The future: Presentation by Gavin Giovannoni
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Transcript of The future: Presentation by Gavin Giovannoni
The future
Gavin Giovannoni
Disclosures
Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.
Professor Giovannoni would like to acknowledge several companies and colleagues for making available data slides for this presentation.
Musings
21 October 2015
4 December 1985
21 October 2015
4 December 1985
21 October 2015
?
The Future
Images courtesy of Professor Gavin Giovannoni /
ESRFend-stage renal failure
Epstein Bar Virus
Genetics
Vitamin D
Smoking
Risks
Adverse events
DifferentialDiagnosis
At risk
RIS CIS
Minimal impairment
Moderateimpairment
Severeimpairment
Terminal
Phase
MRI
EvokedPotentials
Lumbar puncture
BloodTests
DiagnosticCriteria
Cognition
Depression
Fatigue
Bladder
Bowel
Sexual dysfunction Tremor
PainSwallowing
SpasticityFalls
Balance problems Insomnia
Restless legsFertility
Clinical trials
Gait
Pressuresores
Oscillopsia
Emotionallability
Seizures
Gastrostomy
Rehab
Suprapubiccatheter Intrathecal
baclofen
Physio-therapy
Speech therapy
OccupationalTherapy
Functional neurosurgery
Colostomy
Tendonotomy
Studying
EmploymentRelationships
Travel
Vaccination
Anxiety
Driving
Nurse specialists
Family counselling
Relapses
1st line2nd line
Maintenance Escalation Induction
Monitoring
Disease-free
Disease progression
DMTs
Side Effects
Advanced Directive
Exercise
Diet
AlternativeMedicine
PregnancyBreastFeeding
Research
Insurance
Visual loss
PalliativeCare
Assistedsuicide
Socialservices
Legalaid
Genetic counselling
PreventionDiagnosis
DMTSymptomatic
Therapist
Terminal
Counselling
Intrathecalphenol
Fractures
Movement disorders
Osteopaenia
Brain atrophy
Hearing loss
Tinnitus
Photophobia
Hiccoughs
DVLA
Neuroprotection
Psychosis
Depersonaliation
BrainHealth
CognitiveReserve
Sudden death
SuicideOCD
Narcolepsy
ApnoeaCarers
Respite
Hospice
Respite
Dignitas
Advanced Directive
Rhiztomy
Wheelchair
Walking aids
Blood/Organdonation
Brain donation
Exercise therapy
NABs
Autoimmunity
Infections
Outcome measures
WebResources
Pathogenesis
Doublevision
What isMS?
NEDA
T2TOCT
Neurofilaments
JCV statusPharma
Anaesthesia
www.ms-res.org
CISEnd-
organPPMS
The therapeutic pyramid
Neuroreparation
Remyelination
Neuroprotection
Anti-inflammatory
The therapeutic pyramid
The Future
or
Futility?
Neuroreparation
Remyelination
Neuroprotection
Anti-inflammatory
The therapeutic pyramid
Consequences of increasing EDSS scores: loss of employment
0
10
20
30
40
50
60
70
80
90
Work Capacity by Disability Level
0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0EDSS Score
Prop
ortio
n of
MSe
rs ≤
65 Y
ears
Old
Wor
king
(%)
The proportion of MSers employed or on long-term sick leave is calculated as a percentage of MSers aged 65 or younger.1. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926;2. Pfleger CC et al. Mult Scler. 2010;16:121-126.
Spain
Sweden
Switzerland
United Kingdom
Netherlands
Italy
Germany
Belgium
Austria
~10 yrs2
57%
7%
-20%
0%
20%
40%
60%
CISersn = 40
Feuillet et al. Mult Scler. 2007.
Healthy Controlsn = 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
Brain atrophy occurs across all stages of the disease
De Stefano, et al. Neurology 2010
n= 963 MSers
11,000 to 1
Trapp, et al. NEJM 1998;338:278-85
Juxtacortical gray matter lesion Intra-cortical gray matter lesions Subpial gray matter lesions
CortexWhite matter
Types of cortical lesions
Social functioning
Pfleger et al. Multiple Sclerosis 2010; 16(7) 878–882.
‘Rebranding’ MS a dementia - 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.
• Interfere with 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.”
