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.

1. Targeting Progression
The Progressive MS Alliance
Alan Thompson
UCL and MSIF

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

5. Relapses and Impairment
MRI Activity
Brain Atrophy
Preclinical
SPMS (and PPMS) represents a
significant unmet clinical need
RR-MS
10 FDA-approved
therapies
0
SP-MS
1 FDA-approved therapy
(mitoxantrone - rarely used)
5-10
Disease Duration (Years)
15-20+

6. Prevalence of MS

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51% published epidemiological research, 20% unpublished research/ registers

8. 1. Delayed Progression
3. Improved Function
2. Stabilised Progression
4. Recovered Function

9. WHAT ARE YOUR
EXPECTATIONS OF A THERAPY
FOR PROGRESSIVE MS?
3
2
1
www.ms-res.org
9

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

11. Onset of progressive phase
determines disability
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

14. MRI in
primary
progressive
MS
Thompson et al. Ann Neurol 1991

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!

16. Inflammation
in Progressive
MS
(Revez et al Brain 1994)

17. Compartmentalized
inflammation in
progressive MS
Bradl and
Lassmann, Semin
Immunopathol 2009

18. Pathologic Mechanisms in Early vs. Late MS
0
5
10
15
20
Years After MS Onset
25
30

19. Key areas
Inflammation
White matter demyelination/remyelination
Gray matter involvement
Axonal loss

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

21. Key areas
Inflammation
White matter demyelination/remyelination
Gray matter involvement
Axonal loss

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

24. Key areas
Inflammation
White matter demyelination/remyelination
Gray matter involvement
Axonal loss

25. Spinal cord axonal loss correlates with
disease duration and disability
Schirmer et al., Brain Pathol 2011

26. Summary
Lassmann et al., Nat. Rev. Neurol. 2012

27. Progressive MS
• Defining the issue – impact and mechanisms
• Exploring interventions
=> Trial Design/Outcomes
• Current studies
• Future direction – International initiative

28. Previous
trials

29. Studies to date
Conventional trial design
• Large numbers
• Lengthy
• Very expensive
Targeting inflammation (largely)
=> Need to focus on neuroprotection/repair?

31. Treatment A
Placebo
Treatment B
Placebo
Treatment C
Placebo
Moving to adaptive trials

32. The interim measure
Δ EDSS
Δ MRI
MRI
0
EDSS 0
6
12 18 24 30 36
Interim

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

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

40. Baseline

41. Registered
Year 2

42. Screening
showing
BBSI
colour
overlay

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

44. Change
whole
brain
volume
(%/yr)

45. Change in EDSS
0 to 24 months
Change in EDSS from Baseline to 24 months

46. Cannabinoid trials
12 month follow-up (80%)
N=657 CAMS
Zajicek Lancet 2003; JNNP 2005

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.

48. 1.0
P(EDSS progression)
0.8
0.6
0.4
0.2
Treatment group
Active
Placebo
0.0
0
200
400
600
800
Time to EDSS progression (days)
1000
1200

49. 1.0
P(EDSS progression)
0.8
0.6
0.4
Baseline EDSS score
4
4.5
5
5.5
6
6.5
0.2
0.0
0
200
400
600
800
Time to EDSS progression (days)
1000
1200

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

52. Kapoor et al. Lancet Neurol 2010; 9: 681–88.

53. Kapoor et al. Lancet Neurol 2010; 9: 681–88.

54. MS-STOP>>MS-SMART
4 arms [1 placebo + 3 active]
Multiplex Phase IIb trial
– 4*110=440
– allowing for drop-outs [10%+10%]
– Primary outcome=SIENA PBVC
– Gives 90% power for 35% treatment effect

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

57. Acute
neuroprotection

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)

60. Environmental
Factors:
Vitamin D
UVB
Skin
7-dehydrocholesterol
Cholecalciferol
(Vitamin D3)
Diet
“Vitamin D Status”
Biomarker
Liver
25-hydroxyvitamin D
Serum 25(OH)D
Kidney - and many other cells.
1,25-dihydroxyvitamin D
Active
metabolite
Courtesy H. Hanwell
Calcium/Bone
Cell growth, immune function, etc

61. Vitamin D-binding protein
in cytoplasm of neurons in
spinal cord

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

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

66. Exercise increases
fitness and walking
ability
VO2 peak (trial 1-5, p=0.04)
6MWT (p=0.008)
Briken et al., in press MSJ

67. Exercise improves
learning and
memory
CVLT learning (trial 1-5, p=0.02)
CVLT delayed recall (trial 7, p=0.01)
Briken et al., in press MSJ

70. Mission
To expedite the development of
therapies for effective disease
modification and symptom
management in progressive MS

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

78. Countries actively involved in the Alliance

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

81. REQUEST FOR
APPLICATIONS
(RFA)
PRE-APPLICATIONS DUE
APPLICATIONS DUE
31 January 2013
15 January 2013
http://www.endprogressivems.org
ANNOUNCEMENT OF
DECISIONS
May 2014
START
July 2014

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