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NAME:
Curcumin
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OTHER NAMES:
diferuloylmethane, Longvida™
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FDA PHASE:
Phase II/IIa/IIb
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MECHANISMS:
Curcumin has pleiotropic neuroprotective effects that include anti-inflammatory, antioxidant, and anti-amyloid activities.
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ROLE IN ALZHEIMER'S DISEASE:
Curcumin has been shown to reduce amyloid plaque and
accumulated Aβ in APP transgenic mice and reduces oxidative
damage, inflammatory response and cognitive deficits
induced
by infused Aβ into rat CNS (reviewed in Cole et al 2007).
Reviewed extensively by Frautschy and Cole (2010), curcumin
has been shown bind and clear Aβ plaques and oligomers in
animal models, inhibit tau aggregation, limit inflammatory
cytokine production, and protect against oxidative damage.
Longvida™ is a solid-lipid curcumin particle formulation
that increases bioavailability. Natural curcumin has
limited bioavailability and brain permeability due to poor
water solubility and rapid metabolism.
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NAME:
CX516
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OTHER NAMES:
Ampalex
|
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FDA PHASE:
Discontinued
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MECHANISMS:
AMPAkines
|
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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.
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NAME:
Dapsone
|
|
OTHER NAMES:
Avlosulfon
|
|
FDA PHASE:
Phase II/IIa/IIb
|
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ROLE IN ALZHEIMER'S DISEASE:
As an anti-inflammatory drug, Dapsone might slow the
progression of Alzheimer Disease.
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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
|
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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.
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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.
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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).
Results from phase III clinical trial NCT00440050
showed that administration of daily DHA for 18 months did
not slow cognitive or functional decline in AD patients
(Quinn et al 2010).
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NAME:
Donepezil
|
|
OTHER NAMES:
Aricept™
|
|
FDA PHASE:
FDA approved
|
|
MECHANISMS:
cholinesterase inhibitors
|
|
ROLE IN ALZHEIMER'S DISEASE:
Improves cognition, global function, and activities of
daily living.
|
|
|
|
NAME:
EHT 0202
|
|
OTHER NAMES:
Etazolate
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
MECHANISMS:
Stimulates the neurotrophic α-secretase (non-amyloidogenic) pathway and inhibits β-amyloid induced-neuronal death.
|
|
ROLE IN ALZHEIMER'S DISEASE:
EHT 0202 redirects APP processing toward the
non-amyloidogenic pathway, providing symptomatic relief and
modifying disease progression.
In vitro, EHT 0202 (0.2-2 μM) is neuroprotective
against Aβ42 and associated stresses in a
GABAA-dependent manner, and neuroprotection is associated
with sAPPα induction (Marcade et al., 2008). EHT 0202
demonstrated procognitive properties in various rodent
preclinical models. In humans, blood exposure is fully
relevant to preclinical efficacy models. EHT 0202 also
showed efficacy in a scopolamine Phase 1 study in healthy
volunteers. A Phase 2A study is currently ongoing to assess
EHT 0202 safety, tolerability, and preliminary efficacy on
cognition and behavior in AD patients, as well as
quantification of sAPPα in blood.
|
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|
NAME:
ELND005
|
|
OTHER NAMES:
AZD-103, cyclohexane-1,2,3,4,5,6-hexol, myo-inositol, Scyllo-inositol
|
|
FDA PHASE:
Phase II/III
|
|
MECHANISMS:
Block accumulation of Aβ oligomers; prevent Aβ oligomer formation
|
|
ROLE IN ALZHEIMER'S DISEASE:
Phase II testing of ELND005 was completed in August 2010.
Primary outcome measures included cognition and function.
Safety and tolerability were also tested. See related Alzforum
News August 13, 2010 and Alzforum
News Dec 16, 2009.
Scyllo-inositol is a specific stereoisomer of the cyclic
sugar alcohol inositol, occurring naturally in coconut palm,
dogwood flowers and oak bark. McLaurin
et al 2006
showed that scyllo-inositol can inhibit aggregation of Aβ in
transgenic mice, improves many AD-like phenotypes and
protects from cognitive decline.
The Phase II trial completed the treatment of patients
receiving 250 mg twice daily dosing. Elan has reported the
study's cognitive (NTB) and functional (ADCS-ADL) co-primary
endpoints did not achieve statistical significance. However,
Elan reported that 250mg bid dose “demonstrated a
biological effect” on Aβ in the cerebrospinal fluid (CSF),
although no details have been provided. (See Elan
press release). Twenty subjects total
volunteered to provide CSF samples at beginning and end of
trial. CSF analysis provided evidence that the 250 mg bid
dose “achieved targeted drug levels in the CSF, and showed
some effects on clinical endpoints in an exploratory analysis”.
|
|
|
|
NAME:
epothilone D
|
|
OTHER NAMES:
BMS-241027, KOS-862
|
|
FDA PHASE:
Phase I
|
|
MECHANISMS:
Epothilone D is a micotubule stabilizing agent
|
|
ROLE IN ALZHEIMER'S DISEASE:
Alzheimer’s disease is characterized by insoluble deposits
of hyperphosphorylated tau protein within neurons.
