J11 Pridopidine exerts beneficial effects in preclinical models and in clinical trials via activation of the sigma-1 receptor, in a biphasic manner. (12th September 2022)

• Record Type: Journal Article
• Authors: Geva, Michal; Abdulhayoglu, Deniz Akinc; Wang, Shao-Ming; Gershoni-Emek, Noga; Boulanger, Bruno; Goldberg, Y Paul; Su, Tsung-Ping; Hayden, Michael R
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 93(2022)Supplement 1
• Page Start: A98
• Page End: A98
• Publication Date: 2022-09-12
• Subjects: pridopidine -- biomarkers -- neurofilament -- total functional capacity -- sigma-1 receptor; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2022-ehdn.261
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : Background: Pridopidine is a selective, potent Sigma-1 Receptor (S1R) agonist in clinical development for HD and ALS. S1R agonists enhance neuroprotective pathways in a biphasic manner, demonstrated in numerous preclinical and clinical studies. Results: Pridopidine demonstrates the biphasic dose response typical of S1R agonists in preclinical HD models. It increases BDNF secretion, rescues mitochondrial function and increases synaptic plasticity with maximal effect at 1μM. Higher and lower concentrations show diminished effect. Pridopidine also demonstrates a biphasic dose response in clinical trials. The PRIDE-HD 52-week Ph2 trial evaluated pridopidine 45, 67.5, 90 and 112.5 mg bid in HD patients. Increased levels of neurofilament light chain (NfL) indicate neuronal injury and serve as a biomarker correlating with longitudinal decline in Total Functional Capacity (TFC). Post-hoc analysis examined the effect of pridopidine on plasma NfL, and its association with TFC in early HD (TFC 7-13). 45 mg bid shows highest efficacy for TFC maintenance ΔTFC +0.09 vs -1.0, placebo, (p=0.0006). Combined higher doses were less efficacious (ΔTFC -0.55, p=0.002). 45 mg bid was most efficacious showing stabilization of plasma NfL levels (ΔNfL -0.06 log2pg/ml, n=31). Higher doses show less effect (ΔNfL -0.009 log2pg/ml, n=82). We used S1R-BiP dissociation and S1R oligomerization assays to assess pridopidine's biphasic response. S1R agonists facilitate S1R-BiP dissociation, freeing S1R to act on different targets. Pridopidine causes S1R-BiP dissociation in a biphasic manner with maximal effect at 1μM. Conclusions: Pridopidine's effect on plasma NfL levels associates with TFC and adheres to classic S1R agonist biphasic dose response.