MS Update 2012
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MS Update
Gavin Giovannoni Barts and The London School of Medicine and Dentistry
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P
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CLINICAL SERVICE
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Dr Janet Williamson National Director, NHS Improvement
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www.ms-res.org
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Gastrostomy
Primary Care Referral Diagnosis Minimal impairment
Moderate impairment
Severe impairment
End of life care
Prevention
Cognition
Depression
Fatigue
Bladder
Bowel
Sexual dysfunction Tremor
Pain
Swallowing
Spasticity
Falls
Balance problems
Insomnia
Restless legs
Studying
Employment
Relapses DMTs
Fertility
Rehab
Suprapubic catheter
Intrathecal baclofern
Palliative Care
Physiotherapy
Speech therapy
Occupational Therapy
Nurse specialists
Counselling
Neuroradiology
Neurophysiology
Clinical trials
Gait
Neuroimmunology
Pressure sores
Driving
Anxiety
DMTs
Functional neurosurgery
Oscillopsia
Sexual dysfunction
Pseudobulbar affect
Seizures
Advanced directive
Assisted suicide
Colostomy
Tendonotomy
Relationships
Travel vaccination
Social services Legal aid
1st line
2nd line
maintenance escalation
induction
risks
adverse events
monitoring
disease-free
family counselling
vD
A ‘holistic’ approach to MS
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Life expectancy
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Survival in MSers is shortened by 8 to 12 years
Survival Probability of Norwegian Patients with RRMS (Hordaland County, Western Norway, 1953–2003)
RRMS=relapsing-remitting MS. Adapted from Torkildsen NG et al. Mult Scler. 2008;14:1191-1198.
50 0 5 10 15 20 25 30 35 40 45 0
10
20
30
40
50
60
70
80
90
100
Surv
ival
(%
)
Years After Onset
30 35 40 45 50 55 60 65 70 75 80 Approximate Patient Age
General Population
RRMS
95% CI
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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
Source: Poster Goodin et al AAN 2011
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)
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Disease modification
13
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The pipeline
Interferons
Phase I
Phase II
Phase III
Marketed
Anti-proliferation agents
Avonex
Atacicept
Campath Rituximab
Novantrone
Rebif
Betaferon/ Extavia
Teriflunomide
Tysabri
Zenapax
Pixantrone
Targeted mAbs/Fc-Ab
Cladribine
Fingolimod
Azathioprine
= oral administration
= injectable
Riluzole
Symptomatic Tx
Vaccine, tolerisation
Tovaxin
ATL-1102
MM-093 BG12
AJM-300
Nerispirdine
Interferon Tau
Interferon omega
Peg IFNb (BIIB017)
Fc- IFb
ATX-MS-1467
Firategrast
Ofatumumab
Sativex
Lymphocyte trafficking
TBC4746
MLN-0002
Targeted Immune regulation
PI2301
R1295
Copaxone
Laquinimod
Fampridine SR
683699 (T-0047)
Ocrelizumab
LY-2127399
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Disability
Time
6 months 12 months 24 months
Active
Placebo
6 months
Relapsing MS
1. Delay attacks / onset of MS 2. Reduce number of attacks 3. Reduce severity of attacks 4. Reduce disability 5. Delay onset of SPMS
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Treat early
Natural course of disease
Later intervention
Later treatment
Treatment at diagnosis Intervention
at diagnosis
Time Disease Onset
Disability
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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%
Source: Poster Goodin et al AAN 2011
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Emerging DMTs
18
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Emerging DMTs for relapsing MS phase 3 & 4
Oral
1. Fingolimod – 53% reduction in ARR relative to placebo
2. Cladribine – 55% reduction in ARR relative to placebo
3. BG12 – 53% reduction in ARR relative to placebo
4. Teriflunomide – 31% reduction in ARR relative to placebo
5. Laquinimod – 21% reduction in ARR relative to placebo
Parenteral
1. Alemtuzumab (anti-CD52) – 55% reduction in ARR relative to IFNβ-1a
2. Ocrelizumab (anti-CD20) – 80% reduction in ARR relative to placebo
3. Daclizumab (anti-CD25) – 54% reduction in ARR relative to placebo
?
Recruiting
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Oral therapies
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BG12
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22
Annualized Relapse Rate at 2 Years (Secondary Endpoint)
0
0.1
0.2
0.3
0.4
0.5
0.6
Placebo(n=408)
BG-12 BID(n=410)
BG-12 TID(n=416)
AR
R (
95%
CI)
*
0.364
0.172 0.189
53% reduction
vs. placebo
P<0.0001
48% reduction
vs. placebo
P<0.0001
*ARR calculated with negative binomial regression, adjusted for baseline EDSS score (≤2.0 vs >2.0), baseline age (<40 vs ≥40), region, and number of relapses in the 1 year prior to study entry.
