Navitoclax safety, tolerability, and effect on biomarkers of senescence and neurodegeneration in aged nonhuman primates
Edward F. Greenberg, Martin J. Voorbach, Alexandra Smith, David R. Reuter, Yuchuan Zhuang, Ji-Quan Wang, Dustin Wooten, Elizabeth Asque, Min Hu, Carolin Hoft, Ryan Duggan, Matthew Townsend, Karin Orsi, Karen Dalecki, Willi Amberg, Lori Duggan, Heather Knight, Joseph S. Spina, Yupeng He, Kennan C. Marsh, Vivian Zhao, Suzanne E. Ybarra, J Mollon, Y. K. Fang, Aparna Vasanthakumar, Susan V. Westmoreland, Mathias Droescher, Sjoerd J. Finnema, Hana Florian
Abstract
Alzheimer's disease (AD) is the most common global dementia and is universally fatal. Most late-stage AD disease-modifying therapies are intravenous and target amyloid beta (Aβ), with only modest effects on disease progression: there remains a high unmet need for convenient, safe, and effective therapeutics. Senescent cells (SC) and the senescence-associated secretory phenotype (SASP) drive AD pathology and increase with AD severity. Preclinical senolytic studies have shown improvements in neuroinflammation, tau, Aβ, and CNS damage; most were conducted in transgenic rodent models with uncertain human translational relevance. In this study, aged cynomolgus monkeys had significant elevation of biomarkers of senescence, SASP, and neurological damage. Intermittent treatment with the senolytic navitoclax induced modest reversible thrombocytopenia; no serious drug-related toxicity was noted. Navitoclax reduced several senescence and SASP biomarkers, with CSF concentrations sufficient for senolysis. Finally, navitoclax reduced TSPO-PET frontal cortex binding and showed trends of improvement in CSF biomarkers of neuroinflammation, neuronal damage, and synaptic dysfunction. Overall, navitoclax administration was safe and well tolerated in aged monkeys, inducing trends of biomarker changes relevant to human neurodegenerative disease.