Transcript 2.15 Zicht op nieuwe medicijnen

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WORLD ALZHEIMER REPORT 2010
Executive Summary
The total estimated worldwide costs of dementia are US$604 billion in 2010.
About 70% of the costs occur in Western Europe and North America.
Costs were attributed to informal care (unpaid care provided by family and others), direct
costs of social care (provided by community care professionals, and in residential home
settings) and the direct costs of medical care (the costs of treating dementia and other
conditions in primary and secondary care).
Prevalentie dementie in de EU:
Zicht op nieuwe medicijnen tegen de
ziekte
van
Costs of informal
care Alzheimer
and the direct costs of social care generally contribute similar
10M
proportions of total costs, while the direct medical costs are much lower. However, in low
and middle income countries informal care accounts for the majority of total costs and
direct socialDr.
careNiels
costs are
negligible.
Prins
Moderne Dementiezorg,
Background
NBC
Nieuwegein 24 november 2014
• Dementia is a syndrome that can be caused by a number of progressive disorders that affect
memory, thinking, behaviour and the ability to perform everyday activities. Alzheimer’s disease
is the most common type of dementia. Other types include vascular dementia, dementia with
Lewy bodies and frontotemporal dementia.
• Dementia mainly affects older people, although there is a growing awareness of cases that start
before the age of 65. After age 65, the likelihood of developing dementia roughly doubles every
five years.
• In last year’s World Alzheimer Report, Alzheimer’s Disease International estimated that there are
35.6 million people living with dementia worldwide in 2010, increasing to 65.7 million by 2030
and 115.4 million by 2050. Nearly two-thirds live in low and middle income countries, where the
sharpest increases in numbers are set to occur (figure 1).
• People with dementia, their families and friends are affected on personal, emotional, financial
and social levels. Lack of awareness is a global problem. A proper understanding of the
societal costs of dementia, and how these impact upon families, health and social care
services and governments may help to address this problem.
Figure 1
The growth in numbers of people with
Figure 2
Cost of dementia compared to company
in high income countries and low and
revenue
Dementie dementia
is income
een
wereldwijd probleem
middle
countries
Numbers of people with dementia (millions)
US$ billions
120
600
100
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400
60
300
40
200
20
100
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0
2010
2020
2030
2040
2050
Dementia
Wal-Mart
Exxon Mobil
Alzheimer is de meest voorkomende
oorzaak van dementie
Leeftijd >65 jaar
Leeftijd ≤65 jaar
Year
ALZHEIMER’S DISEASE INTERNATIONAL
ADI World Alzheimer Report 2010
Hersenvocht laat specifiek biomarker patroon
zien bij de ziekte van Alzheimer
Amyloid PET toont Amyloid-β
in de hersenen
Controle
Alzheimer
±90% correct
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Ziekte van Alzheimer
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Mild AD
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MMSE=26
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MMSE=20-21
MMSE=7
Donepezil, Rivastigmine
Galantamine
(Nieuwe generatie AchEI’s)
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Auguste D
Identificatie andere
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glutamaat en NMDA
Memantine
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Final Thoughts
• 3 syndromes, 3 genes, 3 pathologies
Cholinesterase
remmers verbeteren cognitie bij
• Powerful model to study emotion, social
vaninAlzheimer
cognitionde
andziekte
language
the brain
Memantine verbetert cognitie bij AD
Pooled data from six fase III, placebo-controlled studies in moderate AD
(baseline MMSE 10–19)
-2
ADAS-cog (0-70) Weighted Mean Difference after 6 months
• Neuroimaging
plays a critical role in
treatment versus placebo
the
diagnosis Dose
of FTD
Treatment
(mg)
ADAS-cog
(95% CI)
WMD
– Specific anatomic patterns
of neurodegeneration
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16
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24
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E. Scarpini, Lancet Neurol. 2003 Sep;2(9):539-47.
