future of ms treatments

The future of MS treatments for people living with MS

Gavin Giovannoni

Blizard Institute

Barts and The London, United Kingdom

1

Holistic approach

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events

Differential Diagnosis

MRI

Evoked Potentials

Lumbar puncture

Blood Tests

Diagnostic Criteria

Cognition

Depression

Fatigue

Bladder

Bowel

Sexual dysfunction Tremor

Pain Swallowing

Spasticity Falls

Balance problems Insomnia

Restless legs Fertility

Clinical trials

Gait

Pressure sores

Oscillopsia

Emotional lability

Seizures

Gastrostomy

Rehab

Suprapubic catheter Intrathecal

baclofern

Physio- therapy

Speech therapy

Occupational Therapy

Functional neurosurgery

Colostomy

Tendonotomy

Studying

Employment Relationships

Travel

Vaccination

Anxiety

Driving

Nurse specialists

Counselling

Family counselling

Relapses

1st line

2nd line

Maintenance Escalation Induction

Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet

Alternative Medicine

Pregnancy Breast Feeding

Research

Insurance

Visual loss

Palliative Care

Assisted suicide

Social services

Legal aid Genetic counselling

Prevention

Diagnosis

DMT Symptomatic

Therapist

Terminal

Counselling An holistic approach to MS; beta ver. 2.1

Intrathecal phenol

Fractures

Movement disorders

Osteopaenia

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events


MRI

Evoked Potentials

Lumbar puncture

Blood Tests

Diagnostic Criteria

Cognition

Depression

Fatigue

Bladder

Bowel


Pain Swallowing

Spasticity Falls



Clinical trials

Gait

Pressure sores

Oscillopsia

Emotional lability

Seizures

Gastrostomy

Rehab

Suprapubic catheter

Intrathecal baclofern

Physio- therapy

Speech therapy



Colostomy

Tendonotomy

Studying


Travel

Vaccination

Anxiety

Driving

Nurse specialists

Counselling

Family counselling

Relapses

1st line

2nd line


Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet



Research

Insurance

Vision

Palliative Care

Assisted suicide

Social services

Legal aid Family counselling

Prevention

Diagnosis

DMT Symptomatic

Therapist

Terminal

Counselling

Graeme Wilson MSer born 6th December 1973, died 4th December 2012

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

Mortality or Survival

Survival in MSers is shortened by 8 to 12 years

Survival Probability of Norwegian Patients with RRMS (Hordaland County, Western Norway, 1953–2003)

RRMS=relapsing-remitting MS. Adapted from Torkildsen NG et al. Mult Scler. 2008;14:1191-1198.

50 0 5 10 15 20 25 30 35 40 45 0

10

20

30

40

50

60

70

80

90

100

Surv

ival

(%

)

Years After Onset

30 35 40 45 50 55 60 65 70 75 80 Approximate Patient Age

General Population

RRMS

95% CI

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

Source: Poster Goodin et al AAN 2011

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

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

live

Time (Years)

Any Negative EDSS=6 SPMS Wheelchair

% R

isk R

ela

tive t

o L

ow

Exp

osu

re

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

Source: Poster Goodin et al AAN 2011

responders vs. non-responders

100 MSers

Who are responders?

~20% - responders

~40% - partial-responders

-40% - non-responders

vs.

1

2

3

Clinical

MRI

NABs

early vs. delayed treatment

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

Post-inflammatory neurodegeneration

Treat early

Natural course of disease

Later intervention

Later treatment

Treatment at diagnosis Intervention

at diagnosis

Time Disease Onset

Disability

Disability

Time

12 months 24 months 36 months

Active

Placebo Progressive 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 MS 2. Reduce number of attacks 3. Reduce severity of attacks 4. Reduce disability 5. Delay onset of SPMS

Delayed Progression 1 Stabilised Progression 2

Improved Function 3 Recovered Function 4

WHAT ARE YOUR EXPECTATIONS OF A THERAPY FOR PROGRESSIVE MS?

22

1

2

3

www.ms-res.org

Progressive MS Trials

Active tablet

Placebo tablet

Year 1 Year 2 Year 3

560 MS’ers

280 MS’ers

280 MS’ers

Disability

Time


Active

Placebo

Aims of CUPID study

• to assess the value of Δ9-THC in slowing progressive MS over 3 years.

• to assess the safety of Δ9-THC over the long-term. • to improve research methodology by using new,

patient-orientated methods.

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

0 200 400 600 800 1000 1200

0.0

0.2

0.4

0.6

0.8

1.0


P(E

DS

S p

rog

ressio

n)

Baseline EDSS score

4

4.5

5

5.5

6

6.5

0 200 400 600 800 1000 1200

0.0

0.2

0.4

0.6

0.8

1.0


P(E

DS

S p

rog

ressio

n)

Treatment group

Active

Placebo

Log rank test P = 0.01

MS-STAT trial

High dose oral Simvastatin in Secondary Progressive Multiple Sclerosis

Jeremy Chataway

for the MS-STAT Collaborators

CTN:NCT00647348

EUDRACT NUMBER 2006-006347-31

Brain atrophy

or shrinkage

Whole Brain Atrophy

Change whole brain volume (%/yr)

