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NAME:
Leuprolide
|
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OTHER NAMES:
Leuprolide acetate
|
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FDA PHASE:
Discontinued
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ROLE IN ALZHEIMER'S DISEASE:
May improve cognitive function and slow the
progression of Alzheimer's disease. For more on underlying
rationale, see ARF
news story
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NAME:
Linopirdine
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OTHER NAMES:
DuP996
|
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FDA PHASE:
Discontinued
|
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ROLE IN ALZHEIMER'S DISEASE:
Improvement of cognitive symptoms.
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NAME:
LU25-109
|
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FDA PHASE:
Discontinued
|
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NAME:
LY450139 Dihydrate
|
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OTHER NAMES:
hydroxylvaleryl monobenzocaprolactam, Semagacestat
|
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FDA PHASE:
Discontinued
|
|
MECHANISMS:
γ-secretase inhibitor
|
|
ROLE IN ALZHEIMER'S DISEASE:
Eli Lilly has halted development and further testing of
Semagacestat (LY450139), announced on Aug 17 2010.
Preliminary analysis of from two Phase III trials
(NCT00762411 and NCT00594568) have shown that 'patients
treated with semagacestat worsened to a statistically
significantly greater degree than those treated with
placebo' and furthermore, 'semagacestat is associated with
an increased risk of skin cancer compared with those who
received placebo'. See related Alzforum News Lilly
Halts IDENTITY Trials as Patients Worsen on Secretase
Inhibitor and Lilly press release Lilly
Halts Development of Semagacestat for Alzheimer's Disease
Based on Preliminary Results of Phase III Clinical Trials.
γ-secretase inhibitor LY450139 completed Phase 2
clinical testing in June 2007. This was a collaborative
effort of the Alzheimer’s
Disease Cooperative Study (ADCS) group and sponsor
company. In a multicenter, randomized, double-blind,
dose-escalation, placebo-controlled trial, biomarker
analysis of the treatment group showed that plasma Aβ40
decreased by 58.2 percent in the 100 mg/day group, and by
64.6 percent in the 140 mg/day group; the decrease in CSF
Aβ40 was smaller and not statistically significant. See
ARF
related news story. Using a novel radiolabeling
technique to identify newly synthesized protein in the CSF,
LY450139 has been shown to decrease synthesis of Aβ without
affecting clearance (see ARF
related news story and Bateman et al., 2009)
|
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NAME:
MABT5102A
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
MECHANISMS:
Designed to bind and remove the Aβ peptide that accumulates in the brain.
|
|
ROLE IN ALZHEIMER'S DISEASE:
MABT5102A (crenezumab)is a humanized monoclonal antibody,
which binds to Aβ. Aβ is the main constituent of amyloid
plaque in the brains of patients with Alzheimer's disease
and is proposed to be causative in the development of the
disease.
|
|
|
|
NAME:
Melatonin
|
|
FDA PHASE:
Not FDA regulated
|
|
ROLE IN ALZHEIMER'S DISEASE:
A number of studies have documented disturbances in
circadian rhythm associated with Alzheimer's disease,
resulting in changes of body temperature, hormonal
concentrations, sleep and wakefulness patterns, and rest-
activity cycles. These cycles are regulated by the daily
rise and fall of melatonin levels, and as one of the
symptoms associated with the aging process has been a
decline in the amplitude of the melatonin rhythm, there is
currently interest in using melatonin to treat circadian
disturbances in Alzheimer's disease. In both in vivo and
in vitro experiments melatonin has been shown to reduce
lipid peroxidation and oxidative damage to nuclear DNA. A
variety of studies also suggest melatonin may inhibit
Abeta toxicity. Some researchers hypothesize that an age-
related decline in melatonin could be a cause of
Alzheimer's, but it is just as probable that the
disruption of the melatonin cycle is the result of an
underlying disease process.
|
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|
|
NAME:
MEM 1003
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
MECHANISMS:
MEM 1003 is a neuronal L-type calcium channel antagonist.
|
|
ROLE IN ALZHEIMER'S DISEASE:
One of the earliest manifestations of Alzheimer disease is
an impaired regulation of calcium within CNS neurons.
Neuronal calcium levels are regulated by specific proteins
known as L-type calcium channels. Abnormal regulation of
these channels is believed to be an early step in the
Alzheimer disease process, first impairing the pathways
required for memory and other cognitive functions and
eventually causing the death of neurons. In support of
this hypothesis, Yagami et al. (2004) have shown that a
selective L-type calcium channel blocker (S-312-d)
significantly prevented primary rat cortical neurons from
Aβ-induced Ca2+ influx, suppressed apoptotic features
such as DNA fragmentation, and reduced cell death.
Acting independently of NMDA receptors, postsynaptic L-
type voltage-gated calcium channel activity is required
for LTP in the CA1 region of the hippocampus. Hippocampus-
specific inactivation of L-type Ca channel gene Cav1.2 in
mice resulted in severely impaired hippocampus-dependent
spatial memory (Moosmang et al., 2005). Thus, calcium is
believed to be an essential mediator of long-term memory
formation. However, it has also been shown that 1 μM
Aβ42 significantly impairs LTP in rat hippocampal CA1
pyramidal neurons without affecting voltage dependent
calcium channel currents (Nomura et al., 2005).
