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

The window of therapeutic opportunity in multiple sclerosis

1. Filippi M & Agosta F. J Magn Reson Imaging 2010; 31:770–788; 2. Giorgio A, et al. Neuroimaging Clin N Am 2008; 18:675–686.

1997 2002 20031995 2005

Acute Neuroprotection

Phenytoin is neuroprotective in acute optic neuritis: Results of a phase 2 randomized controlled trial

R Kapoor1, 2, R Raftopoulos1,2, S Hickman4, A Toosy1,2, B Sharrack4, S Mallik1,2, D Altmann2, P Malladi1, M Koltzenburg1,2, C Wheeler-

Kingshott2, K Schmierer3, G Giovannoni3, and DH Miller2

National Hospital for Neurology and Neurosurgery1, UCL Institute of Neurology2, and Queen Mary University of London3, London UK, and Royal Hallamshire

Hospital, Sheffield UK4

Primary outcome: RNFL

• Active-placebo adjusteddifference 7.15 mm(95% CI 1.08, 13.22p=0.02)

• 30% reduction of atrophyin active group

• PP comparison:Active-placebo adjusteddifference 7.40 mm(95% CI 0.76, 14.04p=0.03)

50

10

01

50

RN

FL

ave

rag

e m

m

Placebo Phenytoin

baseline UNaffected eye

Placebo Phenytoin

6m affected eye

Bars are standard errors around the unadjusted group means

Chronic Neuroprotection

Limp tail

Impaired righting reflex

hindlimb paralysis

Moribund

partial paralysis

Normal

Remission

Day 7

0

1

2

3

4

5

(1)

Clinical Score

Induction and assessment of chronic relapsing EAE

Day 0

Spinal cord homogenate in Freund’s complete adjuvant in ABH

Slide courtesy David Baker

ACUTE RELAPSE 1 RELAPSE 2 RELAPSE 3 CHRONIC

Average disease course

ACUTE RELAPSE 1 RELAPSE 2

RELAPSE 3CHRONIC

Slide courtesy Sam Jackson

Prevention of relapsing CREAE after three paralytic episodesdoes not inhibit secondary progression and deterioration of mobility

Pryce et al. J Neuroimmunol 2005.

Neuroprotection Trials

Trial activity targeting progressive pathology

MRI Events

1st clinicalattack

Time (Years)

Subclinical disease

Inflammation

Brain volume loss

Neuroaxonal loss

Dis

ease

Sev

erit

y

SPMSRRMS

1st MRI lesion

Relapses

CISRIS 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 STUDYfluoxetine, amiloride, riluzole

Early SPMS:oxcarbazepine

CIS: PHENYTOIN RRMS: ? DE-FLAMES STUDY

PPMS

PPMS: Fingolimod, Ocrelizumab, Laquinimod

SP&PPMS: Ibudilast

X

www.ms-res.org

WWW.MS-RES.ORG

What are we trying to do?

Disability

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

Window of Opportunity

Therapeutic pyramid

Neuro-restoration

Remyelination

Neuroprotection

Anti-inflammatory

Disability

Time

Year 1 Year 2 Year 3

Active

Placebo

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.

=

Danish study

CSF markers of axonal damage and demyelination:

Speeding up drug discovery?

Key milestones in the development of Fingolimod

1992: Fingolimod (FTY720) first synthesized by Japanese scientists

1997: Fingolimod in-licensed by Novartis for clinical development

1998: First studies in man (Phase 1 trials) and subsequent start of transplantation trials

2003: Start of MS Phase II trial

June 2005: Presentation of Phase II study results followed by publication in NEJM 2006

Jan 2006: Start of Phase III FREEDOMS study in RRMS

May 2006: Start of Phase III TRANSFORMS study in RRMS

June 2006: Start of Phase III FREEDOMS II study in RRMS

July 2008: Start of Phase III INFORMS trial to assess suitability for treatment of PPMS