Hyperphosphorylated tau is thought to contribute to disease
pathogenesis via both gain-of-function as well as
loss-of-function toxicities. Normal tau plays an important
role in stabilizing microtubules. When the function of
normal tau is compromised it leads to impaired axonal
transport and neuronal dysfunction. Epothilone is a
brain-penetrant microtubule-stabilizing agent which may
partially compensate for impaired tau function.
In studies in aged PS19 tauopathy mice, epothilone-treated
animals retained more healthy axons, lost fewer hippocampal
neurons, and performed better on memory tests compared to
vehicle-treated animals (Zhang et al., 2012).
|
|
|
|
NAME:
Eptastigmine
|
|
OTHER NAMES:
MF 201
|
|
FDA PHASE:
Discontinued
|
|
ROLE IN ALZHEIMER'S DISEASE:
Improve cognition.
|
|
|
|
NAME:
Estrogen
|
|
OTHER NAMES:
Premarin™
|
|
FDA PHASE:
Discontinued
|
|
ROLE IN ALZHEIMER'S DISEASE:
Several epidemiological studies suggests the use of
estrogen in postmenopausal women may delay the onset or
risk of AD.
|
|
|
|
NAME:
Etanercept
|
|
OTHER NAMES:
Enbrel™
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
MECHANISMS:
Anti-inflammatory, lowering TNF-alpha in CNS.
|
|
ROLE IN ALZHEIMER'S DISEASE:
Aβ peptide and oligomers inhibit LTP in a TNFα-mediated
mechanism, preventable by TNFα-neutralizing ligands (Rowan et
al., 2007). TNFα levels are 25x elevated in CSF of AD
patients compared with controls (Tarkowski et al., 1999)
whereas lowered TNFα in plasma is a diagnostic marker for AD
(Ray et al 2007). Microglial cells produce
TNFα and Aβ-activated microglia increase TNF production
(Combs et al., 2001). TNFα is associated with increased
amyloidogenesis (Blasko et al., 1999) and glutamate
excitotoxicity (De et al., 2005; Taylor et al., 2005; Zou et
al., 2005).
Efficacy of etanercept in Alzheimer Disease was initially
reported in results from a open-label, uncontrolled, pilot
study of 12 mild
to severe AD patients, treated for 6 months, administering
25-50 mg etanercept via once weekly
perispinal infusion (Tobinick et al, 2006; Tobinick and
Gross, 2008). In all
measures of cognitive function including MMSE, ADAS-Cog, and
SIB, the treatment demonstrated improvement over baseline
scores. No control patients were included.
In a single case study, one patient improved significantly
within minutes of etanercept injection (Tobinick and Gross,
2008; comment Griffin, 2008). The mechanisms responsible
for rapid improvement
have not been defined, but may include interference with
glial TNFα functions as a regulator of synaptic
transmission (Beattie et al 2002), or TNFα involvement
of Abeta peptide inhibition of LTP (Wang et al 2005). See Alzforum
news 'Breakthrough or False Hope? Etanercept Case Report
Draws Scrutiny' and comments.
|
|
|
|
NAME:
EVP-6124
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
MECHANISMS:
EVP-6124 is a nicotinic α7 receptor agonist.
|
|
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 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.
EVP-6124 has demonstrated improved learning and memory
function in a small Phase II clinical trial (See ARF
related news story and EnVivo
ICAD 2009 Poster).
Also see related Alzforum News story posted 5 November
2010. Experimental
Drug Sensitizes Receptor, Boosts Cognition
|
|
|
|
NAME:
Exelon™
|
|
OTHER NAMES:
Rivastigmine tartrate
|
|
FDA PHASE:
FDA approved
|
|
MECHANISMS:
cholinesterase inhibitors
|
|
ROLE IN ALZHEIMER'S DISEASE:
It improves cognition, participation in activities of
daily living, and global evaluation ratings in patients
with mild to moderately severe Alzheimer's disease.
|
|
|
|
NAME:
Flurizan™
|
|
OTHER NAMES:
MPC-7869, r-flurbiprofen, tarenflurbil
|
|
FDA PHASE:
Discontinued
|
|
MECHANISMS:
Selective amyloid-lowering agent (SALA). Flurizan lowers levels of Aβ42, a major constituent of plaques and a key pathogenic agent of Alzheimer disease.
