Early intervention in MS

Early intervention in MS:early switch of treatment and treatment goals

Professor Gavin Giovannoni

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

Disclosures

Professor Giovannoni has received personal compensation for participating on AdvisoryBoards in relation to clinical trial design, trial steering committees and data and safetymonitoring 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 VertexPharmaceuticals.

Regarding www.ms-res.org survey results in this presentation: please note that nopersonal identifiers were collected as part of these surveys and that by completing thesurveys participants consented for their anonymous data to be analysed and presentedby Professor Giovannoni.

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

Professor Giovannoni’s trip to Sweden has been kindly sponsored by Biogen, thereforeplease interpret anything he says about Biogen’s products in this context.

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

Risk of MS

Rapid Decline in Health Status With Increasing Disability Occurs Early in MS (Before EDSS 2.5)

a Utility score <0 indicates MSers felt their health status was worse than death.

EDSS=Expanded disability Status Scale

1. Orme M et al. Value Health 2007;10:54-60; 2. Zwibel HL, Smrtka J. Am J Manag Care 2011;17( Suppl 5):S139-45.

Figure adapted from Naci H et al. J Med Econ 2010;13:78-89.

Relationship Between EDSS and Health Status1,2

1.0

0.8

0.6

0.4

0.2

0

–0.2

–0.4

0 1 2 3 4 5 6 6.5 7 8 9

He

alth

Sta

tus

(Uti

lity)

EDSS

Essentially restricted to bed, chair, or wheelchair

Rapid fall in utility on EDSS 0.5–2.5

AustriaBelgiumGermany Italy The NetherlandsSpainSwedenSwitzerlandUK UKa

5

QoL worse than death

Perfect health

Death

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 M

Se

rs ≤

65

Ye

ars

Old

Wo

rkin

g (

%)

The proportion of MSers employed or on long-term sick leave is calculated as a percentage of MSers 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

Disability Accumulation in MS Has a Negative Impact on Multiple Aspects of Life

Employment

1. Approximately 20% of MSers with MS for <5 years are unemployed1

2. More than 50% of MSers are unemployed 10 years after diagnosis2

3. Approximately 80% of MSers with an EDSS of 6.0 are unemployed3

1. Zwibel HL, Smrtka J. Am J Manag Care 2011;17:S139-45; 2. Pfleger CC et al. Mult Scler 2010;16:121-6; 3. Kobelt G et al. J Neurol

Neurosurg Psychiatry. 2006;77:918-926;

MS disability impacts life roles

and reduces quality of life1

7

20:50:80

57%

7%

-20%

0%

20%

40%

60%

Impact of MS: cognitive functioning in the CIS stage

Feuillet et al. MSJ 2007

CISersn = 40

Healthy Controlsn = 30

p < 0.0001

Deficits were found mainly in memory, speed of information

processing, attention and executive functioning

Subject failing ≥ 2 cognitive

tests

AAN 2013

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.

Reduced head and brain size for age and disproportionately smaller thalami

in child-onset MS

Kerbrat Neurology. 2012 Jan 17;78(3):194-201.

Control Multiple sclerosis

Slide courtesy of Dr Klaus Schmierer

Pathological substrate for brain atrophy: 11,000 to 1

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

Brain atrophy survey

15www.ms-res.org

Brain atrophy survey

16www.ms-res.org

Early treatment

Theoretical model: treat early and effectively

Natural course of disease

Laterintervention

Latertreatment

Treatmentat diagnosis Intervention

at diagnosis

Time Disease Onset

Dis

abili

ty

Time is brain

The Traditional Approach to MS Treatment

• Heterogeneity of disease course across different MSers and over time can

affect treatment response1-3

• Depending on the definition used, up to 49% of MSers treated with a first-line

injectable therapy (IFNB) still have clinical disease activity1

1. Rio J et al. Ann Neurol 2006;59:344-52; 2. Miller A et al. J Neurol Sci 2008;274:68-75; 3. Rudick RA et al. Lancet Neurol 2009;8:545-59.

Figure adapted from Rio J et al. Curr Opin Neurol 2011; 24:230-7.

