TIME MATTERS Monday, 10 June 2013, 11:45–13:15 Plenary Hall, Fira Barcelona, Convention Centre Gran Via, Barcelona, Spain

Treatment decisions debate: motion for

switching to a high-efficacy therapy early

Gavin Giovannoni

London, UK

38-year-old teacher with relapsing–remitting MS under the care of a hospital in central London

• Glatiramer acetate treatment for 3 years (good adherence and tolerance)

• Relapse with a mild left sensory loss

• Referred for a second opinion

• Switched to IFN β-1a IM; (www.msdecisions.org.uk)

• Mild persistent flu-like side effects and lymphopenia

• 12/12’s neutralizing antibodies screen negative

• Volunteers for new research programme, which included a gadolinium-enhanced MRI protocol

Teacher

38-year-old teacher with relapsing–remitting MS

• As a result of fatigue and cognitive problems she is forced to take

early retirement

• Although fully functional she develops depression and anxiety

• In her spare time she spends a lot of time on the web and becomes

an expert patient

– Widely read

– Net savvy; regular follower of www.ms-res.org

Teacher X

Unemployment

Probability of remaining actively employed after onset of MS (N = 2,538)

Time (years)

Pro

babili

ty

0.8

0.6

0.4

0.2

0.0

1.0

5 10 15 20 25 0

Control persons

MS patients

Pfleger CC, et al. Mult Scler 2010; 16:121–126.

Costs and quality of life of patients with MS in Europe

Kobelt G, et al. J Neurol Neurosurg Psychiatry 2006; 77:918–926.

Expanded Disability Status Scale score

Pro

port

ion o

f patients

≤ 6

5 y

ea

rs o

f a

ge

wo

rkin

g

80

70

60

50

40

30

20

10

0

90

2 3 4 5 6 6.5 7 8/9 0/1

Austria

Belgium

Germany

Italy

The Netherlands

Spain

Sweden

Switzerland

UK

Proportion of patients employed or on long-term sick leave (N = 13,186)

Predictors of long-term outcome in MS patients treated with IFN β-1a

IFN, interferon; IM, intramuscular; LOCF, last observation carried forward; MSCRG, Multiple Sclerosis Collaborative Research Group. Bermel RA, et al. Ann Neurol 2013; 73:95–103.

2-year participation MSCRG study: 172

Patients located: 149 (87%)

Consented and enrolled in ASSURANCE: 136 (79%)

Alive: 122 (90%)

Originally

randomized

to IM IFN β-1a:

63 (52%)

Originally

randomized

to placebo:

59 (48%)

Died (LOCF): 14 (10%)

Originally

randomized

to IM IFN β-1a:

6 (43%)

Originally

randomized

to placebo:

8 (57%)

Predictors of long-term outcome in MS patients treated with IFN β-1a

Gd+, gadolinium enhancing; IM, intramuscular. a ≥ 2 gadolinium-enhancing lesions (cumulative) ≥ 3 new T2 lesions on Year 2 MRI compared with baseline; and ≥ 2 relapses over 2 years. Bermel RA, et al. Ann Neurol 2013; 73:95–103.

IM in

terf

ero

n β

-1a

40 30 20 10 1

Pla

ce

bo

Odds ratio of advancing into the

worst quartile of EDSS change after 15 years

Disease activity

during the

2-year triala

New T2

Relapse

Gd+

New T2

Relapse

Gd+

Odds ratio

(confidence interval)

2.62 (0.93, 7.43)

1.53 (0.56, 4.19)

1.79 (0.65, 5.16)

2.89 (0.88, 9.54)

4.44 (1.43, 13.85)

8.96 (2.53, 31.65)

p value

0.069

0.408

0.284

0.080

0.010

< 0.001

Study or subgroup

Odds ratio

IV, random, 95% CI

Kinkel 2008

Prosperini 2009

Total (95% CI) 9.86 (2.33, 41.70)

MRI to monitor treatment response to IFN β: a meta-analysis

CI, confidence interval. Dobson et al. Submitted 2013.