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Fingolimod
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24
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LAQUINIMOD
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0.1
0.2
0.3
0.4
An
nu
aliz
ed R
elap
se R
ate*
Placebo Laquinimod 0.6 mg
0.29
0.37
IM IFN-β-1a 30 mcg (Avonex®)
0.27
21% Reduction P=0.03
*Adjusted for baseline EDSS, number of relapses in 2-year pre-study, country, baseline T2 lesion volume and GdE-T1 status at baseline scan.
0
29% Reduction P=0.002
PRIMARY ENDPOINT: ANNUALIZED RELAPSE RATE*
27
Vollmer T, et al. Presented at: 5th Joint Triennial Congress of the European and Americas Committee for Treatment and Research in Multiple
Sclerosis. October 19-22, 2011. Amsterdam, NL. Abstract 148. Multiple Sclerosis. 2011;17:S507.
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Teriflunomide
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Teriflunomide significantly reduced relapse rate
by 31% in both dose groups vs placebo
0.369
0.370
0.539
0 0.1 0.2 0.3 0.4 0.5 0.6
14 mg
7 mg
Placebo
Teri
flu
no
mid
e
Adjusteda annualised relapse rate
RRR: 31.2% p=0.0002
RRR: 31.5% p=0.0005
aAdjusted for EDSS score strata at baseline and takes duration of treatment into account
ARR, annualised relapse rate; RRR, relative risk reduction;
EDSS, Expanded Disability Status Scale
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Injection therapies
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Efficacy and safety of ocrelizumab in patients with relapsing-remitting multiple sclerosis
Results of a Phase II, randomised, placebo-controlled, multicentre trial
Ludwig Kappos, University Hospital, Basel, Switzerland
David Li, University of British Columbia, Vancouver, Canada
Peter A Calabresi, Johns Hopkins University, Baltimore, MD, USA
Paul O’Connor, University of Toronto, Toronto, ON, Canada
Amit Bar-Or, McGill University, Montreal, Canada
Frederik Barkhof, VU Medical Center, Amsterdam, The Netherlands
Ming Yin, Genentech Inc, South San Francisco, CA, USA
David Leppert, F Hoffmann-La Roche Ltd, Basel, Switzerland
Robert Glanzman, F Hoffmann-La Roche Ltd, Nutley, NJ, USA
Jeroen Tinbergen, F Hoffmann-La Roche Ltd, Basel, Switzerland
Stephen L Hauser, UCSF, San Francisco, CA, USA
ECTRIMS, 13–16 OCTOBER 2010, GÖTEBURG, SWEDEN
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ARR at Week 24
OCR 2000 mg
0-24
(n=55)
OCR 600 mg
0-24
(n=55)
Placebo
0-24
(n=54)
IFN beta-1a
0-24
(n=54)
ARR
0.169 0.125
0.636
0.364
0.0
0.2
0.4
0.6
0.8
1.0 p=0.0014
p=0.0005
0-24 weeks
80% 73%
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A Randomized, Double-Blind, Placebo-controlled
Study to Evaluate the Safety and Efficacy of
Daclizumab HYP Monotherapy in Relapsing Remitting
Multiple Sclerosis: Primary Results of the
SELECT Trial
Gavin Giovannoni1, Ralf Gold,2 Krzysztof Selmaj,3 Eva Havrdova,4
Xavier Montalban,5 Ernst-Wilhelm Radue,6 Dusan Stefoski,7 Randy
Robinson,8 Katherine Riester,9 Jacob Elkins,9 Gilmore O’Neill9
1Queen Mary University of London, Barts and The London School of Medicine and
Dentistry, UK2St. Josef-Hospital/Ruhr-University Bochum, Bochum, Germany; 3Medical University of Lodz, Lodz, Poland;4Charles University in Prague, Prague,
Czech Republic; 5Hospital Vall d'Hebron University, Barcelona, Spain; 6University
Hospital Basel, Basel, Switzerland. 7Rush University Medical Center, Chicago, IL.
