By Dr Martin Duddy

1. drugs on the horizon
new and emerging drugs for
progressive MS
Dr Martin Duddy
Consultant Neurologist
Royal Victoria Infirmary
Newcastle upon Tyne, UK

2. RRMS: the field
interferon-b
(Betaferon/Extavia
Avonex
Rebif)
pegylated interferon
(Plegridy)
glatiramer acetate
(Copaxone)
teriflunomide
(Aubagio)
dimethyl fumarate
(Tecfidera)
fingolimod
(Gilenya)
cladribine
(Mavenclad)
daclizumab
(Zynbryta)
natalizumab
(Tysabri)
alemtuzumab
(Lemtrada)
ocrelizumab
(Ocrevus)

3. benchmark 2013

4. benchmark 2013

5. proposed explanations
• wrong pathology
• wrong drugs – inadequately anti-inflammatory
• wrong time – too late
• wrong place – limited CNS penetration

6. INFORMS
• n=970
• initially fingolimod 0.5mg,
1.25mg and PBO
• 1.25mg dose dropped
• composite endpoint
• EDSS
• 9HPT
• 25’TW
• 90% power
• 3 year
Lublin FD, et al. Lancet 2017;387:1075.

8. “MS is typically a two-stage disease”
MRI, magnetic resonance imaging; MS, multiple sclerosis
Adapted from Hersh C, Fox R. 2014. Available from:
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis
? 10–15 20+
Years
Relapsing-remitting phasePreclinical phase Secondary-progressive phase
Brain volume
Disease burden
MRI activity
Clinical disability

9. challenging the dichotomy
*Activity determined by clinical relapses and/or MRI activity (contrast-enhancing lesions; new or unequivocally enlarging T2 lesions assessed at least annually);
if assessments are not available, activity is “indeterminate.” **CIS, if subsequently clinically active and fulfilling current multiple sclerosis (MS) diagnostic criteria,
becomes relapsing-remitting MS (RRMS).
PP, primary progressive; PR, progressive remitting; SP, secondary progressive Lublin FD, et al. Neurology 2014;83:278-286.
1996
SP
PP
PR
Progressive
disease
RRMS
With full
recovery
from
relapses
With
sequelae/
residual
deficit after
incomplete
recovery
2013
Active*
with
progression**
PP
SP
CIS
Not
active*
Active*,**
Not
active*
Active*
Active without
progression
Not active with
progression
Not active
without
progression
RRMS
Progressive
disease

10. when does progression begin?
unmeasured, relapse-independent disability in RRMS
MRI, magnetic resonance imaging
Adapted from Hersh C, Fox R. 2014. Available from:
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis
? 10–15 20+
Years
Relapsing-remitting phasePreclinical phase Secondary-progressive phase
Brain volume
Disease burden
MRI activity
Clinical disability

11. atrophy is an early event
De Stefano et al. Neurology 2010:74:1868–1876

12. progression: sub-clinical or uncaptured?
CIS, clinically isolated syndrome; MS, multiple sclerosis Feuillet L, et al. Mult Scler 2007;13:124–127.
Patientsfailing≥2cognitivetests
CIS patients
n=40
Healthy controls
n=30
p<0.0001
Deficits were found mainly in
memory, speed of information
processing, attention and
executive functioning
0
20%
40%
60%
57%
7%

13. 1. Kobelt G, et al. Mult Scler J 2017 (doi/10.1177/1352458517694432);
2. Simmons RD, et al. J Neurol 2010;257:926–936.
Workforce participation: percentage of patients below retirement age employed
(N=13,391) or self-employed (N=6,769) by EDSS score1
Qualitative study2:
Main reasons for loss of
employment
• Fatigue
• Cognition
• Stress
• Mobility
• Arm-hand
• Not meeting own standards
• Only 17.6% asked to leave or
were dismissed
EDSS, expanded disability status scale
90
80
70
60
50
40
30
20
10
0
Employed(%)
0 1 2 3 4 5 6 6.5 7 8 9
EDSS
82%
77%
68%
54%
49%
39%
29% 28%
16% 15%
8%
progression: sub-clinical or uncaptured?