A

B

C

D

E

YX

Moderate

efficacy

High efficacy or

very high efficacy

Initial

Treatment

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

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

Moderate

Severe

TNFantagonist

± IMS

Steroids +IMS

Steroids

TNFantagonist

± IMS

Steroids +IMS

IMS + TNFantagonist

± IMS

Conventionalstep-care

Acceleratedstep-care

Earlytop-down

“FLIPPING THE PYRAMID”

22

•

•

•

•

•

•

•

•

•

• β

•

•

•

•

•

Evolving Paradigm: Individualised Treatment Based on Projected Disease Course

Giovannoni et al. MSARD 2015 in press.

Baseline prognostic factors

Good prognosis Poor prognosis

Young

Female sex

“Unifocal” onset

Isolated sensory symptom (optic neuritis, sensory)

Full recovery from attack

Long interval to second relapse

No disability after 5 years

Normal MRI / low lesion load

No posterior fossa lesions

No brain atrophy

CSF negative for OCBs

Older age of onset

Male sex

“Multifocal“ onset

Efferent system affected (motor, cerebellar, bladder)

Partial or no recovery from a relapse

High relapse rate in the first 2 years

Disability after 5 years

Abnormal MRI with large lesion load

Posterior fossa lesions

Brain atrophy

CSF positive for OCBs

Adapted from Miller et al., Lancet Neurology 2005: 4; 281-288

Number of Risk Factors Predicts Short-term Prognosis in Early MS

Risk Factors Evaluated (N=98)

1. Age at onset (<40 yrs vs >40 yrs)

2. Symptoms at onset (isolated sensory or cranial nerve vs motor or sensory plus motor)

3. MRI status before or at diagnosis (negative or suspicious vs suggestive)

4. Interval between the first and second attack (>2.5 yrs or <2.5 yrs)

5. Attack frequency in the first 2 yrs (≤2 vs >2)

6. Completeness of recovery from initial attacks (good vs poor)

Scott TF et al. Neurology 2000;55:689-93.

0

0.5

1

1.5

2

2.5

3

3.5

4

Low0 to 1

Risk Factors

Medium2 to 3

Risk Factors

High>3

Risk Factors

EDSS

Disability Accumulation by Risk Group

At MS diagnosis

Follow-up (mean 37 mos)

2.64

1.09

1.69

2.13

-0.87

-1

-0.5

0

0.5

1

1.5

2

2.5

3

Pyramidal Cerebellar Sphincteric Visual Sensory

Clinical Features: Symptoms at Disease Onset Predict Disability Progression

• Involvement of pyramidal, visual, sphincteric and cerebellar systems were associated with poor prognosis

Predictors of disability are shown for the entire sample (n=224).

Amato MP, Ponziani G. Neurol Sci 2000;21:S831-8.

Predictors of Disability (EDSS=6.0)H

azar

d R

atio

25

Clinical Features: Early Relapse Activity Predicts Disability Progression

• Complete recovery from first relapse predicts longer time to reach landmarks of irreversible disability1

• Attack frequency in the first 2 years after diagnosis predicts shorter time to disability milestones2

1. Confavreux C et al. Brain 2003;126:770-82; 2. Scalfari A et al. Brain 2010;133:1914-29.

13.1

27.1

34.1

1.0

13.0

25.1

0

5

10

15

20

25

30

35

40

EDSS=4 EDSS=6 EDSS=7

Complete recovery (n=1288)Incomplete recovery (n=274)

Me

dia

n T

ime

Fro

m D

ise

ase

O

nse

t to

Eve

nt

(yrs

)

19.9

22.7

33.2

16.718.7

28.9

15.1 15.1

20.4

0

5

10

15

20

25

30

35

40

Steady Progression EDSS=6 EDSS=8

1 Relapse (n=389)

2 Relapses (n=183)

≥3 Relapses (n=158)

Me

an T

ime

Fro

m D

ise

ase

O

nse

t to

Eve

nt

(yrs

)

