Beyond NEDA: preventing end-organ damage in MS

Gavin Giovannoni

Blizard Institute, Barts and The London School of Medicine

December 2014

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 like to acknowledge and thank Abbvie, Biogen-Idec, Genzyme and Novartis for making available data slides for this presentation. He would also like to thank numerous colleagues for providing him with data and/or slides for this, and other, presentations.

Professor Giovannoni’s tour to Canada has been kindly sponsored by Biogen-Idec, therefore please interpret anything he says about Biogen-Idec’s products in this context.

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

Who thinks multiple sclerosis should be redefined as a dementia?

Definition of dementia

Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness.

• Normal activities of daily living

• Physical

• Mental

• Social

• Occupational

• Lasting more than six months

• Not present since birth

• Not associated with a loss or alteration of consciousness

Consequences of increasing EDSS scores: loss of employment1

0

10

20

30

40

50

60

70

80

90

Work Capacity by Disability Level

0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0

EDSS Score

Pro

po

rtio

n o

f P

ati

en

ts ≤

65

Ye

ars

Old

Wo

rkin

g (

%)

The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger.

1. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926;

2. Pfleger CC et al. Mult Scler. 2010;16:121-126.

Spain

Sweden

Switzerland

United Kingdom

Netherlands

Italy

Germany

Belgium

Austria

~10 yrs2

Impact of MS: cognitive functioning in the CIS stage

Feuillet et al. MSJ 2007

CIS Patients n = 40

57%

7%

-20%

0%

20%

40%

60%

Healthy Controls n = 30

p < 0.0001

Deficits were found mainly in memory, speed of information

processing, attention and executive functioning Patients failing

≥ 2 cognitive tests

163 patients with “benign” MS

(disease duration >15 years and EDSS <3.5):

45% cognitive impairment

49% fatigue

54% depression

What is benign MS?

Definition of dementia

Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness.

• Normal activities of daily living

• Physical

• Mental

• Social

• Occupational

• Lasting more than six months

• Not present since birth

• Not associated with a loss or alteration of consciousness

“Multiple sclerosis is a preventable dementia.”

Control Multiple sclerosis

Slide courtesy of Dr Klaus Schmierer

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

Association of MRI metrics and cognitive impairment in radiologically isolated syndromes

Amato et al. Neurology. 2012 Jan 31;78(5):309-14.

AAN 2013

AAN 2013

11,000 to 1

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

Kutzelnigg, et al. Brain 2005

Is MS a gray matter disease?

Female

Age 46y

SPMS for 16y

Mean ~ 13% GML SPMS ~ 0-69% PPMS ~ 0-39%

Mean ~ 24% WML (SP)

Mean ~ 7% WML (PP)

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

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.

Pseudoatrophy and the reversal of pseudoatrophy

Baseline Year 1/2 Year 3

No evidence of disease activity: NEDA-3

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

No evidence of disease activity defined as:1,2

× No relapses

× No sustained disability progression

× No MRI activity

× No new or enlarging T2 lesions

× No Gd-enhancing lesions

• Post-hoc analysis of a pivotal clinical trial of IFN β-1a IM1

• Treatment with IFN β-1a IM resulted in a 55% reduction in brain atrophy vs. placebo during the second year of a clinical trial (N = 140)

• Analysis of the MRI cohort of the European IFN β-1a IM dose comparison study2

• Derived from a double-dose study; all patients on-treatment; modelled from pre-treatment rate

IFN β-1a IM

BPF, brain parenchymal fraction; IFN β, beta-interferon; IM, intramuscular; MRI, magnetic resonance imaging; n.s., not significant. 1. Rudick RA, et al. Neurology 1999; 53:1698−1704; 2. Hardmeier M, et al. Neurology 2005; 64:236−240.

–1.06% per year

–0.33% per year

Treatment initiation

Month

0.795

0.800

0.805

0.810

0.815

0.820

0.825

0.830

–3 0 3 6 9 12 18 24 30 36 21 15 27 33

BP

F

p < 0.01

n.s.

