2 Years

OR=3.03P<0.0001

CO-CZ-0056l

He et al. JAMA Neurol. 2015 Apr;72(4):405-13.

Comparison of switch to fingolimod or GA in active MS

Early treatment with fingolimod improved time to confirmed relapse vs switching after 12 months

*Number of patients who completed the study during M36–48. #Interval non-completers are patients who did not continue to the next yearly time interval. For interval non-completers, M0–24 summarises the aggregate ARR from M0 to M24 for patients who discontinued during the interval of M12–24. M0–36 summarises the aggregate ARR from M0 to M36 for patients who discontinued during the interval of M24–36. M0–48 summarises the aggregate ARR from M0 to M48 for patients who discontinued during the interval of M36–48. Cohen JA et al. J Neurol Neurosurg Psychiatry 2015

Time to first confirmed relapse up to the end of study (core ITT population)

ECTRIMS 2013

TEMSO & TOWER: Evaluation of the Effect of Teriflunomide in Subgroups Defined by Prior Treatment (Pooled Analyses)

Adjusted ARR by Prior Treatment Disability Progression by Prior Treatment

ARR, annualized relapse rate; DMT, disease-modifying therapy; RRMS, relapsing-remitting MS.Adapted from Freedman M et al. Presented on ACTRIMS/ECTRIMS, 2014, P046.

An

nu

aliz

ed r

elap

se r

ate

Pro

bab

ility

of

dis

abili

ty p

rogr

essi

on

Teriflunomide 14 mgTeriflunomide 7 mgPlacebo

46.7%

41.6% 27.7%

16.4%35.9%

30.2%

78.6%

33.4%

46.6%

5.0%

17.4%

20.8%

Patients (n) 41 32 36 189 193 192 498 547 523 Patients (n) 41 32 36 189 193 192 498 547 523

∙ Post hoc analysis of pooled data of ARR and 12-week confirmed disability progression conducted on patient subgroups defined by prior MS therapy

Beyond NEDA

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

Etc.

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

NED

A

END

-ORG

AN

DA

MA

GE

BEYOND NEDA-3BRAIN ATROPHY

Treat-2-Target

Relapses

Unreported relapses




Brain atrophy


Etc.

Clinical activity

Focal MRI activity



Biomarkers

NED

A

END

-ORG

AN

DA

MA

GE

Brain atrophy occurs across all stages of the disease

n= 963 MSers

De Stefano N, et al. Neurology 2010;74:1868-76.

Baseline Cognitive Function Predicts Clinical Disability Progressionin an Integrated RRMS Clinical Trial Database

Raghupathi et al. Baseline Cognitive Function Predicts Clinical Disability Progression in an Integrated RRMS Clinical Trial Database. ECTRIMS 2015: P317

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.

Baseline Month 6

Month 12 Month 18

Baseline Month 6

Month 12 Month 18

Patient 1 Patient 2

End-organ damage

www.ms-res.org

NEDA-4BRAIN ATROPHY DATA

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

-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

Mea

n (S

E) p

erce

ntag

e ch

ange

in 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)

****

**

60 12 24Time (months)

0

-0.4

-0.8

-1.2

-1.6

-2.0

−38% vs placebo

p<0.001

Chan

ge in

mea

n BV

from

ba

selin

e (%

)

TRANSFORMS, 1 year

0 12Time (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

Chan

ge in

mea

n BV

from

ba

selin

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

CARE-MS I: Slowing of BVL Through 5 Years in Alemtuzumab-Treated Patients

• Alemtuzumab slowed the reduction in brain volume by 42% versus SC IFNB-1a at the end of the core CARE-MS I study

• BVL in the alemtuzumab group at Year 5 was still lower than that observed at Year 2 in the SC IFNB-1a group

Year

Med

ian

BPF

Cha

nge

From

Bas

elin

e, %

(95%

CI)

–325

322

–320

–

Percentage BVL From Baseline

**

No. of Patients

185 176 171371 367 352

68% of patients received no

alemtuzumab retreatment since

Month 12

No. of Patients

367

351

320 312

314

Median Annual Brain Volume Change

Core Study Extension Study

−0.59

−0.25 −0.19−0.15 −0.20

11

Core Study Extension Study

*Alemtuzumab vs SC IFNB-1a, P<0.0001.