Relapse Recovery Relapses in First 2 Years

26

1. O’Riordan JI et al. Brain 1998;121:495-503; 2. Fisniku LK et al. Brain 2008;131:808-817.

MRI Activity: T2 Lesions Predict Disability Progression

• Number of T2 lesions at baseline predicts disease progression in MS1

• Change in first 5 years has the strongest correlation with EDSS at 20 years2

MSe

rs W

ith

ED

SS >

5.5

in 1

0 Y

ear

s (%

)

60

40

20

0

Me

dia

n T

2Le

sio

n V

olu

me

0 5 10 14 20

Year

2728

20

21

26

17

18

28

14

15

25

13

30

33

11

Clinically isolated syndromeRelapsing-remitting MSSecondary progressive MS

T2 Lesion Count T2 Lesion Volume

20.0

35.0

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

40.0

4–10T lesions

at baseline(n=15)

>10T lesions

at baseline(n=20)

2 2

27

The data presented for years 5, 10, 14, and 20 were obtained from different publications based on the same longitudinal study.

The exact relationship between MRI findings and the clinical status of the patient is unknown.

Fisniku LK et al. Brain. 2008;131:808-817; Morrissey SP et al. Brain. 1993;116:135-146; O’Riordan JI et al. Brain. 1998;121:495-503;

Brex PA et al. N Engl J Med. 2002;346:158-164.

Baseline number of brain lesionspredicts progression to EDSS Score ≥3.0

Queen Square Study

Brain Atrophy Rate (End Organ Damage) Correlated With Disease Course

• Brain atrophy accelerated in MSers with more advanced disease over 4 years of follow-up• Gray matter atrophy was significantly correlated with disability accumulation at 4 years

WMF=white matter fraction; GMF=gray matter fraction; BPF=brain parenchymal fraction

Fisher E et al. Ann Neurol 2008;64:255-65.

-0.45

-0.35

-0.25

-0.15

-0.05

0.05

0.15

Δ BPF Δ WMF Δ GMF

Control

CIS

CIS→MS

RRMS

RRMS→SPMS

SPMS

29

Benefits of Treatment

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

-2.5

-1.5

-0.5

0.5

1.5

2.5

Me

an

Pe

rce

nt

Ch

an

ge

Fro

m

Ba

se

lin

e in

SF

-36

Sc

ore

Week 104

Placebo Natalizumab

MCS PCS

P<0.05 P<0.01

IMSE Swedish registry2

Multiple Sclerosis Impact Scale (MSIS-29)

Natalizumab and Quality of Life

MCS=mental component summary.

1. Rudick RA et al. Ann Neurol. 2007;62:335-346; 2. Holmén C et al. Mult Scler. 2011;17:708-719.

AFFIRM1

Short Form-36 (SF-36)

-15

-13

-11

-9

-7

-5

-3

-1

Month 24

Me

an

Pe

rce

nt

Ch

an

ge

F

rom

Ba

se

lin

e in

MS

IS-2

9

Sc

ore

P<0.05

P<0.05

Physical

PsychologicalWORSENING

IMPROVEMENT

IMPROVEMENT

32

First

Relapse

3 6 9 12 15 18 21 24 27 30

Months Since Relapse

0

10

20

30

40

50

60

70

80

90

100

Pa

tie

nts

wit

h c

om

ple

te r

ec

ove

ry (

%)

PlaceboNatalizumab

Natalizumab and Clinical Recovery from Relapses

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

Overall population : Subjects with an increase of EDSS ≥ 1.0 point at relapse*Based on Cox Proportional Hazards model adjusted for baseline EDSS, age, gender, relapses in year prior to enrollment, disease

duration, baseline Gd-enhancing lesions and baseline T2 lesion volume.

AFFIRM: Probability of 12-week confirmed complete

recovery from relapses

76.0%

43.1%

Adjusted HR for natalizumab vs placebo=1.673

(95% CI:1.046–2.678); 67% increase; P=0.0319*

33

Placebo (N=86)Natalizumab (N=70)

84%91%

70%71% 74%68%

0%

20%

40%

60%

80%

100%

Overallpopulation

BaselineEDSS<3.0

Baseline EDSS≥3.0

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

Pro

po

rtio

n o

f p

ati

en

ts (

%)

