Secondary progressive MS

Professor Gavin Giovannoni

Blizard Institute, Barts and The London School of Medicine and Dentistry

Disclosures

Over the last 15 years 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, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

Professor Giovannoni would like to acknowledge and thank Biogen-Idec and Genzyme for making available data slides on natalizumab and alemtuzumab for this presentation. He would also like to thank numerous colleagues for providing him with data and/or slides for this, and other, presentations.

Professor Giovannoni’s visit to Lebanon has been kindly sponsored by Novartis, therefore please interpret anything he says about Novartis’s product in this context.

This presentation has been designed and prepared by Professor Giovannoni with no input from any other parties.

What is SPMS?

? SPMS

The age at onset and the speed of progression in SPMS does not depend on preceding relapses

Kremenchutzky et al. Brain 2006

SPMS

SPMS

“The diagnosis of SPMS is done retrospectively”

The age at onset and the speed of progression in SPMS does not depend on preceding relapses

Time to sustained EDSS 6 in the London, Ontario cohort

PP: Primary Progessive MS

SP: Secondary Progressive MS

SAP: Single Attack-Progressive MS

Kremenchutzky et al. Brain 2006

From the onset of MS

From the onset of the progressive phase

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

Can we modify the course of SPMS?

Kappos et al, Neurology 2005

The effect of immunomodulation by interferon ß in SPMS depends on residual inflammation

Kappos et al, Neurology 2005

The effect of immunomodulation by interferon ß in SPMS depends on residual inflammation

Hartung et al. Lancet 2002:360:2018-25.

Hartung et al. Lancet 2002:360:2018-25.

12

Window of therapeutic efficacy

Coles et al. J Neurol. 2006 Jan;253(1):98-108..

13

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

DS

S S

co

re

Years from clinical onset of MS

6

5

4

3

2

1

0

0 5 10 15 20 25 30

7

Phase 2

Phase 1

Natural History

Leray E et al. Brain 2010;133:1-14.

14

TOP: Natalizumab Stabilises EDSS Scores in Patients with

Either a High or Low Starting EDSS Score at Baseline

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

0 6 12 18 24 30 36 42 48

Med

ian

ED

SS

Sco

re

Time (months)

Kappos L et al. Presented at ENS; June 9–12, 2012; Prague, Czech Republic. O261.

Baseline EDSS Score ≤3.0 (n=1591)

Baseline EDSS Score >3.0 (n=1840)

Therapeutic lag hypothesis

therapeutic lag

Gd

T2

CU

R

DP

Therapeutic lag: NEDA

Havrdova et al. Lancet Neurol. 2009 Mar;8(3):254-60.

Gd

T2

CU

R

DP

15% vs 47% Δ 32%

13% vs 68% Δ 55%

6% vs 37% Δ 31%

Therapeutic lag: effect of natalizumab on NEDA

Havrdova et al. Lancet Neurol. 2009 Mar;8(3):254-60.

Natalizumab Effect on EDSS Progression by Treatment Duration

TOP Trial: Multiple event analyses per treatment epoch

9.5%

5.7%

0%

5%

10%

15%

20%

25%

30%

Month 0-24 Month 25-48

n=496 n=496 P

rop

ort

ion

of

pat

ien

ts w

ith

12

-mo

nth

su

stai

ned

1 p

oin

t ED

SS p

rogr

essi

on

P=0.0167*

40% 10.9%

8.5%

0%

5%

10%

15%

20%

25%

30%

Month 0-24 Month 25-48

n=496 n=496

Pro

po

rtio

n o

f p

atie

nts

wit

h 6

-mo

nth

su

stai

ned

1 p

oin

t ED

SS p

rogr

essi

on

P=0.1630

6-month sustained progression 12-month sustained progression

Difference of rates of EDSS progression between the two treatment epochs was significant for the 12-month confirmed progression

Wiendl H. et al. ECTRIMS 2013, Copenhagen October 2-5 , Poster P1050.

Biogen Idec data on file.

The vast majority of patients who experienced disability progression in the first two years remained free of disability progression in the next 2 years

6/496 (1.2%) patients had a 12-month confirmed

progression in the two treatment epochs.

11/496 (2.2%) patients had a 6-month confirmed

progression in the two treatment epochs.

Wiendl H. et al. ECTRIMS 2013, Copenhagen October 2-5 , Poster P1050.

Biogen Idec data on file.