AAN 2016

Percentage BVL From Baseline

CARE-MS II: Slowing of BVL Through 5 Years in Alemtuzumab-Treated Patients

• Alemtuzumab slowed the reduction in brain volume by 24% versus SC IFNB-1a at the end of the core CARE-MS II study

199

187

167

428

414

405

*

360 335 317– – –

12

Median Annual Brain Volume Change

60% of patients received no

alemtuzumab retreatment since

Month 12

No. of Patients 414

398

356 303

330

−0.48

−0.22−0.10

−0.19−0.07

Core Study Extension StudyCore Study Extension Study

No. of Patients

Med

ian

BPF

Cha

nge

From

Bas

elin

e, %

(95%

CI)

Year

*Alemtuzumab vs SC IFNB-1a, P=0.0121.

AAN 2016

34

Daclizumab: annualized Whole Brain Volume Change

p-value based on analysis of covariance model based on ranks adjusted for normalized brain volume, baseline age (≤35 vs >35) and history of prior IFN beta. Missing values were imputed.

p=0.0325

Week 0-24 Week 24-96

Per

cent

age

of m

ean

annu

aliz

ed b

rain

vol

ume

chan

ge p<0.0001

IFN beta-1a 30 mcg(n=880)

DAC HYP 150 mg(n=876)

IFN beta-1a 30 mcg(n=886)

DAC HYP 150 mg(n=881)

35

ITT (EDSS ≥ 2.0)*Compared using the Cochran–Mantel–Haenszel test stratified by geographic region (US vs ROW) and baseline EDSS score (<4.0 vs. ≥4.0).

NEDAPercentage Change in Brain Volume

from Baseline to Week 9674%NEDA

improvement vs IFN β-1a

p<0.0001

NEDA is defined as: no protocol-defined relapses, no CDP events, no new or enlarging T2 lesions, and no

Gd-enhancing T1 lesions

Week

Higher proportion of patients with No Evidence of Disease Activity (NEDA) compared with IFN β-1a

OPERA I

36

ITT (EDSS ≥ 2.0)*Compared using the Cochran–Mantel–Haenszel test stratified by geographic region (US vs ROW) and baseline EDSS score (<4.0 vs. ≥4.0).

81%NEDA

improvement vs IFN β-1a

p<0.0001

NEDA is defined as: no protocol-defined relapses, no CDP events, no new or enlarging T2 lesions, and no

Gd-enhancing T1 lesions

NEDAPercentage Change in Brain Volume

from Baseline to Week 96

Higher proportion of patients with No Evidence of Disease Activity (NEDA) compared with IFN β-1a

OPERA II

ORATORIO (PPMS) Study: reduction in the rate of whole brain volume loss

37

nPlacebo 203 200 150Ocrelizumab 407 403 325

17.6% reduction in rate of brain volume loss

vs. placebop=0.0206

Percent Change of Whole Brain Volume from Week 24 to Week 120

Analysis based on ITT population with week 24 and at least one post-week 24 assessment; p-value based on MMRM at 120 week visit adjusted for week 24 brain volume, geographic region and age

Brain volume loss at Month 24 as a predictor of long-term disability (FREEDOMS study)

Patients received fingolimod (0.5 or 1.25 mg) or placebo. Patients reached EDSS ≥4 if they had an EDSS ≥4 at any time post-baseline. Patients who already met the corresponding criterion at baseline were excluded from the analysis. OR and p-value were derived from a logistic regression of EDSS ≥4 on PBVC quartiles and baseline EDSS. PBVC Q4 was used as reference category.Jeffery D et al. Oral FC2.3 presented at ECTRIMS-ACTRIMS 2014.

N 256 254 257 262

Annualised rate of BVL, % (mean / median)

–1.457 / –1.266 –0.601 / –0.588 –0.246 / –0.243 0.225 / 0.135

% change in brain volume from Mo 24 –13.5% –1.7% –0.8% –0.2% 3.0%

PBVC Q1 PBVC Q2 PBVC Q3 PBVC Q4

Patients with more BVL at24 months had a higher risk for

disability progressionover time

Time to first event (months)

Cum

ulat

ive

prob

abili

ty

of E

DSS

≥4

Cumulative probability of EDSS ≥4

Low BVL (PBVC Q4)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57

0

0.1

0.2

0.3

0.4

0.5

35.8%

13.8%

OR = 2.8 p=0.001 vs Q4

High BVL (PBVC Q1)

Effect of fingolimod on NEDA-4 status

• A higher proportion of patients achieved NEDA-4 status across a range of BVL thresholds when treated with fingolimod compared with placebo or IFN β-1a IM therapy1,2

1. Kappos L, et al. Mult Scler 2015; Epub ahead of print;2. Montalban X, et al. AAN 2015; P4.001.

OR 1.92(95% CI: 1.42–2.60)

p < 0.0001

OR 2.06(95% CI: 1.49–2.86)

p < 0.0001

OR 1.93(95% CI: 1.36–2.73)

p = 0.0002

OR 1.94(95% CI: 1.30–2.90)

p = 0.0011

0 5 10 15 20 25 30

SPINAL FLUID NEUROFILAMENT LEVELSNEDA-5

Treat-2-Target

Relapses

Unreported relapses




Brain atrophy


Etc.

