Pathogenesis of ms and treatment effects

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.

http://www.ms-res.org/

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


distal or anterograde axonal degeneration


vs.

Short axon

Long axon

= chronic inactive lesions


proximal or retrograde axonal degeneration

distal or anterograde axonal degeneration


vs.

Short axon

Long axon

= chronic inactive lesions

secondaryneuronal loss


35

Therapeutic window 5

Asynchronous progressive MS hypothesis

Motor system to legs

Lower limb sensory

BladderTherapeutic window 1



Upper limb sensory

Upper limb motor

Cognition

Vision

Etc.





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

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

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

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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

Pathogenesis of ms and treatment effects

Health & Medicine

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