Disease Management
Holistic Approach: Benefit Risk from HCP & Patient Perspective
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 Novartis for making available data slides on natalizumab, alemtuzumab and fingolimod for this presentation.
How much of my time is taken up with DMTs?
10%
60%
5%
15%
5%
DMTs
Symptomatic
Diagnostic
Admin
Blog
My clinical time
Epstein Bar Virus
Genetics
Vitamin D
Smoking
Risks
Adverse events
Differential Diagnosis
MRI
Evoked Potentials
Lumbar puncture
Blood Tests
Diagnostic Criteria
Cognition
Depression
Fatigue
Bladder
Bowel
Sexual dysfunction Tremor
Pain Swallowing
Spasticity Falls
Balance problems Insomnia
Restless legs Fertility
Clinical trials
Gait
Pressure sores
Oscillopsia
Emotional lability
Seizures
Gastrostomy
Rehab
Suprapubic catheter Intrathecal
baclofen
Physio- therapy
Speech therapy
Occupational Therapy
Functional neurosurgery
Colostomy
Tendonotomy
Studying
Employment Relationships
Travel
Vaccination
Anxiety
Driving
Nurse specialists
Family counselling
Relapses
1st line
2nd line
Maintenance Escalation Induction
Monitoring
Disease-free
Disease progression
DMTs
Side Effects
Advanced Directive
Exercise
Diet
Alternative Medicine
Pregnancy Breast Feeding
Research
Insurance
Visual loss
Palliative Care
Assisted suicide
Social services
Legal aid
Genetic counselling
Prevention
Diagnosis
DMT Symptomatic
Therapist
Terminal
Counselling An holistic approach to MS; beta ver. 3.2
Intrathecal phenol
Fractures
Movement disorders
Osteopaenia
Brain atrophy
Hearing loss
Tinnitus
Photophobia
Hiccoughs
DVLA
Neuroprotection
Psychosis
Depersonaliation
Brain Health
Cognitive Reserve
Sudden death
Suicide
OCD
Narcolepsy
Apnoea Carers
Respite
Hospice
Respite
Dignitas
Advanced Directive
Rhiztomy
Wheelchair
Walking aids
Blood/Organ donation
Brain donation
Exercise therapy
NABs
Autoimmunity
Infections
Outcome measures
Web Resources
Pathogenesis
Double vision
What is MS?
NEDA
T2T OCT
Neurofilaments
JCV status Pharma
Anaesthesia
The hypothetical Ideal
Reliable
long-term efficacy
Maintaining
QOL
Maintaining
independence
Maintaining the
ability to work
No issue for
pregnancy/fertility
Maximum reduction
of MS disease activity
Maximum
tolerability
Maximum
safety
Ease of
use
Minor impact on
everyday life
Risks vs. Benefits
How bad is MS?
MS Infographic
www.ms-res.org
Audience Response Question
What proportion of MSers are unemployed by the time they need a walking aid (EDSS 6.0)?
1. <20%
2. 25-50%
3. 50-60%
4. >60%
> 60%
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
The Gambler’s Dilemma
What about benign MS?
Audience Response Question
What proportion of MSers have benign MS?
1. >50%
2. 40-50%
3. 30-40%
4. <30%
Hospital-based populations (EDSS < 3.5) • 15 years ~30% • 25 years ~15% • 30 years ~5% • 50 years ~2.5% Community-based populations • 15 years ~45%
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
Audience Response Question
Do you believe in the concept of a therapeutic window?
1. Yes
2. No
3. Maybe
Coles et al. J Neurol. 2006 Jan;253(1):98-108.
Post-inflammatory neurodegeneration
Early vs. Late?
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.
Natalizumab STRATA: 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
21
Tur et al. Interferon Beta-1b for the Treatment of Primary Progressive Multiple Sclerosis: Five-Year Clinical Trial Follow-up. Arch Neurol. 2011 Nov;68(11):1421-7.
Therapeutic Lag
Motor system to legs
Cerebellar or balance systems
Bladder Therapeutic window 1
Therapeutic window 2
Therapeutic window 3
Upper limbs
Sensory
Cognition
Vision
Etc.
