An Intermediate-Size Expanded Access Protocol for Amyotrophic Lateral Sclerosis with Pridopidine

The Sigma 1 Receptor (S1R) has emerged as an attractive therapeutic target in ALS. Mutations in the S1R are causative of ALS and the degree of loss of function in S1R protein determines age of onset. S1R knock-down exacerbates phenotypes in ALS mouse models, and S1R activation impacts pathways that are known to be implicated in ALS, i.e., nucleocytoplasmic transport, protein quality control, endoplasmic reticulum (ER) stress, mitochondrial function, and autophagy. Riluzole, edaravone, and PB-TURSO, the current standard-of-care medications for ALS in the US, offer only modest clinical benefit and are not known to act through the S1R. Nuedexta, a non-selective S1R agonist, is approved for the treatment of pseudobulbar affect and has been shown to improve bulbar function in a subset of people living with ALS. Pridopidine (Prilenia Therapeutics) is a potent and highly selective small molecule S1R agonist. The S1R shows high expression throughout the brain, particularly in brainstem motor nuclei. In the G93A SOD1 ALS mouse model, pridopidine modified disease progression. The safety and efficacy of pridopidine are currently being tested inthe HEALEY ALS Platform Trial. The trial design includes an efficacy randomized controlled trial (RCT) followed by an open label extension (OLE). The RCT portion of the pridopidine regimen enrolled 162 ALS participants. While it did not reach the primary endpoint, it showed trends toward beneficial effects of pridopidine on several outcome measures, with the greatest identifiable effect on functional scores, quantitative motor speech, and neurofilament light levels in early and faster progressing participants. The OLE is ongoing. A second efficacy trial targeting a selected population of people with ALS is being planned. Unfortunately, a large segment of the real-world ALS population won’t be eligible to enroll in this second efficacy study due to the restrictive eligibility criteria. The current proposal is an expanded access protocol (EAP) of pridopidine in 200 individuals with ALS who are ineligible for clinical trials. Participants would receive pridopidine for up to 24 months, while the OLE and the planned second efficacy trial are ongoing. This study will provide real- world data by evaluating the effects of the drug in a population that is broader than the one included in the efficacy trials and by collecting safety, clinical, and biological outcomes over longer term exposure.