DSM IV
Remyelination
Neuroreparation
Remyelination
Neuroprotection
Anti-inflammatory
The therapeutic pyramid
Remyelination
Nogo, MAG, OMgP
Lingo-1-NgR-p75NTR
GAP-43
NCAM
Neuregulin
Slide courtesy of Klaus Schmierer.
Premyelinating oligodendrocytes in chronic MS lesions1
Negative regulators of OPC differentiation have been identified2,3
Investigating LINGO-1 as a target for remyelinationand neuroprotection/neuroreparation
OPC=oligodendrocyte precursor cells; NCAM=neural cell adhesion molecule; PSA=polysialic acid; RNAi=ribonucleic acid interference.1. Chang A et al. N Engl J Med. 2002;346:165-173; 2. Adapted from Rudick RA et al. Expert Opin Biol Ther. 2008;8:1561-1570; 3. Mi S et al. Ann Neurol. 2009;65:304-315; 4. Mi S et al. Nat Neurosci. 2005;8:745-751; 5. Cadavid D et al. Presented at AAN; Philadelphia, USA; 2014:P2.262.
In vivo effects of anti-LINGO-1 in rat optic nerve crush model5
Reduced neurodegeneration and increased axonal outgrowth (arrows) vs control
Control RNAiLINGO-1 RNAi
In vitro effects of LINGO-1 blockade4
Mature oligodendrocyteOPCs
Differentiation
LINGO-1,PSA-NCAM,
Notch
Anti-LINGO-1treatment
Proximal Distal
Control treatment
Fluorescein isothiocyanate-conjugated cholera toxin B–labeled axons after optic nerve crush
and vehicle injection
Premyelinating oligodendrocytes in chronic MS lesions1
Negative regulators of OPC differentiation have been identified2,3
Investigating LINGO-1 as a target for remyelinationand neuroprotection/neuroreparation
OPC=oligodendrocyte precursor cells; NCAM=neural cell adhesion molecule; PSA=polysialic acid; RNAi=ribonucleic acid interference.1. Chang A et al. N Engl J Med. 2002;346:165-173; 2. Adapted from Rudick RA et al. Expert Opin Biol Ther. 2008;8:1561-1570; 3. Mi S et al. Ann Neurol. 2009;65:304-315; 4. Mi S et al. Nat Neurosci. 2005;8:745-751; 5. Cadavid D et al. Presented at AAN; Philadelphia, USA; 2014:P2.262.
In vivo effects of anti-LINGO-1 in rat optic nerve crush model5
Reduced neurodegeneration and increased axonal outgrowth (arrows) vs control
Control RNAiLINGO-1 RNAi
In vitro effects of LINGO-1 blockade4
Mature oligodendrocyteOPCs
Differentiation
LINGO-1,PSA-NCAM,
Notch
Anti-LINGO-1treatment
Proximal DistalFluorescein isothiocyanate-conjugated cholera
toxin B–labeled axons after optic nerve crush and vehicle injection
Anti-LINGO-1 results in remyelination in animal models of CNS demyelination2
LPC=lysophosphatidylcholine/lysolecithin; mAb=monoclonal antibody.Adapted from 1. Mi S et al. Nature Neurosci. 2004;7:221-228; 2. Mi S et al. Ann Neurol. 2009;65:304-315.
1 µm
Control mAb Anti-LINGO-1
1 µm
Cuprizone
LPC
*
**
*
Demyelinated axons *Remyelinated axons
EAE
New phase 2 study designs: Acute optic neuritis to assess neuroprotection and remyelination
1. Cadavid D et al. Presented at AAN; Philadelphia, USA; 2014:P2.2622. Cadavid D et al. Presented at AAN; Washington, USA; 2015:P7.202.
RENEW1,2
Anti-LINGO-1(multi-centre)
Anti-LINGO-1 (100 mg/kg IV Q4W x 6)
Placebo (IV Q4W x 6)
Participants with first episode of unilateral
AON (n=82)
Randomised within 4 weeks of symptom onset
Dosing period20 weeks
Assessments at24 and 32 weeks
3–5 days’ IV steroids
End of studyfollow-up 32 weeks
Primary outcome: VEP
RENEW primary outcome: Anti-LINGO-1 and recovery of full-field VEP latency in AON
*Adjusted mean change in optic nerve conduction latency of the affected eye compared with the unaffected fellow eye at baseline, Week 24 (ANCOVA), Week 32 (MMRM). ANCOVA=analysis of covariance; ITT=intent-to-treat; MMRM=mixed-effect model repeated measure; PP=per-protocol.Adapted from 1. Cadavid D et al. Presented at AAN; Washington, USA; 2015:P008; 2. Cadavid D et al. Presented at AAN; Washington, USA; 2015:P7.202.