Therapeutic window 4
Therapeutic window 5
Therapeutic window 6
Therapeutic window 7
Therapeutic window 8, etc….
Diagnosis of Progressive MS
Effective DMTs could still target the remaining windows of therapeutic opportunity for individual neurological
systems
The Asynchronous Progressive MS hypothesis
Audience Response Question
Do you believe in the concept of a therapeutic window?
1. Yes
2. No
3. Maybe
No I think there are
multiple windows
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?
26
Mo
nito
rin
g
Tre
atm
ent
Clin
ica
l O
ccu
p &
so
cia
l
PML
17%
17% 85%
>800,000 SlideShare Views
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?
34
Mo
nito
rin
g
Tre
atm
ent
Clin
ica
l O
ccu
p &
so
cia
l
Redefining our treatment target
No evident 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
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
Relapses
Unreported relapses
Clinical disease progression
Subclinical relapses: focal MRI activity
Focal gray and white matter lesions not detected by MRI
Brain atrophy
Spinal fluid neurofilament levels
MS Iceberg
Clinical activity
Focal MRI activity
Hidden focal and diffuse MRI activity
Microscopic or biochemical pathology
Biomarkers
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?
39
Mo
nito
rin
g
Tre
atm
ent
Clin
ica
l O
ccu
p &
so
cia
l
Dec 2007 Jul 2010 Jul 2013
Relapses
Unreported relapses
Clinical disease progression
Subclinical relapses: focal MRI activity
Focal gray and white matter lesions not detected by MRI
Brain atrophy
Spinal fluid neurofilament levels
MS Iceberg
Clinical activity
Focal MRI activity
Hidden focal and diffuse MRI activity
Microscopic or biochemical pathology
Biomarkers
End-organ damage
Rheumatoid arthritis End-stage joint disease
Control Multiple sclerosis
Brain atrophy occurs across all stages of the disease
De Stefano, et al. Neurology 2010
n= 963 MSers
Treatment-effect on atrophy correlates with treatment-effect on disability
Sormani et al. Ann Neurol 2014;75:43–49.
Treatment effect on disability predicted by effect on T2-lesion load and brain atrophy
Meta-analysis of treatment effect on EDSS worsening (y) vs effects on MRI lesions
and brain atrophy, individually or combined, in 13 placebo-controlled RRMS trials
(13,500 patients)
Sormani MP et al. Ann Neurol. 2014;75:43-49.
-1.0%
-0.8%
-0.6%
-0.4%
-0.2%
0.0% Years 0-2
-0.82%
-0.80%
P=0.822†
Placebo (N=315) Natalizumab (N=627)
Year 0-1* Year 1-2
-0.40%
-0.56%
-0.43%
-0.24%
P=0.004†
P=0.002†
†Difference between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401.
AFFIRM Study: natalizumab and brain atrophy
Mean
(S
E)
perc
en
tag
e c
han
ge i
n B
PF
Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM
FREEDOMS, 2 years
Fingolimod 0.5 mg (n = 356)
Placebo (n = 329)
***
*
**
6 0 12 24
Time (months)
0
-0.4
-0.8
-1.2
-1.6
-2.0
−38%
vs placebo p<0.001
Ch
ange
in m
ean
BV
fro
m
bas
elin
e (%
)
TRANSFORMS, 1 year
0 12
Time (months)
0.0
-0.4
-0.6
-1.0
IFNb-1a IM (n = 359)
Fingolimod 0.5 mg (n = 368)
−40%
vs IFNb-1a IM p<0.001
*** -0.2
-0.8
Ch
ange
in m
ean
BV
fro
m
bas
elin
e (%
)
ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24 BV, brain volume; ITT, intent-to-treat. Gilenya™ Prescribing Information 19 April 2012. Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: 387-401, and Cohen JA et al. N Engl J Med 2010; 362: 402-415. Copyright © 2011 Massachusetts Medical Society. All rights reserved
Reduction in brain atrophy on alemtuzumab
Alemtuzumab Improves Brain MRI Outcomes
in Patients With Active Relapsing-Remitting
