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Alzhemed: A Potential Treatment for Alzheimer's Disease
Paul S. Aisen1,*, Serge Gauthier2, Bruno Vellas3, Richard Briand4, Daniel Saumier4, Julie Laurin4
and Denis Garceau4
1
Georgetown University, Washington, DC, US. 2McGill University, Montreal, Canada, 3Alzheimer Clinical and Research Center, Toulouse, France, 4 Neurochem Inc. Laval, Canada
Abstract: As a potential disease-modifying treatment for AD, Alzhemed (tramiprosate) is a compound that binds to soluble amyloid-beta peptide (A) and inhibits the formation of neurotoxic aggregates that lead to amyloid plaque deposition
in the brain. The safety, tolerability, and pharmacodynamic effects of Alzhemed were assessed in a double-blind study in
which 58 individuals with mild-to-moderate AD (MMSE 13-25) were randomized to receive placebo or Alzhemed 50,
100 or 150 mg BID for 3 months. At the end of the double-blind phase, 42 of these subjects entered a 36-month openlabel (OL) phase in which they received Alzhemed 150 mg BID. Assessments included plasma and cerebrospinal fluid
(CSF) Alzhemed concentrations, CSF levels of A, as well as cognitive (Alzheimer’s Disease Assessment Scale-cognitive
subscale, Mini-Mental State Examination) and clinical performance (Clinical Dementia Rating scale, Sum-of-Boxes)
measures. Alzhemed was safe and well tolerated, crossed the blood-brain barrier, and dose-dependently reduced CSF A42
levels after 3 months of treatment. Mild AD subjects (MMSE 19-25 at entry) displayed greater reduction of CSF A42
levels than moderate AD participants (MMSE 13-18 at entry). There was no effect of Alzhemed on the cognitive or clinical measures after 3 months of treatment. The OL follow-up suggested a stabilization of cognitive function especially in
mild AD subjects over the 36-month study period. Alzhemed thus appears to be well tolerated with long-term exposure
and reduces CSF A42 levels in mild-to-moderate AD subjects. These findings will be discussed in the context of two
large-scale randomized, double-blind, placebo-controlled Phase III clinical trials that are currently being conducted to test
the long-term safety and efficacy of Alzhemed.
INTRODUCTION
Alzheimer’s disease (AD), among the most important
health care problems worldwide, is a progressive neurodegenerative disorder causing decline in memory, learning and
other aspects of cognitive function associated with impaired
activities of daily living, frequent behavioral complications,
and eventually death. AD is now a treatable condition. Elucidation of the central role of cholinergic dysfunction in the
symptoms of the disease led to the development of cholinergic therapies, specifically the acetylcholinesterase inhibitors,
for AD treatment [1]. These drugs partially compensate for
the cholinergic deficiency by slowing acetylcholine clearance from the synapse via inhibition of the primary clearance
enzyme. Treatment with cholinesterase inhibitors donepezil,
rivastigmine and galantamine results in modest improvement
on cognitive symptoms evident in the first few months of
treatment, as well as stabilization of daily function and behavior.
Current AD treatment options also include memantine.
Memantine acts on glutamate neurotransmission; it is a moderate affinity antagonist at the NMDA receptor. While it was
hoped that NMDA inhibition might reduce excitotoxic neuronal damage and thus slow disease progression, clinical
study results suggest symptomatic improvement without
clear evidence of altered rate of decline. The apparent ab*Address correspondence to this author at the Department of Neurology,
Georgetown University Medical Center, Building D, Room 202B, 4000
Reservoir Rd NW, Washington, DC 20057, USA; Tel: 202-784-6671; Fax:
202-784-4332; E-mail: [email protected]
1567-2050/07 $50.00+.00
sence of disease modification may be explained the high
drug concentrations necessary to provide neuroprotection
[2]. Memantine treatment appears to be particularly useful in
moderate to severe AD, either as monotherapy [3] or in
combination with a cholinesterase inhibitor [4].
