P2‐012: Phase 1 Development of ALZ‐801, a Novel Beta Amyloid Anti‐Aggregation Prodrug of Tramiprosate with Improved Drug Properties, Supporting Bridging to The Phase 3 Program

Background:ALZ-801 is a novel, orally bioavailable, small-molecule prodrug of tramiprosate with improved pharmacokinetics and oral tolerability. The initial tramiprosate Phase 3 program in mild-to-moderate Alzheimer’s disease (AD) included two studies with >2,000 patients but did not show significant separation on co-primary outcomes. In these studies,w60% of patients were carriers of the e4 allele of the apolipoprotein E gene (APOE4), and w14% were homozygous for APOE4. A subgroup intention-totreat analysis of APOE4/4 patients showed that tramiprosate 150mg BID produced a significant and clinically meaningful improvement on cognition (ADAS-cog), and a positive trend on function (CDR-SB), at 65 and 78 weeks, on top of standard of care symptomatic therapy. Tramiprosate also showed a favorable safety profile: the most common AE was nausea. Safety data from Phase 3 tramiprosate studies support bridging to the ALZ801 safety database, based on bioequivalence.Methods: To advance the clinical development of ALZ-801 into Phase 3, we have completed single dose and 14-day multiple ascending dose Phase 1 bridging studies in healthy elderly volunteers to evaluate safety, tolerability and pharmacokinetics. Results: Compared with oral tramiprosate, oral ALZ-801 delivered an equivalent plasma exposure of tramiprosate with over 50% lower inter-subject variability. Oral ALZ-801 also prolonged plasma tramiprosate terminal half-life to w24 hours. Administration of ALZ-801 with food markedly reduced the incidence of GI symptoms as compared to the fasted state, while maintaining plasma tramiprosate exposure. An immediate release tablet formulation of ALZ-801 was developed, which displayed exposure and low variability similar to the loose filled capsule formulation. ALZ-801 also showed excellent dose proportionality without accumulation or decrease in plasma exposure of tramiprosate over 14 days. Conclusions: Based on the single and multiple dose pharmacokinetics of ALZ-801, the steady-state plasma exposure of the active drug tramiprosate following oral BID dosing of ALZ-801 immediate release tablet has been determined. The data indicate that 265mg BID of ALZ-801 will achieve a steady-state tramiprosate exposure that is equivalent to 150mg BID of oral tramiprosate. These bridging data will support the Phase 3 development of ALZ-801, an optimized prodrug of tramiprosate with improved GI toleration and low inter-subject pharmacokinetic variability, in APOE4/4 homozygous AD subjects.