J.A. Hey, P. Kocis, S. Abushakra, J. Yu , A. Power, K. Blennow, M. Tolar
OBJECTIVES: ALZ-801 is a prodrug of tramiprosate with improved pharmaceutical properties in development for treatment of Alzheimer’s disease (AD). Tramiprosate inhibits beta amyloid (Aβ) oligomer formation and neurotoxicity. In prior Phase 3 trials, oral tramiprosate demonstrated cognitive and functional efficacy in APOE4/4 homozygous AD patients (Abushakra 2016). We elucidated a novel multi-ligand enveloping stabilizing effect of tramiprosate on Aβ42, mediating its anti-aggregation activity (Kocis et al. 2017). To select the ALZ-801 dose for upcoming clinical trials, we performed an integrated analysis that links tramiprosate exposures in the brain and its clinical effects in prior trials, to the anti-Aβ effect. Bridging pharmacokinetic studies between tramiprosate and ALZ-801 are presented.
METHODS: Plasma and CSF concentrations of tramiprosate from the previous Phase 3 study were determined by LC-MS/MS. CSF Aß42 concentrations in AD patients, measured by ELISA, were used for PK/PD analyses. Steady-state brain drug levels were determined from brain/plasma ratio from preclinical studies. The pharmacokinetics (PK) of ALZ-801 was evaluated in elderly subjects in Phase 1 studies, and a dose of ALZ-801 that provides equivalent plasma exposures to tramiprosate dose of 150 mg BID was established.
RESULTS: The projected molar excess of tramiprosate versus Aß42 that yielded full inhibition of Aß42 oligomer formation in vitro was 1,000x. Projected steady state brain exposure at 150 mg BID effective dose was 130 nM, for a full anti-aggregation effect. The stoichiometry of tramiprosate-Aß42 interaction aligns with the projected brain PK and clinical efficacy, providing a clinical translation of the mechanism of action and necessary clinical dose. ALZ-801 administered as tablet demonstrated excellent PK with improved PK performance and gastrointestinal tolerability. PK/PD analyses show that ALZ-801, at 265 mg BID, will achieve brain exposure of tramiprosate required for full Aß42 anti-oligomerization effect.
CONCLUSIONS: Aβ oligomers are considered a key driver of synaptic dysfunction and toxicity in AD. The 265mg dose of ALZ-801 is projected to provide tramiprosate plasma exposure that is bioequivalent to the clinically effective dose in completed Phase 3 studies, and to fully inhibit Aß42 oligomer formation in the brain. This ALZ-801 dose will now be evaluated in an upcoming confirmatory pivotal program in APOE4/4 homozygous AD patients.