Pridopidine (developmental code name PL-101) is an orally administrated small molecule investigational drug. Pridopidine is a selective and potent Sigma-1 Receptor agonist. It is being developed by Prilenia Therapeutics and is currently in late-stage clinical development for Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS).
Mechanism of action
Pridopidine works by binding and activating an intracellular protein called the Sigma-1 receptor (S1R) located at the mitochondria-associated membrane (MAM) of the endoplasmic reticulum (ER). The S1R regulates key cellular processes crucial to neuronal health and survival. Selective activation of the S1R is a promising therapeutic target for treating neurodegenerative and neurodevelopmental disorders.
Pridopidine activation of the S1R demonstrates neuroprotective effects in numerous models of neurodegenerative diseases including HD, ALS, Glaucoma, Parkinson's disease (PD) and Alzheimer's disease (AD).[1][2][3]
Pridopidine exhibits a neuroprotective effect against mutant Huntingtin (mHTT)-induced cell death in mouse primary HD neurons and human HD iPSCs.[4] It restores the impaired synaptic plasticity in HD neurons,[5] enhances mitochondrial function,[6] upregulates BDNF transport and secretion, reduces ER stress and restores dendritic spine abnormalities in HD and AD models.[7][8][9][10] In models of ALS, pridopidine protects neuron-muscle connectivity and restores muscle integrity and contractility.[1] These beneficial effects are exclusively mediated by the S1R as either deletion of this gene, or selective inhibition of its function, completely abolish pridopidine's beneficial effects.
Initially, the primary target of pridopidine was postulated to be the dopamine D2/D3 receptors. However, in-vitro binding assays show that pridopidine has high affinity for the S1R and low affinity for other targets including the dopamine D2/D3 receptors, adrenergic a2C receptor and the Sigma-2 receptor.[11] Furthermore, selective and robust occupancy of the S1R, with no or negligible occupancy of the D2/D3 receptors was demonstrated by in-vivopositron emission tomography (PET) imaging studies in rats and human.[12][13]
Potential indications
Huntington's disease (HD)
HD is a progressive fatal neurodegenerative disease caused by a mutation in the Huntingtin gene (expanded CAG repeat >35). The disease is characterized by progressive motor abnormalities, cognitive decline, and psychiatric and behavioral symptoms.[14] Adult-onset HD usually begins between 35 and 45 years of age. Following onset, motor, cognitive and functional outcomes steadily decline over 15 to 20 years, ultimately leading to a state of profound incapacity and death. The disease is inherited in an autosomal dominant manner, and thus each child of a parent with HD has a 50% chance of inheriting the mutated HD gene.[15] For patients and their families, maintaining functional capacity is vital as it translates to a patient's ability to maintain their occupation, continue to manage their daily lives, and live independently.[16][17]
A meta-analysis of four randomized controlled trials (RCTs) involving 1,130 patients (816 in the pridopidine group and 314 in the placebo group) found that pridopidine led to a slight, though not statistically significant, improvement in overall motor symptoms, as measured by the Unified Huntington's Disease Rating Scale Total Motor Score, compared to placebo. However, the drug significantly improved voluntary movements, as indicated by the Modified Motor Score.[18] Pridopidine was generally well tolerated, with no significant differences in adverse events or serious adverse events compared to placebo. The findings suggest that pridopidine has potential for treating motor symptoms in HD, with a favorable safety profile, warranting further clinical trials to confirm its benefits.[18]
Amyotrophic lateral sclerosis
ALS is a devastating progressive fatal neurodegenerative disease characterized by upper and lower motor neuron degeneration. