Highly effective early induction therapy Canada 2013

Why treat MS early with highly effective induction therapies?

Gavin Giovannoni

Barts and The London

Disclosures

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-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni.

Professor Giovannoni would like to acknowledge and thank Biogen-Idec, Genzyme, Merck-Serono and Novartis for making available data slides on natalizumab, alemtuzumab, oral cladribine and fingolimod for this presentation.

early therapy

highly-effective therapy

induction therapy

Getting your ducks in a row!

+ +

Why early?

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.

STRATA: subjects had stable EDSS scores for up to 5 years

*P<0.0001

Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520.

1 Year 2 Years 3 Years 4 Years 5 Years

Cessation/

Treatment Gap* Original Placebo

Original Natalizumab

Original Placebo – Now on Natalizumab

Mean

ED

SS

Sco

re

n = 380 707 381 707 280 552 385 709 274 569 230 479 205 462 194 427 174 393

6

TOP: earlier natalizumab treatment favors annualized relapse rate outcomes

7

P values from a negative binomial regression model adjusted for gender, baseline EDSS score (<3.0 vs ≥3.0l), relapse status in the prior

year (≤1 vs >1), prior DMT use (<3 vs ≥3), disease duration (<8 vs ≥8 years), and treatment duration (≥3 vs <3 years), except for the factor

of interest. Error bars represent 95% CIs.

DMT=disease-modifying therapy; CI=confidence interval.

Wiendl et al. Presented at ENS; June 8–11, 2013; Barcelona, Spain,. P372.

Baseline EDSS Score

<3.0 ≥3.0

Prior DMTs Used

0 1 ≥2

P<0.0001 P<0.0001

Theoretical model: treat early and effectively

Natural course of disease

Later intervention

Later treatment

Treatment at diagnosis Intervention

at diagnosis

Time Disease Onset

Dis

abili

ty

Time is brain

Does the biology of MS change with time?

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

Post-inflammatory neurodegeneration

The current dogma

Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17.

MRI Events

Time (Years)

Inflammation

Brain volume

Axonal loss

Dis

eas

e S

eve

rity

SPMS RRMS CIS RIS

The current paradigm: S&S

safe & slow

S&S treatment paradigm

A

B

C

D

E

N M

Y X Moderate

Efficacy

Intermediate

Efficacy

High

Efficacy

1st-line

2nd-line

3rd-line

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 lesions predicts progression to EDSS Score ≥3.0

Queen Square Study

100 MSers

Who are the

responders?

~20% responders

~40% sub-optimal responders

~40% non-responders

vs.

1

2

3

Clinical

MRI

NABs

How bad is MS?

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

What about benign MS?

163 patients with “benign” MS

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

45% cognitive impairment

49% fatigue

54% depression

What is benign MS?

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

Relapses don’t count!

Weinshenker et al. Brain. 1989 Dec;112 ( Pt 6):1419-28.

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.

Bermel et al. Ann Neuol 2012.

Predictors of long-term outcome in

MSers treated with interferon beta-1a

Treatment vs. Natural History

MRI activity doesn’t count!

Bermel et al. Ann Neuol 2012.

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 2013.

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 2013.

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

Including brain atrophy!

Control Multiple sclerosis

RIP

TREATMENT EFFECT ON BRAIN ATROPHY CORRELATES WITH

TREATMENT EFFECT ON DISABILITY IN MULTIPLE SCLEROSIS

Sormani et al. Ann Neurol 2013, In Press.

TREATMENT EFFECT ON BRAIN ATROPHY CORRELATES WITH

TREATMENT EFFECT ON DISABILITY IN MULTIPLE SCLEROSIS

Sormani et al. Ann Neurol 2013, In Press.

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-beta-1b trial

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

Why highly-effective treatments?

STRATA: Patients Had Stable EDSS Scores for up to 5 years

*P<0.0001

Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520.

