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NAME:
PBT2
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FDA PHASE:
Phase II/IIa/IIb
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MECHANISMS:
Inhibits oligomer formation, disaggregates plaques, neutralizes Aβ toxicity.
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ROLE IN ALZHEIMER'S DISEASE:
Designed to modify the course of AD by preventing metal-
dependent aggregation, deposition, and toxicity of Aβ
(Ritchie et al., 2003). Aβ is a high-affinity metal
binding protein which adopts a toxic gain of function in
the presence of copper and zinc. PBT2 acts at three levels
of the “amyloid cascade”: it inhibits the redox-dependent
formation of toxic soluble oligomers, prevents deposition
of Aβ as amyloid plaques, and promotes clearance by
mobilizing and “neutralizing” Aβ from existing
deposits (Cherny et al., 2001).
A 12 week Phase IIa study testing safety and efficacy of
PBT2, with biomarker analysis, in a double-blind,
randomized, placebo-controlled trial showed that treated
patients had a dose-dependent and significant reduction of
CSF Aβ, and demonstrated significant improvement in two
tests of executive function: the category fluency test and
trail making part B test (Lannfelt et al., 2008).
The parent compound clioquinol (PBT1) was tested in
clinical trials for AD. It was not clear from this trial
that clioquinol showed any positive clinical result. The
two statistically significant positive results were seen
for the more severely affected subgroup of patients;
however, this effect was not maintained at the 36-week end-
point, and this group was small (eight treated subjects).
The sample size was small. Details of randomization
procedure or blinding were not reported (Jenagaratnam &
McShane, 2006).
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NAME:
PF-04494700
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OTHER NAMES:
TTP488
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|
FDA PHASE:
Discontinued
|
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MECHANISMS:
Inhibitor of Receptor for Advanced Glycation Endproducts (RAGE)
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ROLE IN ALZHEIMER'S DISEASE:
RAGE plays multiple roles in the pathogenesis of AD. RAGE
mediates the effects of Aβ on microglia, blood-brain
barrier (BBB) and neurons through activating different
signaling pathways. The adverse consequences of RAGE
interaction with Aβ include disruption of neuronal
properties and functions, amplification of glial
inflammatory responses, elevation of oxidative stress and
amyloidosis, increased Aβ influx at the blood brain
barrier and vascular dysfunction, and induction of
autoantibodies. Data from autopsy brain tissues, in vitro
cell cultures and transgenic mouse models suggest that
Aβ-RAGE interaction exaggerates neuronal stress,
accumulation of Aβ, impaired learning and memory, and
neuroinflammation. Inhibition of RAGE protects against
Aβ-mediated cellular disruption.
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NAME:
Phenserine
|
|
FDA PHASE:
Inactive
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|
MECHANISMS:
Acetylcholinesterase inhibitor; Aβ modulator
|
|
ROLE IN ALZHEIMER'S DISEASE:
Phenserine was in clinical study for Alzheimer disease for
several years, after preclinical demonstrations of
cognitive improvement in both rodents and dogs. Three
Phase 3 clinical trials were initiated in 2003 and 2004.
Phenserine showed no statistically significant effect on
cognition endpoint ADAS-Cog in each of these two Phase 3
trials. Post-hoc analysis of all three Phase 3 clinical
trials identified that the group of subjects receiving the
highest tested dose (15 mg per day) for more than 12 weeks
demonstrated a statistically significant benefit of
phenserine over placebo in ADAS-Cog, but only a trend
toward improvement in the CIBIC+ measure.
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NAME:
Physostigmine Salicylate
|
|
OTHER NAMES:
Synapton
|
|
FDA PHASE:
Discontinued
|
|
ROLE IN ALZHEIMER'S DISEASE:
Improvment of short-term memory.
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|
NAME:
Ponezumab
|
|
OTHER NAMES:
PF-04360365
|
|
FDA PHASE:
Discontinued
|
|
MECHANISMS:
Designed to bind and remove the Aβ peptide that accumulates in the brain.
|
|
ROLE IN ALZHEIMER'S DISEASE:
Phase 1 studies of Ponezumab have been completed and have
shown that plasma Aβ and time to Cmax (Tmax) increased
dose-dependently. At the 10 mg/kg dose group, mean CSF Aβ
percentage change from baseline at Day 29 increased 38%,
29%, and 15% for Aβ1-x, Aβ1-40, and Aβ1-42, respectively
(Zhao et al 2010). Immunoprecipitation followed by
MALDI-TOF MS (IP/MS) revealed the Aβ peptide profile in
cerebrospinal fluid (CSF) from patients with
mild-to-moderate AD before and after a single dose of
ponezumab. Acute administration of ponezumab to AD patients
elevated Aβ1-40 and Aβ11-40 in CSF, demonstrating that
peripheral administration of ponezumab affects central Aβ
levels (Wood et al., 2010).
