Thursday, November 21, 2024
11/21/2024
SUMMARY/ABSTRACT 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 specialized 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 compounds. 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 lower the rate of brain atrophy in AD subjects. In this Phase II, proof-of-concept, rigorous translational clinical study, mild AD subjects will be randomized 2:1 and receive a slow up-titration regimen of siponimod up to 1 mg/day (N=70) or placebo (N=35) for 12 months, followed by a 6-month washout period. Primary objectives are drug safety and tolerability in AD subjects assessed via regular clinical tests throughout the dosing period. Critically, eventual treatment-emergent toxicities will drive our go/no-go decision process to pursue or stop dosing. The secondary objective is to determine drug effect on relative annual brain atrophy rates in the two groups by comparing pre- and post- exposure volumetric MRI data. Tertiary objectives are cognition and CSF markers of AD (amyloid, tau, p-tau) and inflammation. As an exploratory objective, we will also investigate whether blood cell counts and blood biomarkers can be used as dynamic surrogate markers of drug efficacy. Because siponimod has demonstrated positive immunomodulatory and neuroprotective actions in MS, and because its toxicity profile is favorable for use in older individuals, this drug has a strong potential to alter markers of AD pathology and disease trajectory.
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