Endogenous Metabolite of Tramiprosate and ALZ-801: Inhibitor of Beta Amyloid Oligomerization in Alzheimer's Disease

ALZ-801, an oral inhibitor of beta amyloid oligomer formation, is in development for Alzheimer's disease (AD) and is a prodrug of tramiprosate with enhanced pharmacokinetics and gastrointestinal tolerability. The primary metabolite of tramiprosate, 3-sulfopropanoic acid (3-SPA), is an endogenous molecule found in the cerebrospinal fluid (CSF) of patients with AD and other neurodegenerative disorders.

The research aimed to identify 3-SPA in CSF samples from elderly patients with memory deficits, quantify its levels in AD patients from a phase III trial, evaluate its anti-Aβ42 oligomer activity, and characterize its pharmacokinetics and brain penetration. CSF samples from 64 drug-naive patients with cognitive deficits and six AD patients treated with tramiprosate were analyzed using liquid chromatography-tandem mass spectrometry and ion-mobility spectrometry-mass spectrometry.

The study confirmed 3-SPA's presence in CSF with a mean concentration of 11.7 nM in cognitive deficit patients and 135 nM in AD patients treated with tramiprosate. In vitro studies showed 3-SPA's multi-ligand interaction with Aβ42 monomers, inhibiting the formation of small oligomers. Rat studies demonstrated 3-SPA's 100% oral bioavailability and 25% brain penetration.

The conclusion highlights 3-SPA's endogenous presence in CSF, its increased levels in AD patients treated with tramiprosate, and its potent anti-Aβ oligomer activity. The metabolite's oral availability and brain penetration in rats suggest that higher CSF concentrations of 3-SPA after ALZ-801 or tramiprosate administration may be due to its CNS penetration. The data indicate that 3-SPA could be an endogenous agent with potential to stabilize Aβ monomer conformational flexibility, inhibiting misfolding and toxic oligomer formation, thus preventing AD's initial pathogenic step. The clinical improvements observed in AD patients with the ε4 allele in phase III studies may be partly due to the metabolite's therapeutic effects. The protective and therapeutic potential of 3-SPA in AD and other neurodegenerative disorders requires further exploration.