Progressive MS is an unmet clinical need with limited treatment options. This document discusses defining progressive MS, exploring disease mechanisms and interventions, current clinical trials, and the need for an international initiative. It summarizes research showing inflammation, demyelination, gray matter involvement, and axonal loss contribute to progression. Clinical trials have targeted inflammation with limited success. Future trials aim to test neuroprotective agents, lifestyle factors, and remyelination/rehabilitation approaches. An international collaborative is needed to expedite therapies through target identification, preclinical models, clinical outcome measures, trial design, and engaging the research community. The goal is to accelerate development of effective treatments for disease modification and symptom management in progressive MS.
2. Progressive MS
• Defining the issue – impact and mechanisms
• Exploring interventions
=> Trial Design/Outcomes
• Current studies
• Future direction
=> International initiative
3. Increasing disability
Progressive Forms of MS
Many MS patients begin
with a relapsing form and
convert to a progressive
form
Increasing disability
Time
A small percentage
of MS patients have nearly
continuous progression of
disability with no distinct
relapses
Time
4. Defining
Progressive MS
•
Neurologist:
– accumulation of disability,
– gradual change over time (Progressive myelopathy)
•
Imager:
– Progressive atrophy
– Decreasing MTR, NAA, fractional anisotropy
•
Pathologist:
– Axonal pathology
– Oligodendrocyte pathology
•
Rehabilitationist:
– Loss of function; worsening symptoms
•
Patient:
– Loss of independence
– Inability to work, worsening symptoms
Progressive MS is defined differently from different perspectives
7. Estimated number of people with MS
Worldwide
2008: 2.1 million
2013: 2.3 million
2008: 30% of countries cited sources of data
2013: 71% cited sources of data
51% published epidemiological research, 20% unpublished research/ registers
10. Development of secondary progression
is the dominant determinant of long-term
prognosis, independent of disease
duration and early relapse frequency
Scalfari et al Neurology 2011
12. Progressive MS
• Defining the issue – impact and mechanisms
• Exploring interventions
=> Trial Design/Outcomes
• Current studies
• Future direction
=> International initiative
13. Key areas
Inflammation
White matter demyelination/remyelination
Gray matter involvement
Axonal loss
15. Brain
Enhancement
• 42% patients with early PPMS (<
5 years) had at least one
enhancing lesion on their
baseline scan
• Number of enhancing lesions
associated with
- younger age (r=0.5, p= 0.003)
- higher T2 load (r= 0.5, p=0.02)
- worse outcome!
20. Remyelination often incomplete
in progressive MS
score 0
% o f lesio n s
40
30
20
10
0
0
score 1
1
2
sco r e
188 lesions, 33 patients
0: completely demyelinated
1: less than 50 % remyelinated
2: more than 50 % remyelinated
3: complete remyelination
score 3
Goldschmidt et al., Neurology 2009
3
22. Cortical demyelination
is extensive in
progressive MS
SPMS/
PPMS
RRMS
Cortical lesion area
forebrain (%)
White matter lesion
area (%)
RRMS
2.96
10.3
PPMS
12.54
6.54
SPMS
13.29
24.13
Kutzelnigg et al., Brain 2005
23. High cortical lesion load at
baseline
High number of new CLs
High rate of GM atrophy
progression
Characterize patients with
disability progression after 5
years
27. Progressive MS
• Defining the issue – impact and mechanisms
• Exploring interventions
=> Trial Design/Outcomes
• Current studies
• Future direction – International initiative
29. Studies to date
Conventional trial design
• Large numbers
• Lengthy
• Very expensive
Targeting inflammation (largely)
=> Need to focus on neuroprotection/repair?