These symptomatic AD treatments, all developed within
the past 15 years, provide modest but clinically meaningful
benefits to people with AD and their caregivers. But there is
no definitive evidence that any of these drugs alters the underlying disease process, or significantly slows the relentless
progression of dementia. This remains the major goal of current drug development efforts in AD research.
AMYLOID HYPOTHESIS
As noted above, the current treatments target neurotransmission, and thus modulate cognitive function without
addressing the initiating events in the neurodegenerative
cascade. But steady progress in identifying the pivotal events
in that cascade presents clear targets for disease-modifying
therapy.
The two principal pathological lesions in the AD brain
are the extracellular amyloid plaque and the intracellular
neurofibrillary tangle. The primary constituent of the amyloid plaque is the A peptide, a fragment derived by two
sequential cleavages from a parent protein, the amyloid precursor protein (APP). The A peptides aggregate into oligomers and amyloid fibrils, and ultimately deposit as amyloid plaques. Neurofibrillary tangles consist primarily of
hyperphosphorylated tau protein. Tau is an essential micro©2007 Bentham Science Publishers Ltd.
474 Current Alzheimer Research, 2007, Vol. 4, No. 4
tubule stabilizing protein; hyperphosphorylation is associated with conformational change, fibrillization and loss of
function. Both amyloid and tau cascades have been viewed
as plausible therapeutic target systems for disease modifying
AD treatments [5].
However, compelling evidence suggests that it is the
amyloid cascade that is pivotal in driving the neurodegenerative process [6]. Most convincing is the genetic evidence.
Each of the three genes that, when mutated, can cause familial autosomal dominant AD (FAD), are directly involved in
the cleavage of APP to release the A peptide; these genes
code APP itself (the mutations increase susceptibility to secretase cleavage at the or sites at either end of the A
sequence), and presenilins 1 and 2 (components of the secretase complex, that when mutated increase secretase
cleavage). This means that the cause of FAD must be related
to APP cleavage with generation of A. Since FAD and sporadic AD differ only in age of onset and inheritance, it follows that APP cleavage must be pivotal in sporadic AD as
well (though in sporadic AD there are no pathogenic mutations; rather, insufficiently characterized processes presumably related to aging must increase A generation).
The mechanism by which APP cleavage to release A
initiates the neurodegenerative cascade is less clear. The
amyloid plaques may contribute, as suggested by the characteristic neuritic changes surrounding plaques. But there is
growing evidence that A is damaging in its diffusible
monomeric and oligomeric forms (Klein, 2006). It has long
been known that A is highly toxic to neurons in culture;
recent studies using transgenic mouse models show that oligomeric A is implicated in synaptic dysfunction [7] and tau
hyperphosphorylation [8].
It is thus clear that the amyloid pathway is pivotal in AD,
and offers primary targets for disease modifying drug development [9]. But whether the specific goal of treatment
should be reduction of plaque density, or reduction of diffusible forms of A, or even protection of neurons against
damage caused by either or both, remains uncertain.
ANTI-AMYLOID DRUG DEVELOPMENT
In theory, the first step in the amyloid cascade, APP
cleavage, is optimal for drug intervention. But there have
been some practical obstacles to this approach. An inhibitor
of -secretase would be a promising candidate, as this enzyme is required for A generation, though inessential for
life [10, 11]. But development of a specific and drug-like secretase inhibitor has proven to be technically difficult [9].
Inhibitors of the -secretase complex have been identified,
but -secretase activity is essential, and toxicity has been an
issue with some drug candidates. A subset of non-steroidal
anti-inflammatory drugs show -secretase modulating activity with reduction in amyloid accumulation in transgenic
mice [12], though tolerable doses may be insufficient for
brain amyloid reduction; R-flurbiprofen, an NSAID enantiomer that is tolerated at relatively high doses (because it
lacks the cyclooxygenase inhibition of the L-form), is currently being tested in a Phase III AD trial [13].
