Drug repurposing of Pirlindole for Multiple Sclerosis

MS is an immune-driven chronic inflammatory disease of the central nervous system (CNS) with varied clinical presentations and heterogeneous histopathological features. In MS, permanent neurological disability accumulates as the disease progresses; the inflammatory processes that underlie the early relapsing-remitting phenotype are gradually replaced by neurodegeneration, which manifests as neuronal and axonal loss and leads to accumulating neurological dysfunction. Neurodegeneration is a hallmark feature of primary and secondary progressive MS. 

Although immunosuppressive or immunomodulatory drugs provide a significant reduction in the rate of relapses (in the order of 30%-67%), they are associated with mild-to-often fatal adverse events, such as in the case of Natalizumab which induces Progressive Multifocal Leukoencephalopathy (PML), a rare, but life-threatening disease. This highlights the need for developing drugs that could tackle neuronal dysfunction in MS.

Based on in silico and animal model experiments, we sought to test our hypothesis that Pirlindole would reduce neuronal dysfunction in MS. In in vivo experiments using the MOG (Myelin Oligodendrocyte Glycoprotein)-induced Experimental Autoimmune Encephalomyelitis (EAE) murine model of progressive MS, pirlindole (BVA-201), at 30mg/kg (a pharmaceutically relevant dose) induced a sizeable improvement in disease progression, as represented by EAE severity clinical scores (Figure 1). Moreover, histological data showed that the drug’s MoA is not anti-inflammatory, but rather, pirlindole protects neuronal cells and myelin in a direct manner (Figure 2). The above data is supported by previous observations that Pirlindole acts not only as a MAO-A inhibitor, but is also involved in the reduction of oxidative stress and inhibition of lipid peroxidation. 

In terms of safety, Pirlindole exhibits a favorable pharmacokinetics and Adverse Event (AE) profile with only mild and transient AEs recorded from clinical trials and post-marketing surveillance. 

Overall, our observations lead to the validation of the hypothesis involving repositioning of pirlindole as a neuroprotectant in MS. The use of pirlindole in MS as a new indication is protected by international patent applications. The patent applications also cover administration in several different dose ranges, routes of administration, as well as a number of drug combinations.