33. Progressive MS
• Defining the issue – impact and mechanisms
• Exploring interventions
=> Trial Design/Outcomes
• Current studies
• Future direction
=> International initiative
34. • Progressive MS Trials:
–
–
–
–
–
–
–
–
–
Phenytoin Optic Neuritis Study (Phase II)
PROXIMUS Trial - oxcarbazepine in SPMS (Phase II)
INFORMS – fingolimod in SPMS (Phase III)
ASCEND – natalizumab in SPMS (Phase III)
ORATORIO – ocrelizumab (rituximab cousin ) in PPMS (Phase III)
EXPAND – siponimod (fingolimod cousin) in SPMS (Phase III)
MS Smart Trial – riluzole, amiloride, ibudilast in SPMS (Phase II)
SPRINT-MS – ibudilast in PPMS/SPMS (Phase II)
rituximab, mesenchymal stem cells, mastitinib, lipoic
acid, erythropoietin, hydroxyurea, idebenone, simvastatin
35.
36. Time to
Confirmed
Disease
All Intent-to-Treat Patients (N=439)
Progression
HR: 0.77
Proportion of Patients
50
(95% CI: 0.55 -1.09)
p-value=0.1442
40
30
Rituximab
Placebo
20
10
0
12
24
36
48
60
72
84
96 108
Time to Confirmed Disease Progression (weeks)
37. Time to
Confirmed
Disease
Progression
Subgroup Analysis
Age <51
Gd (-) at Baseline
n=143
50
Proportion of Patients
50
HR: 0.63
(95% CI: 0.34-1.18)
p=0.1427
40
Age <51
Gd (+) at Baseline
n=72
HR: 0.33
(95% CI: 0.14-0.79)
p=0.0088
40
30
30
20
20
10
10
0
12
24
36
Rituximab
Placebo
48
60
72
84
96 108
0
12
24
36
48
60
72
84
96 108
Time to Confirmed Disease Progression (weeks)
38. MS-STAT trial
High dose oral Simvastatin
in Secondary Progressive Multiple Sclerosis
Jeremy Chataway
for the MS-STAT Collaborators
Lancet in press
39. • High-dose simvastatin (80mg) in SPMS
• Established secondary progression
(narrative/EDSS) for ≥ 2years
• EDSS 4.0 (500m) - 6.5 (20m/2 sticks)
– Relapse free/no corticosteroids >3 months
– DMT >6months
– Mitoxantrone >12 months
– Never alemtuzumab/natalizumab
43. Primary outcome: BBSI change in
whole brain volume (%/year)
Mean (SD)
placebo
Mean (SD) Difference
simvastatin means
(95% CI)*
Change WBV (%/year)
0.589
(0.528)
0.298
(0.562)
Number patients evaluated
64
66
*Adjusting for minimisation variables and MRI site
-0.254
(-0.423 to -0.085)
in p-value
0.003
47. Aims of CUPID study
•
assess the value of Δ9-THC in slowing progressive MS over 3 yrs
•
assess the safety of Δ9-THC over the long-term.
•
improve research methodology; using new, patient-orientated
methods.
50. Progressive MS
• Defining the issue – impact and mechanisms
• Exploring interventions
=> Trial Design/Outcomes
• Current studies
• Future direction
=> International initiative
51. More trials of Neuroprotective agents
Lifestyle
Remyelination
Rehabilitation
Enhancing plasticity
56. •
•
•
UK-based Phase II trial in SPMS
4 arms: riluzole, amiloride, ibudilast, placebo
Primary outcome: atrophy
–
–
•
Clinical measures
Subset: advanced imaging, CSF
Evaluates 3 therapies with using one placebo group
US-based Phase II trial in SPMS/PPMS
Uses NIH-sponsored Phase II trial network
2 arms: ibudilast, placebo
Outcomes: atrophy, DTI, MTR, OCT
Standardized advanced imaging at all sites
Clinical measures
Head-to-head comparison of imaging
measures
Longitudinal validation to clinical outcomes
Ideally, trials should both test a therapy and develop
progressive MS trial methodology
58. Autologous mesenchymal stem cells for the treatment of
secondary progressive multiple sclerosis:
an open-label phase 2a proof-of-concept study
Peter Connick, Madhan Kolappan, Charles Crawley,Daniel J Webber,
Rickie Patani, Andrew W Michell,Ming-Qing Du, Shi-Lu Luan,
Daniel R Altmann, Alan J Thompson, Alastair Compston,
Michael A Scott, David H Miller, Siddharthan Chandran
Lancet Neurology Feb 2012
10 patients with secondary progressive MS
Studied visual system
Possible benefit in visual acuity, latency of evoked
potentials and area of optic nerve
59. ENVIRONMENTAL
AGENTS
Diagnosis
Cigarette
In utero
1st clinical symptom
Microbial
Smoke
EBV
Exposures ↓Vitamin D
Minor tissue
Birth
injury
Altered host
immune response
Genetic
Predisposition
-HLA phenotype
-Exposure of circulating
T cells to tissue antigens
Active disease
-B cell transformation
-Proliferation of
T cells (against EBVAg)
62. Median time from MS symptom onset to PDDS 8 according to study variables :
sun exposure before MS diagnosis (a) and cod liver oil intake from 6 to 15 years (b)
McDowell et al
Neuroepidemiology 2011; 37: 52-57
63.
