MS treatment and preservation of end-organ damage in MS

Gavin Giovannoni

Barts and The London

.

Thomas Blizard Curling 1811 – 1888

• Assistant-surgeon to The Royal London Hospital in 1883 and full surgeon in 1849

• President of the Royal College of Surgeons

• Seminal work on tetanus, winning the Jacksonian prize for his work

• Famous for his skill in treating diseases of the testes and rectum

ESRF end-stage renal failure

Does the brain fail in MS?

Should multiple sclerosis be redefined as a dementia?

www.multiple-sclerosis-research.org

Definition of dementia

Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness.

• Normal activities of daily living

• Physical

• Mental

• Social

• Occupational

• Lasting more than six months

• Not present since birth

• Not associated with a loss or alteration of consciousness

Occupational functioning

Pfleger et al. Multiple Sclerosis 2010; 16(1) 121–126.

At what level of physical disability does unemployment occur?

Kobelt et al. Neurol Neurosurg Psychiatry 2006;77:918–926.

57%

7%

-20%

0%

20%

40%

60%

CISers n = 40

Feuillet et al. Mult Scler. 2007.

Healthy Controls n = 30

p < 0.0001

Deficits were found mainly in memory, speed of information processing, attention and executive functioning.

MSers failing ≥ 2 cognitive

tests

Cognition in early multiple sclerosis

Definition of dementia

Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness.

• Normal activities of daily living

• Physical

• Mental

• Social

• Occupational

• Lasting more than six months

• Not present since birth

• Not associated with a loss or alteration of consciousness

“Multiple sclerosis is therefore a dementia.”

What is the pathological substrate of MS dementia?

11,000 to 1

Trapp, et al. NEJM 1998;338:278-85

Control Multiple sclerosis

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

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(m

L)

Age (years)

Brain atrophy curves

Lower limit of normal

Average

Upper limit of normal

Hypothetical treatment effects

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Brain atrophy curves

MS lower limit

MS Average

MS Upper limit

-5%

-30%

Hypothetical treatment effects

Laquinimod: Percent of brain volume

change from baseline to month 24

% C

ha

ng

e F

rom

Ba

se

line

-1.2

-0.4

-1.6

-0.8

Placebo (n = 1006)

Laquinimod 0.6 mg (n = 984)

0

-1.188

-0.834

POOLED

30% P<0.0001

Vollmer T et al. Presented at 64th American Academy of Neurology Annual meeting, New Orleans 2012 Session S01.007

BRAVO: reduced rate of brain volume loss

*Adjusted for baseline characteristics.

Reference: 1. Vollmer T et al. Presented at: 5th Joint Triennial Congress of the European and Americas Committee for Treatment and Research in Multiple Sclerosis; October 19-22, 2011; Amsterdam, Netherlands. Abstract 148. Mult Scler. 2011;17:S507.

35

27.5% Reduction P<0.0001

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

-27.4% Improvement P<0.0001

LAQUINIMOD 0.6mg

PLACEBO

-1.14% -0.83% Percent Brain Volume

Change* (Months 0-24)

-1.25%

AVONEX® 30mcg

+9% Deterioration P=0.14

Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM

FREEDOMS, 2 years

Fingolimod 0.5 mg (n = 356)

Placebo (n = 329)

***

* **

6 0 12 24

Time (months)

0

-0.4

-0.8

-1.2

-1.6

-2.0

−38%

vs placebo p<0.001

Ch

ange

in m

ean

BV

fro

m

bas

elin

e (%

)

TRANSFORMS, 1 year

0 12

Time (months)

0.0

-0.4

-0.6

-1.0

IFNb-1a IM (n = 359)

Fingolimod 0.5 mg (n = 368)

−40%

vs IFNb-1a IM p<0.001

*** -0.2

-0.8

Ch

ange

in m

ean

BV

fro

m

bas

elin

e (%

)

ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24 BV, brain volume; ITT, intent-to-treat. Gilenya™ Prescribing Information 19 April 2012. Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: 387-401, and Cohen JA et al. N Engl J Med 2010; 362: 402-415. Copyright © 2011 Massachusetts Medical Society. All rights reserved