Nimodipine, the parent compound of MEM 1003, has shown
some benefits in clinical trials with Alzheimer disease
(Fritze and Walden, 1995) and has demonstrated efficacy in
reduction in Aβ42 production in rat cortical neurons
that is specifically induced by increases in cytosolic
calcium concentration (Pierrot et al., 2004). However,
meta-analysis of clinical studies that test nimodipine for
efficacy in dementia demonstrated that nimodipine does not
swiftly improve manifestations of the disease but rather
seems to slow progression (Lopez-Arrieta and Birks,
2002). MEM 1003 has demonstrated enhanced learning
effects as compared to vehicle in aged rabbits tested on
eyeblink conditioning tests of learning, supporting the
notion that MEM 1003 may reduce age-related cognitive
impairment in a manner similar to its parent compound
(Rose et al., 2006). Of note: the rabbit eyeblink study
was conducted with subcutaneous administration of MEM
1003; aged rodent trace fear conditioning was IP and PO
administration (Lowe et al., 2006).
Further, modulation of the calcium flow may impact the
progression of the disease by protecting these neurons
from further damage caused by the amyloid plaques.
|
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NAME:
Memantine
|
|
OTHER NAMES:
Ebixa™, Namenda™
|
|
FDA PHASE:
FDA approved
|
|
MECHANISMS:
NMDA receptor antagonist
|
|
ROLE IN ALZHEIMER'S DISEASE:
Improves cognitive, social and motor impairment.
See Live Discussion:
Memantine: Implications for
Treating Alzheimer's led by Steven T. DeKosky and
Bengt Winblad.
|
|
|
|
NAME:
Metrifonate
|
|
FDA PHASE:
Discontinued
|
|
ROLE IN ALZHEIMER'S DISEASE:
Improve cognition and behavioral symptoms in mild/moderate
AD.
|
|
|
|
NAME:
Milameline
|
|
OTHER NAMES:
CI 979
|
|
ROLE IN ALZHEIMER'S DISEASE:
Enhances cognition. Appears to be well tolerated.
|
|
|
|
NAME:
MKC-231
|
|
FDA PHASE:
Inactive
|
|
ROLE IN ALZHEIMER'S DISEASE:
Cholinergic signalling is sharply reduced early in the
course of AD, MKC-231 may increase the amount of choline
available to synthesize acetylcohline.
|
|
|
|
NAME:
Naproxen
|
|
OTHER NAMES:
Aleve™, Anaprox™, Naprosyn™
|
|
FDA PHASE:
Discontinued
|
|
MECHANISMS:
Anti-inflammatory
|
|
ROLE IN ALZHEIMER'S DISEASE:
May be useful in the treatment of the inflammatory process
in Alzheimer's disease.
|
|
|
|
NAME:
Nefiracetam
|
|
FDA PHASE:
Discontinued
|
|
ROLE IN ALZHEIMER'S DISEASE:
May improve cognitive function in AD patients by
activating central cholinergic transmission.
|
|
|
|
NAME:
NeoTrofin
|
|
OTHER NAMES:
AIT-082
|
|
FDA PHASE:
Discontinued
|
|
MECHANISMS:
Neotrophic Agents
|
|
ROLE IN ALZHEIMER'S DISEASE:
General improvement in mild-moderately demented
Alzheimer's disease patients.
|
|
|
|
NAME:
Neramexane
|
|
OTHER NAMES:
1-amino-1,3,3,5,5-pentamethyl-cyclohexane hydrochloride, MRZ 2/579
|
|
FDA PHASE:
Discontinued
|
|
MECHANISMS:
Uncompetitive NMDA receptor channel blocker
|
|
ROLE IN ALZHEIMER'S DISEASE:
Neramexane is similar to memantine and
acetylcholinesterase inhibitors in that neramexane targets
the cognitive decline in Alzheimer’s Disease by altering
neurotransmitter signaling, but not the underlying
pathological mechanisms that cause the disease (amyloid
production or neurofibrillary tangle accumulation).
|
|
|
|
NAME:
NGX267
|
|
OTHER NAMES:
AF267B
|
|
FDA PHASE:
Inactive
|
|
ROLE IN ALZHEIMER'S DISEASE:
Potential to improve cognitive function as well as to slow
the progression of Alzheimer's disease.
|
|
|
|
NAME:
NIC5-15
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
MECHANISMS:
NIC5-15 is a naturally occurring anti-diabetic agent with insulin-sensitizing properties. It has also been shown to act as a gamma-secretase inhibitor that spares Notch.
|
|
|
|
NAME:
Nicotinamide
|
|
OTHER NAMES:
Enduramide™, Niacinamide, Nicotinic acid amide, Vitamin B3
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
MECHANISMS:
competitive inhibitor of the sirtuins or class III NAD+ dependent HDACs
|
|
ROLE IN ALZHEIMER'S DISEASE:
In transgenic mouse models of Alzheimer's Disease (Green et
al 2008), nicotinamide has been shown to restore cognition
in water maze tests and improves contextual learning,
preventing fear memory deficits. Nicotinamide did not
reduce plaque deposition or reduce either soluble or
insoluble Ab in 3xTg AD mice, but did decrease tau pathology
and selectively reduced Thr231 phosphorylated tau, known to
inhibit microtubule polymerization. Nicotinamide was also
shown in this study to inhibit sirtuin deacetylase and
increases microtubule stability. Also see Alzforum
News.
|
|
|
|
NAME:
NS2330
|
|
OTHER NAMES:
Tesofensine
|
|
FDA PHASE:
Discontinued
|
|
ROLE IN ALZHEIMER'S DISEASE:
The compound enhances the function of the neurotransmitters
acetylcholine, noradrenaline and dopamine, which are all
impaired in Alzheimer's patients.
|
|
|
|
NAME:
PBT2
|
|
FDA PHASE:
Phase II/IIa/IIb
|
|
MECHANISMS:
Inhibits oligomer formation, disaggregates plaques, neutralizes Aβ toxicity.
|
|
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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