Year 1

Year 2

Year 3

Month 4−12

Baseline− Month 4

p < 0.05

p < 0.01

n.s.

–1.6

–1.4

–1.2

–1.0

–0.8

–0.6

–0.4

0.0

–0.2

Annual MRI group (n = 368)

Frequent MRI subgroup (n = 138)

Re

lati

ve B

PF

chan

ge (

%)

–0.482% (+/ –0.58)

–0.228% (+/ –0.73)

–0.348% (+/ –0.61)

–0.393% (+/ –0.58)

–0.686% (+/-0.79)

–0.377% (+/-0.77)

–0.378% (+/-0.73)

Teriflunomide

TEMSO: 2-year, randomized, placebo-controlled Phase III trial of teriflunomide in patients with RMS (N = 1,088)

Change from baseline in white matter volume

Teriflunomide: white matter atrophy

RMS, relapsing MS. Wolinsky JS, et al. Mult Scler 2013; 19:1310−1319.

• Whole brain atrophy: − no significant effect

• Grey matter atrophy:

− no significant effect

Me

an ±

SE

chan

ge

fro

m b

ase

line

(m

l)

Week

Placebo Teriflunomide 7 mg Teriflunomide 14 mg

2.4

0.8

–0.8

–2.4

–4.0

–5.6

0 24 48 72 108

p = 0.0002

p = 0.0609

No. of patients

Placebo 358 329 309 270 256

7 mg 359 339 301 273 262

14 mg 355 328 293 273 260

Dimethyl fumarate

Dimethyl fumarate

DEFINE: 2-year, randomized, placebo-controlled study of DMF in patients with RRMS (N = 1,237)1

CONFIRM: 2-year, randomized, placebo-controlled active reference (GA) comparator study of DMF in patients with RRMS (N = 1,430)2

BID, twice daily; DMF, dimethyl fumarate; TID, three times daily. 1. Arnold DL, et al. AAN 2012. Abstract IN3-2.002; 2. Miller D, et al. ENS 2012. O259.

Week 24−Year 2

−30% vs. placebo (p = 0.02)

−17% vs. placebo (p = 0.2478)

• Significant reduction in brain volume loss vs. placebo with DMF BID but not TID

• No significant reduction in brain volume loss vs. placebo with both doses

−6% vs. placebo

(p = 0.831)

−3% vs. placebo

(p = 0.562)

−16% vs. placebo

(p = 0.706)

Week 24−Year 2

Me

dia

n c

han

ge

in w

ho

le b

rain

vo

lum

e (

%)

Me

dia

n c

han

ge

in w

ho

le b

rain

vo

lum

e (

%)

Natalizumab

-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

Brain atrophy in natalizumab-treated patients: 3-year follow-up

Sastre-Garriga et al. MSJ 2014.

-0.6%

-1.4%

-0.1% -0.5%

-0.7%

-0.2%

Alemtuzumab

Reduction in brain atrophy on alemtuzumab

Fingolimod

• In all three studies: PBVC assessed for all patients, prospectively, using the SIENA method • Fingolimod significantly reduced brain volume loss over 2 years vs. placebo

• These reductions were observed after 6 months (first post-baseline scan) • Fingolimod significantly reduced brain volume loss over 1 year vs. IFN β-1a IM

Atrophy data from three fingolimod trials

SIENA, Structural Image Evaluation, using Normalisation, of Atrophy. ITT population with evaluable MRI images at baseline and end of core study phase (Month 24). p values are for comparisons over Months 0–6, Months 0–12, Months 0–24. TRANSFORMS: *** p < 0.001 vs. IFN β-1a IM. Wilcoxon rank sum test; FREEDOMS/FREEDOMS II: * p < 0.05; ** p < 0.01; *** p < 0.001 vs. placebo. Rank ANCOVA adjusted for treatment, region and baseline normalized brain volume. 1. Cohen JA, et al. N Engl J Med 2010; 362:402–415; 2. Kappos L, et al. N Engl J Med 2010; 362:387–401; 3. Radue EW, et al. ECTRIMS 2012. P724.