Placebo 100 mg/kg anti-LINGO-1
25
20
15
10
5
0PP ITT
22.24
14.69
20.83
17.34
Week 24
34% LatencyrecoveryP=0.05
17% LatencyrecoveryP=0.33
Adju
sted
mea
n ch
ange
inFu
ll-fie
ld V
EP la
tenc
y* (m
s)
n=36 n=33 n=41 n=41
PP=Subjects who completed the study, did not miss >1 dose of treatment and did not receive MS modifying therapy
ITT=All randomised subjects who received ≥1 dose of study treatment
PP ITT
22.35
13.22
21.15
15.08
Week 32
41% LatencyrecoveryP=0.01
29% LatencyrecoveryP=0.07
n=36 n=33 n=41 n=41
Remyelination
Nogo, MAG, OMgP
Lingo-1-NgR-p75NTR
GAP-43
NCAM
Neuregulin
Slide courtesy of Klaus Schmierer.
Agents in trial
1. GSK239512: histamine H(3) receptor antagonist
2. BIIB033: anti-LINGO-1 3. Clemastine: anti-histamine4. IRX4204 & Bexarotene: RXR-
agonist 5. Etc.
Neuroprotection
Neuroreparation
Remyelination
Neuroprotection
Anti-inflammatory
The therapeutic pyramid
Acut
e ax
onal
tran
sect
ion
“Inflammatory scissors or shredder”
Acute neuroprotection
AxonNO
Microglia
Na+
Na+/K+
ATPaseNaV1.6Reverse
NCX
ATPATP
Ca2+ ATPase
Ca2+
Na+
NaV1.6
Na+
Figure courtesy of Dr Raju KapoorATP=adenosine triphosphate; NaV1.6=Sodium channel, voltage gated, type VIII, alpha subunit; NCX=sodium-calcium exchanger.1. BD Trapp et al. N Engl J Med. 1998;338:278-285; 2. Bittner S et al. Ther Adv Neurol Disord. 2013;6:322-336.
Acute neuroprotection: targeting axonal energy levels may achieve acute neuroprotection1,2
Acute optic neuritis (AON) to assess phenytoin (neuroprotection)
Phenytoin
Participants with AON N=86
Phenytoin (4 mg/kg OD)
Placebo
Randomised within 2 wks of symptom onset
Treatment period3 months
Monitoring period3 months
Primary outcome measures
Primary outcome measure: RNFL thickness
RNFL thickness Macular volume
1. Kapoor R et al. Presented at AAN; Washington, USA; 2015; 2. https://clinicaltrials.gov/ct2/show/NCT01451593;
Primary outcome: RNFL
• Active-placebo adjusted difference 7.15 mm (95% CI 1.08, 13.22 p=0.02)
• 30% reduction of atrophy in active group
• PP comparison: Active-placebo adjusted difference 7.40 mm (95% CI 0.76, 14.04 p=0.03)
5010
015
0
RNFL
ave
rage
mm
Placebo Phenytoin
baseline UNaffected eye
Placebo Phenytoin
6m affected eye
Bars are standard errors around the unadjusted group means
Delayed/ongoing secondary neurodegeneration1
“Post-inflammatory slow-burn”
Ongoing neuroprotection
Treatment Targets
1. Inflammation2
a. Adaptive (B-cell follicles)3
b. Innate (activated microglia4 and astrocytes5)
2. Axonal mechanisms6
a. Mitochondrial/energetics7
b. Axonal targets6
3. Remyelination8
4. Comorbidities/ageing (simvastatin)9
1. Trapp BD et al. N Engl J Med. 1998;338:278-285; 2. Loleit V et al. Curr Pharm Biotechnol. 2014;15:276–296; 3 Magliozzi R et al. Brain. 2007;130:1089-1104; 4. Rissanen E et al. J Nucl Med. 2014;55:939-944; 5. Mayo L et al. Nat Med. 2014;20:1147-1156; 6. Haines JD et al. Mt Sinai J Med. 2011;78:231-243; 7. Mahad D et al. Neuropathol Appl Neurobiol. 2008;34:577-589; 8. Münzel EJ et al. Drugs. 2013;73:2017-2029; 9. Chataway J et al. Lancet. 2014;383:2213-2221.