Study or subgroup

Odds ratio

IV, random, 95% CI

Kinkel 2008

Pozzilli 2005

Prosperini 2009

Sormani 2011

Total (95% CI) 2.69 (0.72, 10.04)

0.01 0.1 1 10 100

Disease less likely Disease more likely

One new T2 lesion

Two or more new T2 lesions

100 10 1 0.1 0.01

Disease less likely Disease more likely

0.01 0.1 1 10 100

Disease less likely Disease more likely

0.01 0.1 1 10 100

Disease less likely Disease more likely

Study or subgroup

Odds ratio

IV, random, 95% CI

Kinkel 2008

Pozzilli 2005

Tomassini 2006

Total (95% CI) 3.34 (1.36, 8.22)

Study or subgroup Odds ratio

IV, random, 95% CI

Kinkel 2008

Rio 2008

Total (95% CI) 5.46 (2.48, 12.04)

One new Gd-enhancing lesion

Two or more new Gd-enhancing lesions

MRI to monitor treatment response to interferon β: a meta-analysis

CI, confidence interval; Gd, gadolinium. Dobson et al. Submitted 2013.

The relapsing MS DMT doughnut

CIS, clinically isolated syndrome; DMT, disease-modifying therapy; GA, glatiramer acetate; IFN, interferon; RIS, radiologically isolated syndrome; RRMS, relapsing–remitting MS.

Inactive RRMS

CIS

RIS or asymptomatic MS

Suboptimal responders?

Active

RRMS IFN β

or

GA

IFN β

Highly active RRMS Fingolimod Natalizumab

Predictors of long-term outcome in MS patients treated with IFN β-1a

Gd+, gadolinium enhancing; IM, intramuscular. a ≥ 2 gadolinium-enhancing lesions (cumulative) ≥ 3 new T2 lesions on Year 2 MRI compared with baseline; and ≥ 2 relapses over 2 years. Bermel RA, et al. Ann Neurol 2013; 73:95–103.

IM in

terf

ero

n β

-1a

40 30 20 10 1

Pla

ce

bo

Odds ratio of advancing into the

worst quartile of EDSS change after 15 years

Disease activity

during the

2-year triala

New T2

Relapse

Gd+

New T2

Relapse

Gd+

Odds ratio

(confidence interval)

2.62 (0.93, 7.43)

1.53 (0.56, 4.19)

1.79 (0.65, 5.16)

2.89 (0.88, 9.54)

4.44 (1.43, 13.85)

8.96 (2.53, 31.65)

p value

0.069

0.408

0.284

0.080

0.010

< 0.001

Consultant Neurologist

84%

Academic/Honorary Consultant Neurologist

14%

Associate specialist 2%

What is your position? (N = 50)

8%

26%

26%

24%

16%

Yes – routinely

Yes – frequently

Yes – occasionally

Yes – rarely

No – never

0% 5% 10% 15% 20% 25% 30%

MRI – Do you use conventional MRI to monitor for a response or non-response to DMTs? (N = 50)

Only 8% of HCPs ‘regularly’ use

conventional MRI to monitor for a

response/non-response to DMTs

Is conventional MRI used to monitor response or non-response to DMTs?

DMT, disease modifying therapy; HCP, healthcare professional.

Teacher X

Teacher X

fingolimod

natalizumab

Summary of natalizumab data vs. placebo

Polman CH, et al. N Engl J Med 2006; 354:899–910.

Study Treatment arms 2-year outcomes

AFFIRM

• N = 942

• Relapsing MS

• 18–50 years of age

• EDSS score 0–5.0

• 2-year study

1. Natalizumab 300 mg

2. Placebo

Outcome, reduction vs. placebo Natalizumab 300 mg

Annualized relapse rate 68% (p < 0.001)

New/enlarging T2 lesions 83% (p < 0.001)

Gadolinium-enhancing lesions 92% (p < 0.001)

42% relative reduction in risk

of progression (p < 0.001)

Pro

po

rtio

n o

f p

atie

nts

with

3-m

on

th

su

sta

ine

d p

rogre

ssio

n o

f d

isab

ility

29%

17%

Time (weeks)

Placebo

(n = 315)

Natalizumab

(n = 627)

120 108 96 84 72 60 48 36 24 12 0

0.4

0.3

0.2

0.1

0.0

AFFIRM: 2-year results

Summary of fingolimod data vs. placebo

ITT, intention-to-treat. a Includes patients who received both 0.5 mg and 1.25 mg fingolimod. 1. Kappos L, et al. N Engl J Med 2010; 362:387–401; 2. Kappos L, et al. AAN 2012. S41.004.

