treat 2-target ms trust meeting november 2013
DESCRIPTION
TRANSCRIPT
The new treatment paradigm for MS: treat-2-target of NEDA
Zero Tolerance = ZeTo
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 and Merck-Serono for making available data slides on natalizumab, alemtuzumab and oral cladribine for this presentation.
Who should decide?
WWW.MS-RES.ORG
WWW.MS-RES.ORG
RRMS Active MS
Clinical or
MRI
What are the arguments for early treatment?
21-year long-term follow-up of IFNb-1b study time from study randomization to death
Early treatment (3 years) with IFNb-1b was associated with a 47% reduction in the risk of dying over 21 years compared with initial placebo treatment
Goodin et al Neurology. 2012 Apr 24;78(17):1315-22.
At risk:
IFNB-1b 250 µg
Placebo
124
123
124
120
121
117
118
109
104
88
HR=0.532 (95% CI: 0.314–0.902)
46.8% reduction in hazard ratio
Log rank, P=0.0173
IFNB-1b 250 µg
Placebo
65%
70%
75%
80%
85%
90%
95%
100%
0 2 4 6 8 10 12 14 16 18 20 22
Pro
po
rtio
n o
f p
ati
en
ts w
ho
are
sti
ll a
live
Time (Years)
Coles et al. J Neurol. 2006 Jan;253(1):98-108..
Post-inflammatory neurodegeneration
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
How bad is MS?
Untreated MS is a devastating disease
Cognitive Dysfunction
• Prevalence: 43% to 65%1,2
• Affects employment, activities of daily living, and social functioning2
Life Shortening
• 5- to 11-year decrease in life expectancy3-7
• 2- to 7-fold increase in suicide risk5,8
• 50% MS patients die of disease-related causes5,6,8
1. Rao SM et al. Neurology. 1991;41:685-691; 2. Rao SM et al. Neurology. 1991;41:692-696; 3. Sadovnick AD et al. Neurology. 1992;42:991-994;
4. Ebers GC. J Neurol Neurosurg Psychiatry. 2001;71:16-19; 5. Torkildsen G et al. Mult Scler. 2008;14:1191-1198; 6. Smestad C et al. Mult Scler.
2009;15:1263-1270; 7. Kingwell E et al. J Neurol Neurosurg Psychiatry. 2012;83:61-66; 8. Sadovnick AD et al. Neurology. 1991;41:1193-1196;
9. Orme M et al. Value Heath. 2007;10:54-60; 10. De Marco R et al. Diabetes Care. 1999;22:756-761; 11. Petty DW et al. Mayo Clin Proc.
2005;80:1001-1008; 12. Hooning MJ et al. Int J Radiat Oncol Biol Phys. 2006;64:1081-1091; 13. Pfleger CC et al. Mult Scler. 2010;16:121-126;
14. Beg J et al. Eur J Health Econ. 2006;7(suppl 2):S75-S85.
*In this study, utility measures were derived from EQ-5D using the EuroQoL instrument; †in patients with type 2 diabetes; ‡in patients with valvular heart disease in Olmsted County,
Minnesota; §MS patients with EDSS ≥6.
EDSS=Expanded Disability Status Scale; QOL=quality of life; CV=cardiovascular;
EQ-5D=European Quality of Life-5 Dimensions.
QOL EDSS and utility* have shown a
significant inverse relationship9
Mortality Mortality ratio of patients with MS
exceeds CV disease,†,10 stroke,‡,11 and
early breast cancer12
Employment 50% of patients with MS are
unemployed as of EDSS 3.0 and/or
after 10 years from diagnosis13
Healthcare costs Bulk of cost attributed to services
(28.5%) and long-term sick leave and
early retirement (30%)§,14
Relationships Compared with general population, patients
with MS have a higher probability of
separating/divorcing and doing so sooner13
MS has a negative
impact on…
Consequences of Increasing EDSS Scores: Loss of Employment1
14
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
14
Uti
lity
EDSS Status
EDSS and utilitya show a significant inverse relationship
1,b
aUtility measures are derived from EQ-5D using the EuroQoL instrument. bError bars depict 95% confidence intervals. Half points on EDSS are not shown on graph axis, except at EDSS 6.5.
• MS is one of the most common
causes of neurological disability
in young adults2
• Natural history studies indicate
that it takes a median time of 8,
20, and 30 years to reach the
irreversible disability levels of
EDSS 4, 6, and 7, respectively3
1. Adapted from Orme M et al. Value In Health. 2007;10:54-60. 2. WHO and MSIF. http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1 &codcol=15&codcch=747. Accessed October 6, 2010. 3. Confavreaux, Compston. 2005. 4. Compston A, Coles A. Lancet 2008
The effect of MS on quality of life
15
What about benign MS?
What prognostic group does the Mser fall Into?
Good Prognosis:
Younger age at onset1,2
Female sex1-3
Optic neuritis4
Isolated sensory symptoms4
Complete recovery from first attack5
Long interval to second relapse4
No disability after 5 years4
Normal MRI / low lesion load4
CSF negative for oligoclonal bands2,6
Poor Prognosis:
Older age of onset1,2
Male sex1-3
“Multifocal” onset4
Efferent systems affected (motor, cerebellar, bladder)4
Incomplete recovery from first attack5
High relapse rate in the first 2–5 years4
Substantial disability after 5 years4
Abnormal MRI with large lesion load4
CSF positive for oligoclonal bands2,6
17
CSF=cerebrospinal fluid
1. Scalfari A et al. J Neurol Neurosurg Pschiatry 2013;00:1-9; 2. Fernandez O. J Neurol Sci 2013;331:10-3; 3. Damasceno A et al. J Neurol Sci
2013;324:29-33; 4. Miller D et al. Lancet Neurol 2005:4;281-8; 5. Confavreux C et al. Brain 2003;126:770-82; 6. Villar LM et al. J Clin Invest
2005;115:187-94.