Clinical activity

Focal MRI activity



Biomarkers

NED

A

END

-ORG

AN

DA

MA

GE

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


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

NIND Mean +/- 95% CI

p=0.03

CSF

Neu

rofi

lam

ent

lligh

t n

g/L

Natalizumab → SPMS (ASCEND STUDY)ClinicalTrials.gov ID: NCT01416181Romme Christensen et al. Neurology. 2014 Apr 29;82(17):1499-507.

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

Fingolimod → PPMS (INFORMS STUDY)ClinicalTrials.gov ID:NCT00731692

Siponimod → SPMS (EXPAND STUDY)ClinicalTrials.gov ID: NCT01665144Kuhle et al. Neurology. 2015 Apr 21;84(16):1639-43.

No evident disease activity: NEDA-5


Treat-2-target What is NEDA?

× No relapses× No sustained disability progression (EDSS)× No MRI activity


✓ Normalisation of brain atrophy rates✓ Normalisation of CSF neurofilament levels

DAF1,2

OCBsNEDA-9

NEDA-6, 7, ….9





✓ Normalisation of brain atrophy rates✓ Normalisation of CSF neurofilament levels

✓ Normalisation of retinal nerve fibre layer thickness loss✓ PROM✓ Cognition

✓ OCBs

DAF1,2

NEDA outcomes with alemtuzumab:3-year follow-up of the CARE-MS studies

MRI, magnetic resonance image; CI, confidence interval.Adapted from Havrdova E et al. Presented on ACTRIMS/ECTRIMS, 2014, FC1.4.

↑32.2%P=0.0062

↑45.8%P<0.0001

CARE-MS I: NEDA by year

SC IFNB-1aALEM 12 mg

174369

170 356

—349

SC IFNB-1aALEM 12 mg

187405

173434

— 393

↑61.2%P<0.0001

CARE-MS II: NEDA by year

↑84.3%P<0.0001

MS Endophenotype

Ramagopalan SV, Dobson R, et al. Lancet Neurol. 2010.

Intrathecal Antibody Response

local OCBs

local & systemic OCBs

systemic OCBs

normal / polyclonal

CSFSerum

Intrathecal or central compartment

Systemic or peripheral compartment

C

S

C

S

C

S

C

S

Meningeal Perivascular

Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology

Magliozzi et al. Brain 2007; 130:1089-1104.

Cortical and white matter demyelination

Female

Age 47 years

MS for 30 years

Proportion of cortex demyelinated= 59%

Schmierer-Lab, Blizard Institute

Accumulation of disability in PPMS:stratified by intrathecal IgG abnormalities

Proportion Progressing as Percent

Epoch CSF- CSF+

6 mo 7.3 9.8

12 mo 15.0 20.4

18 mo 22.8 28.1

24 mo 25.4 34.3

Years to Progression

2.43 2.26

Based on data from a second meeting of the DSMB and assume no therapeutic effect

0 1 2 3Years

0.0

0.2

0.4

0.6

0.8

1.0

Prop

ortio

n Pr

ogre

ssin

g

PositiveNegative

CSF

Slide courtesy of Jerry Wolinsky

P =0.03

Intrathecal Antibody Response

local OCBs

local & systemic OCBs

systemic OCBs

normal / polyclonal

CSFSerum

Intrathecal or central compartment

Systemic or peripheral compartment

C

S

C

S

C

S

C

S

Meningeal Perivascular

RECOVERY OF FUNCTION

NEDA-6, 7, ….10





✓ Normalisation of brain atrophy rates✓ Normalisation of CSF neurofilament levels✓ Normalisation of retinal nerve fibre layer thickness loss✓ PROM✓ Cognition✓ OCBs

✓ Recovery of function

DAF1,2

Pathogenesis of MS

immune activationinnate and adaptive responses

focal inflammation

BBB breakdown

oligodendrocyte toxicity & demyelination

Acute axonal transection and loss

“autoimmune endophenotype”

axonal plasticity & remyelination

delayed neuroaxonal loss and gliosis

Gd-enhancement

T2 & T1 lesions

brain & spinal cord atrophy

release of soluble markers

Clinical Attack

Disease Progression

Clinical Recovery

- biology

- clinical outcomes

- biomarkers

Factors to consider regarding recovery

Anti-inflammatory

Neuro-protective

Remyelination

Axonal plasticity

Axonal sprouting

Synaptogenesis

Reserve capacity

Cortical plasticity

Rehabilitation

Ageing

Co-morbidities

Lifestyle

59

n=140 n=93 n=80n=143

Prop

ortio

n of

pat

ient

s (%

)