It is also feasible to reduce amyloid accumulation by increasing clearance of amyloid by enhancing phagocytosis or
Aisen et al.
transport to the periphery. The interrupted active amyloid
vaccination program, while unsuccessful (because of a serious adverse effect, encephalitis, in some subjects), demonstrated the promise of this approach [14]. The vaccine apparently induced clearance of amyloid plaques by augmenting
phagocytosis, with cognitive benefit. At present, a number of
companies and investigators are pursuing passive immunization programs aiming to augment phagocytosis, or alternatively promote clearance by sequestering A peptides in the
periphery [15, 16].
Reducing aggregation of amyloid and fibrillogenesis may
increase clearance of insoluble amyloid from brain. There
are several approaches to reducing aggregation. Since heavy
metals promote the aggregation process, chelating agents
may increase clearance; this has been demonstrated with the
zinc and copper binding compound clioquinol [17, 18]. Derivatives of -sheet binding dyes have also been considered
candidate anti-aggregation compounds [19].
THE ALZHEMED PROGRAM
The strategy that led to the development of Alzhemed
(tramiprosate) focused on the role of proteoglycans in the
amyloid aggregation and fibrillogenesis process [20, 21].
The polyanionic glycosaminoglycan (GAG) chains of tissue
proteoglycans bind to amyloid peptides promoting aggregation in brain. Small sulfated or sulfonated molecules were
developed to interfere with this binding and slow the process
of fibrillogenesis. One such low molecular weight molecule,
Alzhemed, proved to be a potent inhibitor of aggregation and
fibrillogenesis in vitro, and also inhibited the neurotoxicity
of amyloid peptides [20, 21].
A study in an APP transgenic mouse model confirmed
the impact of systemic Alzhemed treatment on amyloid accumulation in brain [20]. Treatment of 9 week old
TgCRND8 mice for 8 weeks reduced the area occupied by
amyloid plaques in brain by 29%. There was a reduction of
similar magnitude in brain levels of both soluble and insoluble amyloid peptides.
While there continues to be debate regarding the relative
contribution of fibrillar amyloid versus other forms of the
peptide to neurodegeneration, increasing evidence points to
the importance of diffusible oligomeric forms. For example,
treatment of transgenic mice with anti-amyloid antibodies
produces a rapid improvement in memory prior to any
change in amyloid plaque burden [22]; this suggests that the
interaction of the antibodies with diffusible rather than
plaque-bound amyloid peptide improves function. It has
been confirmed that oligomeric A peptides inhibit long
term potentiation in brain slices, a model for synaptic information storage. The rapid cognitive improvement reported
with treatment of AD with pooled human immunoglobulin
(which contains natural anti-amyloid antibodies) [23] may be
mediated by an immediate impact on diffusible A.
The growing acceptance of the importance of oligomeric
A in the pathophysiology of Alzheimer’s disease provides a
strong rationale for targeting non-fibrillar A with antiamyloid interventions against AD. There is even concern
that drugs or antibodies that interact with fibrillar deposits
may increase levels of diffusible A, aggravating cognitive
Alzhemed: A Potential Treatment for Alzheimer's Disease
dysfunction. It is notable that, in contrast to the amyloid vaccine, Alzhemed specifically targets diffusible A; there is no
interaction between the drug and fibrillar deposits [20].
Preclinical studies of Alzhemed support its potential as a
drug candidate [20]. Genotoxicity studies including AMES
testing, the mammalian cell cytogenetic test and the mouse
micronucleus test have been negative. hERG testing did not
suggest any adverse effect on cardiac conduction. Long term
oral toxicity studies in rats and dogs demonstrate safety over
a wide dosing range, with only mild gastrointestinal symptoms at high doses. Studies with systemically-administered
14
C labeled drug demonstrated brain penetration. The half
life of the drug after oral administration was about 3 hours in
plasma and at least 16 hours in brain.
CLINICAL DEVELOPMENT OF ALZHEMED
A series of Phase I studies in both young and elderly
adults explored the safety and tolerability of Alzhemed in
humans (unpublished data provided by Neurochem, Inc.).
Single (up to 200mg orally) and repeated doses (up to
200mg, bid orally) were safe and generally well tolerated;
treatment with higher doses was limited by gastrointestinal
side effects, specifically nausea and vomiting. The time to
reach peak plasma level was 5 hours, with estimated terminal
plasma half life in the range of 1.5 to 5 hours.
