Critical appraisal of the role of davunetide in the treatment of progressive supranuclear palsy

Abstract

Michael Gold1, Stefan Lorenzl2, Alistair J Stewart1, Bruce H Morimoto1, David R Williams3, Illana Gozes1,41Allon Therapeutics Inc, Vancouver, BC, Canada; 2Interdisciplinary Center for Palliative Medicine, Munich University Hospital Klinikum Grosshadern, Munich, Germany; 3Van Cleef/Roet Centre for Nervous Diseases, Monash University, Melbourne, Australia; 4The Dr Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology, The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Adams Super Center for Brain Studies, and the Department of Human Molecular Genetics and Biochemistry, School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelAbstract: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of tau protein aggregates in the basal ganglia, brainstem and cerebral cortex leading to rapid disease progression and death. The neurofibrillary tangles that define the neuropathology of PSP are comprised of aggregated 4R tau and show a well-defined distribution. Classically, PSP is diagnosed by symptoms that include progressive gait disturbance, early falls, vertical ophthalmoparesis, akinetic-rigid features, prominent bulbar dysfunction and fronto-subcortical dementia. There are currently no effective therapies for the treatment of this rapidly degenerating and debilitating disease. Davunetide is a novel neuroprotective peptide that is thought to impact neuronal integrity and cell survival through the stabilization of microtubules. Preclinical activity in models of tauopathy has been translated to clinical studies, demonstrating pharmacologic activity that has supported further development. Davunetide's efficacy and tolerability are being tested in a placebo-controlled study in PSP patients, making it the most advanced drug candidate in this indication. This review examines the disease characteristics of PSP, the rationale for treating PSP with davunetide and assesses some of the challenges of clinical trials in this patient population.Keywords: tau protein aggregates, neurodegenerative, neurofibrillary tangles