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NAME:
Propentofylline
|
|
OTHER NAMES:
HWA 285
|
|
FDA PHASE:
Discontinued
|
|
ROLE IN ALZHEIMER'S DISEASE:
General improvement in mild-moderately demented
Alzheimer's disease patients.
|
|
|
|
NAME:
PRX-03140
|
|
OTHER NAMES:
7-isopropyl-6-oxo-5(3-piperidin-1-yl-propylcarbamoyl)-6,7-dihydro-thieno[2,3-b]pyridine-4-olate, potassium salt
|
|
FDA PHASE:
Inactive
|
|
MECHANISMS:
Partial 5-HT4 receptor agonist
|
|
ROLE IN ALZHEIMER'S DISEASE:
Increases acetylcholine (ACh) production and/or release
(Mohler, 2005). Neuroprotective, with potential for
disease modification. Stimulates sAPPα production
(Lezoualc'h, 2005); increases NGF (Shachem, 2006) and BDNF
(Shachem, 2006; Granholm, 2005) brain levels; reduces Aβ1-
40/42 levels (Shachem, 2006).
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|
NAME:
Resveratrol
|
|
OTHER NAMES:
trans-3,4',5-trihydroxystilbene
|
|
FDA PHASE:
Phase III
|
|
MECHANISMS:
neuroprotectant
|
|
ROLE IN ALZHEIMER'S DISEASE:
Blass and Gordon (2004) have demonstrated positive effects
in AD with an oral preparation of combined glucose, malate
and resveratrol. Glucose is the physiological precursor of
the substrates of oxidative metabolism in the brain, malate
is a primer of the energy-providing Krebs-cycle. Glucose and
malate therefore can provide reducing equivalents
(electrons) to regenerate the reduced form of resveratrol,
and do so under the normal regulation of brain cell
metabolism. Resveratrol has been shown to lower the levels
of secreted and intracellular amyloid-beta (Abeta) peptides
produced from different cell lines by promoting
intracellular degradation of Abeta via a mechanism that
involves the proteasome (Marambaud et al, 2005).
Resveratrol, a SIRT1 activating agent, has been shown to
promote neuronal survival. Resveratrol may also enhance the
gene expression of antioxidative genes and promote DNA
repair by stimulating the deacetylation of forkhead FOXO3/4
transcription factors (Kim et al, 2007).
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|
NAME:
RO5313534
|
|
OTHER NAMES:
MEM 3454, RG3487
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
MECHANISMS:
RO5313534 is a selective nicotinic alpha-7 receptor partial agonist with 5HT3 receptor antagonist properties.
|
|
ROLE IN ALZHEIMER'S DISEASE:
The nicotinic α7 receptor is highly expressed within
the brain and has limited peripheral expression (e.g.,
macrophages, ganglionic neurons). Selective nicotinic
α7 agonists like RO5313534 have been shown to increase
cholinergic neurotransmission in a brain region-specific
manner. Thus, it is hypothesized that α7 agonists may
contribute to symptomatic treatment of Alzheimer disease
through cholinergic mechanisms and have a better safety
profile than observed with current therapies (Kem, 2000).
In addition to neurodegeneration, the brains of Alzheimer
disease patients display an abnormal accumulation of amyloid
plaques and accumulations of abnormal tau filaments as
neurofibrillary tangles. Amyloid plaques are insoluble
aggregates of protein that are toxic to neurons. The major
constituent of these plaques is the protein β amyloid.
Preclinical data from several laboratories suggests that the
amyloid protein from which these plaques are formed disrupts
the function of the nicotinic α7 receptor. Furthermore,
the most vulnerable neurons appear to be those that
abundantly express the nicotinic α7 receptor, and
internalization of amyloid-β1-42 (Aβ1-42) appears
to be facilitated by the high-affinity binding of
Aβ1-42 to the nicotinic α7 receptor on neuronal
cell surfaces (D’Andrea and Nagele, 2005). Therefore, the
nicotinic α7 receptor is a potentially important
therapeutic target for disease modification treatment.