64. • Data from intervention studies evaluating disease progression do not
support a disease modifying effect of exercise
• MRI data, patient-reported data and EAE data indicate a possible
disease-modifying effect of exercise
• Further studies with better methodologies are required
65. Exercise improves aerobic fitness and
cognition in progressive MS
a randomised controlled pilot trial
Birken S, Gold SM, Patra S, Harbs D, Tallner A,
Ketels G, Schulz KH, Heesen C
Institute for NeuroImmunology & Clinical MS Research
University Medical Centre Eppendorf, Hamburg
70. Mission
To expedite the development of
therapies for effective disease
modification and symptom
management in progressive MS
71.
72. Efforts
Underway
2012 Global Progressive MS Portfolio
$85.5 M USD
Plus ~45 interventional clinical trials currently recruiting patients
(www.clinicaltrials.gov)
73. Progressive MS Research Initiatives
1. Over 100 investigator initiated research projects
2. MS Outcomes Assessment Consortium
3. Clinical Trials- MS SMART, SPRINT MS
4. SUMMIT natural history and risk factors study
5. Revision of Lublin-Reingold Clinical Course Descriptor
6. International Progressive MS Alliance
74. Target pathways
identification
Experimental
models
&
validation
POC
Clinical Outcome
Trial Design
Measurements
Symptomatic
Management
Strategies
Trial design
Therapies
(Phase II)
(Phase III)
Rehabilitation
Strategies
Repurposing
P. Stys
P.Goodfellow
K. Lee
P. Zaratin
F. Lublin
J. Hobart
P. Feys
T. Coetzee
D. Brown
K. Zuidwijk
COMMUNITY ENGAGEMENT
TO IDENTIFY RESEARCH GAPS
TO PROPOSE FUNDING STRATEGIES AND COLLABORATIVE MODELS
TO DETERMINE RESEARCH AGENDA PRIORITIES
TO EXPEDITE THERAPIES DISCOVERY & DEVELOPMENT
MS SOCIETIES & MSIF: 2013 CALL FOR PROPOSALS ?
75. Timeline and
milestones
Research community
engagement – working groups to
fill gaps, propose strategies and
funding models
April - August 2012
November 2012
Working groups present
recommendations to
Steering committee
First International
Scientific Conference
on Progressive MS
February 2013
Sept 2013
First Request for
Applications (RFA) by
Alliance
76. Governance
• MOU fully executed. Signed by
USA, UK, Italy and MSIF
• These are ‘managing members’
who have voting rights on the
Executive Committee
• A Contributing Member
(Denmark) is also providing
funds. The CEO can nominate a
scientist to join the SSC.