Placebo

Natalizumab

**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

61%71%

43%49% 50% 48%

0%

20%

40%

60%

80%

100%

Overallpopulation

BaselineEDSS<3.0

Baseline EDSS≥3.0

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

Pro

po

rtio

n o

f p

ati

en

ts (

%)

*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 AFFIRM

EDSS change from pre-relapse to at relapse

34

Natalizumab and Clinical Recovery from Relapses

-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

Natalizumab-Treated Patients with Multiple Sclerosis Have Low Rates of Brain Volume Decrease and Low MRI Disease Activity in the Long-Term STRATA Study

Rate of PBVC between annual MRI scans

Patients with a PBVC equal to the upper end of an interval are included in the bar to the left of that value. PBVC = percentage brain volume change.

Goodman et al. Annual Meeting. 23 April 2015. Washington, DC. P7.260.

~72%

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%

Risks of Treatment

Risk is Both Quantitative and Qualitative

39

1. Tysabri (natalizumab) EU Summary of Product Characteristics, Biogen Idec Ltd, August 2013; 2. GILENYA (fingolimod). Summary of Product Characteristics. 2014. Novartis Europharm Ltd., West Sussex, United Kingdom; 3. Lemtrada (alemtuzumab). Summary of Product Characteristics. Genzyme Therapeutics Ltd, United Kingdom; September 2013.

Benefits Risks

Risk:benefit assessment important for high-efficacy DMTs: natalizumab, fingolimod, alemtuzumab)1,2,3

Labelling(SAEs, events of special interest)

How many are at risk?

1. Do the SAEs typically result in morbidity or mortality?

2. Do the SAEs resolve with conventional treatments?

3. What are the long-term outcomes for MSers who experience SAEs?

Qualitative Risk: opportunistic infection as an illustrative example

40

1. Tysabri (natalizumab) EU Summary of Product Characteristics, Biogen Idec Ltd, August 2013; 2. Lemtrada (alemtuzumab). Summary of Product Characteristics. Genzyme Therapeutics Ltd, United Kingdom; September 2013; 3. Wray WE et al. CMSC 2013:Poster DX60; 4. GILENYA (fingolimod). Summary of Product Characteristics. 2014. Novartis Europharm Ltd., West Sussex, United Kingdom.

Benefits Risks

Risk:benefit assessment important for high-efficacy DMTs: natalizumab, fingolimod, alemtuzumab)1,2,3

Opportunistic infections

Common and expected

1. Progressive multifocal leukoencephalopathy (PML)a) Typically results in death or severe disability1

b) Currently, there is no known specific antiviral agent against John Cunningham virus (JCV)

2. Herpesa) Risk may be reduced with prophylactic aciclovir2

b) May resolve with anti-viral treatment, even in serious cases3

c) Cases of disseminated disease may be fatal4

3. Common infections (eg, appendicitis, gastroenteritis, bronchitis, pneumonia)

a) Treatable with standard therapy2,4

D D D D D D D D D D D D D D D D D D D DD D D D D D D D D D D D D D D D D D D DD D D D D D D D D D D D D D D D D D D DD D D D D D D D D D D D D D D D D D D DD D D D D D D D D D

D MSers with increase in disability 170MSers with at least 1 relapse 280MSers with hypersensitivity reactions 40MSers with no significant harm 680

1000 MSers without natalizumab

290540

0460

Polman CH et al. N Engl J Med. 2006;354:899-910; Bloomgren G et al. N Engl J Med. 2012;366:1870-80.Adapted after Wolfgang Gaissmaier, with thanks.

1000 MSers with natalizumab, anti-JCV− D D D D D D D D D D D D D D D D D D D DD D D D D D D D D D D D D D D D D D D DD D D D D D D D D D D D D D D D D D D DD D D D D D D D D D D D D D D D D D D D

D D D D D D D D D D

D D D D D D D D D D D D D D D D D D D DD D D D D D D D D D D D D D D D D D D DD D D D D D D D D D D D D D D D D D D DD D D D D D D D D D D D D D D D D D D D


D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D

D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D DD D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D

Anti-JCV Ab status and weighing risk of disease vs. risks and benefits of treatment.

Anti-JCV Ab status and weighing risk of disease vs. risks and benefits of treatment.