14. progression independent of relapse activity (PIRA)
– unacknowledged
Cumulative probabilities (Kaplan–Meier analysis) of 24-week-confirmed Expanded Disability
Status Scale (EDSS) overall worsening or progression and of 24-week confirmed EDSS
progression unrelated to relapses identified using a conventional study baseline reference for
events occurring ⩾24 weeks apart. *Defined as a relapse that was recorded from ⩽30 days prior
to the reference EDSS assessment to ⩽30 days post progression assessment.
Kappos L, et al. Multiple Sclerosis Journal 2017: doi:
10.1177/1352458517709619. [Epub ahead of print].
Cumulativeprobability(%)
100
90
80
70
60
50
40
30
20
10
0
0 24 48 72 96 120 144 168 192 216 240 264 288
Weeks from the first treatment infusion
Confirmed EDSS progression unrelated to concurrent relapse*
Overall confirmed EDSS worsening
20.3%
10.2%

15. early progressive MS: the field?
interferon-b
(Betaferon/Extavia
Avonex
Rebif)
pegylated interferon
(Plegridy)
glatiramer acetate
(Copaxone)
teriflunomide
(Aubagio)
dimethyl fumarate
(Tecfidera)
fingolimod
(Gilenya)
cladribine
(Mavenclad)
daclizumab
(Zynbryta)
natalizumab
(Tysabri)
alemtuzumab
(Lemtrada)
ocrelizumab
(Ocrevus)

16. what drives later progressive MS?

17. energy failure in demyelinated axons
Waxman SG. Nat Rev Neurosci. 2006 Dec;7(12):932-41
Mahad DH, et al. The Lancet Neurology. 2015,14:183-193
ACTIVE DISEASE PROGRESSIVE DISEASE
Time
Persistent depolarisation leads to:
• persistent sodium influx
• reversal of calcium pumps
• calcium elevation triggers axonal injury via
secondary intracellular cascade mechanisms
Focal inflammation
Demyelination
Reversible disruption of
neurotransmission
Irreversible neuroaxonal loss
Chronic inflammation
Neurodegeneration
Mitochondrial
Energy failure
Inflammation
Na+/K+
ATPase
Na+
influx
Depolarisation
Ca2+
Na+
Hypoxia
ischaemia
Altered gene
expression
NO
Ca2+
influx
Unmyelinated axon

18. inflammatory damage to mitochondria
Mahad et al. Lancet Neurol 2015;14:183–93.

19. diffuse microglial activation: in, around & outside plaques
MS, multiple sclerosis; NAWM, normal appearing white matter; SPMS, secondary progressive MS;
TSPO PET, translocator protein-18 kDa positron emission tomography; WM, white matter Rissanen E, et al. J Nucl Med 2014;55:939-944.
Seeing the
heterogeneous
inflammation in the
NAWM as variable
TSPO uptake by PET
PET radioligand
binding to TSPO in the
brains of patients with
MS primarily reflects
activated microglia
and macrophages

20. ongoing inflammatory pathology in existing lesions in SPMS:
chronic microglial activation and phase rims
AbsintaMetal.NatRevNeurol2016;12:358–368.
A, Pre-existing lesion with phase rim; B, New enhancing lesion with phase rim
SPMS, secondary progressive multiple sclerosis
PostcontrastT1-weighted
T2*-weightedmagnitude
Phase
0 6 7 12Time (months)

21. chronic cortical inflammation: TSPO PET
RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple
sclerosis; TSPO PET, translocator protein-18 kDa positron emission tomography Politis M, et al. Neurology 2012:79:523-530.
A B C
High
Low
Healthy control RRMS SPMS

22. leptomeningeal enhancement:
7T on post-contrast MP2RAGE images
MP2RAGE, magnetization prepared rapid gradient echo Harrison DM et al. J Neuroimaging 2017;27:461–68.

23. subpial demyelination:
B-cell aggregates and cortical atrophy
a) A CD20+ B-cell aggregate in the deep
sulcus of an SPMS case
b) MOG immunostaining shows extensive
demyelination along the cortical
ribbon (* is location of aggregate)
c) An SPMS case characterized by sparse
meningeal inflammation with a few B
cells
d) Here, corresponding MOG staining
shows only discreet subpial and
intracortical demyelinated areas
CD, cluster of differentiation; MOG, myelin-oligodendrocyte glycoprotein;
SPMS, secondary progressive multiple sclerosis Magliozzi R et al. Ann Neurol 2010 68:477-493.

24. pathological drivers in PMS
• new plaques
• activity in old plaques
• slowly expanding lesions
• cortical lesions
• sub-pial demyelination
• axonal energy failure
• secondary to inactive inflammation
• role of chronic inflammation

25. relook at negative trials

26. some bad luck?
Kapoor R, et al. Lancet Neurol 2010;9:681.

