OBJECTIVES: ALZ-801 is a novel prodrug of tramiprosate with improved pharmacokinetics (PK) and oral tolerability in development for the treatment of Alzheimer’s disease (AD). Tramiprosate acts to prevent β-amyloid (Aβ) oligomer formation and neurotoxicity. Tramiprosate achieved compelling cognitive and functional efficacy in a subset of patients homozygous for the e4 allele of apolipoprotein E (Abushakra 2016). We present a summary of the bridging pharmacokinetic/pharmacodynamic (PK/PD) data and a dose projection underpinning the anti-amyloid activity that supports the pivotal ALZ-801 Phase 3 program.
METHODS: We determined the ALZ-801 clinical dose based on the single- and multiple-dose Phase 1 studies in healthy elderly volunteers, and established AUC bioequivalence to the 150 mg BID dose from the tramiprosate Phase 3 studies. Steady-state brain drug exposure was projected using the brain/plasma relationships.
RESULTS: ALZ-801 administered as loose-filled capsule or tablet demonstrated excellent PK dose linearity under fasted and fed conditions, supporting a clinical dose that yields an AUC equivalent to tramiprosate 150 mg BID. Improved intersubject PK variability and gastrointestinal toleration were observed. PK/PD analyses indicate that ALZ-801, at 265 mg BID, achieved target human brain exposure of tramiprosate three orders of magnitude higher than soluble Aβ42 levels.
CONCLUSIONS: We established a 265 mg clinical dose of ALZ-801 that produces an exposure of tramiprosate bioequivalent to the 150 mg dose in tramiprosate Phase 3 studies. This dose is projected to achieve steady-state brain drug levels that block toxic Aβ oligomer formation and amyloid aggregation, and will be evaluated in a confirmatory study in APOE4/4 homozygous AD subjects.