Extra Slides
Nieuwe symptomatische
behandelingen zijn in ontwikkeling
AChEI
•  Huperzine A and patch
α7 nicotinic agonist
•  EVP-6124, ABT-126
α4 β2 nicotinic agonist
•  AZD 3480/TC 1734
Glutamatergic neurotransmission facilitators
•  PDE9 inhibitor, AMPA modulator
8
2
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De alpha-7 agonist EVP-6124 verbetert
cognitie in een fase 2 AD trial
EVP-6124-010: ADAS Cog-13
Alzheimer’s Disease Assessment Scale Cog-13
EVP-6124 0.3 mg
EVP-6124 1 mg
-2.5
EVP-6124 2 mg
LSMEAN Change From Baseline
(± S.E.M.)
Placebo
-2
-1.5
-1
-0.5
0
0.5
1
0
4
Huperzia Serrata
8
12
16
20
Patients on the 2mg dose experienced an improvement in cognition (not
just maintenance of current cognitive function) over the 23 weeks of dosing
and were still separating from the placebo group at the end of the trial
6
De amyloid cascade is de belangrijkste
hypothese voor het ontstaan van Alzheimer
2 mg vs. Placebo
Hilt,EVP-6124
AAIC
2012
Week 23: P-value = 0.0189
Effect Size = 0.39
(Preliminary Draft Data)
PIB-PET maakt Amyloid-β in
de hersenen zichtbaar
Normaal
Analyse van het hersenvocht helpt bij het
diagnosticeren van Alzheimer
24
Study Visit (Week)
Alzheimer
Therapeutische strategieën gericht
op de amyloid cascade
•  Opruimen van amyloid-β (Immuuntherapie)
•  Remming amyloid-β productie (Secretase remmers)
•  Verbeteren synaps-functie (medische voeding)
!
!
Gezond
Alzheimer
•  Anders….
Mulder, Clinical Chemistry 2010
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Immunisatie met Amyloid-β vermindert
AD pathologie in PDAPP transgene muizen
Immuuntherapie kan Amyloid β uit
de hersenen verwijderen
Hippocampal Dentate Gyrus
Transgenic mouse:
APP mutation
Aβ42 injected mouse
at 6 weeks
Weiner en Frenkel, Nat. Rev. Immunol. 2006
Schenk, et al. Nature 1999;400:173-77
Post-vaccinatie meningoencephalitis bij 6%
van de patiënten behandeld met AN1792
Vergelijk tussen immunotherapie met Aβ42
fragmenten en passieve immunotherapie
Strategy
Actieve immunotherapie
met fragmenten Aβ42
Advantages
Disadvantages
•  Voorkomt
problemen
samenhangend met
T-cel respons
•  Antilichaam respons kan laag
zijn
•  Risico of APP cross-reactiviteit
•  Irreversibel
Nicoll JAR, et al. Nature Medicine 2003;9(4):448-452
Vergelijk tussen immunotherapie met Aβ42
fragmenten en passieve immunotherapie
Strategy
•  Passieve
immunotherapie met
monoclonale
antilichamen gericht
tegen Aβ
Advantages
•  Geen
immunologische
respons nodig
Amyloid-β immune therapy:
passive vaccination
Phase III
Epitopes
Bapineuzumab
N-terminal
Solanezumab
Mid region
Gantenerumab
Central and Nterminal
Disadvantages
•  Vasogeen oedeem
•  Microbloedingen
•  Herhaalde toediening nodig
Disappointing results
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Vasogeen oedeem op MRI in fase II
studie met Bapineuzumab
Pre-dose
7 Weeks
13 Weeks
Gantenerumab phase III:
“Scarlet RoAD” trial design
•  Multi-center, randomized, double-blind placebo-controlled 24-month
clinical trial
19 Weeks
•  770 patients
•  Prodromal AD (MMSE 24 or above)
•  Treatment: gantenerumab 105 mg, gantenerumab 225 mg, or placebo
S.C. every 4 weeks
•  Primary Clinical Endpoints: change in the Clinical Dementia Rating scale
Sum of Boxes (CDR-SOB)
Cohort: 1.0 mg/kg; ApoE4 carrier (asymptomatic)
•  Secondary Endpoints: ADAS-Cog, FAQ, Safety, Pharmacokinetics
Remming van BACE 1 voorkomt de
vorming van Amyloid β
Secretase remmers voorkomen
de productie van Amyloid-β
1232 | S. Schilling et al.
