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NAME:
ABT 418
|
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FDA PHASE:
Discontinued
|
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|
NAME:
ACC-001
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
ROLE IN ALZHEIMER'S DISEASE:
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
|
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FDA PHASE:
Discontinued
|
|
ROLE IN ALZHEIMER'S DISEASE:
Lessen cognitive deterioration
|
|
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|
NAME:
AF 102B
|
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OTHER NAMES:
cevimeline HCL, Evoxac™
|
|
FDA PHASE:
Discontinued
|
|
ROLE IN ALZHEIMER'S DISEASE:
Improve neuronal responsiveness to neurotrophic factors.
|
|
|
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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).
|
|
|
|
NAME:
AN 1792
|
|
OTHER NAMES:
AIP 001
|
|
FDA PHASE:
Discontinued
|
|
ROLE IN ALZHEIMER'S DISEASE:
AN-1792 is a synthetic form of the 42 amino acid beta
amyloid peptide. It is hypothesized that immunization with
AN-1792 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.
|
|
|
|
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.
|
|
|
|
NAME:
AZD3480
|
|
OTHER NAMES:
ispronicline, TC-1734
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
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.
|
|
|
|
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.
|
|
|
|
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.)
|
|
|
|
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.
|
|
|
|
NAME:
CX516
|
|
OTHER NAMES:
Ampalex
|
|
FDA PHASE:
Discontinued
|
|
MECHANISMS:
AMPAkines
|
|
ROLE IN ALZHEIMER'S DISEASE:
May improve cognitive function in AD patients by
pharmacologically stimulate AMPA receptor-mediated
synaptic responses. Reported to enhance memory performance
in healthy elderly subjects.
|
|
|
|
NAME:
Dapsone
|
|
OTHER NAMES:
Avlosulfon
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
ROLE IN ALZHEIMER'S DISEASE:
As an anti-inflammatory drug, Dapsone might slow the
progression of Alzheimer Disease.
|
|
|
|
NAME:
Dimebon
|
|
OTHER NAMES:
3,6-dimethyl-9-(2-methyl-pyridyl-5)-ethyl-1,2,3,4-tetrahydro-γ-carboline dihydrochloride, Dimebolin, Latrepirdine, Pf-01913539
|
|
FDA PHASE:
Phase III
|
|
MECHANISMS:
Has activity as an inhibitor of cholinesterase and NMDA receptors. Inhibits neuronal death, potentially by mitochondrial-mediated inhibition of apoptosis.
|
|
ROLE IN ALZHEIMER'S DISEASE:
As a cognitive enhancer, Dimebon has shown efficacy in all
measures of cognition and behavior in mild-to-moderate
Alzheimer Disease patients. Phase II clinical trial results
(ClinicalTrials.gov NCT00377715) have been reported (Doody
et al, 2008). Treatment with dimebon resulted in
significant benefits in ADAS-cog compared with placebo at
week 26 (p<0.0001). Patients given dimebon were
significantly improved over baseline for ADAS-cog (p=0.0005).
In vitro Dimebon protected primary neuron cultures against
Aβ toxicity (EC50=25 μM) and inhibits both
acetylcholinesterase (I50=42 μM) and
butyrylcholinesterase (IC50=7.9 μM), as well as
inhibiting NMDA receptors (IC50 range of 10-70
μM) (Bachurin et al., 2001; Grigoriev et al., 2003).
Neuroprotective effects of Dimebon has also been observed
in a transgenic Drosophila model of Huntington
Disease, protecting photoreceptor neurons against death
induced by human Huntington protein (htt) (unpublished
data, Medivation disclosure).
In a recent clinical trial in mild-to-moderate AD in
Russia (completed summer 2006), Dimebon demonstrated
positive clinical efficacy in cognition and behavior using
five independent measures of cognitive impairment.
|
|
|
|
NAME:
Docosahexanoic acid (DHA)
|
|
OTHER NAMES:
Omega 3 fatty acids
|
|
FDA PHASE:
Phase III
|
|
MECHANISMS:
DHA is a major component of neuron membranes and has multiple functions, including modulation of presenilin.
|
|
ROLE IN ALZHEIMER'S DISEASE:
Alzheimer disease patients have significantly lower DHA
levels compared to control subjects, and serum cholesteryl
ester-DHA levels are progressively reduced with severity
of clinical dementia (Tully et al., 2003). A previous
omega-3 fatty acid treatment (a mixture of DHA and EPA)
clinical trial in Sweden demonstrated a significant (P
<.05) reduction in MMSE decline rate in the omega-3 fatty
acid-treated group compared with the placebo group in a
subgroup of patients with a very mild cognitive
dysfunction, observed at 6 and 12 months (Freund-Levi et
al., 2006).
Two Phase III clinical trials of purified DHA from
microalgae have been performed in the US. The MIDAS study
was a 6 month study in 485 healthy older adults with
age-related cognitive decline (not MCI or AD). No ApoE
genotyping was done in this study. Statistically
significant improvements with 900mg/d algal DHA were
observed over placebo on the PAL test with nearly double the
reduction in errors on the test in the DHA group compared to
placebo, demonstrating improvements in learning and episodic
memory function over 6 months in these subjects (Yurko-Mauro
et al 2009). An 18-month study in mild to moderate AD
patients did not meet its primary endpoints, but a secondary
analysis of data by ApoE4 genotype showed significant
effects on the ADAS-Cog with DHA in patients without the
ApoE4 gene. Significant results were also seen on MMSE
scores at 18mths versus baseline in this group (Quinn et al
2009).
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