ms roadshow 2015 - chelmsford
TRANSCRIPT
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 [email protected]
2. Barts Health – [email protected]
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: [email protected]
With many thanks to all those involved in the project
Questions?