1 Year 2 Years 3 Years 4 Years 5 Years

Cessation/

Treatment Gap* Original Placebo

Original Natalizumab

Original Placebo – Now on Natalizumab

Mean

ED

SS

Sco

re

n = 380 707 381 707 280 552 385 709 274 569 230 479 205 462 194 427 174 393

50

CAMMS2231

(completed)

CARE-MS I2

(completed)

CARE-MS II3

(completed)

Extension4,5,a

(ongoing)

Phase 2 3 3 3

Patient

population

Active RRMS,

treatment-naïve

Active RRMS,

treatment-naïve

Active RRMS,

relapsed on prior therapy

RRMS patients enrolled

into phase 2 and 3

studies

Patients, n 334 581 840 1322

Study

duration, yrs 3 2 2 4

Inclusion

criteria

EDSS ≤3

Onset ≤3 yrs

Enhancing lesion

EDSS ≤3

Onset ≤5 yrs

EDSS ≤5

Onset ≤10 yrs

CAMMS223,

CARE-MS I & II

patients

Treatment

arms

Alemtuzumab 12 mg

Alemtuzumab 24 mg

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

—

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

Alemtuzumab 24 mgb

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

(Re-treatment as needed

after 2 fixed courses)

Co-primary

outcomes

Relapse rate

Sustained accumulation of disability (SAD)

Relapse rate

SAD

Long-term safety and

efficacy outcomes

Alemtuzumab clinical development program vs. high-dose sc IFNB-1a

a Enrolling patients from all 3 studies; b Exploratory arm, discontinued enrollment early

CARE-MS=Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; EDSS=Expanded Disability Status Scale; SC IFNB=subcutaneous

interferon beta

1. Coles AJ et al. N Engl J Med 2008;359:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3. Coles AJ et al. Lancet 2012;380:1829-39; 4.

Brinar V et al. ENS 2011. P912; 5. Fox E et al. AAN 2013. S41.001.

Rebif® is a registered trademark of EMD Serono, Inc.

Demographics and baseline clinical characteristics in treatment-naïve subjects

Gd=gadolinium; SD=standard deviation a Inclusion criteria included EDSS ≤3, onset of symptoms within 3 years, ≥2 relapses in the previous 2 years, and ≥1 Gd-enhancing lesion. b Inclusion criteria included EDSS ≤3, disease duration ≤ 5 years, ≥2 relapses in the previous 2 years and ≥1 relapse in the previous year;

1. Coles AJ et al. N Engl J Med 2008;259:1786-801; 2. Data on file, Genzyme Corporation; 3. Cohen JA et al. Lancet 2012;380:1819-28.

CAMMS2231-2,a CARE-MS I3,b Pooled CAMMS223 and

CARE-MS I1-3

SC IFNB-1a

44 μg

N=111

Alemtuzumab

12 mg

N=112

SC IFNB-1a

44 μg

N=187

Alemtuzumab

12 mg

N=376

SC IFNB-1a

44 μg

N=294

Alemtuzumab

12 mg

N=483

Age, years mean (SD) 32.8 (8.8) 31.9 (8.0) 33.2 (8.5) 33.0 (8.0) 33.1 (8.6) 32.9 (8.0)

Gender, % female 64 64 65 65 65 65

Time since first relapse,

years, mean (SD) 1.6 (1.0) 1.4 (0.84) 2.0 (1.3) 2.1 (1.4) 1.8 (1.2) 1.9 (1.3)

EDSS, mean (SD) 1.9 (0.8) 1.9 (0.7) 2.0 (0.8) 2.0 (0.8) 1.9 (0.8) 2.0 (0.8)

No. of relapses in prior year,

mean (SD) 1.6 (0.8) 1.7 (0.9) 1.8 (0.8) 1.8 (0.8) 1.8 (0.8) 1.8 (0.8)

Patients with Gd-enhancing

lesions,% 100 100 51 46 69.7 58.6

1. Coles AJ et al. N Engl J Med 2008;259:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28.

Alemtuzumab significantly reduces annualized relapse rate vs. SC IFNB-1a in treatment-naïve subjects

0.39

0.18

0

0.1

0.2

0.3

0.4

0.5

0.6

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

54.9% Risk reduction vs.

