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Alzheon Scientists Discover Endogenous Substance in Human Brain That Inhibits Formation of Toxic Beta Amyloid Oligomers, Key Driver of Alzheimer's Disease


Publication Details Discovery of 3-Sulfopropanoic Acid, the Primary
Metabolite of Tramiprosate and its Prodrug ALZ-801, in Cerebrospinal
Fluid of Healthy Subjects as well as Alzheimer's Patients

Observed Levels of 3-Sulfopropanoic Acid Were Up to 12 times Greater
in Alzheimer's Patients Treated with Tramiprosate, Suggesting
Therapeutic Role

, a clinical-stage biopharmaceutical company focused on
developing new medicines for patients suffering from Alzheimer's disease
(AD) and other neurodegenerative disorders, today announced the
discovery of an endogenous substance in human brain that inhibits the
formation of neurotoxic beta amyloid (Aβ) oligomers, which are key
drivers of AD pathogenesis. The substance was identified as
3-sulfopropanoic acid (3-SPA), the primary metabolite of tramiprosate
and of its prodrug ALZ-801 in humans. The cognitive improvements
observed in AD patients in the tramiprosate Phase 3 studies1,2
may be attributed, in part, to the therapeutic effects of 3-SPA in the
brain. This discovery indicates a potential protective role of 3-SPA in
aging human brains and in AD, and elucidates the beneficial
pharmaceutical attributes of ALZ-801, including a favorable safety
profile, selectivity against Aβ oligomers, and excellent brain

In this new study, Alzheon scientists expanded on the previous finding
that tramiprosate and its prodrug ALZ-801 are consistently metabolized
in humans to a single major metabolite, 3-SPA. The new analyses found
that 3-SPA inhibits the formation of toxic soluble Aβ oligomers,
comparable to the recently described effects of tramiprosate.4
In evaluations of non-treated and treated AD patients, Alzheon
scientists showed that the levels of 3-SPA were up to 12 times greater
in AD patients who received oral tramiprosate, than in drug-naïve or
placebo-treated patients. These data further elucidate the mechanism of
action supporting the development of Alzheon's Phase 3-ready candidate
ALZ-801, an optimized prodrug of tramiprosate, with a substantially
improved pharmacokinetic and safety/tolerability profile compared to

The presence of an endogenous substance that can prevent Aβ oligomer
formation also suggests the possibility of a protective endogenous
anti-Aβ oligomer pathway ("Aβ oligomer brake pathway") within the human
central nervous system, with the potential to prevent or delay the onset
of AD. Such physiological anti-Aβ oligomer pathway could modulate the
neurotoxic effects of abnormal Aβ aggregation in the aging human brain.

"We are excited to contribute to a better understanding of the
pathogenic and therapeutic mechanisms in Alzheimer's disease. The
results from this publication suggest a potential protective role of
endogenous 3-SPA in normal human brains, guarding against the formation
of beta amyloid oligomers that cause neurodegenerative disorders such as
Alzheimer's," said Martin Tolar, MD, PhD, Founder, President and CEO of
Alzheon. "In addition, our results suggest a potential contribution of
3-SPA to the clinical efficacy of ALZ-801 and connect it more closely to
the protective effects against neurotoxic amyloid oligomers. While
targeting soluble amyloid aggregates is the only therapeutic approach to
date that has shown a disease modifying effect in Alzheimer's patients,
no drugs have been approved yet that can slow or stop the disease. This
new discovery and mechanistic data strongly support our therapeutic
approach and strengthen Alzheon's commitment to confirm the efficacy of
ALZ-801 in APOE4 carriers, a genetically-defined subset of Alzheimer's

The study entitled "Discovery and Identification of An Endogenous
Metabolite of Tramiprosate and its Prodrug ALZ-801 that Inhibits Beta
Amyloid Oligomer Formation in Human Brain," appeared in the most recent
issue of the peer-reviewed publication CNS Drugs, and is
available through open access
Key findings of the study include the following:

  • In drug-naïve elderly patients with memory deficits due to a variety
    of neurodegenerative diseases, 3-SPA was present endogenously in
    cerebrospinal fluid and plasma samples, suggesting that this substance
    may be a physiological protective mechanism in aging brain that
    counteracts amyloid aggregation leading to AD.
  • Using advanced molecular methodologies, the scientists showed that
    3-SPA specifically inhibits aggregation of Aβ oligomers, thereby
    confirming the potential role of this endogenous substance in the
    anti-Aβ oligomer mechanism of action of tramiprosate and ALZ-801.
  • In AD patients who received a 150 mg twice-daily dose of oral
    tramiprosate, Alzheon found that the levels of 3-SPA in cerebrospinal
    fluid were up to 12 times greater than in drug-naïve or
    placebo-treated patients. Clinical improvements observed in AD
    patients who received tramiprosate in Phase 3 studies,1,2
    may be partially explained by the therapeutic effects of the
    metabolite in the brains of these patients.
  • Consistent with the favorable clinical and preclinical safety profile
    of oral ALZ-801 and its parent molecule tramiprosate,1,2,3
    their major metabolite, 3-SPA, is also well tolerated, as expected
    since 3-SPA is an endogenous substance.
  • This research builds on the previous discovery by Alzheon scientists
    of the molecular mechanism of action of tramiprosate to inhibit Aβ
    monomer aggregation and formation of toxic Aβ oligomers through an
    ‘enveloping' of the amyloid peptide that prevents misfolding into
    soluble amyloid aggregates.3

"Our published findings suggest that an endogenous substance, 3-SPA, may
protect the human brain against Alzheimer's, and contribute to the
clinical efficacy of ALZ-801 by inhibiting the formation of toxic
soluble amyloid oligomers at therapeutic concentrations," said John Hey,
PhD, Chief Scientific Officer of Alzheon. "Our data support the central
role of amyloid oligomers in the initiation of the pathogenic cascade of
Alzheimer's disease, as well as the potential preventive and therapeutic
approaches that could be applied to counteract these neurotoxic
oligomers. Based on the emerging scientific and clinical trial data from
Alzheon, as well as independent studies which highlight amyloid
oligomers as key drivers of Alzheimer's, we have developed ALZ-801 as a
pioneering small molecule, which directly blocks the formation of
amyloid oligomers, and may slow or stop Alzheimer's disease progression."

About ALZ-801
a novel, oral anti-amyloid drug candidate is an optimized prodrug of
tramiprosate that has shown promising results in analyses of Phase 3
clinical data. ALZ-801 received Fast Track designation by the U.S. Food
and Drug Administration (FDA) in October 2017. The clinical data for
ALZ-8013 and its active agent, tramiprosate, suggest
long-term clinical efficacy in AD patients with the APOE4 genotype,
along with a favorable safety profile.1,2 ALZ-801 acts
through a novel molecular
mechanism of action
 blocking the formation of toxic amyloid oligomers4 associated
with the development and progression of AD. The initial Phase 3 program
for ALZ-801 will focus on patients with the homozygous APOE4/4 genotype
at the Mild stage of AD, with the potential for future expansion to
additional Alzheimer's populations.

About Alzheon
is committed to developing innovative medicines by directly
addressing the underlying pathology of devastating neurodegenerative
disorders. Our lead Alzheimer's clinical candidate, ALZ-801,
is a Phase 3-ready, first-in-class, small molecule oral inhibitor of
beta amyloid aggregation and neurotoxicity – hallmarks of Alzheimer's
disease. ALZ-801 is a novel prodrug that builds on the safety and
efficacy profile of the active compound tramiprosate, which has been
evaluated in clinical trials involving over 2,000 Alzheimer's patients.
Our clinical expertise and technology platform are focused on developing
drug candidates using a
Precision Medicine approach
based on individual genetic and
biological information to advance therapies with the greatest impact for

et al. Journal of Prevention of Alzheimer's Disease, 2016

et al. Journal of Prevention of Alzheimer's Disease, 2017

3 Hey
et al. Clinical Pharmacokinetics, 2018

4 Kocis
et al. CNS Drugs, 2017

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