Secondary outcomes: Disability

Model adjusting for minimisation variables and baseline

Outcome Mean (SD)

placebo

Mean (SD)

simvastatin

Difference in means

(95% CI)

EDSS

(score 0 to 10)

6.35 (0.83) 5.93 (1.11) -0.254 (-0.464 to -0.069)

MSIS total

(score 29 to 116)

76.1 (16.3) 70.1 (15.6) -4.78 (-9.39 to -0.02)

MSIS physical

(score 20 to 80)

56.3 (11.8) 51.7 (11.4) -3.73 (-7.18 to -0.28)

MSIS psychological

(score 9 to 36)

19.8 (6.0) 18.3 (5.8) -1.09 (-2.83 to 0.84)

MSFC Z score -1.21 (2.59) -0.78 (2.06) 0.289 (-0.333 to 0.961)

MSFC walk

(speed ft/s)

1.55 (1.19) 1.83 (1.61) 0.085 (-0.249 to 0.533)

MSFC peg test

(1/s)

0.030 (0.014) 0.033 (0.010) 0.002 (-0.001 to 0.004)

MSFC PASAT

(score 0 to 60)

35.2 (18.0) 38.3 (15.4) 4.45 (-0.11 to 8.84)

Where to next?


~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 designs

Trial 1

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

Spinal fluid neurofilament levels

Spinal fluid

neurofilament levels

Disability (EDSS) and 3 years

Axonal damage in relapsing MS is markedly reduced by natalizumab

Gunnarsson et al. Ann Neurol 2010; Epub.

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

Trial 2

UK Clinical Trial Network (CTN): phase 3 adaptive design

primary outcome EDSS progression

Placebo

Drug A

Drug B

Drug C

Drug D

futility analysis

2yrs 3yrs

7yrs

EDSS 1° outcome

UK Clinical Trial Network (CTN): phase 3 adaptive design

primary outcome EDSS progression

Placebo

Drug A

Drug B

Drug C

Drug D

futility analysis

2yrs 3yrs

7yrs

EDSS 1° outcome

riluzole

amiloride

ibudlast

Trial 3

38 year old woman with left optic neuritis

sTE 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.

Phenytoin Amiloride

Anti-Lingo-1

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events


MRI

Evoked Potentials

Lumbar puncture

Blood Tests

Diagnostic Criteria

Cognition

Depression

Fatigue

Bladder

Bowel


Pain Swallowing

Spasticity Falls



Clinical trials

Gait

Pressure sores

Oscillopsia

Emotional lability

Seizures

Gastrostomy

Rehab

Suprapubic catheter Intrathecal

baclofern

Physio- therapy

Speech therapy



Colostomy

Tendonotomy

Studying


Travel

Vaccination

Anxiety

Driving

Nurse specialists

Counselling

Family counselling

Relapses

1st line

2nd line


Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet



Research

Insurance

Visual loss

Palliative Care

Assisted suicide

Social services

Legal aid Genetic counselling

Prevention

Diagnosis

DMT Symptomatic

Therapist

Terminal

Counselling An holistic approach to MS; beta ver. 2.1

Intrathecal phenol

Fractures

Movement disorders

Osteopaenia

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events


MRI

Evoked Potentials

Lumbar puncture

Blood Tests

Diagnostic Criteria

Cognition

Depression

Fatigue

Bladder

Bowel


Pain Swallowing

Spasticity Falls



Clinical trials

Gait

Pressure sores

Oscillopsia

Emotional lability

Seizures

Gastrostomy

Rehab

Suprapubic catheter

Intrathecal baclofern

Physio- therapy

Speech therapy



Colostomy

Tendonotomy

Studying


Travel

Vaccination

Anxiety

Driving

Nurse specialists

Counselling

Family counselling

Relapses

1st line

2nd line


Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet



Research

Insurance

Vision

Palliative Care

Assisted suicide

Social services

Legal aid Family counselling

Prevention

Diagnosis

DMT Symptomatic

Therapist

Terminal

Counselling

annually

low

normal

Fracture risk

Qfracture/FRAX

DXA imaging

Bone Mineral Density

Treatment of osteopaenia Refer to NICE guidelines TA160

medium/high

low

Investigate for secondary osteoporosis • Vitamin D levels2

• Thyroid function tests3

• Renal & liver function tests

Address lifestyle factors • Diet • Smoking cessation • Alcohol • Exercise

low

below treatment threshold

low

above treatment threshold

2 years

2 years

1Falls risk assessment?

Multiple sclerosis

Falls reduction OT home assessment Targeted physiotherapy Visual assessment and treatment Falls education Management of medical co-morbidities Medication review (antidepressants, sedatives etc). 2 years

medium/high

1. To add separate falls risk assessment scales for MS and PD 2. New vD supplementation guidelines 3. Statement of frequency of checking TFTs

DEXA OR BONE DENSITY SCAN

70

Conclusions

• MS is a serious disease

• Prognostic factors – Disease course

– Response markers

• Treatment

– Effective DMTs for RRMS with an exciting Definitive phase 3 PPMS & SPMS trials underway

– New strategies and trial designs for neuroprotection and remyelination in progressive MS

• Holistic approach to MS – Falls, fractures, ect.

www.ms-res.org

www.ms-res.org

73

Graeme Wilson MSer born 6th December 1973, died 4th December 2012

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

future of ms treatments

Health & Medicine