SC IFNB-1a

p<0.0001

An

nu

ali

ze

d R

ela

pse

Rate

N=187 N=376

CARE-MS I

(Co-primary endpoint)2

0.36

0.11

0

0.1

0.2

0.3

0.4

0.5

0.6

CAMMS223

(Co-primary endpoint)1

An

nu

ali

ze

d R

ela

pse

Rate

69% Risk reduction

vs. SC IFNB-1a

p<0.001

N=111 N=112

53

a CARE-MS I and CAMMS223 pooled data; b Sustained accumulation of disability (SAD) is defined as a ≥1 point increase in Expanded Disability

Status Scale (EDSS) lasting ≥6 months (or ≥1.5 point increase if baseline EDSS=0).

1. Cohen JA et al. Lancet 2012;380:1819-28; 2. Data on file, Genzyme Corporation.

Alemtuzumab reduces the risk of 6-month sustained accumulation of disability in treatment-naïve subjects

Pa

tie

nts

wit

h S

AD

(%

)

50% Risk reduction

vs. SC IFNB-1a

p=0.0029 13.9%

7.1%

30% Risk reduction

vs. SC IFNB-1a

p=0.22

Pa

tie

nts

wit

h S

AD

(%

)

25

15

10

5

0

20

0 3 6 9 12 15 18 21 24

8.0%

11.1%

SC IFNB-1a 44 μg

Alemtuzumab 12 mg

SC IFNB-1a 44 μg

Alemtuzumab 12 mg

Treatment-naïve: CARE-MS I1

(Co-primary Endpoint)

Pooled Treatment-naïve2,a

(Post Hoc Analysis)

Follow-up Month Follow-up Month

25

15

10

5

0

20

0 3 6 9 12 15 18 21 24

54

Treatment-naïve subjects are more Likely to be disease activity-free with alemtuzumab vs. sc IFNB-1a

CDA-freea MRI Activity-freeb MS Disease Activity-

freec

p<0.0001

p=0.0388

OR=1.75 p=0.0064

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

aClinical disease activity (CDA)-free: Absence of relapse or SAD; bMRI activity-free: absence of new Gd-enhancing lesion or new or enlarging T2

hyperintense lesion; cMS disease activity-free: Absence of CDA or MRI activity.

OR=odds ratio;

1. Giovannoni G et al. ENS 2012; 2. Cohen JA et al. Lancet 2012;380:1819-28.

Treatment-naïve: CARE-MS I1,2

(Tertiary Endpoints)

Pooled treatment-naïve

(CAMMS223 and CARE-MS I)

N=4831-3

Patients Who Relapsed on Prior

Therapy (CARE-MS II)

N=4264

Age, years

Mean (SD) 32.9 (8.03)

34.8 (8.4)

Gender

Female, %

64.6

66.0

Years since initial episode

Mean (SD)

1.9 (1.30)

4.5 (2.7)

EDSS

Mean (SD)

2.0 (0.80)

2.7 (1.3)

No. of relapses in prior year

Mean (SD)

1.8 (0.80)

1.7 (0.86)

Prior therapy, %

SC IFNB-1a (22 or 44 μg)

IM IFNB-1a

SC IFNB-1b

Glatiramer acetate

Natalizumab

34

28

36

34

4

Patients with Gd-enhancing

lesions, % 58.6 42.4

Baseline demographics and clinical characteristics of alemtuzumab-treated subjects

1. Coles AJ et al. N Engl J Med 2008;259:1786-801; 2. Data on file, Genzyme Corporation; 3. Cohen JA et al. Lancet 2012;380:1819-28; 4. Coles AJ

et al. Lancet 2012;380(9856):1829-39.

Alemtuzumab significantly reduced clinical disease activity in subjects who relapsed on prior therapy

aSix-month SAD defined as EDSS score increase ≥1.0 point for ≥6 months (or ≥1.5 points when baseline EDSS = 0); bNumber of events among

patients who received prior natalizumab is too small to draw meaningful conclusions.

