PSP is characterized by abnormal tau inclusions and is consequently also known as a tauopathy. Similar to other neurodegenerative diseases, pathophysiologic changes underlying PSP are multifactorial with several genetic and environmental factors likely contributing to tau dysfunction and aggregation.4,5,7,8
Multiple pathways, including genetic mutations, endoplasmic reticulum (ER) stress and the activation of unfolded protein response, mitochondrial dysfunction, and neuroinflammation have been implicated as contributors to tau dysfunction and aggregation.4,6
Tau pathology in turn drives neurodegeneration in PSP. The precise mechanism by which tau pathology drives neurodegeneration is still unclear though two processes are thought to contribute:6,7,9
- Tau dysfunction leading to depolymerization of microtubules and axonal defects
- Pathologic aggregation of abnormal tau leading to the formation of neurofibrillary tangles and widespread neuronal cell death and neurodegeneration in PSP
AMX0035 is proposed to simultaneously mitigate ER stress and mitochondrial dysfunction and hence, has the potential to influence PSP pathophysiology. Additionally, there is preclinical and clinical evidence to support investigation of AMX0035 in PSP.
Based on strong scientific rationale supporting AMX0035 in progressive supranuclear palsy (PSP), we initiated ORION (NCT06122662), a global, pivotal, Phase 3 trial of AMX0035 for the treatment of PSP. ORION is a double-blinded, placebo controlled, clinical trial to assess the impact of AMX0035 compared to placebo on disease progression as measured by the Progressive Supranuclear Palsy Rating Scale (PSPRS).
The ORION Phase 3 trial was designed and planned in collaboration with key global academic leaders, people living with PSP, and advocacy groups.