Targeting ongoing chronic neurodegeneration
Slide courtesy of Jeremy Chataway Chataway et al. Lancet 2014; 383: 2213–21.
BSI (Boundary Shift Integral)
Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial
www.ms-res.org
The off-patent drug bill
Trial activity targeting progressive pathology
MRI Events
1st clinicalattack
Time (Years)
Subclinical disease
Inflammation
Brain volume loss
Neuroaxonal loss
Dise
ase
Seve
rity
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
Late SPMS: SMART STUDYfluoxetine, amiloride, riluzole
Early SPMS:oxcarbazepine
CIS: PHENYTOIN RRMS: ? DE-FLAMES STUDY
PPMS
PPMS: Laquinimod
SP&PPMS: Ibudilast
New antiinflammatories
Neuroreparation
Remyelination
Neuroprotection
Anti-inflammatory
The therapeutic pyramid
Flipping the pyramid
IMS, immunosuppressant; TNF, tumour necrosis factorReproduced from Gut, Ordás I, Feagan BG and Sandborn WJ, 1754–63, 2011 with permission from BMJ Publishing Group Ltd.
Corticosteroids+ IMS
Corticosteroids
TNFantagonist
± IMS
Conventionalstep care
Acceleratedstep care
Moderate
SevereEarly top-down
Leve
l of d
isea
se
Flipping the pyramid
Fingolimod
Fingolimod
Dimethyl fumarate
Alemtuzumab
Natalizumab
Laquinimod
Daclizumab HYP
Rituximab
Cladribine
Teriflunomide
Ocrelizumab
Ofatumumab
Targeting immune regulation has been successful previously in RRMS
Lymph node
APC=antigen-presenting cell; B=B cell; BBB=blood-brain barrier; CD=cluster of differentiation; CNS=central nervous system; IFN=interferon; IL=interleukin; MØ=macrophage; NK=natural killer cell; NO=nitric oxide; PC=plasma cell; S1P-R=Sphingosine-1-phosphate receptor; T=T cell; Th=T-helper cell; TNF=tumour necrosis factor; VCAM=vascular cell adhesion molecule; VLA=Integrin alpha4beta1.Adapted from 1. Barten LJ et al. Drug Des Devel Ther. 2010;4:343-366; 2. Loleit V et al. Curr Pharm Biotechnol. 2014;15:276-296.
BBB CNSPeriphery
Approved therapies
Investigational agents
Daclizumab
Immunomodulatory Effect of Daclizumab Treatment
DAC treatment increases CD56bright NK cell proliferation via intermediate affinity IL-2 signaling1
Martin J et. al., J. Immunol, 2010.
53
Click to edit Master title styleDECIDE Study Design Overview
All patients had a minimum of 2 years and maximum of 3 years of treatmentThe trial ended when the last patient randomized completed 2 years of treatment
96-144 week treatment period
RRMS Patients(N=1841)
0 4 8 12 16 20 24 28 32 36 40 44 48 96 144
IM IFN beta-1a 30 mcg every 1 week (n=922)
SC DAC HYP 150 mg every 4 weeks (n=919)
Follow-up
Brain MRI
EDSS* EDSS* EDSS* EDSS* EDSS* EDSS*
*Also assessed at weeks 60, 72, 84, 108, 120, 132, 144. EDSS, Expanded Disability Status Scale; IFN, interferon; IM, intramuscular; mcg, micrograms; MRI, magnetic resonance imagine; RRMS, relapsing remitting multiple sclerosis; SC, subcutaneous.
Inclusion Criteria:• Age 18-55 years• Confirmed RRMS1
• MRI consistent with MS• Baseline EDSS 0-5• ≥2 relapses within 3 years (≥1
in year prior to study)• ≥1 relapse (or new MRI lesion)
within 2 years (≥1 in year prior to study)
Time (weeks)
1:1 Randomization
53
54
Click to edit Master title styleAnnualized Relapse Rate (ARR)
(n=922) (n=919)
ARR
Estimated from a negative binomial regression model adjusted for baseline relapse rate, history of prior IFN beta use, baseline EDSS (≤2.5 vs > 2.5) and baseline age (≤35 vs >35). Patients were censored at the earliest of the following events: 1) start of alternative MS medication, 2) 180 days post treatment discontinuation or 3) end of treatment period. CI, confidence interval.
