1

Disease-modifying drugs

Gavin GiovannoniBlizard Institute

Barts and The London, United Kingdom

Graeme WilsonMSer born 6th December 1973, died 4th December 2012

http://viaferria.blogspot.co.uk/

http://viaferria.blogspot.co.uk/

21-year long-term follow-up of IFNb-1b studytime 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

Source: Poster Goodin et al AAN 2011

At risk:IFNB-1b 250 µgPlacebo

124123

124120

121117

118109

10488

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

0 2 4 6 8 10 12 14 16 18 20 2265%

70%

75%

80%

85%

90%

95%

100%

Time (Years)

Pro

po

rtio

n o

f p

ati

en

ts w

ho

are

sti

ll a

live

5

What is disease modification?

Disability

Time

6 months 12 months 24 months

Active

Placebo

6 months

Relapsing MS

1. Delay attacks / onset of MS2. Reduce number of attacks3. Reduce severity of attacks4. Reduce disability5. Delay onset of SPMS

Who do we treat with DMTs?

Relapsing MS

Progressive

CIS Active RRMS

SPMS PPMS

Treat early

Natural course of disease

Laterintervention

Latertreatment

Treatmentat diagnosis Intervention

at diagnosis

Time

Disease Onset

Disability

Any Negative EDSS=6 SPMS Wheelchair

% R

isk

Rel

ativ

e to

Lo

w E

xpo

sure

Long-term follow-up 16 yearsIFN-beta exposure 80% vs. 20%

Source: Poster Goodin et al AAN 2011

100 MSers

Who are responders?

~20% - responders

~40% - partial-responders

-40% - non-responders

vs.

1

2

3

Clinical

MRI

NABs

What is the impact of more effective therapies?

Escalation therapies

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

Natalizumab

Natalizumab (Tysabri) – mode of action

Natalizumab (Tysabri)

81%

64%

reduction in annualised relapse rate vs. placebo over 2 years (p < 0.001)

reduction in the risk of disability progression, sustained for 24 weeks, as assessed over 2 years (p =0.008)

1 in 3 Sustained improvement in disability

Natalizumab (Tysabri)

Progressive multifocal leukoencephalopathy (PML)

Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.

207 cases -1st February 2012

44 (21%) died

163 (79%) alive

Mild disability – 10%Moderate disability – 50%Severe disability – 40%

5% NAbs – infusion reactions

Natalizumab PML risk stratification tool

Anti-JC virus antibody status

Negative Positive

Prior immunosuppressant use

Natalizumab treatment>2 Years

Natalizumab treatment>2 Years

No Yes

No Yes No Yes

Lowest HighestRelative PML Risk

< 1 in 10,000 1 in 941 in 256 1 in 6681 in 1887

Mitoxantrone AzathioprineMethotrexate

CyclophosphamideMycophenolate

CladribineRituximab

Etc.

20

Emerging DMTs

Emerging DMTs for relapsing MSphase 3 & 4

Oral1. Fingolimod – 53% reduction in ARR relative to placebo

2. Cladribine – 55% reduction in ARR relative to placebo

3. BG12 – 53% reduction in ARR relative to placebo

4. Teriflunomide – 31% reduction in ARR relative to placebo

5. Laquinimod – 21% reduction in ARR relative to placebo

Parenteral6. Alemtuzumab (anti-CD52) – 55% reduction in ARR relative to IFNβ-1a

7. Ocrelizumab (anti-CD20) – 80% reduction in ARR relative to placebo8. Daclizumab (anti-CD25) – 54% reduction in ARR relative to placebo

?

Recruiting

Progressive MS

www.ms-res.org

Disability

Time

12 months 24 months 36 months

Active

PlaceboProgressive MS

1. Reduce rate of disability progression

Disability

Time

6 months 12 months 24 months

Active

Placebo

6 months

Compared to relapsing MS

1. Delay attacks / onset of MS2. Reduce number of attacks3. Reduce severity of attacks4. Reduce disability5. Delay onset of SPMS

Delayed Progression1 Stabilised Progression2

Improved Function3 Recovered Function4

WHAT ARE YOUR EXPECTATIONS OF A THERAPY FOR PROGRESSIVE MS?

30

1

2

3

www.ms-res.org

Active tablet

Placebo tablet

Year 1 Year 2 Year 3560 MS’ers

280 MS’ers

280 MS’ers

Disability

Time

Year 1 Year 2 Year 3

Active

Placebo

Year 3 Year 4 Year 5~600 MS’ers

~300 MS’ers

300 MS’ers

Year 1 Year 2 Year 6 Year 7

Recruitment Trial Data analysis ? Registration

7 years

New trial design

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

Spinal fluid neurofilament levels

Spinalfluid

neurofilament levels

Disability (EDSS) and 3 years

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

Spinal fluid neurofilament levels

Spinalfluid

neurofilament levels

Disability (EDSS) and 3 years

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 MS’ers

6 months

LP1 LP2 LP3

30 MS’ers active tablet

30 MS’ers placebo tablet

2 years

6 months

600 MS’ers for 7 years 60 MS’ers for 2 years

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

New paradigm

Can we make LPs safer?

   Two types of spinal needle tips: the Quincke and Sprotte

Evans R W et al. Neurology 2000;55:909-914

Traumatic

or

cutting needle

Atraumatic

or

non-cutting needle

Ultrasound-guide lumbar punctures

54%

Neuroprotection & remyelination

Brain atrophy

or shrinkage

Kappos et al. N Engl J Med. 2010 Feb 4;362(5):387-401.

UK Clinical Trial Network (CTN): phase 3 adaptive designprimary outcome EDSS progression

Placebo

Drug A

Drug B

Drug C

Drug D

futility analysis

2yrs 3yrs

7yrs

EDSS1° outcome

38 year old woman with left optic neuritissTE fFLAIR images

Baseline 52 weeks

Hickman et al. Neuroradiology 2001;43:123-8.

Trapp et al. N Engl J Med 1998.

Acute optic neuritis(focal lesion)

Romani et al. Clini Neurophys 2000;111:1602-6.

PhenytoinAmiloride

Anti-Lingo-1

Conclusions• MS is a serious disease• Prognostic factors

– Disease course– Response markers

• Treatment – Effective DMTs for RRMS with an exciting and busy

pipeline– Definitive phase 3 PPMS & SPMS trials underway– New strategies for neuroprotection and

remyelination in progressive MS• MS prevention

www.ms-res.org

Graeme WilsonMSer born 6th December 1973, died 4th December 2012

http://viaferria.blogspot.co.uk/