PlaceboNatalizumab

**P=0.0088 **P=0.0019 P=0.8259

At least 0.5 pointEDSS increase

n=47 n=63

At least 1.0 pointEDSS increase

n=140 n=93 n=80n=143

Prop

ortio

n of

pat

ient

s (%

)

*P=0.0349 **P=0.0048 P=0.5976

n=47 n=63

Lublin F. et al. ECTRIMS 2013, Copenhagen October 3rd , Poster P524.

Disabling Magnitude of Relapses in AFFIRMEDSS change from pre-relapse to at relapse

Natalizumab and Clinical Recovery from Relapses

24-month treatment with MD1003 (high doses of biotin) in progressive multiple sclerosis: results of the MS-SPI trial extension phase

A. Tourbah, C. Lebrun-Frenay, G. Edan, M. Clanet, C. Papeix, S. Vukusic, J. de Sèze, M. Debouverie, O. Gout, P. Clavelou, G. Defer, D. Laplaud,

T. Moreau, P. Labauge, B. Brochet, F. Sedel, J. Pelletier

The study was sponsored by MedDay pharmaceuticalsDisclosures

A. Tourbah has received in the last year, consulting and lecturing fees, travel grants and research support from Medday, Biogen Idec, Sanofi-Genzyme, Novartis, Merck Serono, Teva Pharma, and Roche

CHU Reims, CHU Nice, CHU Rennes, CHU Toulouse, GH Pitié-Salpêtrière Paris, CHU Lyon, CHU Strasbourg, CHU Nancy, FOAR Paris, CHU Clermont-Ferrand,

CHU Caen, CHU Nantes, CHU Dijon, CHU Montpellier, CHU Bordeaux, Medday Pharmaceuticals, CHU Marseille

All MD1003Placebo-controlled

p=0.014*

n=42

n=91

n=82

n=41

*Mann-Whitney U test

months

Mean change in EDSS from baseline

24-month-treatment with-MD1003 (high doses of biotin) in progressive multiple sclerosis: results of the MS-SPI trial extension phase

Remyelination

4 stages of OPC differentiation

Remyelinationtargets in MS

Hartley et al. Curr Neurol Neurosci Rep 2014; 14:485.

Remyelination targets1. BIIB033: anti-LINGO-1 2. GSK239512: histamine H(3) receptor antagonist 3. Clemastine: anti-histamine4. IRX4204 & Bexarotene: RXR-agonists 5. rHIgM22: penatmeric IgM that binds oligodendrocytes6. Benztropine: anticholinergic7. VX15: anti-SEMA4D monoclonal antibody8. ABT555: anti-repulsive guidance molecule (RGMa)

Markers of Remyelination

Image courtesy of Klaus Schmierer.

3 6 9 12 24

EDSS

0

TIME

Active (confirmed improvement)

Placebo (confirmed progression)

Exit EDSS showing improved function

Shadow plaque MRI - MTR

Schmierer et al. Ann Neurol 2004;56:407–415.

BEYOND END-ORGAN DAMAGE

Images courtesy of Professor Gavin Giovannoni /

ESRFend-stage renal failure

Images courtesy of Professor Gavin Giovannoni /

Neuro-restoration

Remyelination

Neuroprotection

Anti-inflammatory

Therapeutic pyramid

Anti-ageing

Brain

Health

Initiative

• Smoking• Exercise• Diet• Alcohol• Sleep• Co-morbidities• Infections• Concomitant medications

• ? Menopause / HRT

MS-specific

MS non-specific

Brain Health

www.msbrainhealth.org

Rheumatoid arthritisEnd-stage joint disease

Images courtesy of Professor Gavin Giovannoni and http://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-symptoms/

Conclusions• MS is a bad disease

• Mortality, disability, unemployment, divorce, cognitive impairment, etc.

• On average early highly-effective therapy is the only realistic option of preventing end-organ damage

• NEDA and T2T are current treatment target (zero tolerance)• Beyond NEDA we need to target end-organ damage (brain atrophy

and CSF NF levels)• New treatment targets

• OCBs - plasma cells• Remeylination - GAP43, NCAM, etc.

• Brain Health• Beyond MS

beyond neda as a treatment target in ms targeting end-organ damage

Health & Medicine