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Progressive multiple sclerosis: a new hypothesis
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, Genzyme and Novartis for making available data slides on natalizumab, alemtuzumab and fingolimod for this presentation. Professor Giovannoni’s travel to Poland has kindly been sponsored by Biogen.
Pathogenesis of MS
&
Pathological substrate of progressive MS
Pathogenesis of MS
immune activationinnate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
Clinical Attack
Disease Progression
Clinical Recovery
- biology
- clinical outcomes
- biomarkers
Pathological substrate for brain atrophy: 11,000 to 1
Trapp, et al. NEJM 1998;338:278-85
Baseline Month 6
Month 12 Month 18
Baseline Month 6
Month 12 Month 18
Patient 1 Patient 2
End-organ damage
www.ms-res.org
Brain atrophy occurs across all stages of the disease
De Stefano, et al. Neurology 2010
n= 963 MSers
Reserve Capacity
9
Window of therapeutic efficacy: what predicts recovery?
Coles et al. J Neurol. 2006 Jan;253(1):98-108..
10
n=140 n=93 n=80n=143
Prop
ortio
n of
pat
ient
s (%
)
PlaceboNatalizumab
**P=0.0088 **P=0.0019 P=0.8259
At least 0.5 pointEDSS increase
n=47 n=63
At least 1.0 pointEDSS increase
n=140 n=93 n=80n=143
Prop
ortio
n of
pat
ient
s (%
)
*P=0.0349 **P=0.0048 P=0.5976
n=47 n=63
Lublin F. et al. ECTRIMS 2013, Copenhagen October 3rd , Poster P524.
Disabling Magnitude of Relapses in AFFIRMEDSS change from pre-relapse to at relapse
Natalizumab and Clinical Recovery from Relapses
Number of functioning nerve fibres
Attack1
Attack2
Attack3
Attack4
Clinical threshold
Increasing impairment of function
50%recovery
40%recovery
30%recovery
20%recovery
Progressivenerve fibre loss
Sick or vulnerable nerve fibres as a result of an attack
Nerve fibres damaged or
destroyed as a result of an attack
Preventable progressivenerve fibre lossbetween attacks.
Progressive nerve fibre loss primed by, but now independent of, attacks or focal inflammation. This is driven by innate immune and other mechanisms.
Early on good recovery with no, or little, nerve fiber loss between attacks
Later poorer recovery of function (less nerve fibers) and progressive loss of function between attacks
Loss of function
Recovery of nerve fibre function after an attack
Loss of neuronal reserve, despite full recovery of function Neuronal
Reserve
“Reserve Capacity” protects against clinically apparent SPMS
Number of functioning nerve fibres
Attack1
Attack2
Attack3
Attack4
Clinical threshold
Increasing impairment of function
50%recovery
40%recovery
30%recovery
20%recovery
Progressivenerve fibre loss
Sick or vulnerable nerve fibres as a result of an attack
Nerve fibres damaged or
destroyed as a result of an attack
Preventable progressivenerve fibre lossbetween attacks.
Progressive nerve fibre loss primed by, but now independent of, attacks or focal inflammation. This is driven by innate immune and other mechanisms.
Early on good recovery with no, or little, nerve fiber loss between attacks
Later poorer recovery of function (less nerve fibers) and progressive loss of function between attacks
Loss of function
Recovery of nerve fibre function after an attack
Loss of neuronal reserve, despite full recovery of function Neuronal
ReserveSTABLE
UNSTABLE
Trajectories
STABLEUNSTABLE
“Reserve Capacity” protects against clinically apparent SPMS
Therapeutic lag
Contemporary dogma: disability progression in two phases
In RRMS, gender, age at onset, residual deficit after the first relapse, and relapses during the first 2 years are independent predictors of disability progression only in phase 1
DSS
Sco
re
Years from clinical onset of MS
6
5
4
3
2
1
00 5 10 15 20 25 30
7
Phase 2
Phase 1
Natural History
Leray E et al. Brain 2010;133:1-14.
