Prospects for individualised

therapy for MS

Gavin Giovannoni

Treat early and actively: who should decide?

Natural course of disease

Later intervention

Later treatment

Treatment at diagnosis Intervention

at diagnosis

Time Disease Onset

Who should decide?

WWW.MS-RES.ORG

WWW.MS-RES.ORG

WWW.MS-RES.ORG

UK Payers or NHS: relapsing MS DMT doughnut

Inactive RRMS

CIS

RIS or asymptomatic MS

Suboptimal responders ?

Clinically active RRMS

Highly active Band 3

(Alemtuzumab) (Ocrelizumab) Natalizumab (Daclizumab)

Band 2 (Cladribine) Fingolimod

(BG12/DMF)

Band 1 (Teriflunomide) Interferon-beta

Glatiramer acetate (Laquinimod)

Sub-clinically active RRMS

MS DMT doughnut: 1st, 2nd & 3rd line therapies

Band 3 (Alemtuzumab) (Ocrelizumab) Natalizumab (Daclizumab)

Band 2 (Cladribine) Fingolimod

(BG12/DMF)

Band 1 (Teriflunomide) Interferon-beta

Glatiramer acetate (Laquinimod)

Inactive R

RM

S

CIS

RIS o

r asymp

tom

atic MS

Sub

op

timal resp

on

ders ?

Clin

ically active

RR

MS

High

ly active

Sub

-clinically active R

RM

S

Eating the doughnut:

Band 3: (Alemtuzumab) / (Ocrelizumab) / Natalizumab / (Daclizumab)

Band 2: (Cladribine) / Fingolimod / (BG12/DMF)

Band 1: (Teriflunomide) / Interferon-beta / Glatiramer acetate / (Laquinimod)

Sub

op

timal resp

on

ders ?

Inactive R

RM

S

CIS

RIS o

r asymp

tom

atic MS

Clin

ically active

RR

MS

High

ly active

Sub

-clinically active R

RM

S

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

Post-inflammatory neurodegeneration

Hartung et al. Lancet 2002:360:2018-25.

Coles AJ et al. Lancet 2012

Alemtuzumab for patients with relapsing MS after disease-modifying

therapy: a randomised controlled phase 3 trial

survival

analysis

median or

mean EDSS

100

90

80

70

60

50

40

0 0 3 6 9 12 15 18 21 24

Hazard ratio 0.53 (95% CI 0.41-0.69); p<0.0001

IFNβ-1a

Alemtuzumab 12 mg

202

426

190

402

139

377

125

354

109

325

101

313

94

303

90

291

79

266

Number at risk

IFNβ-1a

Alemtuzumab 12 mg

Re

lapse-f

ree s

urv

iva

l

30

25

20

15

10

5

0 0 3 6 9 12 15 18 21 24

Hazard ratio 0.58 (95% CI 0.38-0.87); p=0.0084

IFNβ-1a

Alemtuzumab 12 mg

202

426

200

426

184

412

175

404

167

392

162

384

155

380

145

375

131

154

Number at risk

IFNβ-1a

Alemtuzumab 12 mg

Pa

tien

ts w

ith

su

sta

ined

accum

ula

tion

of

dis

abili

ty (

%)

3.25

3.00

2.75

2.50

2.25 0 3 6 9 12 15 18 21 24

IFNβ-1a

Alemtuzumab 12 mg

202

426

198

419

194

419

190

419

185

422

180

415

176

410

172

413

174

413

Number of observations

IFNβ-1a

Alemtuzumab 12 mg

ED

SS

sco

re

We don’t want to throw the baby out with the bathwater!

survival analysis

What is your treatment philosophy?

maintenance-escalation vs. induction

survival analysis

“hit hard and early ”

What is your treatment philosophy?

maintenance-escalation vs. induction

survival analysis

“hit hard and early ”

MS is an autoimmune disease hypothesis

15-20 year experiment

What is your treatment philosophy?

maintenance-escalation vs. induction

Clinical Prognostic Factors

Good Prognosis

1. Optic neuritis

2. Isolated sensory

symptoms

3. Long interval to

second relapse

4. No disability after

5 years

5. Normal MRI or low

lesion load

Poor Prognosis

1. Multifocal CIS

2. Efferent systems

affected

3. High relapse rate in first

2–5 years

4. Substantial disability

after 5 years

5. Abnormal MRI with large

lesion load

Miller D et al. Lancet Neurol. 2005;4:281-288.

vs.

1

2

3

Clinical

MRI

NABs

100 MSers

Who are the responders?

~20% responders

~40% sub-optimal responders

~40% non-responders

Relapses don’t count!

Relapses and residual deficits

Lublin FD et al. Neurology. 2003;61:1528-1532.

Relapse on IFNβ Therapy Increases Risk

of Sustained Disability Progression

Bosca et al. Mult Scler. 2008;14:636-639.