-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

Mea

n (

SE

) p

erc

en

tag

e c

ha

ng

e i

n B

PF

-5%

-30%

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Age (years)

Brain atrophy curves

MS Average

Hypothetical treatment effects

-5%

-20%

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Age (years)

Brain atrophy curves

late treatment

Hypothetical treatment effects

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Age (years)

Brain atrophy curves

-5%

-18%

early treatment

late treatment

Hypothetical treatment effects

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Brain atrophy curves

-5% -11%

early very

highly-effective

treatment

late very

highly-effective

treatment

-15%

Hypothetical treatment effects

Treatment Effect on Disability Strongly Predicted by Effect on T2 Lesion Volume and Brain Atrophy, Combined

Meta-analysis of treatment effect on EDSS worsening (y) vs effects on

MRI lesions and brain atrophy, individually or combined, in 13 placebo-

controlled RRMS trials (13,500 patients)

Sormani MP et al. Ann Neurol. 2014;75:43-49.

Defining the window of opportunity to treat MS?

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

Post-inflammatory neurodegeneration

65%

70%

75%

80%

85%

90%

95%

100%

0 2 4 6 8 10 12 14 16 18 20 22

Pro

po

rtio

n o

f p

ati

en

ts w

ho

are

sti

ll a

liv

e

Time (Years)

21-year long-term follow-up of IFNb-1b study time from study randomization to death

Early treatment (3 years) with IFNb-1b was associated with a 47% reduction in the risk of dying over 21 years compared with initial placebo treatment

Goodin et al Neurology. 2012 Apr 24;78(17):1315-22.

At risk:

IFNB-1b 250 µg

Placebo

124

123

124

120

121

117

118

109

104

88

HR=0.532 (95% CI: 0.314–0.902)

46.8% reduction in hazard ratio

Log rank, P=0.0173

IFNB-1b 250 µg

Placebo

Theoretical model: treat early and effectively

Natural course of disease

Later intervention

Later treatment

Treatment at diagnosis

Intervention at diagnosis

Time Disease Onset

Dis

abili

ty

Defining your treatment strategy?

survival analysis

“hit hard and early ”

MS is an autoimmune disease hypothesis

15-20 year experiment

What is your treatment philosophy? maintenance-escalation vs. induction

Can you name me any diseases that you don’t treat early?

Time is Brain

Conclusion

Definition of dementia

Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness.

• Normal activities of daily living

• Physical

• Mental

• Social

• Occupational

• Lasting more than six months

• Not present since birth

• Not associated with a loss or alteration of consciousness

“Multiple sclerosis is therefore a preventable dementia.”

Stigmatizing

Stigmatizing

Brain Health

Active tablet

Placebo tablet

Year 1 Year 2 Year 3

600 MSers

300 MSers

300 MSers

Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.

Spinal fluid neurofilament levels

Axonal damage in relapsing MS is markedly reduced by natalizumab

Gunnarsson et al. Ann Neurol 2010; Epub.

=

Recruitment Trial Data analysis

6 months

6 months 60 MSers

6 months

LP1 LP2 LP3

30 MSers active tablet

30 MSers placebo tablet

2 years

6 months

600 MSers for 7 years 60 MSers for 2 years

3 LPs = 10x as many trials in a ⅓ of the time

13%

66%

21%

n = 127

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

Late SPMS: SMART STUDY ibudilast, amiloride, riluzole

Early SPMS: PROXIMUS oxcarbazepine

CIS: PHENYTOIN RRMS: ? DE-FLAMES STUDY

PPMS

PPMS: Fingolimod, Ocrelizumab, Laquinimod

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

Late SPMS: SMART STUDY ibudilast, amiloride, riluzole

Early SPMS: PROXIMUS oxcarbazepine

CIS: PHENYTOIN RRMS: ? DE-FLAMES STUDY

PPMS

PPMS: Fingolimod, Ocrelizumab, Laquinimod

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