54
55
Click to edit Master title style3-Month and 6-Month Confirmed DisabilityProgression
Risk reduction: 16%; p=0.16
Proportion with progressionWeek 48: 6% vs. 8% Week 96: 12% vs. 14% Week 144: 16% vs. 20%
BL 12 24 36 48 60 72 84 96 108 120 132 144Time on study (weeks)
BL 12 24 36 48 60 72 84 96 108 120 132 144Time on study (weeks)
Risk reduction: 27%; p=0.0332
Proportion with progressionWeek 48: 4% vs. 7% Week 96: 9% vs. 12% Week 144: 13% vs. 18%
3-month* 6-month†
Prop
ortio
n of
pati
ents
with
co
nfirm
ed p
rogr
essio
n of
disa
bilit
y
*3-month confirmed: Patients censored after tentative progression (n=67) analyzed per primary method in the statistical analysis plan: all imputed as non-progressors; †6-month confirmed: Patients censored after tentative progression (n=108) imputed per observed rate in trial; tertiary endpoint. Estimated proportions are the average over imputed datasets. For both endpoints risk reductions based on Cox proportional hazards model adjusted for baseline EDSS, history of prior IFN use, and age.
Ocrelizumab
Ocrelizumab is a humanized mAb that depletes CD20+ B cells via multiple mechanisms
57
mAb, monoclonal antibody.1. Jaglowski SM, et al. Blood 2010;116:3705–14; 2. Winiarska M, et al. Front Biosci 2011;16277–306; 3. Klein C, et al. MAbs 2013;5:22–33.
COMPLEMENT-DEPENDENTCYTOTOXICITY1-3
DIRECTAPOPTOSIS1-3
ANTIBODY-DEPENDENT CELLULAR PHAGOCYTOSIS1-3
ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY1-3
58
B cells are depleted to a greater extent in lymphoid compartments compared with bone marrow
58LN-ing, lymph node-inguinal; LN-man, LN-mandibular.Gelzleichter T, et al. ACTRIMS-ECTRIMS 2014; Poster 64654.
Cladribine
Cladribine is an analog of deoxyadenosine
• Cladribine is an analog of deoxyadenosine, one of the building blocks of DNA, that differs from the naturally occurring nucleoside, deoxyadenosine by a chlorine substitution for hydrogen1,2
• Cladribine is resistant to deamination by the enzyme adenosine deaminase (ADA) by virtue of its structural design1,2
1. Carson DA et al. Proc Natl Acad Sci USA 1980;77:6865-9. 2. Beutler E. Lancet 1992;340:952-6
G
G
T
TG
T
G
CC
AA
C
A
C
OH
HO O
N NCI
N
NH2
N
2-chlorodeoxyadenosine(cladribine)
OH
HO O
N NH
N
NH2
N
Deoxyadenosine
Nitrogenousbase
SugarPhosphateBackbone
Base pair
Adenine
Ribose
Cladribine Tablets lead to reductions in CD4+ T and CD8+ T cells
Placebo (n=79)
Cladribine Tablets 3.5 mg/kg(n=81)
Months
0100200300400500600700800900
1000
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 LA*
Cells
/µL
050
100150200250300350400450500
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 LA*
Cells
/µL
BLBL
Normal range:500-1500/µL
Normal range:300-1000/µL
CD4+ T cells CD8+ T cells
Months
Arrows indicate administration of Cladribine Tablets. 1 treatment week = 1 or 2 tablets over 4-5 days during a 28-day period.*LA performed at 26 months. BL, baseline; LA, last assessment.Soelberg-Sørensen S et al. ENS 2009 [P359]. Leist TP, Weissert R. Clin Neuropharmacol 2011;34:28-35
Significant reduction in ARR vs placebo over 2 years (primary endpoint)
0.33
0.14 0.15
Placebo(n=437)
Cladribine 3.5 mg/kg
(n=433)
Annu
aliz
ed re
laps
e ra
te (9
5% C
I)
Cladribine5.25 mg/kg
(n=456)
(0.29, 0.38)
(0.12, 0.17) (0.12, 0.17)
0.30
0.20
0.10
0.00
0.403.5 mg/kg vs placebo
57.6% relative reductionp<0.001
5.25 mg/kg vs placebo54.5% relative reduction
p<0.001
ARR, annualized relapse rate.Intent-to-treat population. Giovannoni G et al. N Engl J Med 2010;362:416-26
Significant delay in time to 3-month confirmed disability progression (secondary endpoint)
