Repurposing Siponimod for Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder with several complex neuropathologies suspected to develop sequentially but that overlap over time as symptoms progress to dementia. Thus, to be effective, future intervention strategies will likely require combination therapies or pleiotropic agents to tackle several AD molecular pathogenic pathways simultaneously. For more than a decade, our group has been exploring the repurposing of immunomodulators for AD. Recent discussions with collaborators who specialize in multiple sclerosis suggest that sphingosine-1-phosphate receptor (S1PR) modulators are strong candidates for repurposing in AD. Indeed, S1PR modulators are blood brain barrier (BBB) penetrant and display pleiotropic actions, including immunomodulation and neuroprotective properties. S1P is a versatile endogenous molecule that regulates several signaling pathways by binding to five G-protein-coupled receptors, which are expressed in high levels in cardiac, vascular, immune, and brain cells. This widespread localization of S1PR was the historical basis for Novartis Pharmaceuticals, Inc, to develop oral formulations of S1PR modulators for multiple sclerosis (MS), which proved successful and resulted in two marketed oral compounds (i.e., fingolimod and Siponimod). In the present project, we intend to collaborate with Novartis to use the most recently FDA-approved S1PR modulator, Siponimod. Based on MS and animal experimentation literature, we hypothesize that Siponimod could alter the rate of neurodegeneration as measured by lowering the rate of brain atrophy in mild AD dementia subjects. In this Phase II, proof-of-concept, translational clinical study, mild AD dementia subjects will be randomized 2:1 and will receive gradual titration regimen of Siponimod starting at 0.25mg/day and increasing up to final dosage of 1 mg/day (N=70) or placebo (N=35) for 12 months. This will be followed by a 6-month washout period. Siponimod has demonstrated positive immunomodulatory and neuroprotective actions in MS patients, and because its toxicity profile is favorable for use in older individuals, Siponimod has a strong potential to alter markers of mild AD dementia pathology and disease trajectory.