Natalizumab Effect on EDSS Progression by Treatment Duration

TOP Trial: Multiple event analyses per treatment epoch

-1.0%

-0.8%

-0.6%

-0.4%

-0.2%

0.0% Years 0-2

-0.82%

-0.80%

P=0.822†

Placebo (N=315) Natalizumab (N=627)

Year 0-1* Year 1-2

-0.40%

-0.56%

-0.43%

-0.24%

P=0.004†

P=0.002†

†Difference between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401.

AFFIRM Study: natalizumab and brain atrophy

Mean

(S

E)

perc

en

tag

e c

han

ge i

n B

PF

Brain atrophy in natalizumab-treated patients: 3-year follow-up

Sastre-Garriga et al. MSJ 2014.

-0.6%

-1.4%

-0.1% -0.5%

-0.7%

-0.2%

28

CARE-MS I & II Three-Year MRI Outcomes Change in Brain Parenchymal Fraction (BPF)

Alemtuzumab slowed brain volume loss over 3 years, as assessed by change in BPF

For both patient populations, the median percentage reduction in BPF observed in in Year 3 (0.19% and 0.10%, respectively) was smaller than that observed in Year 1 (0.59% and 0.48%) and Year 2 (0.25% and 0.22%)

Percentage Change in BPF in Formerly Treatment-Naive Patients (CARE-MS I)

Percentage Change in BPF in Patients Who Relapsed on Prior Therapy (CARE-MS II)

Me

dia

n C

ha

ng

e F

rom

Ba

se

lin

e, %

(9

5%

CI)

Year No. of Patients 371 367 351 323

% Change from Previous Year – –0.59% –0.25% –0.19%

Me

dia

n C

ha

ng

e F

rom

Ba

se

lin

e, %

(9

5%

CI)

Year 428 414 405 359

– –0.48% –0.22% –0.10%

No. of Patients

% Change from Previous Year

0 1 2 3

-1 .5 0

-1 .2 5

-1 .0 0

-0 .7 5

-0 .5 0

-0 .2 5

0 .0 0

0 1 2 3

-1 .5 0

-1 .2 5

-1 .0 0

-0 .7 5

-0 .5 0

-0 .2 5

0 .0 0

AAN 2014

Blitz S65-008

Therapeutic lag

Yr -1 Yr -2 Yr +1 Yr +2 Yr +3 Yr +4 Yr +5 Yr +6 Yr +7

IFN-beta-1b

Placebo

No treatment

No treatment

9H

PT,

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

bow parallel because IFN-beta was stopped after

year +2

Delayed effect on disability progression from IFN-beta treatment in years 1 & 2

Time

Glatiramer acetate in PPMS: results of a multinational, multicenter, double-blind, placebo-controlled trial

Wolinsky et al. Ann Neurol 2007;61:14–24.

Length-dependent neuropathy

CNS fibre length – bladder

CNS fibre length – motor

CNS fibre length – visual

vs.

Short axon

Long axon

Length-dependent axonopathy

vs.

= focal acute inflammatory lesions

vs.

Short axon

Long axon

Length-dependent axonopathy

distal or anterograde axonal degeneration

= focal acute inflammatory lesions

vs.

Short axon

Long axon

= chronic inactive lesions

Length-dependent axonopathy

proximal or retrograde axonal degeneration

distal or anterograde axonal degeneration

= focal acute inflammatory lesions

vs.

Short axon

Long axon

= chronic inactive lesions

secondary neuronal loss

Length-dependent axonopathy

Reserve capacity & functional recovery

Acute attack: functional deficit

Reserve capacity & functional recovery

Recovery due to axonal plasticity: no functional deficit, but reduced reserve capacity

Reserve capacity & functional recovery

New focal inflammatory lesions

Reserve capacity & functional recovery

New focal inflammatory lesions; larger deficit in pathway with reduced functional reserve

Reserve capacity & functional recovery

Recovery due to axonal plasticity: fixed deficit in pathway with reduced reserve capacity

44

Therapeutic window 5

Asynchronous progressive MS hypothesis

Motor system to legs

Lower limb sensory

Bladder Therapeutic 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

45

First

Relapse

3 6 9 12 15 18 21 24 27 30

Months Since Relapse

0

10

20

30

40

50

60

70

80

90

100

Pati

en

ts w

ith

co

mp

lete

reco

very

(%

)

Placebo Natalizumab

Natalizumab and Clinical Recovery from Relapses

Lublin F. et al. ECTRIMS 2013, Copenhagen October 3rd , Poster P524.