77. Scientific Steering
Committee
* Alan Thompson, UK, Chair
* Timothy Coetzee, USA
Giancarlo Comi, Italy , co-Chair
* Bruce Bebo, USA
* Kathy Smith, USA
Robert Fox, USA
* Paola Zaratin, Italy
Marco Salvetti, Italy
Peer Baneke, MSIF
* Dhia Chandraratna, MSIF
* Ceri Angood, MSIF
Nick de Rijke, UK
* Susan Kolhaas, UK
Raj Kapoor, UK
Inga Huitinga, Netherlands
Kim Zuitwijk, Netherlands
* Karen Lee, Canada
Anthony Feinstein, Canada
79. REQUEST FOR
APPLICATIONS
(RFA)
CHALLENGES IN PROGRESSIVE MS AWARDS - encourage
scientific innovation in:
• Phenotype/Genotype and pathophysiological mechanisms
• Development of new and existing pre-clinical models for
progressive disease based on community consensus building
• Discovery and validation of proof of concept biomarkers
• Innovative designs for proof of concept trials of therapeutic
agents or therapeutic strategies
80. REQUEST FOR
APPLICATIONS
(RFA)
2. INFRASTRUCTURE AWARDS - to develop enabling
technologies and infrastructure for data sharing to:
• promote and enhance data sharing and knowledge
management
• encourage collaboration among researchers
• support one or more of the Alliance priority research
areas
Awards - €75,000 for 12 months
82. Must Do’s
• Understand relevant aspects of human MS pathology
– Validate a pre-clinical model that emulates human pathology
– Develop high through-put screening tools
• Validate a Phase II outcome biomarker
– Use trials to advance methodology
• Develop accepted clinical outcome measures
• Not forget about symptomatic treatments
• Expand international collaborations
Editor's Notes
The reported prevalence of MS varies considerable between countries and regions.
Baseline scan (native space)
Repeat scans – registered to baseline (spatially aligned)
Screening (baseline) scan showing BBSI colour overlayRed = intensity (brain tissue) lossGreen= intensity (brain tissue) gainBSI measures this across all the brain surfaces to give a volume of change over time
In addition to over 100 investigator initiated research projects, there are several Society initiatives focused on progressive MS that I want to make you aware of. They include:Efforts to develop an updated outcomes measures for MS clinical trials, Funding for a couple of key progressive clinical trialsA multi center risk factor study called SUMMITSupport for a revision of the Lublin/Reingold clinical course descriptorsAnd finally a bold initiative to create an international alliance that accelerates progressive MS research and development of new strategies for treating disease
Workgroups have been engaged for most of last year of each priority area. The workgroups presented their recommendations at a meeting in London in November 2012 and this was followed by the first International Scientific Conference on Progressive MS in Milan in February 2013. Following this meeting the SSC developed a research strategy, and as part of that strategy the first operational phase: a first RFA in Sept 2013.
Managing members give 1 million euroContributing members give ½ million euroWe will be working on developing an additional category for members that contribute less than ½ million euro.
This slide is for use at the world conference and for MSIF Berlin board meetings, not necessarily for use with the Scientific Steering Committee in ECTRIMS.Of course all MSIF members AND other countries can get involved too by sharing the RFA an fundraising and raising awareness.Demonstrate that this is a global initiative, an INTERNATIONAL alliance.IT is growing. Room for moreTop three are on the EC plus Danes: contributing memberDutch and Canada are on the Scientific Steering CommitteeSpanish and Australian are on the Comms team
CHALLENGES IN PROGRESSIVE MS AWARDS: designed to encourage and nurture scientific innovation in the following focus areas: • Phenotype/Genotype and pathophysiological mechanisms of progressive MS• Development of new and existing pre-clinical models for progressive disease based on community consensus building• Discovery and validation of proof of concept biomarkers• Innovative designs for proof of concept trials of therapeutic agents or therapeutic strategies
2. INFRASTRUCTURE AWARDS: to develop enabling technologies and infrastructure for data sharing topromote and enhance data sharing and knowledge management, encourage collaboration among researchersAnd support one or more of the Alliance priority research areasAwards - €75,000 for 12 months (~10 awards per year) – possibility of €500,000 follow on funding for successful projects