PlaceboCladribine Tablets 5.25 mg/kgCladribine Tablets 3.5 mg/kg
~30% reduction in risk of developing
disability progression at any time point over
2 years (96 weeks on study)
Cladribine Tablets:5.25 mg/kg and 3.5 mg/kg
10th percentile = 14.8 Study months
Prop
ortio
n of
pa
tient
s with
pro
gres
sion
0.0
0.1
0.2
0.3
0.4
0.5
0 4 14 16 24
Study months
2 6 8 10 12 18 20 22
Placebo:10th percentile = 11.8 Study months
5.25 mg/kg vs placeboHazard ratio: 0.69 95% CI: 0.49, 0.96
p=0.026a
3.5 mg/kg vs placeboHazard ratio: 0.67 95% CI: 0.48, 0.93
p=0.018a
Prolongation of time to sustained disability
progression by ~3 months
aThe hazard ratio, 95% CI, and p-values were estimated using Cox proportional hazards model with fixed effects for treatment group and region. Intent-to-treat population. Giovannoni G et al. N Engl J Med 2010;362:416-26. Data on file
Significantly more patients achieve NEDAa over 2 years vs placebo
0
10
20
30
40
50
60
15.8
44.3 46
Placebo(n=379)
Cladribine 3.5 mg/kg (n=402)
Prop
ortio
n of
pat
ient
s with
NED
A (%
)
Cladribine 5.25 mg/kg(n=411)
3.5 mg/kg vs placeboOdds ratio: 4.28
95% CI: 3.05, 6.02p<0.0001
5.25 mg/kg vs placeboOdds ratio: 4.62
95% CI: 3.29, 6.48p<0.0001
NEDA, no evidence of disease activity.Post hoc analysis. aNEDA was defined as having no relapses, no 3-month sustained change in EDSS score, no new T1 Gd+ lesions, and no active T2 lesions. Giovannoni G et al. Lancet Neurol 2011;10:329-37
CLARITY EXT demonstrates the durable efficacy of Cladribine Tablets on relapses and reconfirms the efficacy outcomes of CLARITY
3.5 mg/kg CP 5.25 mg/kg CP 7 mg/kg CC 8.75 mg/kg CC 3.5 mg/kg PC0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.14 0.15 0.14 0.15
0.33
0.15 0.16
0.10 0.11 0.10
Cladribine Placebo
98 186 186 244437456456 433433 92
Annu
aliz
ed re
laps
e ra
te
n=CLARITY
EXTCLARITY CLARITY
EXTCLARITY CLARITY
EXTCLARITY CLARITY
EXTCLARITY CLARITY
EXTCLARITY
The similar ARRs seen in CLARITY and CLARITY EXT suggest that treatment with Cladribine Tablets leads to a durable effect on ARR for up to 4 years. In addition, within-treatment group analysis of the 3.5 mg/kg PC group (n=244)
demonstrated that switching to cladribine treatment in Years 3 and 4 led to a significant reduction in ARR in patients previously treated with placebo in Years 1 and 2 (ARR fell from 0.25 to 0.10; p<0.001)a
CP=cladribine (3.5 mg/kg) in CLARITY, placebo in CLARITY EXT; PC=placebo in CLARITY, cladribine (3.5 mg/kg) in CLARITY EXT; CC=cladribine (3.5 or 5.25 mg/kg) in CLARITY, cladribine (3.5 mg/kg only) in CLARITY EXT. For each group, cladribine dose refers to cumulative dose over 4 years in CLARITY EXT. ap-values for within-group comparisons were based on the two-sided Wilcoxon signed–rank test (see slide notes for more details). Giovannoni G et al. N Engl J Med 2010;362:416-26. Giovannoni G et al. AAN 2013 [P07.119]
100
90
80
70
60
50
40
30
20
10
0M3 M6 M9 M12 M15 M18 M21 M24
Time to McDonald MS conversion from randomization date (Months)
203 (0) 165 (37) 119 (82) 113 (87) 108 (88) 87 (95) 71 (96) 39 (98) 1 (99)Cladribine 5.25 mg/kg204 (0) 167 (36) 114 (88) 108 (92) 92 (102) 82 (104) 71 (107) 39 (110) 3 (110)Cladribine 3.5 mg/kg201 (0) 143 (58) 71 (128) 58 (141) 43 (154) 32 (162) 23 (165) 13 (169) 2 (169)Placebo
Patients at risk (conversions):
87.1%
51.4%56.1%
Hazard ratio vs placebob
5.25 mg/kg: 0.425, p<0.00013.5 mg/kg: 0.496, p<0.0001
Cum
ulati
ve in
cide
nce
(%)
Risk reduction5.25 mg/kg: 57.5%3.5 mg/kg: 50.4%
Treatment with Cladribine Tablets reduces the risk of conversion to McDonald 2005 MS in treatment-naïve patients with an FCDEa