Overall population : Subjects with an increase of EDSS ≥ 1.0 point at relapse

*Based on Cox Proportional Hazards model adjusted for baseline EDSS, age, gender, relapses in year prior to enrollment, disease

duration, baseline Gd-enhancing lesions and baseline T2 lesion volume.

AFFIRM: Probability of 12-week confirmed complete

recovery from relapses

76.0%

43.1%

Adjusted HR for natalizumab vs placebo=1.673

(95% CI:1.046–2.678); 67% increase; P=0.0319*

Placebo (N=86) Natalizumab (N=70)

46

84%91%

70%71% 74%68%

0%

20%

40%

60%

80%

100%

Overallpopulation

BaselineEDSS<3.0

Baseline EDSS≥3.0

n=140 n=93 n=80 n=143

Pro

po

rtio

n o

f p

ati

en

ts (

%)

Placebo

Natalizumab

**P=0.0088 **P=0.0019 P=0.8259

At least 0.5 point EDSS increase

n=47 n=63

At least 1.0 point EDSS increase

61%71%

43%49% 50% 48%

0%

20%

40%

60%

80%

100%

Overallpopulation

BaselineEDSS<3.0

Baseline EDSS≥3.0

n=140 n=93 n=80 n=143

Pro

po

rtio

n o

f p

ati

en

ts (

%)

*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 AFFIRM

EDSS change from pre-relapse to at relapse

46

Natalizumab and Clinical Recovery from Relapses

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)

Ceiling & Floor Effects

Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial

Zajicek et al. Lancet Neurol 2013; 12: 857–65.

0 200 400 600 800 1000 1200

0.0

0.2

0.4

0.6

0.8

1.0

Time to EDSS progression (days)

P(E

DS

S p

rog

ressio

n)

Treatment group

Active

Placebo

Slides courtesy of John Zajicek.

Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial

0 200 400 600 800 1000 1200

0.0

0.2

0.4

0.6

0.8

1.0

Time to EDSS progression (days)

P(E

DS

S p

rog

ressio

n)

Baseline EDSS score

4

4.5

5

5.5

6

6.5

Slides courtesy of John Zajicek.

Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial

0 200 400 600 800 1000 1200

0.0

0.2

0.4

0.6

0.8

1.0

Time to EDSS progression (days)

P(E

DS

S p

rog

ressio

n)

Treatment group

Active

Placebo

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

55

Trial activity targeting progressive pathology

MRI Events

1st clinical attack

Time (Years)

Subclinical disease

Inflammation

Brain volume loss

Neuroaxonal loss

Dis

eas

e S

eve

rity

SPMS RRMS

1st MRI lesion

Relapses

CIS RIS R-SPMS

RIS = radiologically isolated syndrome; CIS = clinically isolated syndrome, RRMS = relapsing-remitting MS; R-SPMS = relapsing secondary progressive MS; SPMS = secondary progressive MS; PPMS = primary progressive MS

SPMS: Natalizumab, Siponimod, DMF

Late SPMS: SMART STUDY fluoxetine, amiloride, riluzole

Early SPMS: oxcarbazepine

CIS: PHENYTOIN RRMS: ? DE-FLAMES STUDY

PPMS

PPMS: Fingolimod, Ocrelizumab, Laquinimod

SP&PPMS: Ibudilast

Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial

Chataway Lancet 2014; 383: 2213–21.

57

Therapeutic hierarchy

Neuro-restoration

Remyelination

Neuroprotection

Anti-inflammatory

Therapeutic pyramid

Anti-ageing

Brain

Health

Initiative

• Smoking

• Exercise

• Diet

• Sleep

• Co-morbidities

• Infections

• Concomitant

medications

Conclusions We need to rethink our definition of SPMS

– ~ PPMS (chronic progressive MS)

– length-dependent central axonopathy

– therapeutic lag

– asynchronous progressive model

Major implications for clinical trial design – Can we measure reserve capacity in the individual functional systems?

– What is the optimal trial duration to address the therapeutic lag?

– Can we design better outcome measures to address therapeutic lag?

Asynchronous progressive MS – Should we only be targeting systems with reserve capacity in SPMS?

Holistic approach to SPMS – Smoking

– Exercise

– Diet

– Sleep

– Co-morbidities

– Infections

– Concomitant medications