CI=confidence interval; HR=hazard ratio

1. Coles AJ et al. Lancet 2012;380:1829-39; 2. Freedman MS et al. AAN 2013, P07.111.

ARR Years 0–2: CARE-MS II1

(Co-primary Endpoint)

Alemtuzumab 12

mg

(n=426)

SC IFNB-1a

44 µg

(n=202)

Risk reduction: 49.4%

p<0.0001 21.1%

12.7%

HR: 0.58

42% Risk reduction

p=0.0084

6-Month Sustained Accumulation of

Disability: CARE-MS II

(Co-primary Endpoint)

57

Subjects who relapsed on prior therapy were more likely to be disease activity-free with alemtuzumab vs. sc IFNB-1a

Clinical disease activity-free: absence of relapse or SAD; MRI activity-free: absence of new Gd-enhancing lesion or new or enlarging T2 hyperintense

lesions; MS disease activity-free: absence of clinical disease activity and MRI activity; SAD: Increase of ≥1.0 EDSS point for ≥6 months (or ≥1.5 points if

baseline EDSS = 0).

SC IFNB-1a=subcutaneous interferon beta-1a

1. Hartung HP et al AAN 2013; P07.093; 2. Coles AJ et al. Lancet 2012;380:1829-39.

OR=3.03

p<0.0001

p<0.0001 p<0.0001

Relapsed on Prior Therapy: CARE-MS II

(Tertiary Endpoints)1,2

Alemtuzumab improved pre-existing disability vs. sc IFNB-1a in subjects who relapsed on prior therapy

HR: 2.57

p=0.0002

HR: 3.02

p=0.0003

HR: 3.00

p=0.0001

SRD Timeframeb

SC IFNB-1a 44 µg

Alemtuzumab 12 mg

a SRD defined as a reduction from baselilne of ≥1 EDSS point for ≥6, 9, OR 12 months; assessed in patients with baseline EDSS score ≥ 2. b Includes events that initiated in the core studies and continued into the extension.

1. Coles AJ et al. Lancet 2012;380:1829-39 ; 2. Data on file, Genzyme Corporation.

Sustained Reduction of Disabilitya

Relapsed on Prior Therapy: CARE-MS II1,2

(Tertiary Endpoint) (Post Hoc Analyses)

CARE-MS extension study designed to evaluate long-term outcomes with alemtuzumab

Received SC IFNB-1a

Extension Study (Safety & Efficacy Follow-up)

May receive optional re-treatment course(s)

not sooner than 12 months after the

previous course

No

Yes

Administer 2 annual

alemtuzumab treatment courses

Relapse or 2 active

MRI lesions?

Monitor for MS activity through extension trial

Month 48

Received alemtuzumab

(Month 0 and 12)

CARE-MS I or II

Pivotal Studies

Fox E et al. AAN 2013, S41.001.

Extension study treatments used alemtuzumab 12 mg IV

~80% of patients did not receive re-treatment or other DMT during Year 3

<2% of patients received another DMT during Year 3

CARE-MS extension: majority of subjects treated with alemtuzumab remain relapse-free at year 3

Fox E et al. AAN 2013, S41.001.

Treatment-naïve

(CARE-MS I)

Relapsed on Prior Therapy

(CARE-MS II)

Relapse-free Patients

%P

ati

en

ts

N=376 N=349 N=425 N=387

CARE-MS extension: majority of subjects experience further benefits on disability through year 3

Relapsed on Prior Treatment

(CARE-MS II)

EDSS change (baseline to Year 2)

Data shown are for alemtuzumab 12-mg groups.

Hartung HP et al. ECTRIMS 2013, P592.

Remained stable Years 2-3

Improved Years 2-3

Yr-1 Yr-2 Yr-3 Yr-1 Yr-2 Yr-3

Summary of safety in clinical study population 2-year controlled experience

Treatment-naïve Patients1,a Relapsed on Prior Therapy2

SC IFNB-1a

(N=294)

(%)

Alemtuzumab

12 mg

(N=483)

(%)

SC IFNB-1a

(N=202)

(%)

Alemtuzumab

12 mg

(N=435)

(%)

AEs 94.6 96.7 94.6 98.4

SAEs 16.0 17.1 21.8 19.5

Identified risks

IARs — 91.7 — 90.3

Thyroid disorders 5.4 17.4 5.0 15.9

ITP3,4 0 1.0 0 0.9

Glomerulonephritis 0 0 0 0.2

Serious infections 0.7 1.9 1.5 3.7

aData pooled for CAMMS223 and CARE-MS I studies.