Multiple Sclerosis: Three-Year Follow-up of the
CARE-MS Studies
Douglas L Arnold,1,2 Elizabeth Fisher,3 Jeffrey A Cohen,4 Frederik Barkhof,5
Krzysztof W Selmaj,6 David H Margolin,7 Jeffrey Palmer,7 Edward J Fox8
AAN 2014
Blitz S65-008
1NeuroRx Research, Montréal, Québec, Canada, and 2Department of Neurology and Neurosurgery, Montreal
Neurological Institute, McGill University, Montreal, Québec, Canada; 3Department of Biomedical Engineering,
Cleveland Clinic, Cleveland, OH, USA; 4Cleveland Clinic, Cleveland, OH, USA; 5VU University Medical Centre,
Amsterdam, Netherlands; 6Department of Neurology, Medical University of Łódź, Łódź, Poland; 7Genzyme, a
Sanofi company, Cambridge, MA, USA; 8University of Texas Medical Branch, Round Rock, TX, USA
CARE-MS I & II Three-Year MRI Outcomes Change in Brain Parenchymal Fraction (BPF)
Alemtuzumab slowed brain volume loss over 3 years, as assessed by change in BPF
For both patient populations, the median percentage reduction in BPF observed in in Year 3 (0.19% and 0.10%, respectively) was smaller than that observed in Year 1 (0.59% and 0.48%) and Year 2 (0.25% and 0.22%)
Percentage Change in BPF in Formerly Treatment-Naive Patients (CARE-MS I)
Percentage Change in BPF in Patients Who Relapsed on Prior Therapy (CARE-MS II)
Me
dia
n C
ha
ng
e F
rom
Ba
se
lin
e, %
(9
5%
CI)
Year No. of Patients 371 367 351 323
% Change from Previous Year – –0.59% –0.25% –0.19%
Me
dia
n C
ha
ng
e F
rom
Ba
se
lin
e, %
(9
5%
CI)
Year 428 414 405 359
– –0.48% –0.22% –0.10%
No. of Patients
% Change from Previous Year
0 1 2 3
-1 .5 0
-1 .2 5
-1 .0 0
-0 .7 5
-0 .5 0
-0 .2 5
0 .0 0
0 1 2 3
-1 .5 0
-1 .2 5
-1 .0 0
-0 .7 5
-0 .5 0
-0 .2 5
0 .0 0
AAN 2014
Blitz S65-008
CARE-MS I & II Three-Year MRI Outcomes Proportion of Patients Free of Gd Lesions, T2 Lesions, and MRI Activity
The majority of alemtuzumab-treated patients were free of MRI activity (absence of Gd-enhancing lesions and new/enlarging T2 hyperintense lesions) at Year 2 and Year 3
MRI activity-free: absence of both Gd-enhancing and new or enlarging T2 hyperintense lesions; CARE-MS=Comparison of
Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; CI=confidence interval; DMT=disease-modifying therapy; Gd=gadolinium;
MRI=magnetic resonance imaging; Y=year
No. of Patients 359 370 336 356 370 325 354 369 326
Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3
Pro
po
rtio
n o
f P
ati
en
ts,
% (
95
% C
I)
0
20
40
60
80
100
Gd-enhancing
lesion-free
New/enlarging
T2 lesion-free
MRI
activity-free
% MRI Activity Free in Treatment-Naive
Patients (CARE-MS I)
% MRI Activity Free in Patients Who
Relapsed on Prior Therapy (CARE-MS II)
No. of Patients 412 421 364 405 423 361
Gd-enhancing
lesion-free
New/enlarging MRI
activity-free
402 414 361
Pro
po
rtio
n o
f P
ati
en
ts,
% (
95
% C
I)
0
20
40
60
80
100
Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3
T2 lesion-free
Patients were treated with alemtuzumab 12 mg at baseline and 12 months later
Re-treatment in Year 3 was administered upon recurrence of disease activity
18% of CARE-MS I patients and 20% of CARE-MS II patients were re-treated
with alemtuzumab in Year 3; <3% were treated with another DMT in Year 3
AAN 2014
Blitz S65-008
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
Brain volume loss should be included in our definition for NEDA
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
Treating-2-target
Choosing therapy
X Y Z
Define the Individual’s MS
No
Treatment failure? Yes
• Patient’s preferences?