HR SE P Value 95% CI

No relapses (reference=1) 1

One relapse 3.41 1.47 0.005 1.46–7.98

Two or more relapses 4.37 1.74 0.000 1.90–9.57

HR of EDSS Increase in Patients with No Relapses, 1 Relapse, and 2 or More Relapses During the First 2 Years of IFN Treatment

0 20 40 60 80

0

0.25

0.50

0.75

Analysis Time (Months)

No Relapses One Relapse Two or More Relapses

1.00

EDSS

Pro

gres

sio

n

Surv

ival

Pro

bab

ility

HR=hazard ratio; SE=standard error

Predictors of long-term outcome in

MSers treated with interferon beta-1a

Bermel et al. Ann Neuol 2012; In Press.

Bermel et al. Ann Neuol 2012; In Press.

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

Bermel et al. Ann Neuol 2012; In Press.

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

Bermel et al. Ann Neuol 2012; In Press.

Predictors of long-term outcome in

MSers treated with interferon beta-1a

MRI activity doesn’t count!

Bermel et al. Ann Neuol 2012; In Press.

Predictors of long-term outcome in

MSers treated with interferon beta-1a

MRI to monitor treatment response to IFNβ: a meta-analysis

Dobson et al. Submitted 2012.

Study or Subgroup Odds Ratio

IV, Random, 95% CI

Kinkel 2008

Prosperini 2009

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

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

Favors Experimental Favors Control

100 10 1 0.1 0.01

Two or More New T2 Lesions

Study or Subgroup Odds Ratio

IV, Random, 95% CI

Kinkel 2008

Rio 2008

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

MRI to monitor treatment response to IFNβ: a meta-analysis

Dobson et al. Submitted 2012.

Study or Subgroup Odds Ratio

IV, Random, 95% CI

Kinkel 2008

Pozzilli 2005

Tomassini 2006

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

0.01 0.1 1 10 100 Disease Less Likely Disease More Likely

One New Gd+ Lesion

0.01 0.1 1 10 100

Disease Less Likely Disease More Likely

Two or More New Gd+ Lesions

Disease progression doesn’t count!

Strongest predictor of disability progression on

IFNβ therapy is progression itself

Disease activity during 2 years of treatment and prediction of disability

progression* at 6 years

Group Sensitivity (%)

(CI) Specificity (%)

(CI)

A. An increase of at least one EDSS step confirmed at 6 months 85 (64–95) 93 (86–97)

B. Occurrence of any relapse 80 (58–92) 51 (41–61)

C. Occurrence of two or more relapses 45 (26–66) 81 (72–82)

D. A decrease in relapse rate less than 30% compared with 2 years before therapy

40 (22–61) 86 (77–91)

E. A decrease in relapse rate less than 50% compared with 2 years before therapy

40 (–61) 81 (72–88)

F. No decrease or identical relapse rate compared with 2 years before therapy

35 (18–57) 88 (79–93)

G. Definition A or B 90 (70–97) 48 (38–58)

H. Definition A or E 85 (64–95) 76 (66–83)

I. Definition A and B 75 (53–89) 97 (91–99)

J. Definition A and E 40 (22–61) 99 (94–99)

*EDSS score ≥6.0 or increase in at least 3 EDSS steps.

Río J et al. Ann Neurol. 2006;59:344-352.

Relationship between early clinical characteristics and long term disability

outcomes: 16 year cohort study (follow-up) of the pivotal interferon b-1b trial

Goodin et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):282-7.

How would you define a MS cure?

How would you define a MS cure?

"To claim that someone has been cured of MS

one would have to show that the person who

had the disease had no disease activity for at

least 15 years. The latter would be a composite

of no MRI activity (new gadolinium-enhancing

lesions, new T2 or enlarging T2 lesions and a

lack of progressive whole brain atrophy) and no

clinical activity (relapses or disease

progression).“

GIOVANNONI; WWW.MS-RES.ORG: FRIDAY, 6 APRIL 2012.

Emerging concepts in MS

NEDD; no evidence of detectable disease

T2T; treat-2-target

40

Treat-2-target

NEDA

Treat-2-target “an individualised target”

NEDA

Armour “population budgets”

LET’s MAKE IT A DOUGHNUT FREE ZONE!

Conclusions

• NEDA, T2T and DAF have entered the neurology lexicon

• We need an acceptable working definition of an MS cure

• DAF x 15 years?

• Should the definition be disease-stage specific?

• How do we deal with maintenance and induction therapies?

• Maintenance - absence of NEDA status indicates non-response

• Induction – absence of NEDA status indicates a time to retreat

• Improve risk mitigation tool

• Who should make the decision re early aggressive treatment?

• Regulators

• Payers

• Neurologists

• MSers

• Is it fair to make MSers wait 20 years for the outcome of an experiment?

• For example, alemtuzumab extension study

• Have we finally entered the era of individualised therapy for MS?