Dec 2008: Release of TRANSFORMS study results and presentation at AAN April 2009

Sep 2009: Release of FREEDOMS study results and presentation at AAN April 2010

Dec 2009: Regulatory submission to FDA and EMA (ROW submissions in Q1 2010)

Feb 2010: Results of Phase III TRANSFORMS & FREEDOMS studies published in NEJM

Sep 2010: Approval by Russian Health Authority

Sep 2010: Approval by the US FDA for relapsing MS

April 2015: Negative PPMS (TRANSFORMS) Trial

Active tablet

Placebo tablet

Year 1 Year 2 Year 3

600 MSers

300 MSers

300 MSers

Year 3 Year 4 Year 5

600 MSers

300 MSers

300 MSers

Year 1 Year 2 Year 6 Year 7

Recruitment Trial Data analysis Registration

7 years

Recruitment Trial Data analysis

6 months

6 months 60 MSers

6 months

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

Can we change the way we do LPs?

Two types of LP 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

Targeting progressive MS

1) ON STUDY

2) PROXIMUS STUDY

3) SMART STUDY

UCLP Progressive MS Trials

Thank you

Acknowledgements

• Giovannoni

– Sharmilee Gnanapavan

• David Baker

– Gareth Pryce

– Sarah Al-Izki

• Sam Jackson

– Katie Lidster

• Yuti Chernajovsky

– Alex Annenkov

– Anne Rigby

– Michelle Sclanders

• Larry Steinman

– Peggy Ho

• Charles ffrench-Constant

– Robin Franklin

• Siddharthan Chandran

– David Hampton

• Ian Duncan

– Sam Jackson

• Peter Calabresi

– Avi Nath

• Raj Kapoor

• Jeremy Chataway

• David Miller

• Alan Thompson

• Klaus Schmierer

• Ben Turner

• Dan Altman

• John Zajicek

• Doug Brown

• UK MS Clinical Trial Network

• BioMS

Spasticity and multiple sclerosis

Chelmsford MS Research Meeting

16th June 2015

Dr. Rachel Farrell

Consultant Neurologist

Hon Senior Lecturer UCL

Talk outline

• Spasticity

• Burden of spasticity in MS

• Existing treatment

• CBX-001 Phase II trial MS spasticity

Spasticity and MS

• Spasticity is one of the most common and disabling symptoms in MS

• 60 – 80% PwMS ( Hemmett 2004, Rizzo 2004)

• Spasticity severity score correlates with disease duration and disability

• ~80% report impact on ADLs, motor performance and quality of life

• Treatments are effective but side effects common

Pathophysiology

• Spasticity simply

explained is an

exaggerated stretch

response

• Sensorimotor

phenomenon

• Stretch reflex

generates contraction

• Supraspinal origin

resulting in imbalance

at level of spinal cord

The upper motor neuron syndrome

Positive features

• Spasticity

• Spasms

• Hyper-reflexia

• Clonus

• Babinski response

• Co-contraction

• Associated reactions and other

spastic dystonias

Negative features

• Paresis

• Reduced dexterity / fine control

• Fatiguability

Lack of descending control

and disinhibition of spinal circuits Damage to higher motor areas

Spasticity / UMN syndrome not always negative

Feeding

Sexual activity

Safety

Washing

Dressing

Bladder & Bowel

Mood

Relationships

Posture

May maintain muscle bulk

Likes movement

associated with

spasms

May assist mobility

May maintains

vascular flow,

prevent DVT

Negative PositivePerson

With UMN

Syndrome

Mobility

Transfers

Body Image

©NHNN Spasticity Service

Impact of spasticity in MS

• Poor mobility– Reduced walking speed

– Difficulty transferring from wheelchair

– Difficulty with toileting (increased risk of incontinence)