Stimulation of nicotinic α7 receptors via agonist
administration protects neurons from degeneration induced by
Aβ1-42, further bolstering the idea that reduced
nicotinic α7 receptor signaling is a mediator of
age-related and Alzheimer’s-dependent cognitive decline
(D’Andrea and Nagele 2005). Drugs that activate nicotinic
α7 receptors would theoretically interfere with the
neurotoxic effects of Aβ1-42 and prevent the
pathophysiological and cognitive decline of Alzheimer’s
patients.
Additionally, since amyloid-β1-42 (Aβ1-42)
binds to the nicotinic α7 receptor, agonists at this
receptor site may potentially be important as
disease-modifying treatments by competing with Aβ1-42
to bind to the receptor, thereby reducing the neurotoxic
effects of Aβ1-42 and preventing further disease
degeneration. Along this line, RO5313534 completely reversed
the Aβ25-35-induced toxicity in primary cultured
hippocampal neurons.
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|
|
NAME:
Rofecoxib
|
|
OTHER NAMES:
Vioxx™
|
|
FDA PHASE:
Inactive
|
|
MECHANISMS:
anti-inflammatory
|
|
ROLE IN ALZHEIMER'S DISEASE:
May slow the rate of cognitive deterioration by decreasing
inflammation in the brain.
|
|
|
|
NAME:
Rosiglitazone
|
|
OTHER NAMES:
5-[[4-[2-(methyl-pyridin-2-yl-amino)ethoxy]phenyl]methyl]thiazolidine-2,4-dione, AVANDIA®, Rosiglitazone maleate
|
|
FDA PHASE:
Discontinued
|
|
MECHANISMS:
Rosiglitazone maleate is an oral anti-diabetic agent which acts primarily by increasing insulin sensitivity.
|
|
ROLE IN ALZHEIMER'S DISEASE:
Type 2 diabetes, insulin metabolism, and Alzheimer disease
are linked in a variety of ways. Numerous epidemiological
studies have shown that there is an increased risk of
developing AD among type 2 diabetic patients (Arvanitakis
et al., 2004; Leibson et al., 1997). Diet-induced
peripheral insulin resistance in Tg2576 mice has been
shown to increase γ-secretase activity and decrease
insulin-degrading enzyme activity. These combined changes
result in increased Aβ40 and Aβ42 levels and
amyloid plaque burden in the brain, and impaired
performance in a water maze test of learning and memory
(Ho et al., 2004). ApoE4 allele-positive individuals
account for 40-50 percent of sporadic late-onset AD
(Risner et al., 2006). Glucose is the brain’s primary
fuel, and it is metabolized by the tricarboxylic acid
(TCA) cycle. ApoE4 carriers have declines in brain
mitochondrial TCA enzyme activities (Gibson et al., 2000;
Bubber et al., 2005). Rosiglitazone therapy has been shown
to improve cognitive function in both a subset of human AD
patients (Watson et al., 2005; Risner et al., 2006) as
well as in preclinical AD model mice (Pedersen et al.,
2006).
In two small clinical trials, rosiglitazone
treatment for 24 weeks resulted in a modest but
significant improvement in cognition in non-ApoE4
subjects, but no improvement and rather a decline in
cognition in ApoE4 allele carriers (Risner et al., 2006).
Preliminary results from Phase III clinical study
NCT00428090 were reported at ICAD 2009 (Rabiner et al 2009).
This study failed to demonstrate significant efficacy at
any dose, in any test group (by ApoE genotype) assessed by
either ADAS-cog or CIBIC-Plus (Clinician Interview Based
Impression of Change) tests.
|
|
|
|
NAME:
Sabeluzole
|
|
OTHER NAMES:
R58735
|
|
FDA PHASE:
Discontinued
|
|
|
|
NAME:
SB 202026
|
|
OTHER NAMES:
Memric, Sabcomeline
|
|
FDA PHASE:
Discontinued
|
|
ROLE IN ALZHEIMER'S DISEASE:
Reduce symptoms in mild/moderate Alzheimer.
|
|
|
|
NAME:
SGS-742
|
|
OTHER NAMES:
CGP-36742, DVD-742
|
|
FDA PHASE:
Discontinued
|
|
MECHANISMS:
GABAB receptor antagonist.
