Framingham-Based Company’s Scientists Discover Key Driver of Alzheimer’s Disease

FRAMINGHAM – Alzheon, Inc., a clinical-stage biopharmaceutical company focused on developing new medicines for patients suffering from Alzheimer’s disease  and other neurodegenerative disorders, today, August 6, 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 Alzheimer’s  patients in the tramiprosate Phase 3 studies 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 Alzheimer’s disease, and elucidates the beneficial pharmaceutical attributes of ALZ-801, including a favorable safety profile, selectivity against Aβ oligomers, and excellent brain penetration.

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.

“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 a media statement “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.”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 Alzheimer’s patients, Alzheon scientists showed that the levels of 3-SPA were up to 12 times greater in Alzheimer’s 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.

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.

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,1,2,3their 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.

“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, in a media release. “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.”


Framingham Source Editor Susan Petroni

Susan Petroni Framingham Source Editor Email: Phone: 508-315-7176

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