|
|
ROLE IN ALZHEIMER'S DISEASE:
Selectively lowers production of toxic amyloid (Aβ42)
and thus inhibits the cascade of amyloid accumulation,
plaque formation, and neurodegeneration that are the
hallmarks of dementia. Early intervention, and targeting
the initial stage of the disease process, offers the
potential for a therapy with disease modification
properties. In mouse models, Flurizan™ reduced insoluble
amyloid in the brain and improved spatial reference
learning and memory.
|
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|
|
NAME:
Galantamine
|
|
OTHER NAMES:
Reminyl™
|
|
FDA PHASE:
FDA approved
|
|
MECHANISMS:
cholinesterase inhibitor
|
|
ROLE IN ALZHEIMER'S DISEASE:
Improve cognitive function in mild/moderate AD.
|
|
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|
NAME:
Huperzine A
|
|
OTHER NAMES:
Cerebra capsule, Pharmassure Memorall capsule
|
|
FDA PHASE:
Inactive
|
|
MECHANISMS:
Multiple mechanisms of action include potent and selective inhibition of AChE; alterations in APP processing; reduction of neurotoxicity by Aβ; antioxidant effects; increase of NGF production.
|
|
ROLE IN ALZHEIMER'S DISEASE:
Animal and cell culture studies, along with molecular
structure data, suggest that huperzine A is a potent
acetylcholinesterase (AChE) inhibitor and protects neurons
against glutamate-induced excitotoxicity, while decreasing
glutamate-induced calcium mobilization (Gordon et al.,
2001). Huperzine A increases sAPPa, by increasing levels
of protein kinase C isoform a in ICV infused rats and cell
culture (Zhang et al., 2004). Preincubation of cultured
rat cortical neurons with huperzine A protects cells from
Aβ(25-35)-induced apoptosis and inhibits reactive
oxygen species generation and caspase 3 activation (Xiao
et al., 2002). The molecule's strong specificity for AChE
suggests it may have lower liver toxicity and other
adverse effects.
|
|
|
|
NAME:
Ibuprofen
|
|
OTHER NAMES:
Advil™, Motrin™, Nuprin™
|
|
FDA PHASE:
Discontinued
|
|
ROLE IN ALZHEIMER'S DISEASE:
May aid in preventing or delaying the onset of Alzheimer's
disease by decreasing inflammation in the brain.
|
|
|
|
NAME:
Idebenone
|
|
FDA PHASE:
Discontinued
|
|
ROLE IN ALZHEIMER'S DISEASE:
Improve cognitive and non-cognitive symptoms in
mild/moderate AD. Protect cells from beta amyloid induced
oxidative stress.
|
|
|
|
NAME:
Intravenous Immunoglobulin
|
|
OTHER NAMES:
Gammagard, IVIg
|
|
FDA PHASE:
Phase III
|
|
MECHANISMS:
Natural anti-amyloid antibodies may reduce CNS and peripheral Aβ and improve cognition.
|
|
ROLE IN ALZHEIMER'S DISEASE:
Immunotherapy targeting β amyloid (Aβ) has been
shown to arrest and partially reverse AD brain pathology
in transgenic mouse models of AD. Data suggest that
immunotherapy may have positive effects in some AD
patients (Hock et al., 2003). Intravenous Immunoglobulin
(IVIg) is obtained from the pooled plasma of healthy human
blood donors, and contains natural anti-amyloid
antibodies (reviewed in Hughes et al., 2009). In vitro data
have demonstrated that human
anti-Aβ antibodies inhibit fibril formation and
neurotoxicity (Du et al., 2003).
In the phase 1 safety and preliminary efficacy clinical
trial (U.S.), eight Alzheimer patients were treated with
IVIg (Gammagard S/D Immune Globulin Intravenous Human),
donated by Baxter Healthcare Corporation. Seven patients
completed the study and were evaluated by cognitive
testing after 6 months of therapy. Cognitive function
stopped declining in all seven patients and improved in
six of the seven patients.
In a phase 1 safety and preliminary efficacy clinical
trial (Germany) five “clinically probable or possible”
Alzheimer disease patients were treated with IVIg
(Octagam®, donated by Octapharma [Langenfeld, Germany])
for 6 months.
On the ADAS-cog a slight improvement was observed on
neuropsychological testing at 6 months in all patients
except one where the score did not change between baseline
and at 6 months. A mean improvement of 3.7 ± 2.9 points
was calculated. No patient deteriorated. A reduction in
the CSF of total Aβ of 17.3–43.5 percent was also
observed (Dodel et al., 2004).
Results from the Phase 2 clinical trial testing of Gammagard
presented at AAN in April 2010, showed that IVIg slowed
clinical decline as well as reduced brain atrophy to the
rate of age-matched normal control subjects. See Alzforum
News 'Toronto: In Small Trial, IVIg Slows Brain
Shrinkage'.
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