D D D D D D D D D D D D D D D D D D D DD D D D D D D D D D D D D D D D D D D DD D D D D D D D D D D D D D D D D D D DD D D D D D D D D D D D D D D D D D D DD D D D D D D D D D

D MSers with increase in disability 170MSers with at least 1 relapse 280MSers with hypersensitivity reactions 40MSers developing PML in following 2 years 5MSers with no significant harm 675

290540

00

460


D D D D D D D D D D



D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D

D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D DD D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D

Polman CH et al. N Engl J Med. 2006;354:899-910; Bloomgren G et al. N Engl J Med. 2012;366:1870-80.Adapted after Wolfgang Gaissmaier, with thanks.

1000 MSers without natalizumab 1000 MSers with natalizumab, anti-JCV+ve

PML

PML, progressive multifocal leukoencephalopathy Barts and The London NHS Trust. Natalizumab Information Sheet. July 2010

Barts and the London School of Medicine and Dentistry, PML Risk Education Guide, 2013

17% 85%

MSer Leaflet Allowing Shared Decision Making

http://multiple-sclerosis-research.blogspot.co.uk/2014/01/clinic-speak-what-is-high-pml-risk.html.

Plavina T et al. Ann Neurol. 2014 Dec;76(6):802-12.

What is your risk of

developing PML?

What is

your

JC virus

status?

RISK FACTOR:

Previous treatment with

immunosuppressive (IS) drugs.

These are drugs that reduce the

activity of your body’s immune

system.

RISK FACTOR:

TYSABRI treatment

duration, especially

over 2 years.

Positive

Negative

Have you previously taken

immunosuppressants?

No

Yes

How long have you

been on TYSABRI?

49−72 months

25−48 months

1−24 months

Low PML risk High PML risk

>1.5

1 in 10,000

1 in 1000

≤0.9

≤1.1

≤1.3

≤1.5

Ab level

How long have you

been on TYSABRI?

49−72 months

25−48 months

1−24 months

1 in 89

1 in 556

Insufficient data

1 in 10,000

≤1.1

≤1.3

≤1.5

1 in 2500

1 in 1429

1 in 833

1 in 769

1 in 118

≤0.9

>1.5

Ab level

≤1.1

≤1.3

≤1.5

1 in 3333

1 in 1429

1 in 1000

1 in 833

1 in 123

≤0.9

>1.5

Ab level

RISK FACTOR:

Ab level is the level of

anti-JCV antibodies in

your blood.

www.clinicspeak.com

Defining the therapeutic target

55

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•

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•

•

•

•

• β

•

•

•

•

•

Evolving Paradigm: Individualised Treatment Based on Projected Disease Course

Giovannoni et al. MSARD 2015 in press.

Defining Suboptimal Response: Lack of Consensus

• Suboptimal response and the outcomes of switching therapy have largely been assessedin small, uncontrolled,non-randomised studies1

• 6–12 months on-treatment appear to be a critical window for assessing suboptimal response2

• Relapse criteria for suboptimal response predominantly ≥1–2 relapses in given timeframe

• MRI criteria primarily presence of new Gd-enhancing lesions

• Disability criteria usually sustained ≥1 point increase in EDSS

1. Freedman MS et al. Curr Med Res Opin 2009;25:2459-70; 2. Coyle PK. CNS Drugs 2013;27:239-47.

Definitions of Suboptimal Response From a Review of 19 Studies1

No. of Studies

Suboptimal response parameter(s)Relapse onlyRelapse + MRIRelapse + disabilityRelapse + disability + MRI

5644

Assessment timeframe6 months12 months

48

NEDA (no evident disease activity) vs. MEDA (minimal evident disease activity)

Early On-treatment MRI Activity Predicts 5-Year Disability

aIncrease of ≥1 EDSS point, confirmed on 2 separate neurological examinations ≥6 months apart.

Prosperini L et al. Eur J Neurol 2009;16:1202-9.

Disability Outcomes Stratified by 1-Year

T2 Lesion Outcomes

None 1 2 3 or more

Number of new T2-hyperintense lesions

0

20

40

60

80

100

MS

ers

(%

)

MSers without

disability progressiona

MSers with

disability progressiona

228 24 12 10

11 28 33 48

*Odds of being in worst vs best quartile.