• Pain

• Secondary complications – contractures, pressure ulcers

• Poor sleep– Nocturnal spasms or jerks

– Difficulty rolling-over in bed

– Fatigue

• Associated bladder spasticity– Urinary frequency, urgency and incontinence

Spasticity Management

Oral

Medication

Sativex

Intrathecal

Baclofen

Intrathecal

Phenol

Inpatient

Rehabilitation

Surgical

Options

Physical

measures

Botulinum

toxin

Oral agents for spasticity

Drug Dose Action Half life (hrs) Side effects

Baclofen 5 – 40mg tds GABA - B ~ 4 Sedation

weakness

Tizanidine 2 – 12 mg tds α2 adrenergic

agonist

2.5 – 4 Sedation, dry

mouth

hypotension

BZPs Drug dependent GABA - A 18 – 50 Sedation

dependence

Dantrolene 25 – 100mg qds Ca2+ release 8 – 9 Sedation

GI upset

Liver failure

Gabapentin

Pregabalin

100 – 1200mg tds

50 – 300 mg bd

VGCCh

?GABA

5 – 7 Sedation, poor

concentration,

unsteadiness

Site of actionTizanidine – Inhibits presynaptic excitation of motor neurone at α2

noradrenergic sites. Inhibits of EAA (Glu, Asp) from spinal IN

?Glu/Asp

Coerulospinal

pathway α2 (Tiz)

Tizanidine

Tizanidine

α

When the drugs don’t work

Arroyo 2011

Issues with Oral Drugs - evidence

Cochrane review – limited evidence of efficacy of

existing oral agents

• Review or 26 PCT & 13 comparative studies of

antispasmodic medications

– Not enough evidence to compare their effectiveness.

• More research is needed.

(Shakespeare et al. 2003)

Time

Very Narrow

Therapeutic

Window

Minimal Therapeutic Level (μM)

}

Time

Baclofen/Cannabinoids

Dru

g L

eve

ls

Time

(CNS) Side-Effects

Minimal Therapeutic Level

Time

Baclofen/Cannabinoids

Dru

g L

eve

lsAn ideal drug

Dru

g L

eve

ls

CNS-excluded CB1 agonist - slow release

Dru

g L

eve

ls

CNS-excluded CB1 agonist

Time

Drug

Levels

Therapeutic

Window

(CNS) Side-Effects

Minimal Therapeutic Level

Wide

Therapeutic

Window

Dru

g L

eve

ls

(CNS) Side-Effects

Minimal Therapeutic Level(nM)

Time

CNS-excluded CB1 agonist

CNS

Side-Effects

Dose 2Dose 1 Dose 3

Noctural

Spasms

Baclofen/Cannabinoids

Dru

g L

eve

ls

Time

Undertreatment

to reduce

side effects

The Reality

Dose 2Dose 1 Dose 3

Dru

g L

eve

ls

Time

SpasmsSpasms

Time

Ideal Drug

Dose 1 Dose 2

Spasticity pipeline

BGG492Sativex

Arbaclofen

VSN16

Smoked cannabis

AV650IPX056

Baclofen ER

Oral cannabis

CNS excluded cannabinoids

SAB 378, SAD448, CT3

Leg moved

to full

flexion for

assessment

Spastic

Leg

Experimental Model of Multiple Sclerosis

Slides courtesy of Prof David Baker MS@UCLP, Blizard Institute, QMUL

Mouse Movement

in a Open Field Activity Monitor

Drug (same dose) Sedation(Side-Effects)

Inhibition of Spasticity

*P<0.05, ***P<0.001

Compared to baseline

VSN16 R

Water Soluble

Orally-Active

High Therapeutic Window

No/Low Side Effects

CoI: UCL spin-Out CompanyVSN16R -ve

Sativex x2 Dose +ve

Sativex +ve

Baclofen +ve

Vehicle -ve

Time Post-Administration (min)

0 30 60 90 120

Change in H

indim

b S

tiff

ness (

%)

±S

EM

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

5

10

15

20

Vehicle

Baclofen

***

***

***

Sativex

**

***

Sativex x2

***

****** ***

VSN16R ***

***

Canbex - Phase II proof of concept trial

VSN16R

• Investigators: R Farrell (CI) UCLH, C Liu Barts

Health, J Hobart Plymouth - tbc

• 4 phases

– I screening and wash out

– II daily single escalating dose – 5 days

– III three weeks twice daily stable dosing

– IV washout and end of study review

62

Canbex - Phase II proof of concept trial

VSN16R

Who can take part?

