An endogenous substance in the human brain which inhibits the formation of neurotoxic beta amyloid (Aβ) oligomers, key drivers of Alzheimer’s disease pathogenesis, has been discovered by scientists. The moleculae, 3-sulfopropanoic acid (3-SPA), is present in the cerebrospinal fluid (CSF) of patients with AD and other neurodegenerative brain diseases.

The finding was announced by the clinical-stage biopharmaceutical company Alzheon, Inc.

3-SPA is the primary metabolite of tramiprosate and of its prodrug ALZ-801 in humans. The cognitive improvements observed in AD patients in tramiprosate Phase 3 studies may be attributed, in part, to the therapeutic effects of 3-SPA in the brain.

The finding 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 penetration.


Tramiprosate (3-amino-1-propanesulfonic acid), also known as Homotaurine, is a natural organic compound found in seaweed. It is analogous to taurine, but with an extra carbon in its chain.

In 2012 Homotaurine was investigated in a Phase III clinical trial as a potential treatment for Alzheimer’s disease that did not show efficacy in its primary endpoints but did show positive and significant effects of homotaurine on secondary endpoints and subgroups of patients, including a reduction in hippocampal volume loss and lower decline in memory function in the overall cohort, as well as a reduction in global cognitive decline in APOE4 allele carriers, suggesting a disease-modifying effect.

[caption id=“attachment_96789” align=“aligncenter” width=“680”]on-mobility spectrometry–mass spectrometry drift time as a function of mass/charge (m/z) after 24 h of incubation shows the profile of Aβ42 oligomers with 1000-fold excess of 3-sulfopropanoic acid Ion-mobility spectrometry–mass spectrometry drift time as a function of mass/charge (m/z) after 24 h of incubation shows the profile of Aβ42 oligomers with 1000-fold excess of 3-sulfopropanoic acid.
Credit: Hey, J.A., et al. CC-BY[/caption]

In 2018 a new phase 3 study for genetically-defined subpopulation of high risk patients who are homozygous for the ε4 allele of apolipoprotein E (APOE4/4 homozygotes) at the Mild stage of AD has been filed with the FDA under the name ALZ-801 by Alzheon.

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.

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 tramiprosate.

Anti-amyloid Oligomer Brake Pathway

The presence of an endogenous substance that can prevent amyloid beta 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 Alzheimer’s disease. 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.

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 patients.”

said Martin Tolar, MD, PhD, Founder, President and CEO of Alzheon.

Key Findings

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 Ab oligomers, thereby confirming the potential role of this endogenous substance in the anti-Ab 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.

Hey, J.A., Kocis, P., Hort, J. et al. Discovery and Identification of an Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in the Human Brain CNS Drugs (2018).

Top Image: Representation of molecular dynamics experiment showing semi-cyclic conformation of Aβ42 in the presence of 1000:1 excess of 3-sulfopropanoic acid. Credit: Hey, J.A., et al. CC-BY

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