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NAME:
ABT 418
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FDA PHASE:
Discontinued
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NAME:
AC-1204
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OTHER NAMES:
caprylic triglyceride, long-chain triglyceride
|
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FDA PHASE:
Phase II/III
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MECHANISMS:
Chronic induction of ketosis to improve mitochondrial metabolism
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ROLE IN ALZHEIMER'S DISEASE:
AC-1204 increases ketone body production and targets glucose
hypometabolism by providing increased ketone bodies as an
alternative energy source in the brain. Accera's Ketasyn
(AC-1202) was FDA approved as a medical food in 2009. See
related Alzforum News article Medical Foods—Fallback
Option for Elusive AD Drug Status?. Results of clinical
testing of AC-1202 was published by Henderson et al 2009.
In vitro data shows that ketone body beta-hydroxybutyrate (BHB)
preserves neuronal integrity and stability (Izumi et al
1998). BHB has been shown to reduce the total Abeta40 and
Abeta42 and reduces Abeta toxicity (Kashiwaya et al 2000;
Van der Auwera et al 2005).
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NAME:
ACC-001
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FDA PHASE:
Phase II/IIa/IIb
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ROLE IN ALZHEIMER'S DISEASE:
ACC-001 is a short
amino-terminal Aβ(1-6) fragment that is derived from the
N-terminal B cell epitope of Aβ while avoiding T cell activation
(reviewed in Lemere and Masliah 2010). This vaccine aims to
avoid the
safety concerns associated with AN1792 vaccine (Aβ1-42) that
implicated residues Aβ15-42, the most common T cell
epitope, as the cause of Th1 lymphocyte activation and
predominantly responsible for autoimmune
meningoencephalitis. Elan research
indicates that antibodies specific for Aβ peptide can cross
the blood-brain barrier and act directly in the central
nervous system to induce plaque clearance. These findings
suggest that this novel method may clear plaques in human
patients.
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NAME:
Acetyl-l-carnitine HCI
|
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OTHER NAMES:
ALCAR
|
|
FDA PHASE:
Discontinued
|
|
ROLE IN ALZHEIMER'S DISEASE:
Lessen cognitive deterioration
|
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|
NAME:
AF 102B
|
|
OTHER NAMES:
cevimeline HCL, Evoxac™
|
|
FDA PHASE:
Discontinued
|
|
ROLE IN ALZHEIMER'S DISEASE:
Improve neuronal responsiveness to neurotrophic factors.
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NAME:
Affitope AD02
|
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OTHER NAMES:
Mimotope Aβ(1-6)
|
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FDA PHASE:
Phase II/IIa/IIb
|
|
MECHANISMS:
Aβ(1-6) immunotherapy
|
|
ROLE IN ALZHEIMER'S DISEASE:
Affitope AD02 is a short amino-terminal Aβ fragment (Aβ1-6)
that is derived from the N-terminal B cell epitope of Aβ
while avoiding T cell activation (reviewed in Lemere and
Masliah 2010). This immunogen thus potentially avoids the
safety concerns associated with AN1792 vaccine (Aβ1-42)
which presented residues Aβ15-42, the most common T cell
epitope, the most likely cause of Th1 lymphocyte activation
and therefore predominantly responsible for autoimmune
meningoencephalitis. At the Global Vaccine Research Forum
2008, Achim Schneeberger of Affiris presented preclinical
mouse data demonstrating that Affitope induced antisera
stained plaques but not APP on cells and was effective in
reducing total plaque area with accompanying reductions in
astrocytic foci, microgliosis.
(See Schneeberger
2008).