1. Data on File. Genzyme Corporation; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3.Coles AJ et al. Lancet 2012;380:1829-39; 4. Fox E et al. AAN

2013, S41.001.

Alemtuzumab summary of safety

Well-characterized safety and tolerability profile across alemtuzumab

clinical development program1-3

– Most common adverse events were mild/moderate infusion reactions,

which were manageable with appropriate pre-medication and/or treatment,

and patient education1-3

– Low rates of serious infection, consistent with relative sparing of both

innate immune cells and specific lymphocyte subpopulations1,2

– Autoimmune adverse events, including thyroid-related events, ITP, and

nephropathies, were detected with safety monitoring program and

generally responded to conventional therapy1-3

Incorporation of proactive risk-minimization procedures into clinical

trials allowed for early detection and management of identified risks1-3

– Clinical trial experience has informed the Risk Mitigation Plan for

alemtuzumab in the EU

1. Cohen JA et al. Lancet 2012;380:1819-28; 2. Coles AJ et al. Lancet 2012;380:1829-39; 3. Fox E et al. AAN 2013, S41.001.

Summary of recommended risk mitigation strategies for alemtuzumab in the EU

Identified Risks Mitigation Strategies Timing

Infusion-associated

reactions (IARs)

Corticosteroids Immediately prior to

alemtuzumab administration

On each of the first 3 days of

any treatment course

Antihistamines and/or

antipyretics (optional)

Prior to alemtuzumab

administration

Serious infections Oral prophylaxis for herpes

infection

Starting on the first day of

each treatment course

Continuing for a minimum of

1 month following treatment

with alemtuzumab

HPV screening Annually for female patients

Active or inactive (“latent”)

tuberculosis infection

evaluation

Before initiation of therapy

Immune

thrombocytopenia

(ITP) and other

cytopenias

Complete blood count with

differential

Prior to initiating

alemtuzumab treatment

Monthly until 48 months after

last infusion.a

Nephropathies,

including anti-GBM

disease

Serum creatinine Prior to initiating

alemtuzumab treatment Monthly until 48 months after

last infusiona

Urinalysis with microscopy Prior to initiating

alemtuzumab treatment Monthly until 48 months after

last infusiona

Thyroid disorders Thyroid function tests (such as

TSH) Prior to initiating

alemtuzumab treatment Every 3 months until 48

months after last infusiona

aAfter 48 months, testing should be performed based on clinical findings suggestive of the adverse event.

LEMTRADA EU Summary of Product Characteristics, September 2013.

What is your treatment philosophy?

survival analysis

“hard and early ”

What is your treatment philosophy? maintenance-escalation vs. induction

survival analysis

“hard and early ”

MS is an autoimmune disease hypothesis

15-20 year experiment

What is your treatment philosophy? maintenance-escalation vs. induction

Another example: treat early and effectively

Emerging concepts in MS

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

NEDD – no evidence of detectable disease (oncology)

NEDA - no evidence of disease activity (msologoy)

DAF – disease activity free

T2T; treat-2-target (rheumatology)

10 9 7 6 5 4 3 2 1 0 8

0.8

0.6

0.4

0.2

0.0

1.0

Adjuvant (n = 50)

Salvage (n = 118)

p = 0.002

Su

rviv

al

Time since radiotherapy (years)

Biochemical relapse-free survival

ZeTo; zero tolerance

No evidence of disease activity: NEDA

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 and CSF neurofilament levels 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

T2T - NEDA

Zero Tolerance

Functional

Improvement

Maintain reserve

capacity

Treatment objectives in relapsing MS

Freedom from

disease

activity/disease

activity free

Reduced ongoing

damage

CNS Repair

Healthy

ageing

Improved Quality of Life

Treat Early

73

17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:

Normal walking 300m, unable to run &

exercise. Intermittent sensory symptoms

in L arm. Mild urinary frequency

Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

Early or late?