(a)
(c)
X
Cheng H et al. Nat Clin Pract Neurol 2007
β-secretase remmers
Phase I
Phase II
•  γ-secretase (b)
Niet specifiek voor APP, knipt ook NOTCH
Fig. 5 Photomicroscopy
of representative
sections of four different rat brains 24 h
after bilateral injection of either vehicle or
PBD150 followed by Ab(3–40). IHC-based
detection of pGlu-Ab(3–40), using diaminobenzidine as substrate, was performed.
Panels a–d provides representative sections at the level of the injection site in all
four animals.
•  β-secretase (d)
Specifieker voor APP
Complexe vorm (remmer-eiwit groot genoeg om te
binden, en klein genoeg om BHB te passeren)
using 2% SDS and 70% formic acid consecutively. The vast
majority of the Ab peptides was extracted by 2% SDS (not
shown). The extracted Ab peptides were quantified applying
ELISAs detecting either total Ab40, i.e. N-truncated variants
and also partially rodent Ab, and specifically pGlu-Ab(3–
40). The total amounts of Ab were determined and the ratio
of pGlu-Ab and total Ab calculated. The ratio illustrates the
effect of the QC-inhibitor specifically on the pGlu-Ab
formation and provides, in fact, the percentage of the Ab,
which was converted by QC.
In general, based on the ELISA analysis, only about
2–10% of the injected Ab was recovered after extraction,
implying a rapid clearance of the peptide after injection (not
shown). Interestingly, about 2.5–5% of the recovered Ab
after injection of Ab(3–40) was converted into pGlu-Ab
(Fig. 6). In comparison, the generation of pGlu-Ab(3–40)
from Ab(1–40), however, was only marginal, substantiating
the findings of the Ab-immunohistochemistry (compare
with Fig. 4). Thus, apparently the removal of the first two
N-terminal amino acids from Ab(1–40) occurs only very
slowly in vivo compared with N-terminal cyclization. The
pGlu-content after injection of Ab(1–40) increased slightly
after 48 h, indicating an initial aminopeptidase driven slow
removal of the first two amino acids and the subsequent
generation of the Ab(3–40), which is prone to cyclization.
Co-injection of the inhibitor did not affect the pGlu-Ab
generation, most likely because of the rapid clearance of the
compound after injection.
In contrast, based on the results obtained with the inhibitor
PBD150, the conversion of Ab(3–40) into pGlu-Ab(3–40)
was substantially decreased. The injection of 5 lmol
PBD150 resulted in a significant reduction in the pGlu-Ab
level after 24 and 48 h. In a second trial, the inhibitor was
reduced to 1 lmol (Fig. 6, inset). Consequently, the reduction in the pGlu-Ab content in relation to the total extracted
Ab lacked statistical significance. This, in turn, indicates a
dose dependency of the inhibitory effect. Notably, none of
the enzyme
animal deceased
after injection of PBD150 solution,
The
glutaminyl
suggesting
that the
QC-inhibition
does not exert acute toxic
cyclase
(QC)
catalyzes
the
effects.
PBD150 inhibits QC, and reduces
formation of toxic Aβ species
Phase III
LY-2886721
MK-8931
formation of the toxic pyroglutamyl
Aβ (pE- Aβ) stainings following injection
Double-immunofluorescence
JNJ-54861911
AZD3293
E2609
RG7129
Fig. 6 Ratio of the N-terminally pGlu-modified and total Ab40 determined using ELISAs after deep cortical injection and sequential
extraction of the Ab peptides. Injection of Ab(3–40) resulted in significant formation of pGlu-Ab(3–40) 24 h after injection. In contrast, pGluAb formation was marginal after injection of Ab(1–40). The co-injection
of the inhibitor PBD150 (5 lmol) reduced the pGlu-Ab concentration
significantly (hatched bars). Reduction of the compound to 1 lmol
exerted a reduced effect, suggesting a dose dependency and thus
inhibitory specificity (inset) (*p < 0.05, unpaired t-test).