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|
NAME:
Alpha-tocopherol
|
|
OTHER NAMES:
Vitamin E
|
|
FDA PHASE:
Phase III
|
|
ROLE IN ALZHEIMER'S DISEASE:
Thought to prevent brain cell damage by destroying toxic
free radicals.
|
|
|
|
NAME:
Alzhemed™
|
|
OTHER NAMES:
3-amino-1-propanesulfonic acid, 3-aminopropylsulfonic acid, 3-APS, homotaurine, NC-531, Tramiprosate
|
|
FDA PHASE:
Not FDA regulated
|
|
MECHANISMS:
Designed to cross the blood-brain barrier, tramiprosate is an amyloid-β antagonist.
|
|
ROLE IN ALZHEIMER'S DISEASE:
Tramiprosate was designed to prevent amyloid formation and
deposition in the brain, and thus modify the course of AD.
It has been tested extensively in clinical trials in both
the U.S. and the EU for mild to moderate AD. The recent
U.S. Phase 3 trial is widely considered to have failed
(see ARF related news story and comments). The EU
Phase 3 trial has been discontinued (see ARF
related news story). Recent published evidence
demonstrates that tramiprosate alters tau aggregation (see
Santa-Maria et
al., 2007 and comments and ARF
related news story).
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NAME:
AN1792
|
|
OTHER NAMES:
AIP 001
|
|
FDA PHASE:
Discontinued
|
|
MECHANISMS:
Active immunotherapy
|
|
ROLE IN ALZHEIMER'S DISEASE:
AN1792 is a synthetic form of the 42 amino acid beta
amyloid peptide. Extensive preclinical evidence shows that
immunization with Aβ1-42 peptide can prevent or reverse the
development of the neuropathological hallmarks of
Alzheimer's diseases, including extensive amyloid plaque
formation, neuritic dystrophy, synaptic loss and gliosis
(Schenk et al 1999). The history of AN1792 has been
extensively chronicled in Alzforum News: See Vaccinating
Against Plaques and
Live
Discussion: Alzheimer Immunotherapy Trial Grounded
Phase II clinical trial NCT00021723
was initiated in 2001 and abruptly terminated in January
2002 due to the development of aseptic meningoencephalitis
and leukoencephalopathy in 6% Aβ1-42 vaccinated patients
(Orgogozo et al 2003; Gilman et al 2005). Despite this trial
termination, follow up studies of the Phase IIa trial
participants have shown that AN1792 immunization-induced
plaque clearance improved neurite abnormalities induced by
plaque (Serrano-Pozo et al 2010), although positive
anti-amyloid effects did not prevent severity of end-stage
dementia nor improved survival (Holmes et al 2008).
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|
|
NAME:
Atorvastatin
|
|
OTHER NAMES:
Lipitor™
|
|
FDA PHASE:
Inactive
|
|
ROLE IN ALZHEIMER'S DISEASE:
A multi-center analysis of over 60,000 patients indicated
a decreased prevalence of AD in patients taking lovastatin
and pravastatin, two statin drugs commonly used in lowering
cholesterol. Several possible roles of statins in AD have
been proposed, see our drug sheet on statins.
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|
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|
NAME:
AZD1446
|
|
OTHER NAMES:
TC-6683
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
MECHANISMS:
α4ß2 nicotinic (nAChR) receptor activator
|
|
ROLE IN ALZHEIMER'S DISEASE:
AZD1446 selectively activates the α4ß2 specific subtype
(alpha4beta2) of neuronal nicotinic receptor found on nerve
cells throughout the central nervous system. AZD1446 may
thus act in a mechanism similar to AZD3480,
by enhancing the
release of acetylcholine from the cortex and thereby be
memory-enhancing.
The α4ß2 nAChR has been shown to be involved in nicotinic
ligands effects to both promote sAPPα release and attenuate
Aβ production, and thereby augmenting the non-amyloidogenic
APP processing (Mousavi & Hellström-Lindahl, 2009).
|
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|
|
NAME:
AZD3480
|
|
OTHER NAMES:
ispronicline, TC-1734
|
|
FDA PHASE:
Inactive
|
|
MECHANISMS:
AZD3480 is an orally active novel neuronal nicotinic agonist with high selectivity for neuronal α4β2 nicotinic (nAChR) receptors.
|
|
ROLE IN ALZHEIMER'S DISEASE:
AZD3480 has been tested in normal elderly human subjects
with age-associated memory impairment (Dunbar et al.,
2007) in a double-blind, placebo-controlled cross-over
study, which tested ascending oral doses in the range of
50-150 mg given as a single morning dose for a period of 3
weeks. Cognitive function was assessed with the
computerized Cognitive Drug Research (CDR) test battery. A
peak in beneficial cognitive effect was observed in
attention and episodic memory, at 50 mg dose, although
beneficial effects were observed across the dose range.