• Your choice?
Individual measures:
• Evidence of disease activity?
• Tolerability/safety?
• Adherence?
• Drug or inhibitory markers?
Monitoring
• MS prognosis
• Life style and goals
• Shared goals for therapy
Rebaseline
Rebaseline:
• IFNβ, natalizumab, fingolimod,
teriflunomide, DMF=3-6 months
• Glatiramer acetate=9 months
• Alemtuzumab=24 months
DMF=dimethyl fumarate.
Pros and cons of maintenance vs. induction therapies
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
T2T - NEDA
Zero Tolerance
Treatment objectives in relapsing MS
NEDA
Reduced ongoing
damage
Treat Early
T2T - NEDA
Zero Tolerance
Functional
Improvement
Maintain reserve
capacity
Treatment objectives in relapsing MS
NEDA
Reduced ongoing
damage
Treat Early
T2T - NEDA
Zero Tolerance
Functional
Improvement
Maintain reserve
capacity
Treatment objectives in relapsing MS
NEDA
Reduced ongoing
damage
CNS Repair
Healthy
ageing
Treat Early
T2T - NEDA
Zero Tolerance
Functional
Improvement
Maintain reserve
capacity
Treatment objectives in relapsing MS
NEDA
Reduced ongoing
damage
CNS Repair
Healthy
ageing
Improved Quality of Life / Brain Health
Treat Early
Audience Response Question
Who is more risk averse?
1. MSers
2. Neurologists
3. Equally risk averse
Neurologists
Risk acceptance of PML (Survey 2009)
Putative risk rate to stop Tysabri treatment
Heesen et al. (2010) MSJ
WWW.MS-RES.ORG
WWW.MS-RES.ORG
Audience Response Question
Do you believe that we can cure MS?
1. Yes
2. No
3. Not sure
Possible
cure
The hypothetical Ideal
Reliable
long-term efficacy
Maintaining
QOL
Maintaining
independence
Maintaining the
ability to work
No issue for
pregnancy/fertility
Maximum reduction
of MS disease activity
Maximum
tolerability
Maximum
safety
Ease of
use
Minor impact on
everyday life
Survival Curves
85%
50%
30%
0%
15yrs 25yrs 40yrs 50yrs
100%
Natural history
Survival Curves
85%
50%
30%
0%
15yrs 25yrs 40yrs 50yrs
100% Benign MS
Natural history
Survival Curves
85%
50%
30%
0%
15yrs 25yrs 40yrs 50yrs
100% Benign MS
Natural history
Delayed onset of SPMS
Survival Curves
85%
50%
30%
0%
15yrs 25yrs 40yrs 50yrs
100% Benign MS
Natural history
Unrealistic expectation
Delayed onset of SPMS
Survival Curves
85%
50%
30%
0%
15yrs 25yrs 40yrs 50yrs
100% Benign MS
Proportioned of treated MSers are cured
Natural history
Unrealistic expectation
Delayed onset of SPMS
Defining a cure: a working definition
85%
50%
30%
0%
15yrs 25yrs 40yrs 50yrs
100%
Proportioned of treated MSers are cured
Natural history
A cure is NEDA (no evident disease activity) x 15 years
Audience Response Question
Do you believe that we can cure MS?
1. Yes
2. No
3. Maybe
Maybe The experiment is ongoing
Conclusions • MS is a bad disease
• Mortality, disability, unemployment, divorce, cognitive impairment, etc.
• Early highly-effective therapy is the only realistic option of preventing end-organ damage
• Now an established treatment option in the EU
• NEDA and T2T are current treatment target (zero tolerance)
• Beyond NEDA we need to target end-organ damage (brain atrophy and CSF NF levels)
• We need an acceptable working definition of an MS cure • NEDA x 15 years?
• Only possible with induction therapies (alemtuzumab, cladribine, BMT)
• Is it fair to make MSers wait 20 years for the outcome of an ongoing experiment?
• Can we cure MS?
• Risks and benefits • Who should take the risks?
• Who should make the decisions?
• What is the role of the healthcare professional in decision-making?