74

Mo

nito

rin

g

Tre

atm

en

t C

linic

al

Occu

p &

so

cia

l

What does the future hold?

75

17yr female,

diagnosed with CIS

after presenting

with myelitis

18yr, 1st year

university diagnosed

with MS after having

L optic neuritis

Abnormal MRI; >9 T2 lesions

on brain MRI and spinal cord

lesion at C5

2000 2001

clumsy

left hand

pins &

needles in

legs

IFN-beta

2001 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time employment

Off work

~3 months of the

year

Dec 2007

Brainstem

syndrome;

diplopia and

ataxia

? glatiramer acetate

Cervical cord relapse

weak L arm with pain

High lesion load

with brain

atrophy Gd-enhancing lesion

of upper cervical

cord

Splits from her

partner

depression , anxiety and

fatigue

Reduced mobility

Occupational health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:

Normal walking 300m, unable to run & exercise. Intermittent

sensory symptoms in L arm. Mild urinary frequency

Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

mo

nit

ori

ng

trea

tmen

t cl

inic

al

Occ

up

. & s

oci

al

JCV

high positive

Final

year of

school

University

Pregnancy Old

Age

17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:

Normal walking 300m, unable to run &

exercise. Intermittent sensory symptoms

in L arm. Mild urinary frequency

Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

Early or late?

Mo

nito

rin

g

Tre

atm

en

t C

linic

al

Occu

p &

so

cia

l

Dec 2007 Jul 2010 Jul 2013

Maintenance vs. Induction

Maintenance therapies

• Continuous treatment

• Low to very high efficacy

• Reversible

• Perceived to be lower risk

• Examples • Laquinimod, GA, IFN-beta, teriflunomide, BG12,

fingolimod, natalizumab, daclizumab

• Breakthrough disease • Suboptimal or failure to respond

• NEDA reliable metric for efficacy

• Rebound activity • Highly likely

• Can be life threatening

• Pregnancy • Contra-indicated

• No potential for a cure • Rebound

• SPMS & progressive brain atrophy

Induction therapies

• Short-courses or pulsed therapy

• Very high efficacy

• Irreversible

• Perceived to be higher risk

• Examples • Mitoxantrone, cladribine, alemtuzumab, anti-

CD20 (?), BMT

• Breakthrough disease • Marker for retreatment

• NEDA unreliable to assess efficacy

• Rebound activity • Less likely

• Unlikely to be life-threatening

• Pregnancy • Strategy of choice

• Potentially curative • 15-20 year experiment

• BMT, alemtuzumab, cladribine

Who should decide?

WWW.MS-RES.ORG

WWW.MS-RES.ORG

Case studies

Ian Rogers. ACNR 2007: 7(3);14.

Conclusions • MS is a bad disease

• Mortality, disability, unemployment, divorce, cognitive impairment, etc.

• Early highly-effective treatment is the only realistic option of offering a cure

• Now an established treatment option, which has become safer

• NEDA, T2T and DAF are entering the neurology lexicon

• Zero tolerance or ZeTo

• We need an acceptable working definition of an MS cure

• NEDA x 15 years?

• Induction therapies (alemtuzumab, cladribine)

• Improved risk mitigation tools

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

• Alemtuzumab, BMT, natalizumab, cladribine extension studies

early therapy

highly-effective therapy

induction therapy

Any questions?

+ +

ZeTo – zero tolerance

Treat-2-Target proposed NEDA treatment algorithm for relapsing MS

NEDA=no evidence of disease activity.

A

B

C

D

E N

M

Y X Moderate

Efficacy

Intermediate

Efficacy

High

Efficacy

FTY Efficacy

Ris

ks

+

+ -

-

IFNb

GA

BMT

Mx

Nz

Alemz

? CD20

Lq

BG12

? Dac

Teri

Nz

Clad