• Be between 18 and 70 years of age

• Have MS

• Able to walk 20 metres ( with aid as needed)

• Have spasticity

• Not on medication or willing to withdraw current medication

64

Spasticity and MS

• MS related spasticity affects up to 80 % people

with MS

• It leads to significant disability

• Current treatments are suboptimally effective,

poorly tolerated or invasive

• Clinical need to develop better therapies

• Canbex trial hopes to bring us one step closer

Spasticity pipeline

BGG492Sativex

Arbaclofen

VSN16

Smoked cannabis

AV650IPX056

Baclofen ER

Oral cannabis

CNS excluded cannabinoids

SAB 378, SAD448, CT3

VSN16

Thank you

If interested please contact your Neurologist or Research teams at:

1. NHNN – spasticity team rachel.farrell@uclh.nhs.uk

2. Barts Health – Maria.Espasandin@bartshealth.nhs.uk

Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial

Floriana De Angelis and Domenico Plantonefor the MS-SMART trialists

69

Efficacy and Mechanism Evaluation Programme

"This report is independent research funded by the Medical ResearchCouncil (MRC) and Multiple Sclerosis Society (MS Society) andmanaged by the National Institute for Health Research (NIHR) onbehalf of the MRC-NIHR partnership. The views expressed in thispublication are those of the authors and not necessarily those of theMRC, NHS, NIHR, MS Society or the Department of Health."

70

Types of Multiple sclerosis

(preclinical phase)

Animal/laboratory: first evidence of efficacy. Accumulation of evidence.

Phase I: small number of patients to test safety

Phase II: larger number of patients to test efficacy (it allows to identify the markers of efficacy of a drug)

Phase III: very large number of patients to confirm efficacy e compare the study drug with the standard

one.

Phase IV: post marketing.

Mandatory phases to approve all kind of drugs… A very

long process!

MULTI-ARM trials: an effective way of

speeding up the therapy evaluation process!

Treatment A PlaceboVS

Treatment B PlaceboVS

Treatment C PlaceboVS

Treatment A

Treatment B

Treatment C

Placebo

25%

25%

25%

25%

50% 50%

STANDARD

TRIALS

Placebo = dummy drug!!!

Interventions

Amiloride 5 mg bd

Riluzole 50mg bd

Fluoxetine 20mg bd

Why these drugs?Experts analyzed several drugs.

Repurposing of drugs!

Successful repurposing of drugs is not new!

Examples include:

- Aspirin – originally used as a anti-inflammatory, now used

for cardiovascular or cerebrovascular diseases

-Gabapentin - originally developed as anti-epileptics, is

now used for neuropathic pain

- Dimethyl fumarate (Tecfidera) DMT for RRMS - originally

marketed as a therapy for psoriasis

AMILORIDEHigh blood pressure

More recent sudies evidence suggests that cellular protection

can be exerted through blockade of the neuronal proton-gated

acid-sensing ion channel 1 (ASIC1), which is increased within

axons and oligodendrocytes in acute multiple sclerosis lesions.

Blocking ASIC1 with amiloride exerts neuroprotective and

myeloprotective effects in acute and chronic experimental

models of multiple sclerosis.

In this study, they tested the

neuroprotective effects of

amiloride in patients with

primary progressive multiple

sclerosis.

RILUZOLEMotor Neuron Disease

Killestein J, Kaljers NF, Polman CH, et al. Glutamate inhibition in MS: the neuroprotective properties of riluzole.J Neurol Sci 2005;233:113–115

A common pathological

event shared by a number

of neurological conditions

is extracellular

accumulation of

glutammate. High levels of

free glutammate may lead

to injury of neurons an glial

cells. The maintenance od

subtoxic extracellular

glutammate levels seem to

be crucial. The uptake of

excessive glutamate into

glial cells seems to be

carried out by glutamate

transporters.