Study Treatment arms 2-year outcomes

FREEDOMS1

• N = 1,272

• RRMS

• 18–55 years of age

• EDSS score 0–5.5

• 2-year study

1. Fingolimod 0.5 mg

2. Fingolimod 1.25 mg

3. Placebo

Outcome, reduction vs. placebo Fingolimod 0.5 mg/day

Annualized relapse rate 54% (p < 0.001)

New/enlarging T2 lesions 74% (p < 0.001)

Gadolinium-enhancing lesions 82% (p < 0.001)

0 1 2 3 4 5

100

90

80

70

60 0

Time (years)

FREEDOMS extension: > 4-year results (core ITT population)2

74%

66%

Fingolimod 0.5 mg

(n = 425 core/n = 331 extension)

Placebo

(Month 0–24, n = 418)

Placebo–fingolimod switcha

(n = 300)

27% relative reduction in risk

of progression (p = 0.017)

Pa

tie

nts

fre

e o

f 3

-mo

nth

co

nfirm

ed

ED

SS

dis

ab

ility

pro

gre

ssio

n (

%)

TRANSFORMS extension study: fingolimod vs. interferon β-1a

a EOS (end of study) is the last available visit for the randomized patients between initiation and completion of the study; b Includes patients who received both 0.5 mg and 1.25 mg fingolimod; c Occurring during Year 1 on treatment; d Positive status defined as a 1-point increase on the EDSS; e Positive status if the sum of the number of new or newly enlarged T2 lesions at Month 12 compared with baseline and the number of Gd-enhanced T1 lesions at Month 12 was > 2. 1. Khatri B. et al. ENS 2012. O218; 2. Hartung HP, et al. ENS 2013. P380.

Between-group comparison of aggregate ARR

(up to 4.5 years)1

Disease activity status at end of Year 2 in patients

switched from interferon β-1a to fingolimod2

0.4

0.2

0

0.1

0.2

0.3

0.4

0.5

44.3

66

0

25

50

75

Disease activity free*(n = 296)

Year 1: IFN β-1a

Year 2: IFN β-1a–fingolimodb

*Disease activity variables: ● confirmed relapsec ● 3-month confirmed disability progressiond ● MRI activitye

AR

R

Month 0-12: IFN β-1a

Month 12-EOSa: IFN β-1a–fingolimodb

n = 341 n = 431

Pro

po

rtio

n o

f p

atie

nts

–0.6

–0.2

–1.0

–0.9

–0.8

–0.7

–0.6

–0.5

–0.4

–0.3

–0.2

–0.1

0.0

PRIMUS activities

–0.3

0

–0.5

–0.4

–0.3

–0.2

–0.1

0.0

FSS

–3.2

–0.8

–4.0

–3.5

–3.0

–2.5

–2.0

–1.5

–1.0

–0.5

0.0

BDI-II

Beneficial effect of fingolimod on fatigue and depressive symptoms

BDI-II, Beck Depression Inventory-II; CI, confidence interval; FSS, Fatigue Severity Scale; LOCF, last observation carried forward; PRIMUS, Patient-Reported Indices for Multiple Sclerosis. Higher scores indicate worse functioning, fatigue or depressive symptoms. Crayton H, et al. CMSC 2013. DX20.

Difference, 0.3

(95% CI, 0.18 to 0.51)

p < 0.001

Difference, 2.5

(95% CI, 1.50 to 3.44)

p < 0.001

Ch

an

ge

fro

m b

ase

line to

Mo

nth

6 (

LO

CF

),

lea

st squ

are

s m

ea

n

Fingolimod 0.5 mg Standard of care disease-modifying therapy

Difference, 0.4

(95% CI, –0.26 to 0.96)

p = 0.258

Activities of daily living Fatigue Depressive symptom score

Beneficial effect of fingolimod on physical and mental aspects of HRQoL

CI, confidence interval; DMT, disease-modifying therapy; HRQoL, health-related quality of life; LOCF, last observation carried forward; SF-36 Short Form (36) Health Survey v2 standard. Lower scores indicate worse quality of life. Crayton H, et al. CMSC 2013. DX20.

