ALZ-801 prevents the formation of toxic soluble oligomers – aggregates of beta amyloid protein (β amyloid, Aβ) that are the key pathogenic agent in Alzheimer’s disease (AD). This anti-oligomer mechanism is mediated by tramiprosate, the active molecule in a substantially optimized prodrug ALZ-801. Tramiprosate binds directly to beta amyloid Aβ42 and Aβ40 peptides in the brain to inhibit the formation of oligomers that subsequently aggregate into beta amyloid fibrils and plaque (Gervais et al. 2007; Martineau et al. 2010).
Following cleavage from ALZ-801, tramiprosate is released in the body and penetrates the brain, where it directly interacts with beta amyloid peptide monomers to block the pathological beta amyloid cascade. New data recently published by Alzheon uncovered a novel mechanism of action for tramiprosate demonstrating how it envelops Aβ42 by preventing monomers from assembling into toxic soluble amyloid oligomers (Kocis et al. 2017) . Blocking the formation of oligomers prevents subsequent damage to brain cells – and tramiprosate has been found to maintain beta amyloid protein in a non-toxic, non-fibrillary, soluble form.
In preclinical in vivo studies, tramiprosate treatment of TgCRND8 mice resulted in a significant reduction (∼30%) in brain beta amyloid plaque load, quantified via histopathology. Treatment with tramiprosate further significantly reduced both soluble and insoluble beta amyloid fractions (Gervais et al. 2007).
Phase 1b development of ALZ-801 has identified the dose of ALZ-801 that will provide brain exposure of tramiprosate equivalent to the dose of tramiprosate which showed efficacy in APOE4 carriers in the Phase 3 program. ALZ-801 demonstrated substantially improved pharmacokinetic properties and tolerability in human volunteers compared to tramiprosate.
Long-term oral therapy with ALZ-801 is expected to prevent beta amyloid aggregation in patients and to inhibit the development of beta amyloid oligomers and resultant neurotoxicity (Lacor et al. 2007; Demuro et al. 2010).