ClinicalTrials.gov NCT00501111 was completed August 2008.
In the 12-week placebo-controlled study, known as the
Sirocco trial, neither the active comparator donepezil nor
AZD3480 met the trial’s criteria for statistical
significance on the primary outcome measure, ADAS-Cog
(Alzheimer’s Disease Assessment Scale – Cognition Subscale.)
Both results were impacted by an improvement in the placebo
group.
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|
|
|
NAME:
Bapineuzumab
|
|
OTHER NAMES:
AAB-001
|
|
FDA PHASE:
Phase III
|
|
MECHANISMS:
Designed to bind and remove the Aβ peptide that accumulates in the brain.
|
ROLE IN ALZHEIMER'S DISEASE:
Results from Phase II were reported at ICAD 2008. (See ARF
related news story.) This 18 month study was a
double-blind, placebo-controlled multiple ascending dose
trial intended to primarily assess the safety, tolerability
and secondarily, efficacy of bapineuzumab in
mild-to-moderate Alzheimer Disease and had 234 patients
randomized to receive one of four doses of bapineuzumab
(0.15 mg/kg [n=31], 0.5 mg/kg [n=33], 1.0 mg/kg [n=30] or
2.0 mg/kg [n=30]) or placebo [n=110] by intravenous
infusion
every 13 weeks. Efficacy endpoints were change from
baseline
in Alzheimer's Disease Assessment Scale-Cognitive Subscale
(ADAS-cog), Disability Assessment Scale for Dementia (DAD)
the Neuropsychological Test Battery (NTB), the Clinical
Dementia Rating Sum of Boxes (CDR-SB) and brain volume as
measured by MRI. Efficacy was assessed from baseline for 78
weeks.
In ApoE4 non-carriers, statistically significant
differences
were observed in favor of bapineuzumab treated patients on
both cognitive and functional efficacy endpoints ADAS-Cog,
NTB and CDR-SB.
In the ApoE4 carrier patients, no statistically significant
changes were observed in any of the cognitive or functional
efficacy endpoints.
In March 2010, imaging analysis of AD patients demonstrated
that bapineuzumab reduces cortical PiB retention, a
measurement of fibrillar plaque (Rinne et al 2010).
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|
|
|
NAME:
Besipirdine HCl
|
|
OTHER NAMES:
HP 749
|
|
FDA PHASE:
Discontinued
|
|
|
|
NAME:
BMS-708163
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
MECHANISMS:
γ-secretase inhibitor
|
|
ROLE IN ALZHEIMER'S DISEASE:
BMS-708163 is a potent and selective γ-secretase
inhibitor (GSI). Phase I clinical trial studies showed that
in humans, it decreased CSF Aβ40 and Aβ42
approximately 30 percent following daily dose of 100 mg
after 28 days and by 60 percent at daily dose of 150 mg.
While it has an IC50 for APP cleavage of 0.3 nM,
significantly more potent than GSI-953, another selective
GSI (15 nM), BMS-708163, is 190-fold more selective for APP
than Notch, having an IC50 of 58 nM for Notch (Albright et
al., 2008). (See also ARF
related news story.)