A randomized double-blind placebo-controlled Phase II
study was conducted at six U.S. centers; the aims were to
assess safety, tolerability, pharmacokinetics and pharmacodynamic effects. The mechanism of action of the drug
indicates that the impact on disease will be slowed progression with long-term treatment rather than symptomatic improvement; since no measurable decline in the placebo group
is expected in 12 weeks, no effect of treatment on cognitive
or clinical measures at 12 weeks was anticipated.
A total of 58 individuals with mild to moderate AD were
randomly assigned to one of four treatment groups: placebo,
or Alzhemed 50mg bid, 100mg bid or 150mg bid orally. Eligible subjects had MMSE scores ranging from 13 to 25
(stratified into two groups, mild [19-25] and moderate [1318]), and could be taking stable doses of cholinesterase inhibitors. Study medication was administered for 12 weeks.
Outcome measures included clinical and laboratory examinations, and cognitive (Mini Mental State Examination, or
MMSE [24] and the cognitive subscale of the Alzheimer’s
Disease Assessment Scale, or ADAScog [25]) and clinical
(Clinical Dementia Rating Sum of Boxes, or CDR-SB [26])
assessments. Lumbar punctures were performed before and
after the 12 week course of treatment, for measurement of
drug and biomarker levels.
The results of this Phase II trial indicated that treatment
with Alzhemed at these doses was safe. There was a dosedependent occurrence of gastrointestinal symptoms, particularly transient nausea and vomiting. There were no serious
adverse events related to treatment, and no adverse effects on
vital signs, laboratory studies or electrocardiograms. As expected, there was no decline in cognitive or clinical measures
in the placebo group during the 12 week blinded phase, and
no difference on these measures between groups.
Current Alzheimer Research, 2007, Vol. 4, No. 4
475
Analysis of plasma drug levels indicated that the time to
maximum level was between 4.5 and 6 hours after dosing;
the elimination half-life was approximately 2-2.5 hours.
There was no evidence of plasma accumulation with repeated dosing. Measurement of Alzhemed levels in CSF
confirmed penetration into the central nervous system; CSF
levels were measurable in 21/36 actively treated subjects,
with concentrations ranging from 2.6 to 7.3 ng/ml.
Of particular interest, a regression analysis performed on
A CSF concentration changes as a function of Alzhemed
dosage level revealed a significant linear relation (p = 0.041)
between decrease in A42 concentration and dose of Alzhemed administered after three months of treatment. The
magnitude of the change in CSF A42 in these two groups
was greater for the mild subgroup (32% decline) than the
moderate subgroup (14% decline). In general, CSF A42 levels reflect diffusible levels of the peptide in brain [27-29];
though amyloid plaque load influences CSF A42 levels,
since plaque levels presumable remain stable over 12 weeks,
change in CSF level should be an accurate indicator of
change in diffusible A levels. Thus, the CSF A results
suggest that Alzhemed has the anticipated pharmacodynamic
impact in individuals with AD.
Subjects in the Phase II study were invited to participate
in an open-label extension trial; 42 individuals elected to
participate. In the extension, subjects were treated with Alzhemed 150mg po bid, and were followed with cognitive and
clinical assessments at 3 month intervals for up to 36
months. In the absence of a concurrent control group, the
open-label extension assessment data must be interpreted
with caution. However, the rate of decline, particularly in the
mild group, appeared to be slow in comparison to expectations based on published data [30] (Figs. 1 and 2). The open
label experience confirmed the long term tolerability of Alzhemed in individuals with AD.