Me

an P

BV

C f

rom

bas

elin

e

TRANSFORMS1

Time (months)

−32%

reduction

0.0

–0.4

–0.6

–1.4

–0.2

–0.8

–1.2

–1.0

0 24 12

*** n = 429

n = 431

0.0

–0.4

–0.6

–1.4

–0.2

–0.8

–1.2

–1.0

0 24 12 6

FREEDOMS2

Time (months)

−35%

reduction

*

**

***

n = 357

n = 331

0.0

–0.4

–0.6

–1.4

–0.2

–0.8

–1.2

–1.0

0 24 12 6

FREEDOMS II3

Time (months)

−33%

reduction

* ***

*** n = 358

n = 355

Placebo Fingolimod 0.5 mg IFN β-1a IM

• For all annual BVL thresholds, significantly more NEDA-4 patients were in the fingolimod-treated group than in the placebo group

Results: NEDA-4 by Annual BVL Thresholds

aORs were derived from logistic regression of freedom from disease activity on treatment.

Kappos et al. ACTRIMS/ECTRIMS 2014. FC1.5

80% of subjects fail treatment on this criteria

Case Study

Residual deficits: • Walking distance >500m

• Unable to run

• Exercise induces intermittent

sensory symptoms in L arm

• Mild urinary frequency

17-yr girl, myelitis

Jun-2000

1st-yr University

L-optic neuritis

Feb-2001

clumsy

left hand

Jan -2002

pins & needles

in legs

Oct-2003

R optic neuritis

Mar-2004

Brainstem

syndrome;

diplopia and

ataxia

Dec 2007

Cervical cord

relapse

weak L arm

with pain

Jan 2008

Bladder

dysfunction

depression,

anxiety and

fatigue

Reduced

mobility

Mild urinary frequency

No depression ,anxiety

or fatigue

Fully mobile

NEDA (no evident disease activity)

Feb-2008 to May-2014

IFN-beta

Feb-2001

Natalizumab

Jan-2008

ED

SS

IFN-beta Natalizumab Jun-2000 May-2014

6.0

3.5 3.5

MRI – progressive brain atrophy

Dec 2007 Jul 2010 Jul 2013

Is this patient in long-term remission?

Overview DMTs and brain atrophy

IV, intravenous.

Therapy Administration Reduction in PBVC

IFN β/GA SC IM

IFN β-1a IM: positive effect Year 2

Teriflunomide Oral Not significant

DMF Oral −30% (for BID in DEFINE); not significant for TID Not significant for both doses in CONFIRM

Fingolimod Oral –35% (FREEDOMS); –33% (FREEDOMS II); –32% (TRANSFORMS)

Natalizumab IV Significant in year 2

Alemtuzumab IV –42% (naive vs. IFN); –24% (previously treated vs. IFN)

No evidence of disease activity: NEDA-4

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

No evidence of disease activity defined as:1,2

× No relapses

× No sustained disability progression

× No MRI activity

× No new or enlarging T2 lesions

× No Gd-enhancing lesions

Should we be adding a brain atrophy metric to our definition of NEDA?

Normalisation of brain atrophy rates

Rheumatoid arthritis End-stage joint disease

Treating beyond symptoms with a view to improving patient outcomes in inflammatory bowel diseases

Sandborn et al. Journal of Crohn's and Colitis 2014(8):927–935

X

41

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

• MS is a bad disease

• MS is as much a gray matter disease as it is a white matter disease

• Brain volume loss or atrophy

• Present from the earliest stages of the disease

• Occurs at a constant rate (>2x normal)

• Predicts long-term disability

• Associated with cognitive impairment

• Should MS be reclassified as a dementia?

• Or at least a preventable dementia?

• Being accepted as a preventable dementia will help drive adoption of early effective treatment and zero tolerance (T2T-NEDA-ZeTo)

• Should we include brain atrophy as part of our treatment target?

• NEDA-4