Therapeutic lag hypothesis
therapeutic lag
Sensitivity analysis between year 2 versus year 3
Biogen Idec data on file.
Natalizumab Effect on EDSS Progression by Treatment Duration
TOP Trial: Multiple event analyses per treatment epoch
Slowing of Brain Volume Loss Through 5 Years in Patients Receiving Only the Initial 2 Courses of Alemtuzumab
• Median yearly BVL progressively decreased over 3 years and remained low in Years 4 and 5
Percentage BVL From Baseline
AAN 2016
Year
Med
ian
Cha
nge
From
B
asel
ine,
% (9
5% C
I)
No. of Patients 43
8432
430
407
384
373
Extension StudyCore Studies
Alemtuzumab 12 mg (no retreatment or other DMT)
Median Annual Brain Volume Change
Extension StudyCore StudiesNo. of Patients 432 429 407 378 358
Alemtuzumab 12 mg (no retreatment or other DMT)
Year
BPF=brain parenchymal fraction; BVL=brain volume loss
Therapeutic lag
Yr -1 Yr -2 Yr +1 Yr +2 Yr +3 Yr +4 Yr +5 Yr +6 Yr +7
IFN-beta-1b
Placebo
Notreatment
No treatment
9HPT
, co
gnit
ion
, bra
in a
tro
ph
y
Progression from inflammation in years -2 and -1
Progression from inflammation in years +1 and +2
Progression from inflammation in years +3 to +5
Note the slopes are now parallel
because IFN-beta was stopped after
year +2
Delayed effect on disability progression from IFN-beta treatment in years 1 & 2
Time
Tur et al. Arch Neurol. 2011 Nov;68(11):1421-7.
THERAPEUTIC LAG: IS TREATMENT EFFECT DELAYED IN PROGRESSIVE MS?
Maria Pia SormaniDipartimento Scienze della Salute
Università degli Studi di Genova, Genova, Italy
Gavin GiovannoniBlizard Institute, Queen Mary University London,
Barts and The London School of Medicine and Dentistry, London, UK
Background
IFNbeta-1a
RRMS (PRISMS trial) SPMS (SPECTRIMS trial)
*p<0.05 *p=n.s.
Background
RRMS PPMS (PROMISE trial) (Copolymer 1 MS Study Group trial)
GA
22
Hypothesis
• In subjects with reserve capacity an impact of treatments on sustained disease progression can be seen early, as the affected neuronal pathway is able to recover, partially or completely, via compensatory mechanisms.
• Pathways that lack reserve capacity, and cannot recover spontaneously, may demonstrate a therapeutic lag.
• Therapeutic lag manifests as a delay in the slowing down, or a plateauing out, in the rate of progression in a particular pathway.
23
Datasets
SPECTRIMS trial extension:• Drug: IFNβ-1a vs placebo• Duration : 3 years + 3 years extension• Population: patients with SPMS• N=618 (IFNβ-1a 44µg=204, IFNβ-1a 22µg=209, PBO=205)
• Patients entering the extension n=525 (85%)
PROMISE trial:• Drug: GA vs placebo• Duartion : 3 years • Population: patients with PPMS• N=943 (GA=627, PBO=316)
24
Datasets
25
Methods and results
Standard analysis:
KM survival curves and Cox model
(proportional hazard assumption=HR constant over time)
SPECTRIMS PROMISE
HR=0.88 (0.72-1.07), p=0.19 HR=0.88 (0.71-1.07), p=0.18
26
Time dependent analysis
Analysis with a ‘time dependent’ treatment effect :
1. Treatment effect :
SPECTRIMS : best time lag= 2.5 years
HR=0.65 (0.43-0.98), p=0.041
Fixed time lag
PROMISE : best time lag= 2 years
HR=0.65 (0.42-0.99), p=0.044
Time dependent analysis
Analysis with a ‘time dependent’ treatment effect :
2. Treatment effect : time lag dependent on baseline EDSS
• A merged dataset was used• Cox model selecting the best time lag for treatment effect, after
adjusting for trial effect was run (stepwise procedure)
• EDSS dependent time lag:(EDSS-3)
EDSS-dependent time lag
EDSS=3-4N=562
EDSS=4.5-6N=678
EDSS=6.5+N=313
Length-dependency
CNS fibre length – motor vs. visual
vs.