of Ab(3–40)
The ELISA analysis suggested that Ab(3–40) was only
partially converted into pGlu-Ab. Therefore, it was a further
aim to investigate, whether pGlu-Ab and Ab(x–40) form
common aggregates after injection. Previous studies in vitro
suggested a generation of such deposits (Schilling et al.,
2006), and also studies in human AD brain support the
abundance of different Ab forms in amyloid plaques (Saido
et al. 1995). In the present study, double-immunofluorescent
stainings applying antibody 4G8 and the pGlu-specific
antibody revealed a co-staining near the injection site
(Fig. 7a–i). This, in turn, clearly substantiates that different
N-terminal Ab variants may form mixed aggregates also
in vivo. According to the observation of pGlu-Ab seeding
in vitro, the QC-catalyzed formation of pGlu-Ab could
precede the deposition of the other peptides. As implied by
the reduced staining for pGlu-Ab and total Ab following
! 2008 The Authors
Journal Compilation ! 2008 International Society for Neurochemistry, J. Neurochem. (2008) 106, 1225–1236
5
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TauRx Therapeutics Ltd.
CONFIDENTIAL – NOT TO BE PHOTOCOPIED
Methylthioninium (MT)
Investigator Brochure
Tau aggregation is a central process
in neurodegeneration
Figure 3:1
Tau Aggregation as a Central Process in Neurodegeneration
Defective Amyloid
Precursor Protein
(APP) processing
Defective
mitochondrial
membrane protein
autophagy
LMTM 60 mg reduces cognitive decline in
phase 2 trial
TauRx Therapeutics Ltd.
CONFIDENTIAL – NOT TO BE PHOTOCOPIED
Methylthioninium (MT)
Investigator Brochure
This is illustrated in Figure 6:8.
Figure 6:8
ADAS-Cog Score Change from Baseline over 50 Weeks by Randomised Treatment Group
(ITT / LTOCF Population, n=294)
Tau Mutations
Nucleation
Event
Tau
Aggregation
Cascade
Axonal
Failure
Cell
Death
•  Intention to treat analysis
•  n=294
•  Mild to moderate AD
(MMSE 26-10)
TAU AGGREGATION INHIBITOR (TAI)
TARGET
Defective Presenilin
protein processing
Wischick et al 2010
While the precise mechanism of initiation is unknown, the process of aggregation, once initiated,
is self-propagating and de novo tau polymers that accumulate are intrinsically cytotoxic (Wischik
et al., 1996). Recent reports indicate that intracellular tau aggregates can also be propagated by
transfer to neighbouring neurons (Frost et al., 2009; Clavaguera et al., 2009), a hypothesis that
would explain the predictable distribution pattern for tau lesions as defined by Braak stages and
the slow rate of disease progression (Braak and Del Tredici, 2011). The latter study suggests that
the primary site of initiation of the aggregation cascade is the locus coeruleus. The progression
of tau aggregation in the neocortext is exponential in character (Lai et al., 1995), a feature that is
consistent with the seeding/propagation model that is now generally accepted. The inherently
exponential dynamic of this process provides an opportunity for both therapeutic and ultimately
preventive intervention based on the Tau Aggregation Inhibition (TAI) paradigm.
The net effect is a shift of the available tau protein pool from its functional microtubule-support
role to the formation of toxic polymers (as well as oligomers and other aggregates). The
negative effects of tau polymer formation are two-fold: destabilisation of microtubule-dependent
intracellular transport systems and accumulation of deleterious aggregation products that result
in neurofibrillary degeneration. Tau aggregation occurs prior to failure of axonal transport. It is
unlikely that neuronal death in neocortex is required for the mild or moderate stages of dementia,
although in terminal phases of illness, there is extensive tangle-mediated neuronal destruction in
hippocampus and entorhinal cortex but relatively little tangle-mediated neuronal destruction in
neocortex (Mukaetova-Ladinska et al., 2000).