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|
|
|
NAME:
CAD106
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
MECHANISMS:
Aβ(1-6) immunotherapy
|
|
ROLE IN ALZHEIMER'S DISEASE:
CAD106 is a vaccine that presents multiple copies of Aß1-6
peptide derived from the N-terminal B cell epitope of Aß
while avoiding T cell activation (reviewed in Lemere and
Masliah 2010) coupled to the Qß virus-like particle. In
animals, CAD106 induced Aß-antibody titers without
activating Aß-reactive T-cells. Administration of CAD106 to
APP transgenic mice showed a reduction of amyloid
accumulation in the brain. Data from a first-in-man a
52-week, two-center, randomized, double-blind,
placebo-controlled, parallel group clinical trial in Sweden,
based on 58 mild to moderate AD patients assessed antibody
titers from two doses tested (50 μg at 0/6/18 weeks and 150
μg at 0/2/6 weeks). CAD106 induced a measurable specific
antibody response against Aß with a 2-fold increase observed
in the high dose group. Exploratory outcome measures CSF Aβ
levels and whole brain volume MRI did not show differences
between treated vs placebo patients. (See Winblad
et al 2009).
|
|
|
|
NAME:
CERE-110
|
|
OTHER NAMES:
Nerve Growth Factor Gene Therapy
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
MECHANISMS:
NGF may reduce cholinergic cell loss in Alzheimer disease
|
|
ROLE IN ALZHEIMER'S DISEASE:
NGF specifically targets basal forebrain cholinergic
neurons, which release ACh in the cerebral cortex and
hippocampus. Preclinical data in rats demonstrate that NGF
prevented cholinergic neuron cell death (Hefti, 1986) and
reversed age-related behavioral decline (Fischer, 1987).
NGF gene therapy has been tested in rhesus monkeys
(Tuszynski, 2005), and these studies demonstrated that NGF
ameliorates cholinergic neuron atrophy and restores
cholinergic axonal density in aged monkeys to levels
observed in young monkeys. Dose escalation studies
resulted in toxic secondary effects observed at any dose.
Data from a Down syndrome mouse model showed
that the increased expression of APP due to trisomy
decreased NGF retrograde intra-axonal transport and caused
degeneration of basal forebrain cholinergic neurons
(Salehi, 2006).
Phase I clinical trial NCT00087789 (ClinicalTrials.gov)
is ongoing but not recruiting participants, being conducted
at Rush University Medical Center in Chicago and UCSD. The
open-label study involves 10 participants with
mild-to-moderate AD. The 10 participants underwent cognitive
testing, measures of activities of daily living, MRI scans
and PET (positron emission tomography) scans. Increases in
brain metabolism were observed in several cortical regions
at six months and 12 months (p<0.05) in four participants as
compared to other severity-matched individuals with AD
suggesting a potential reversal of patterns typically
observed in AD.
|
|
|
|
NAME:
Cerebrolysin
|
|
FDA PHASE:
Approved outside U.S.
|
|
MECHANISMS:
Neuroprotection, neurotrophic agent, promotes neurogenesis, may decrease rate of apoptosis.
|
|
ROLE IN ALZHEIMER'S DISEASE:
Cerebrolysin is a peptide-based drug product supporting
the survival, stability, and function of neurons.
Cerebrolysin decreases amyloid production, promotes
synaptic repair, and improves cognitive and behavioral
performance.
|
|
|
|
NAME:
Clioquinol
|
|
OTHER NAMES:
iodochlorhydroxyquin, PBT-1
|
|
FDA PHASE:
Discontinued
|
|
MECHANISMS:
metal-protein-attenuation
|
|
ROLE IN ALZHEIMER'S DISEASE:
Clioquinol inhibits zinc and copper ions from binding to
Aβ, thus promoting the solubilization and clearance
of Aβ. A pilot phase II clinical trial suggests that
clioquinol improves cognition and lowers plasma levels of
Aβ42 in some patients.
|
|
|
|
NAME:
COGNIShunt™
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
ROLE IN ALZHEIMER'S DISEASE:
Cerebrospinal fluid production and turnover diminish with
age and may be further diminished in Alzheimer's disease.
Flow-regulated drainage of CSF may reduce the accumulation
of proteins such as tau and β-amyloid and other inflammatory
mediators implicated in AD.
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