27. Kapoor R, et al. Lancet Neurol 2010;9:681.
wrong primary outcome?

28. EU vs US: Betaferon/Betaseron
Lancet 1998; 352: 1491–97
wrong era?

29. OLYMPUS: rituximab
Hawker K et al. Ann Neurol 2009;66:460
wrong time?
wrong patients?
wrong drug?

30. window of therapeutic efficacy?
Comparisonof the changeinaccumulationof disabilitybetween the secondaryprogressiveandrelapsing-remittingcohorts treatedusingCampath-1H.Gradientsabovethe equatorrepresent
increasingdisabilityandbelowrepresentreducingdisability.
Notethe different time scalebetween the two graphs;the data areannualisedto allowcomparisonbetween the epochsordifferent duration.
EDSS,expandeddisabilitystatus scale; MS,multiplesclerosis ColesAJ,etal.JNeurol.2006;253:98-108.
SecondaryprogressiveMS RelapsingremittingMS
ChangeinEDSS
frombaseline
ChangeinEDSS
frombaseline
Years Months
-7.0
-5.0
-3.0
-1.0
1.0
3.0
5.0
-7.0
-5.0
-3.0
-1.0
1.0
3.0
5.0
0 2 4 6 8 10
0 6 12 18 24 30 36
wrong outcome expected?

31. CDP, confirmed disability progression; HR, hazard ratio; KM, Kaplan-Meier;
SPECTRIMS, secondary progressive efficacy clinical trial of recombinant interferon beta-1a in MS Sormani MP, Giovannoni G. ECTRIMS 2016;Abstract 215.
HR=0.88 (0.72–1.07)
p=0.19
0
20%
60%
40%
100%
80%
CDP(3-months)freesurvival
PROMiSe (PPMS)
Glatiramer acetate
SPECTRIMS (SPMS)
IFN β-1a SC
CDP(3-months)freesurvival
Years
0 2 3 71 54 6
0
20%
60%
40%
100%
80%
Years
0 2 3 71 54 6
post-hoc analysis of SPECTRIMS and PROMiSe
HR=0.88 (0.71–1.07)
p=0.18
wrong duration?

32. ASCEND
• n=889
• SPMS
• already in SP stage
• primary endpoint: % patients whose disability progressed on one or
more measure
• EDSS, walking, 9HPT

33. natalizumab in SPMS (ASCEND Study)
*ITT population
OR, odds ratio, adjusted for baseline EDSS (≤5.5 or ≥6.0) and/or T25FW and/or 9HPT (either hand).
9HPT, 9-hole peg test; CI, confidence interval; EDSS, expanded disability status scale; OR, odds ratio;
Pbo, placebo; SPMS, secondary progressive multiple sclerosis; T25FW, timed 25-foot walk Steiner D, et al. AAN 2016;Poster 009.
Progressors on primary composite endpoint and its individual components at 2 years (N=887*)
Adjusted OR
0.1 101
Greater clinical benefit of natalizumab
Composite 0.86 (0.66–1.13)
p=0.287 44% vs 48%
9HPT 0.56 (0.40–0.80)
p=0.001 15% vs 23%
T25FW 0.98 (0.74–1.30)
p=0.914 35% vs 35%
EDSS 1.06 (0.74–1.53)
p=0.753 16% vs 15%
OR (95% CI)
Confirmed
progressors
(Natalizumab vs Pbo)
looking in the wrong place?

34. where should we look?
asynchronous progressive MS hypothesis
DMT, disease-modifying therapy; MS, multiple sclerosis Giovannoni G, et al. Multiple Sclerosis and Related Disorders 2017;12:70–78.
Therapeutic window 5
Motor system to legs
Lower limb sensory
BladderTherapeutic window 1
Therapeutic window 2
Therapeutic window 4
Upper limb sensory
Upper limb motor
Cognition
Vision
Etc.
Therapeutic window 6
Therapeutic window 7
Therapeutic window 8
Therapeutic window 9
Therapeutic window 10, etc….
Diagnosis of clinically-apparent progressive MS
Effective DMTs could still target the remaining windows of therapeutic opportunity for individual neurological systems despite some
systems having entered the clinically-apparent progressive phase of the disease
Cerebellar or balance systems

35. ASCEND open label extension
• open label extension (all switched to active drug)
• 64% cohort
• up to 3 years (mean 160 weeks)
• overall progression (any of 3): 52% vs 61% OR 0.67 (0.47-0.94); p=0.02
• 9HPT - 19% vs 28% adjusted OR: 0.59; 95% CI: 0.39–0.88; p=0.01
• T25FW - adjusted OR: 0.80 95% CI: 0.57–1.12; p=0.20
• EDSS -adjusted OR: 0.73 95% CI: 0.48–1.10; p=0.13
Neurology April 18, 2017 vol. 88 no. 16 Supplement P5.330

37. ORATORIO - ocrelizumab
• 300 mg x 2 q6m
• placebo controlled
• event-driven
• follow-up to 120 weeks
• 18-55 [44.4, 50%F]
• EDSS 3-6.5 [4.7]
• 10 year of diagnosis [6.1/6.7]
• CSF +ve (IgG index or OCB)
• 80% completed active arm
• 67% PBO
• 25% Gd+ at baseline
Montalban X, et al. ECTRIMS 2015, Barcelona, PS13
ORATORIO
n 488:244
CDP 12wk -24%
(c.50% vs 38%)
CDP 24wk -25%
T25FW -29%
(55% vs 39%)
whole brain volume
wk 24-120
-17.5%
(1.15% vs 0.9% )

38. ORATORIO: clinical
Montalban X, et al. N Engl J Med 2017;376:209–220.

39. ORATORIO: MRI
Montalban X, et al. N Engl J Med 2017;376:209–220.

41. EXPAND
• siponimod
• n=1651
• results persist in
• patients with no relapses in
preceding 2 years
• no Gd at baseline
Kappos L. Neurology 2017;88:Suppl CT.002.