USA; 8Abbott Biotherapeutics, Redwood City, CA, USA; 9Biogen Idec, Cambridge,
MA, USA
Confidential
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0.46
0.210.23
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
Annualized Relapse Rate
Estimated from a negative binomial regression model adjusted for number of relapses in
1-year period prior to study entry, baseline EDSS (≤2.5 vs. >2.5), and age (≤35 vs. >35)
34
An
nu
alize
d r
ela
pse r
ate
Placebo
(n=196)
DAC HYP
150 mg
(n=201)
DAC HYP
300 mg
(n=203)
54%
reduction,
P<0.0001
50%
reduction,
P=0.0002
Confidential
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35 © Copyright 2011 Biogen Idec & Select - Company Confidential
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Safety
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Natalizumab
AFFIRM Highly Active* 1 (n= 148 for TYSABRI, 61 for PBO)
81%
64%
reduction in annualised relapse rate vs. placebo over 2 years (p < 0.001)
reduction in the risk of disability progression, sustained for 24 weeks, as assessed over 2 years (p =0.008)
*Patients with ³ 2 relapses and ³ 1 Gd+ lesion in year prior to entry
1. Natalizumab SmPC
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Natalizumab
Treatment – disease modifying: NATALIZUMAB
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Immunological Velcro
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NATALIZUMAB
Progressive multifocal leukoencephalopathy
Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.
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Natalizumab PML risk stratification tool
Anti-JC virus antibody status
Negative Positive
Prior immunosuppressant use
Natalizumab treatment
>2 Years
Natalizumab treatment
>2 Years
No Yes
No Yes No Yes
Lowest Highest Relative PML Risk
< 1 in 10,000 1 in 94 1 in 256 1 in 668 1 in 1887
Mitoxantrone
Azathioprine
Methotrexate
Cyclophosphamide
Mycophenolate
Cladribine
Rituximab
Etc.
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Progressive MS
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www.ms-res.org
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Disability
Time
12 months 24 months 36 months
Active
Placebo Progressive MS
1. Reduce rate of disability progression
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Disability
Time
6 months 12 months 24 months
Active
Placebo
6 months
Compared to relapsing MS
1. Delay attacks / onset of MS 2. Reduce number of attacks 3. Reduce severity of attacks 4. Reduce disability 5. Delay onset of SPMS
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Delayed Progression 1 Stabilised Progression 2
Improved Function 3 Recovered Function 4
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WHAT ARE YOUR EXPECTATIONS OF A THERAPY FOR PROGRESSIVE MS?
48
1
2
3
www.ms-res.org
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Active tablet
Placebo tablet
Year 1 Year 2 Year 3
560 MS’ers
280 MS’ers
280 MS’ers
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Disability
Time
Year 1 Year 2 Year 3
Active
Placebo
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Disability
Time
Year 1 Year 2 Year 3
Active Placebo
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Year 3 Year 4 Year 5
~600 MS’ers
~300 MS’ers
300 MS’ers
Year 1 Year 2 Year 6 Year 7
Recruitment Trial Data analysis ? Registration
7 years
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Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
Spinal fluid neurofilament levels
Spinal fluid
neurofilament levels
Disability (EDSS) and 3 years
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Axonal damage in relapsing MS is markedly reduced by natalizumab
Gunnarsson et al. Ann Neurol 2010; Epub.
=
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Recruitment Trial Data analysis
6 months
6 months 60 MS’ers
6 months
LP1 LP2 LP3
30 MS’ers active tablet
30 MS’ers placebo tablet
2 years
6 months
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600 MS’ers for 7 years 60 MS’ers for 2 years
3 LPs = 10x as many trials in a ⅓ of the time
New paradigm
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Can we make LPs safer?
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Two types of spinal needle tips: the Quincke and Sprotte
Evans R W et al. Neurology 2000;55:909-914
Traumatic
or
cutting needle
Atraumatic
or
non-cutting needle
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Ultrasound-guide lumbar punctures
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Brain atrophy
or shrinkage
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Kappos et al. N Engl J Med. 2010 Feb 4;362(5):387-401.
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Progressive MS
• Two PPMS clinical trials
• Fingolimod
• Ocrelizumab
• One SPMS clinical trial
• Natalizumab
• ? Oxcarbazepine
• Symptomatic treatments
• Sativex
• Fampridine (Fampyra)
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Walking and spasticity
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Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial
Goodman et al. Lancet 2009; 373: 732–38.
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http://www.youtube.com/watch?v=xZwPlTdEKFE
Fampridine responder 1
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Fampridine responder 2
http://www.youtube.com/watch?v=PTdgJ2m37L0
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Conclusions • Current first-line therapies are only moderately effective
• Safe, but are associated with troublesome side effects and poor adherence
• Escalation therapies (Natalizumab)
• More effective but serious adverse effects
• JCV testing optimises risk:benefit
• A healthy drug pipeline
• 3 oral agents look to emerge from the pipeline
• Alemtuzumab, daclizumab and anti-CD20 most exciting of the parenteral
therapies in phase 2/3
• Symptomatic treatments
• Sativex
• Fampridine
• Patient factors – risk assessment tools, education and a focus on wellness
• Neuroprotection – several phase 2 trials currently been undertaken with oral
agents
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Questions?
www.ms-res.org
Prof. Gavin Giovannoni
Department of Neurology
Royal London Hospital
Whitechapel, London E1 1BB