Moeten wij patiënten met Alzheimer
eerder behandelen?
A total of 40% of the data were imputed in the analysis. A variety of sensitivity analyses
indicate that the interpretation of the results is the same regardless of the approaches used in
imputing missing data or modeling results based on available data or severity at baseline. This is
summarised in Table 6:4. As can be seen, the effect size varies with the estimate of placebo
decline, so that the effect size expressed as a percentage of control decline remains in the range
of 75% to 113%. Using a mixed effects analysis with no imputation in the pooled mild/moderate
population (the preferred regulatory method), the treatment effect was 90% of control decline
with a standard error of 35% (p = 0.012).
Version 12.1 / Dated 19 April 2012
107
In de
grotelarge
Alzheimer
preventie
In VS:
the U.S.
intervention
trialstrials
in AD
are up and running
Overall, there is a close anatomical relationship between tau aggregation and the neuroimaging
features used for routine radiological diagnosis of AD. Tau protein aggregation is essentially a
specific molecular disorder of the pyramidal cell system of the neocortex and medial temporal
lobe structures (hippocampus and entorhinal cortex). These relationships are maintained from
the earliest clinically detectable stages of dementia and progress in parallel with clinical
deterioration. In particular, the entorhinal and transentorhinal cortices that connect the isocortex
and hippocampus are especially vulnerable to neurofibrillary degeneration in the early stages of
the illness (Braak and Braak, 1991; García-Sierra et al., 2001).
TauRx-sponsored development of MT was initiated with the chloride salt, MTC (better known as
methylene blue), and an extensive battery of nonclinical studies and Phase 1 and 2 clinical trials
Sperling,
Alzheimer’s
& Dementia
2011
in healthy volunteers and patients with
AD have
been performed.
When
the MT moiety is dosed
Version 12.1 / Dated 19 April 2012
19
Medische voeding voor de behandeling
van Alzheimer: Souvenaid
Souvenaid verbetert het geheugen bij
patiënten met lichte Alzheimer
Uridine monofosfaat
Omega-3 vetzuren
Choline/fosfolipiden
Vitamine B
Antioxidanten
Vermindert productie en
toxiciteit van Amyloid-β
Mean change from baseline in
NTB Memory domain z-score
0,25
Verbetert synaps formatie
Control
(p=0.023)
Active
0,2
0,15
0,1
0,05
0
0
12
Time (weeks)
24
Scheltens, J Alzheimers Dis. 2012
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Souvenaid verbetert het geheugen,
ook bij 48 weken behandeling
Double'blind+treatment+
Control#?#AcCve#
Open'label+extension+
Mean#change#from#baseline#in##
NTB#memory#domain#z?score#
AcCve#?#AcCve#
0,40#
0,30#
Alzheimer research
0,20#
0,10#
!
0,00#
0#
12#
24#
36#
48#
Time%(weeks)%
Het ARC
•  Expertise centrum voor klinische trials bij Alzheimer
en andere vormen van dementie
•  Partner van VUmc Alzheimercentrum
•  Team bestaat uit: 2 neurologen, 2 studie artsen, 3
studie coördinatoren, 4 neuropsychologen, 1 office
manager
Waarom een gefocust Alzheimer Research
Center?
1.  Moeilijk om de juiste patiënten te vinden voor
Alzheimer trials
2.  Alzheimer trials worden steeds complexer
•  Dienstverlening voor fase 1, 2 en 3 trials
Biomarkers worden steeds vaker gebruikt
bij dementie trials
Dementie trials brengen een netwerk van
interacties met zich mee
Ousset 2014
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Wat doen we in het ARC?
•  Patiënten recrutering vanuit VUmc Alzheimer
centrum en andere regionale geheugenpoli’s
•  Trial ontwerp en implementatie
•  Protocol indiening bij METC
•  Patiënten onderzoek, behandeling en monitoring in
nauwe samenwerking met IAC VUmc, PET
centrum, apotheken en laboratoria
Lopende trials in het ARC
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Alzheimer Research Center
Vragen?
9