Riluzole is a

neuroprotective agent that

inhibits the release of

glutamate from nerve

terminals.

Pilot study in 16 PPMS patients.

The result suggest that riluzole reduces the rate of

cervical cord atrophy and the development of new T1

hypointense lesions on MRI.

FLUOXETINEDepression

University of Groningen, The Netherlands

Fluoxetine, a selective serotonin-reuptake

inhibitor (SSRI), might be able to protect

against axonal loss underlying the

progressive phase of MS because it

stimulates glycogenolysis, necessary for

energy source for axons, and it enhances the

production of brainderived neurotrophic

factor in rodent astrocyte cultures.

Neurons are

damaged and

die.

Brain shrinking

= ATROPHY

Disability

Progression

MS-SMART TRIAL AIM:

neuroprotection!

In other words, testing new

drugs to slow down brain

shrinking and stop disability

progression.

At present, there are no proven drugs

able to slow down the progression!

Primary Outcome: Brain Atrophy

measured by MRI.

All of our brains shrink at a very slow rate, but in MS it happens

more rapidly. This shrinkage, or atrophy as we call it, is linked to

clinical progression and disability.

We are able to assess brain atrophy with a specialised MRI scan,

giving us a measure of brain shrinkage over time.

How can we measure neuroprotection?

Neuroptotective treatments in progressive MS

82

BRAIN SHRINKING

Brain atrophy in MS is about 0.49 – 1.2% per year

In healthy aging is about 0.2% per year

Substudies (participation in any of the sub-studies is optional):

Cervical cord atrophy

Brain MTR and CSI

Substudies:

CSF Neurofilament levels

OCT

Main Inclusion Criteria

Diagnosis of SPMS

Steady progression of clinical disability in the preceding 2 years

Still able to walk at least 20 metres with bilateral support (EDSS: 4.0-6.5)

Aged 25 to 65 (inclusive)

Able to undertake MRI

No on SSRI (fluoxetine, citalopram, escitalopram, sertraline)

Main Exclusion Criteria

Significant organ co-morbidity (e.g. malignancy/ renal or hepatic failure)

Commencement of Fampridine within 6 months of baseline visit

Use of immunosuppressants, disease modifying treatments within 6 months of baseline visit

Use of fingolimod/fumarate/teriflunomide/laquinomod/or other experimental disease modifying treatment (including research of an investigational medicinal product) within 12 months of baseline

Use of mitoxantrone/ natalizumab/ alemtuzumab/ daclizumab if treated within 12 months of baseline visit

Main Exclusion Criteria

Use of: lithium, chlorpropamide, triamterene, spironolactone

Use of potassium supplements

Glaucoma

Epilepsy

Depression

Prescreening

We will be in contact with you to discuss the trial in more detail as soon as we can and we will assess your potential eligibility…

Then…. We will give you an appointment to be formally assessed at the study centre!

Patient Flow0 2yr

6m

-30d

EDSS

MSIS29v2

MSFC

MSWSv2

EDSS

MSIS29v2

MSFC

MSWSv2

EDSS

MSIS29v2

MSFC

MSWSv2

Safety 1 2 3 6 9 1yr 1.5yr 2yr

1yr

11 clinic visits, 8 in the first year, 3 in the second year

Glasgo

w

Edinburgh

Newcastle

Liverpool

North

Staffordshire

Nottingham

Sheffield

Oxford

Truro

London – 3 sites

UCLH, Barts & the

London, Imperial

Brighton/Haywards HPlymouth

T TT

T

TT

Centres440 people

SPMS

UK

Recruitment

into the trial

Started in

Dec 2014

It will

continue

through 2015

Two centres – UCL and

University of Edinburgh

- are currently open and

all centres taking part

will be open soon.

So far at UCL

69 patients screened

52 patients already randomized

More information see MS-SMART.ORG website

Emails: floriana.deangelis@nhs.net

domenico.plantone@nhs.net

With many thanks to all those involved in the project

Questions?