|
|
ROLE IN ALZHEIMER'S DISEASE:
GABA receptors are known to inhibit learning in certain
animal models. SGS-742 is a GABAB receptor
antagonist that is thought to indirectly effect NMDA
receptors, and therefore potentially helping memory
formation/retention and learning. Some new evidence has
also shown that SGS-742 may reduce the expression or
activation of transcription factors believed to act as
memory suppressors.
|
|
|
|
NAME:
Simvastatin
|
|
OTHER NAMES:
Zocor®
|
|
FDA PHASE:
Phase II/III
|
|
MECHANISMS:
High affinity HMG-CoA reductase inhibitor
|
|
|
|
NAME:
Solanezumab
|
|
OTHER NAMES:
LY2062430
|
|
FDA PHASE:
Phase III
|
|
MECHANISMS:
Designed to bind and remove the Aβ peptide that accumulates in the brain.
|
|
ROLE IN ALZHEIMER'S DISEASE:
Solanezumab binds specifically to soluble amyloid-β and
therefore may act to draw the peptide away from the brain
through the blood to be cleared peripherally. In short-term
clinical studies, solanezumab appeared to have
dose-dependent effects on amyloid-β in blood and
cerebrospinal fluid. The correlation between total plasma
Aβ1-42 after treatment and baseline amyloid plaque
burden by single photon emission tomography (SPECT)
scanning, together with the dose-dependent increase in
unbound CSF Aβ1-42, suggest that this antibody may
mobilize Aβ1-42 in AD plaques, and normalize soluble CSF
Aβ1-42 in AD patients. The clinical studies to date
have been too short to evaluate any potential delay in the
progress of Alzheimer disease. Also see ARF
related news story and ARF
news story.
In a 21-day study, 19 mild to moderate AD patients
were tested with single dose infusions of LY2062430
(solanezumab), dose ranging from 0.5 to 10 mg/kg (Siemers
et
al., 2010). The highest dose elicited infusion reaction,
but
the lower doses were well tolerated. CSF and plasma Aβ
increased after treatment, consistent with antibody binding
and stimulated clearance, with no evidence of either
cognitive efficacy or adverse effects.
|
|
|
|
NAME:
ST101
|
|
OTHER NAMES:
spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one, ZSET1446
|
|
FDA PHASE:
Inactive
|
|
ROLE IN ALZHEIMER'S DISEASE:
ZSET1446/ST101 is an azaindolizinone derivative compound
that has demonstrated cognitive enhancer activity in
numerous rodent models of cognitive impairment, improving
methamphetamine-induced memory impairment in rats (Ito et
al
2007), olfactory bulbectomy-induced cognitive deficits in
mice (Han et al 2008). In Alzheimer’s Disease-related
preclinical tests, ZSET1446 improves cognitive function
impaired by ICV Abeta(1-40) infusion or scopolamine-induced
memory deficits, and stimulates acetylcholine release
(Yamaguchi et al 2006). Chronic administration of ZSET1446
improved neurogenesis impairment following olfactory
bulbectomy in mice (Shioda et al 2010), stimulating ERK and
PI3K/Akt pathways in new dentate gyrus neurons.
|
|
|
|
NAME:
Statins
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
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. Reductions in cholesterol by statins
might alter APP metabolism and thus reduce the production
of A-beta. Statins have also been shown to have
immunomodulatory effects, blocking the ability of a
cytokine called interferon-gamma (IFN-gamma) to activate T-
cells. Statins might therefore have a neuro-protective
effect by lowering inflammation. Several studies have also
indicated that therapy with statins may reduce lipoprotein
oxidation and ameliorate free radical injury.
|
|
|
|
NAME:
Suritozole
|
|
OTHER NAMES:
MD 26,479
|
|
FDA PHASE:
Discontinued
|
|
ROLE IN ALZHEIMER'S DISEASE:
An inverse GABA agonist with cognitive enhancement
properties.
|
|
|
|
NAME:
T-817MA
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
MECHANISMS:
T-817M is a neurotrophic and neuroprotective compound
|
|
ROLE IN ALZHEIMER'S DISEASE:
T-817MA prevents Aβ-induced granule cell loss in the
dentate gyrus of the hippocampus (Nguyen et al., 2007) and
increased hippocampal neurogenesis in rats infused ICV with
Aβ40 (Kimura et al., 2009). In Aβ-infused rats,
T-817MA significantly improved place learning task
performance, which may be due to neuroprotective effects in
the hippocampus (Nguyen et al., 2007).
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