– Cladribine 5.25 mg/kg– Cladribine 3.5 mg/kg– Placebo
M0
aPatients enrolled in ORACLE-MS were treatment-naïve with an FCDE at high risk of converting to MS. bCox proportional hazards model controlling for the randomization stratification factor (region). FCDE, first clinical demyelinating event; M, Month. Leist TP et al. Lancet Neurol 2014;13:257-67
Affordable DMTs
Unequal access to DMTs
www.ms-res.org
Vetoing NICE
www.ms-res.org
www.ms-res.org
Adoption of innovations
Rapid adoption of innovations is “biggest unmet need of all”
Adapted from Everett M. Rogers, Diffusion of Innovations
Large disparities exist in access to disease-modifying therapies
1. Hollingworth S et al. J Clin Neurosci 2014;21:2083–7; 2. World Bank, 2015. http://data.worldbank.org/indicator/SP.POP.TOTL; 3. MSIF, 2013. http://www.atlasofms.org; 4. Wilsdon T et al. 2013. http://crai.com/sites/default/files/publications/CRA-Biogen-Access-to-MS-Treatment-Final-Report.pdf
Australia
Denmark
Belgium
Germany
Finland
Italy
United Kingdom
0 20 40 60 80 100
Newer DMTEstablished DMTNo DMT
All people with MS (%)
All data are from 2013
4
4
4
4
4
4
4
4
4
4
4
4
4
1–3
Established DMTsDMTs approved for relapsing forms of MS during the 1990s and reformulations or generic versions of these substances.
Newer DMTsDMTs approved for relapsing forms of MS that have a different mechanism of action from established DMTs.
1st line
2nd line
3rd line
www.msbrainhealth.org
www.msbrainhealth.org
Baseline Month 6
Month 12 Month 18
Baseline Month 6
Month 12 Month 18
www.msbrainhealth.org
Neuro-restoration
Remyelination
Neuroprotection
Anti-inflammatory
Therapeutic pyramid
Anti-ageing
Brain Health Initiative• Smoking• Exercise• Diet• Alcohol• Sleep• Co-morbidities• Infections• Concomitant medications
• ? Menopause / HRT
MS-specific
MS non-specific
Brain Health
Symptomatic therapies
10%
60%
5%
15%
5%
DMTs Symptomatic Diagnostic Admin Blog
Neurologist’s Clinic Time – Prof G
10%
20%
10%
15%
45%
DMTs Symptomatic Counselling Admin Monitoring
Clinical Nurse Specialist (CNS) Clinic Time
Epstein Bar Virus
Genetics
Vitamin D
Smoking
Risks
Adverse events
DifferentialDiagnosis
At risk
RIS CIS
Minimal impairment
Moderateimpairment
Severeimpairment
Terminal
Phase
MRI
EvokedPotentials
Lumbar puncture
BloodTests
DiagnosticCriteria
Cognition
Depression
Fatigue
Bladder
Bowel
Sexual dysfunction Tremor
PainSwallowing
SpasticityFalls
Balance problems Insomnia
Restless legsFertility
Clinical trials
Gait
Pressuresores
Oscillopsia
Emotionallability
Seizures
Gastrostomy
Rehab
Suprapubiccatheter Intrathecal
baclofen
Physio-therapy
Speech therapy
OccupationalTherapy
Functional neurosurgery
Colostomy
Tendonotomy
Studying
EmploymentRelationships
Travel
Vaccination
Anxiety
Driving
Nurse specialists
Family counselling
Relapses
1st line2nd line
Maintenance Escalation Induction
Monitoring
Disease-free
Disease progression
DMTs
Side Effects
Advanced Directive
Exercise
Diet
AlternativeMedicine
PregnancyBreastFeeding
Research
Insurance
Visual loss
PalliativeCare
Assistedsuicide
Socialservices
Legalaid
Genetic counselling
PreventionDiagnosis
DMTSymptomatic
Therapist
Terminal
Counselling
Intrathecalphenol
Fractures
Movement disorders
Osteopaenia
Brain atrophy
Hearing loss
Tinnitus
Photophobia
Hiccoughs
DVLA
Neuroprotection
Psychosis
Depersonaliation
BrainHealth
CognitiveReserve
Sudden death
SuicideOCD
Narcolepsy
ApnoeaCarers
Respite
Hospice
Respite
Dignitas
Advanced Directive
Rhiztomy
Wheelchair
Walking aids
Blood/Organdonation
Brain donation
Exercise therapy
NABs
Autoimmunity
Infections
Outcome measures
WebResources
Pathogenesis
Doublevision
What isMS?
