Hit hard and early!

Gavin Giovannoni

Barts and The London School of Medicine and Dentistry XVIIIth European Charcot Foundation Symposium

Marbella , Spain 29th Nov to 1st Dec 2012

Disclosures

I have received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: 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 Vertex Pharmaceuticals.

Emerging concepts in MS

NEDD; no evidence of detectable disease

TTT; treat-to-target

Emerging concepts in MS

NEDD; no evidence of detectable disease

TTT; treat-to-target

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.

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

Post-inflammatory neurodegeneration

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

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

Treat early

Natural course of disease

Later intervention

Later treatment

Treatment at diagnosis Intervention

at diagnosis

Time Disease Onset

Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFN-1b trial

Goodin et al. Neurology 2012;78:1315-1322.

Any Negative EDSS=6 SPMS Wheelchair

% R

isk R

ela

tive t

o L

ow

Exp

osu

re

Long-term follow-up 16 years

IFN-beta exposure 80% vs. 20%

Goodin et al. PLoS One. 2011;6(11):e22444. Epub 2011 Nov 30.

Establishing long-term efficacy: use of recursive partitioning and propensity score adjustment to estimate outcome in MS

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.

Association between use of interferon beta and progression of disability in MSers with relapsing-remitting multiple sclerosis

Tremlett et al. JAMA. 2012;308(3):247-256.

Association between use of interferon beta and progression of disability in MSers with relapsing-remitting multiple sclerosis

Tremlett et al. JAMA. 2012;308(3):247-256.

100 MSers

Who are the responders?

~20% responders

~40% sub-optimal responders

~40% non-responders

vs.

1

2

3

Clinical

MRI

NABs

Relapses don’t count!

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

Relapses and residual deficits

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

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-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.

Curved Ball

0 3 6 X

Survival analysis and disability progression

0 3 6 X

Survival analysis and disability progression

0 3 6 X

Survival analysis and disability progression

X

X

X

X

X

X

3

X

X

X

X

X

X

3

survival analysis

X

X

X

X

X

X

3

survival analysis

median or mean EDSS

Impact of early interferon beta-1b on disease evolution over 5-years in MSers with CIS

Freedman et al. WCTRIMS 2008.

survival analysis median or

mean EDSS

Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial

Coles et al. Lancet 2012: November 1, http://dx.doi.org/10.1016/

survival analysis

median or mean EDSS

Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial

Coles et al. Lancet 2012: November 1, http://dx.doi.org/10.1016/

56.0

42.0

27.0

74.0

51.0

39.0

0

10

20

30

40

50

60

70

80

Clinical disease

activity-free

MRI

activity-free

MS disease

activity-free

CARE-MS I: Disease Activity Status – Proportion of Patients Free of MS Disease Activity

41.1

Pati

en

ts (

%)

Note: Clinical disease activity-free defined as absence of relapse or SAD; MRI activity-free defined as absence of new Gd-enhancing lesion or new or

enlarging T2 hyperintense lesion; MS disease activity-free defined as absence of clinical disease activity or MRI activity.

Giovannoni et al. ENS 2012.

p<0.0001

p=0.0388

p=0.0064

SC IFNB-1a

Alem 12 mg

“Every clinical trial is an experiment. In fact every time you treat a patient you should view it as an experiment and use it as an opportunity to learn something about the disease!”

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

Who should decide?

WWW.MS-RES.ORG

WWW.MS-RES.ORG

WWW.MS-RES.ORG

Are you prepared to walk where others fear to tread?

Conclusions • NEDD, TTT and DAF are entering 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 DAF status indicates non-response

• Induction – absence of DAF 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? • Alemtuzumab extension study

• What do we do about post-inflammatory neurodegeneration? • We need better outcomes, e.g. regional brain atrophy and CSF neurofilament levels

• Neuroprotective treatments

Conclusions • NEDD, TTT and DAF are entering 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 DAF status indicates non-response

• Induction – absence of DAF 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? • Alemtuzumab extension study

• What do we do about post-inflammatory neurodegeneration? • We need better outcomes, e.g. regional brain atrophy and CSF neurofilament levels

• Neuroprotective treatments

? ?