Short axon
Long axon
Length-dependent axonopathy hypothesis
vs.
= focal acute inflammatory lesions
vs.
Short axon
Long axon
Length-dependent axonopathy hypothesis
distal or anterograde axonal degeneration
= focal acute inflammatory lesions
vs.
Short axon
Long axon
= chronic inactive lesions
Length-dependent axonopathy hypothesis
proximal or retrograde axonal degeneration
distal or anterograde axonal degeneration
= focal acute inflammatory lesions
vs.
Short axon
Long axon
= chronic inactive lesions
secondaryneuronal loss
Length-dependent axonopathy hypothesis
35
Therapeutic window 5
Asynchronous progressive MS hypothesis
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 have entered the clinically-apparent progressive phase of the disease
Cerebellar or balance systems
Goodkin et al. Ann Neurol. 1995 Jan;37(1):30-40.
Goodkin et al. Ann Neurol. 1995 Jan;37(1):30-40.
❌
✓✓
❌
Expanded Disability Status Scale (EDSS)
Slides courtesy of John Zajicek.
Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial
Slides courtesy of John Zajicek.
Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial
Log rank test P = 0.01
Slides courtesy of John Zajicek.
Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial
Natalizumab in SPMS (ASCEND Study)
Steiner et al. AAN 2016
Natalizumab in SPMS (ASCEND Study)
Steiner et al. AAN 2016
Natalizumab in SPMS (ASCEND Study)
Steiner et al. AAN 2016
Ocrelizumab (anti-CD20) in PPMS (ORATORIO STUDY)
Giovannoni et al. ECTRIMS 2016
Ocrelizumab (anti-CD20) in PPMS (ORATORIO STUDY)
Montalban et al. ECTRIMS 2016
Placebon=244
Ocrelizumab 600 mgn=488
Age, yr, mean (SD) 44.4 (8.3) 44.7 (7.9)
Female, n (%) 124 (50.8) 237 (48.6)
Time since symptom onset, yr, mean (SD) 6.1 (3.6) 6.7 (4.0)
Time since diagnosis, yr, mean (SD) 2.8 (3.3) 2.9 (3.2)
MS disease modifying treatment naive, n (%) 214 (87.7) 433 (88.7)
EDSS, mean (SD) 4.7 (1.2) 4.7 (1.2)
MRI findingsGd– lesions, n (%)Number of Gd+ T1 lesions, mean (SD)T2 lesion volume, cm3, mean (SD)
Normalised brain volume, cm3, mean (SD)
183 (75.3%)0.6 (1.6)
10.9 (13.0)11.0 (0.9)
351 (72.5%)1.2 (5.1)
12.7 (15.1)12.8 (0.7)
#ThinkHand
95%Thompson et al. ECTRIMS 2016
“The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.”
Thomas Huxley
4 May 1825 – 29 June 1895
50
Sensory Paradox
Kalincik et al. Risk of relapse phenotype recurrence in multiple sclerosis. MSJ 2014 Oct;20(11):1511-22.
Architecture of the sensory system
Kurtzke. Mult Scler Relat Disord. 2015 Mar;4(2):95-103.
Conclusions
∙ Therapeutic lag and the asynchronous progressive MS hypotheses explain progressive MS trial results
∙ MS a length-dependent central axonopathy
∙ Reserve capacity predicts outcomes
– Rates of progression and recovery
∙ Is the EDSS fit for purpose for progressive MS trials?
∙ What are implications for clinical trial design?
– Should we targeting neuronal systems with reserve capacity?
– Should we be using upper limb function as the primary outcome in patients with more advanced disease?
∙ What are the implications for clinical practice?
– We should continue DMTs in patients who are severely disabled to protect hand and arm function