NEDA
T2TOCT
Neurofilaments
JCV statusPharma
Anaesthesia
www.ms-res.org
Services
NHS 1950
NHS 2000
Uberization of Healthcare
SMS
PrivateePortal
Letters
Clinic
GroupClinics
Tele-phone
Skype
Apps
BlogApps
GroupePortal
SERV
ICE
DEVE
LOPM
ENT
Lateral thinking
Is there a “Black Swan”?
Is the MS dogma wrong?
immune activationinnate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
Clinical Attack
Disease Progression
Clinical Recovery
- biology
- clinical outcomes
- biomarkers
VIRUS(EBV, HERVs)
Neuroreparation
Remyelination
Neuroprotection
Anti-inflammatory
The therapeutic pyramid
Neuroreparation
Remyelination
Neuroprotection
Anti-inflammatory
Prevention
The therapeutic pyramid
Neuroreparation
Remyelination
Neuroprotection
Anti-inflammatory
Prevention
The therapeutic pyramid
EBV Vitamin D
SmokingGenes
www.digestingscience.co.uk
Conclusions: the ‘future’ in MS• MS service development – ‘uberization’ of MS care• Better symptomatic therapies• Need quicker adoption of innovations
• Brain Health Policy (www.msbrainhealth.org)• UK move up the league tables
• Affordable DMTs , particularly in resource-poor settings• New legislation for repurposing of off-patent drugs
• New therapeutic targets• Therapeutic pyramid• Neuroprotection / Remyelination• New trial design• Brain Health
• New anti-inflammatories• Daclizumab• Ocrelizumab• Cladribine
• Black Swan• Viral and other hypotheses• Prevention of MS
Conclusions: the ‘future’ in MS• MS service development – ‘uberization’ of MS care• Better symptomatic therapies• Need quicker adoption of innovations
• Brain Health Policy (www.msbrainhealth.org)• UK move up the league tables
• Affordable DMTs , particularly in resource-poor settings• New legislation for repurposing of off-patent drugs
• New therapeutic targets• Therapeutic pyramid• Neuroprotection / Remyelination• New trial design• Brain Health
• New anti-inflammatories• Daclizumab• Ocrelizumab• Cladribine
• Black Swan• Viral and other hypotheses• Prevention of MS
Rheumatoid arthritisEnd-stage joint disease
Acknowledgements• Neurofilament
• Sharmilee Gnanapavan
• Axel Petzold
• Jens Kuhle
• Andrea Malaspina
• EAE• David Baker
• Gareth Pryce
• Sarah Al-Izki
• Sam Jackson
• Katie Lidster• Siddharthan Chandran• David Hampton
• VSN16• David Baker
• David Selwood
• Rachel Farrell, et al.
• Optic neuritis• Raj Kapoor, et al.
• PROXIMUS• Monica Marta, et al.
• MS Services• Alison Thomson, et al.
• Affordable DMTs• Klaus Schmierer, et al.
• Charcot Project (viruses in MS)• Julian Gold, et al.
• MS@UCLP• Barts-MS, et al.• UCL-UCLH• RFH• Queens Romford
Questions