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
163 patients with “benign” MS
(disease duration >15 years and EDSS <3.5):
45% cognitive impairment
49% fatigue
54% depression
What is benign MS?
CIS Patients n = 40
Impact of MS: cognitive functioning in the CIS stage
Cognitive test performance in an exploratory study*
57%
7%
-20%
0%
20%
40%
60%
Feuillet et al. Mult Scler. 2007.
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
20
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
Is there any other evidence?
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.
0
20
40
60
80
100
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.
Establishing long-term efficacy: use of recursive partitioning and propensity score adjustment to estimate outcome in MS
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
25
TOP: Earlier Natalizumab Treatment Favors Annualized Relapse Rate Outcomes
26
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
TOP: Earlier Natalizumab Treatment Favors Annualized Relapse Rate Outcomes
27
P values from a negative binomial regression model adjusted for gender, baseline EDSS score (<3.0vs ≥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 are 95% CIs.
Wiendl et al. Presented at ENS; June 8–11, 2013; Barcelona, Spain. P372.
Baseline Relapse and Treatment History
Mean
An
nu
ali
zed
Rela
pse R
ate
P<0.0001
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0 DMT 1 DMT ≥2 DMTs 1 DMT 0 DMT ≥2 DMTs
0.16 0.18
0.23 0.24
0.28
0.40
1 Relapse ≥2 Relapses
P<0.0001
The current paradigm is safe and slow!
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!
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-a
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
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.
Do highly-effective treatments stabilise MS?
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
47
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. 48
Demographics and Baseline Clinical Characteristics in Treatment-naïve Patients
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.
CARE-MS I and CAMMS223 were pooled to increase the sample size for
subpopulation analyses − Similar study designs, eligibility rules, baseline demographic characteristics, assessment
schedules, and definitions of the co-primary efficacy endpoints
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
49
0.39
0.18
0
0.1
0.2
0.3
0.4
0.5
0.6
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 Reduced Annualized Relapse Rate vs. SC IFNB-1a in Treatment-naïve Patients
Alemtuzumab provided superior reduction in annualized relapse rate:
– 69% reduction beyond SC IFNB-1a at 3 years in CAMMS2231
– ~55% reduction beyond SC IFNB-1a at 2 years in CARE-MS I2
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
ps
e R
ate
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
ps
e R
ate
69% Risk reduction
vs. SC IFNB-1a
p<0.001
N=111 N=112
50
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 Reduced the Risk of 6-month Sustained Accumulation of Disability in Treatment-naïve Patients
In CARE-MS I, fewer SC IFNB-1a patients accumulated disability than expected, which
may have reduced the ability to detect a significant treatment effect1
In a pooled analysis of treatment-naïve patients, alemtuzumab reduced risk of 6-month
SADb by 50% vs. SC IFNB-1a2
Pa
tien
ts w
ith
SA
D (
%)
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
tien
ts w
ith
SA
D (
%)
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
51
Treatment-naïve Patients Were 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.
Alemtuzumab-treated patients were ~2 times more likely to be free of overall MS disease activity compared with SC IFNB-1a–treated patients over 2 years1,2
Treatment-naïve: CARE-MS I1,2
(Tertiary Endpoints)
52
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 Patients
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.
As expected, baseline EDSS and duration of disease were higher for patients who relapsed on prior compared with treatment-naïve patients
53
Alemtuzumab Significantly Reduced Clinical Disease Activity in Patients Who Relapsed on Prior Therapy
Alemtuzumab significantly reduced relapse rate and risk of 6-month SADa by an
additional 49.4% and 42% beyond SC IFNB-1a, respectively, in patients who relapsed on
prior therapy1
Benefits on clinical disease activity were similar regardless of type, duration, or number of
prior treatments2,b
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)
54
Patients Who Relapsed on Prior Therapy Were More Likely to Be Disease Activity-free with Alemtuzumab vs. SC IFNB-1a
Alemtuzumab-treated patients were 3 times more likely to be free of overall MS disease activity compared with SC IFNB-1a–treated patients over 2 years
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
55
Alemtuzumab Improved Pre-existing Disability vs. SC IFNB-1a in Patients Who Relapsed on Prior Therapy
Alemtuzumab-treated patients were 2.5–3 times more likely to have disability improvement sustained over intervals of up to 1 year vs. SC IFNB-1a
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)
56
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
57
CARE-MS Extension: Majority of Patients Treated with Alemtuzumab Remained 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
Relapse reduction with alemtuzumab treatment was durable; majority of patients remained relapse-free through Year 3
58
CARE-MS Extension: Majority of Patients Experienced 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
• The majority of patients who relapsed on prior therapy and whose EDSS score
improved or remained stable in the core studies (Years 0–2) remained stable or
improved further through Year 3 • Results were consistent with observations in treatment-naïve patients in CARE-MS I
59
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. 60
What is your team’s treatment philosophy?
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 team’s treatment philosophy? maintenance-escalation vs. induction
Another example: treat early and effectively
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
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
Adjuvant (n = 50)
Salvage (n = 118)
p = 0.002
Su
rviv
al
Time since radiotherapy (years)
Biochemical relapse-free survival
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
Treatment objectives in relapsing MS
Freedom from
disease
activity/disease
activity free
Reduced ongoing
damage
Improved Quality of Life
Treat Early
68
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
69
Ian Rogers. ACNR 2007: 7(3);14.
Conclusions
• MS is a bad disease
• Mortality, disability, unemployment, divorce, cognitive impairment, etc.
• Early aggressive 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, natalizumab, cladribine extension studies.
WWW.MS-RES.ORG