These encouraging results led to the launch of a large
Phase III pivotal trial in the U.S. and Canada, followed by a
similar trial in Europe. The Phase III trial design reflects the
expected clinical response: slowing of decline in relatively
mildly impaired individuals. Eligible subjects in the North
Amercian trial are on stable symptomatic treatment (cholinesterase inhibitors, with or without memantine), and have an
MMSE score between 16 and 26. To allow sufficient time
for the cognitive and clinical trajectories for the active and
placebo groups to separate, the treatment period is 18
months. Standard cognitive (ADAScog, MMSE), behavioral
(Neuropsychaitric Inventory, or NPI [31]) and functional
(Disability Assessment for Dementia, or DAD [32]) measures are used. To explore the effect of treatment on amyloid
and the neurodegenerative process, lumbar punctures for
CSF A and tau determination, and structural MRI scans for
hippocampal, entorhinal cortex and whole brain volumes, are
obtained in subsets of study participants.
The U.S./Canada Phase III trial was launched in mid2004, and was fully enrolled with over 1000 subjects in less
than one year. The European study started in the fall of 2005,
with enrollment still in progress.
The primary purpose of these pivotal trials is to establish
the clinical efficacy of Alzhemed using standard cognitive
476 Current Alzheimer Research, 2007, Vol. 4, No. 4
Aisen et al.
Fig. (1). Change in ADAScog scores after 24 months in open-label extension study.
Fig. (2). Change in ADAScog scores after 36 months in open-label extension study.
and clinical assessment tools, and to establish the safety and
tolerability of the medication in a large study population.
Disease-modification will be assessed by examining Alzhemed’s effect on hippocampal entorhinal cortex, and whole
brain atrophy rate, as indicated by structural MRI scanning at
Baseline and following 18 months of treatment. The analysis
of the pattern of effect on cognitive and clinical assessment
scores may also support disease modification. Specifically,
absence of a short term treatment effect (eg, at 6 months),
with increasing treatment group separation at 12 and 18
months (ie, a change in the slope of decline), would be suggestive of disease-modification. Ancillary data will be used
to confirm the pharmacodynamic effect (reduction in soluble
amyloid peptide in brain, as reflected by levels in cerebrospinal fluid).
Alzhemed: A Potential Treatment for Alzheimer's Disease
Current Alzheimer Research, 2007, Vol. 4, No. 4
ANTI-AMYLOID
[7]
The concept that systemic treatment with an anti-amyloid
drug shown pre-clinically to prevent fibril formation and
deposition in tissues leads to clinical benefits has now been
tested in a multicenter trial. In amyloid A (AA) amyloidosis,
the amyloidogenic peptide is derived from serum amyloid
associated protein, or SAA. SAA is an acute phase protein,
elevated in many chronic inflammatory conditions including
rheumatoid arthritis, familial Mediterranean fever and tuberculosis. As in any amyloid related disease, the pathogenic
protein adopts a highly aggregable -sheet conformation,
with resultant deposition in tissue. In AA amyloidosis, the
kidney is a primary site of the deposition, leading to proteinuria and renal insufficiency.
[8]
FIBRILLEX:
STRATEGY
VALIDATION
OF
Fibrillex is an anti-amyloid drug, like Alzhemed, that has
been shown to inhibit amyloid deposition in a mouse model
of AA amyloidosis. To study its clinical efficacy, the trial
enrolled 183 individuals with AA amyloidosis and renal involvement, and followed renal function and other clinical
endpoints during 24 months of treatment. Treatment with
Fibrillex resulted in preservation of renal function as measured by creatinine clearance and need for dialysis. The Fibrillex trial provides some support to this strategy, and suggests that the brain-penetrating, anti-amyloid drug Alzhemed
may reduce amyloid-mediated damage in the AD brain.
CONCLUSION
The leading hypothesis regarding the pathophysiology of
AD suggests that the amyloid peptide is the most promising
target for disease-modifying interventions. Alzhemed is a
small molecule that binds soluble A peptide and prevents
amyloid formation and deposition, and inhibits A-induced
neurotoxicity. The drug penetrates the blood-brain barrier,
and is safe and tolerable in humans. Phase II testing has confirmed an anti-amyloid pharmacodynamic effect, as demonstrated by a reduction of CSF A42 in Alzhemed treated patients. Two pivotal phase III trials will now determine the
efficacy of Alzhemed in slowing progression of AD. If the
anti-amyloid activity of Alzhemed does indeed significantly
slow disease progression, it will represent a major advance in
AD therapeutics.
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