SF-36 summary score changes

1.7

2.2

0.4 0.4

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Physical Component Summary Mental Component Summary

Ch

an

ge

fro

m b

ase

line

to

Mo

nth

6 (

LO

CF

),

lea

st sq

ua

res m

ea

n

Difference, 1.3

(95% CI, 0.30 to 2.31)

p = 0.011

Difference, 1.7

(95% CI, 0.41 to 3.07)

p = 0.011

Fingolimod 0.5 mg Standard of care DMT

Adjuvant (n = 50)

Salvage (n = 118)

p = 0.002

Emerging concepts in MS

Hagan M, et al. Int J Radiat Oncol Biol Phys 2004; 59:329−340.

NEDA; no evidence of disease activity

T2T; treat-2-target

10 9 7 6 5 4 3 2 1 0 8

0.8

0.6

0.4

0.2

0.0

1.0

Su

rviv

al

Time since radiotherapy (years)

Biochemical relapse-free survival

No evidence of disease activity

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

Should brain volume loss be included in our definition for

‘no evidence of disease activity’?

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

Effect of natalizumab on brain paraenchymal fraction

Miller D, et al. Neurology 2007; 68:1390−1401.

0 12 24

0

0.2

0.4

0.6

0.8

1.0

Time (months)

AFFIRM: 2-year results2 M

ean r

eduction in b

rain

pare

nchym

al fr

action (

%)

P = 0.822

Natalizumab

Placebo

P = 0.002 P = 0.004

*

*

Effect of fingolimod on brain volume loss

IFN, interferon; IM, intramuscular; PBVC, percentage brain volume change. TRANSFORMS *** p < 0.001 versus interferon -1a. p value calculated using Wilcoxon rank sum test. FREEDOMS/FREEDOMS II * p < 0.05; ** p < 0.01; *** p < 0.001 versus placebo. p values calculated using rank analysis of covariance adjusted for treatment, region and baseline normalized brain volume. Cohen J, et al. AAN 2013. S51.006.

0 6 12 24

Fingolimod 0.5 mg (n = 358)

Placebo (n = 355)

0 6 12 24

Fingolimod 0.5 mg (n = 425)

Placebo (n = 418)

TRANSFORMS

–1.4

–1.2

–1.0

–0.8

–0.6

–0.4

–0.2

0.0

0 12

Fingolimod 0.5 mg (n = 429)

IFN beta-1a IM (n = 431)

FREEDOMS FREEDOMS II

**

*** *

*** *

***

***

33%

reduction

32% reduction

35% reduction

Me

an

PB

VC

fro

m b

ase

line

Months

Is it time for a paradigm shift? Early treatment with a high-efficacy therapy

Figure: http://multiple-sclerosis-research.blogspot.co.uk/2012/06/research-dmt-slow-onset-of-progression.html; Accessed 4 June 2013. Based on a review of Bergamaschi R, et al. Mult Scler 2012; Epub ahead of print.

Disability

Disease

onset

Time

Later

treatment

Treatment

at diagnosis

Intervention

at diagnosis

Later

intervention

Natural course

of disease

Treatment ladder

1st-line A

1st-line B

1st-line C

1st-line D

1st-line E

2nd-line N

2nd-line M

3rd-line Y

3rd-line X

Conclusions

MS is a bad disease

Disability (physical and cognitive)

High societal costs (unemployment,

healthcare costs, divorce)

Survival compromised

Treat early and aggressively

(TIME MATTERS)

Prognostic factors

Clinical findings, MRI activity and

other emerging biomarkers

Treatment response markers

Clinical (relapses and disability

progression)

MRI (T2 and Gd-enhancing lesions)

Neutralizing antibodies (efficacy

and safety)

Treat-2-Target

No evidence of disease activity

Concerns about using a treatment

ladder (TIME MATTERS)

No fixed treatment algorithms;

no 1st-, 2nd- or 3rd-line therapies

(TIME MATTERS)