42. EXPAND
• CDP6 -26%
• ARR -55.5%
• Gd+ -87%
• new T2 -81%
• T25FW -6.2% )NS)
• atrophy -23.4%
Kappos L. Neurology 2017;88:Suppl CT.002.

43. MD1003 - biotin
*Mann Whitney U test. CGI, Clinical Global Impression Index
Tourbah, A et al. ECTRIMS 2015, Barcelona, LB233
MD1003
n (%)
PBO
n(%)
p
Primary: EDSS/TW25 over 9 and 12 months
ITT N=103
13
(12.62%)
N=51
0 (0%)
0.0051
Per protocol N=87
13 (14.9%)
N=42
0 (0%)
0.0093
Grp 1: MD1003 (n=103)
Grp 2: Placebo (n=51)
Extension phase
All patients treated with
MD1003
Proportion of patients with improvement
EDSS or TW25 at M9 confirmed at M12
Mean change of EDSS from BL
Clinical global impression of change (CGI)
Primary
endpoint:
Main
secondar
y
endpoints
Primary or secondary progressive MS
• Progression in the past 2 years
• Without disease inflammatory activity
M0 M12 M18 M24

44. 36 month follow up: open label extension
Vukusic et al. ECTRIMS 2017, Paris

45. statins
• 140 patients
• 80mg simvastatin or
placebo

46. MS-STAT2

47. ibudilast
• inhibitor of
• PDE-4& 10
• MIF
• TLR-4
• 96 weeks
• n=255
• PPMS or SPMS
• mean age 56yr, EDSS 5
• 30% on IFN/GA
• 48% reduction in brain atrophy
• 77-82% reduction in change in MTR
• awaited:
• clinical
• cortical atrophy
• OCT
• lab
Fox R ECTRIMS 2017 Paris

48. SYNERGY
• opicinumab – anti-LINGO 1
• active RRMS or SPMS; median EDSS 3.5; DD ave 10 year
• all on Avonex
• confirmed improvement >1 in EDSS and/or 25’TW, 9HPT, PSAT-3
• n=412
• dose finding 3, 10, 30, 100mg/kg
• primary outcome – linear trend in improvement
Cadavid D ECTRIMS 2016 London

49. SYNERGY
• no linear trend
• % improved:
• younger, RR, better MTR, better brain volume all did better
• similar response on MTR
PBO 52%
3mg/kg 51%
10 mg/kg 66%
30 mg/kg 69%
100 mg/kg 41%
Cadavid D ECTRIMS 2016 London

50. UK ongoing: MS SMART
• fluoxetine
• amiloride
• riluzole

51. AHSCT
• BEAM-ATG protocol
• 1996-2016
• 52 PMS (70 RMS)
• 5yr probability of progression
free survival 62% for PMS
• 5 yr NEDA 50%
• one death/122
Boffa G et al. ECTRIMS 2017 Paris

52. i.v. mesenchymal stem cells – phase 2
all with moderate walking difficulty and problem
with vision
no significant effects on:
colour vision, visual fields, macular volume,
retinal nerve fibre layer thickness, or optic
nerve magnetisation transfer ratio.
Connick et al. Lancet Neurol 2012; 11:150
acuity
VEPs
optic nerve area

53. intrathecal mesenchymal stem cell-derived neural
progenitors
• PMS
• mean EDSS 6.8
• 3 dose 3 months apart
• MSC cultured to generate
MSC-NP
• 15/20 stable/improved
• best in ambulant SPMS
• FDA phase II initiated
Harris V. et al. ECTRIMS 2017 Paris

54. lifestyle in progressive MS
• exercise
• weight
• smoking
• diet?
• vitamin D?

56. conclusions
• we might already be treating progressive disease within RRMS
• first principles suggest we need to treat early
• we should expect a lag in response
• we need to look in areas where response is possible
• there is encouragement for
• anti-inflammatory drugs – already approved
• neuroprotective drugs
• remyelinating/ restorative strategies
• future in combination therapies?
• don’t forget the basics

57. the horizon on drugs
thank you