*EDSS>4.5.Bermel RA et al. Ann Neurol 2013;73: 95-103.

Ongoing Disease Activity During Interferon Treatment is Predictive of Long-Term Disability

Ongoing clinical or MRI disease activity during interferon treatment in a 2-year trial was

predictive of disability progression 15 years later

Activity During 2-Year TrialOdds of Severe Disability*

15 Years Later

>2 Gd lesions 8.96

>2 Relapses 4.44

>3 New T2 lesions 2.90

Treatment Adherence: Impact on Disability Outcomes

• RRMS MSers treated with IFNB who were adherent to treatmenta had reduced risk of reaching disability landmarks at 16-year follow-up compared with non-adherent MSers

aBased on exposure as determined by medication possession ratio. Detailed records were available for 260 MSers.

Goodin D et al. PLoS ONE 2011;6:e22444. Image reprinted from Goodin D et al. PLoS ONE 2011;6:e22444.

0

20

40

60

80

100

Any negativeoutcome

EDSS=6 EDSS=6 orSPMS

SPMS Wheelchair

% R

ela

tive

Ris

kRelative Risk of Reaching 16-Year Disease Outcomes:

Adherent vs Non-adherent MSers

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

Beyond NEDA (no evident disease activity)

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

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 MSers)

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

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events

DifferentialDiagnosis

MRI

EvokedPotentials

Lumbar puncture

BloodTests

DiagnosticCriteria

Cognition

Depression

Fatigue

Bladder

Bowel

Sexual dysfunction Tremor

PainSwallowing

SpasticityFalls

Balance problems Insomnia

Restless legsFertility

Clinical trials

Gait

Pressuresores

Oscillopsia

Emotionallability

Seizures

Gastrostomy

Rehab

Suprapubiccatheter Intrathecal

baclofen

Physio-therapy

Speech therapy

OccupationalTherapy

Functional neurosurgery

Colostomy

Tendonotomy

Studying

EmploymentRelationships

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

AlternativeMedicine

PregnancyBreastFeeding

Research

Insurance

Visual loss

PalliativeCare

Assistedsuicide

Socialservices

Legalaid

Genetic counselling

Prevention

Diagnosis

DMTSymptomatic

Therapist

Terminal

CounsellingAn holistic approach to MS

Intrathecalphenol

Fractures

Movement disorders

Osteopaenia

Brain atrophy

Hearing loss

Tinnitus

Photophobia

Hiccoughs

DVLA

Neuroprotection

Psychosis

Depersonaliation

BrainHealth

CognitiveReserve

Sudden death

Suicide

OCD

Narcolepsy

ApnoeaCarers

Respite

Hospice

Respite

Dignitas

Advanced Directive

Rhiztomy

Rhiztomy

Wheelchair

Walking aids

Blood/Organdonation

Brain donation

Exercise therapy

NABs

Autoimmunity

Infections

Outcome measures

WebResources

Pathogenesis

Doublevision

What isMS?

NEDA

T2TOCT

Neurofilaments

JCV statusPharma

Anaesthesia

Therapeutic hierarchy

Neuro-restoration

Remyelination

Neuroprotection

Anti-inflammatory

Therapeutic pyramid

Anti-ageing

Brain

Health

Initiative

• Smoking

• Exercise

• Diet

• Sleep

• Co-morbidities

• Infections

• Concomitant

medications

Rheumatoid arthritisEnd-stage joint disease

Summary

1. Disability accumulation and health status deterioration occur early in MS, suggesting an early therapeutic window of opportunity

2. Heterogeneity of treatment response supports that treatment decision-making should be individualised, rather than taking a step-wise “treatment ladder” approach for all MSers

3. Evaluation of the benefits and risks of treatment vs the risk of MS disease progression requires consideration of both the physician’s and MSers’ perspectives

4. Optimising therapy requires ongoing assessment to identify MSers who are experiencing suboptimal response to current therapy

5. Treatment adherence is an important consideration both at treatment initiation and in the face of suboptimal treatment response

Early intervention in MS

Health & Medicine

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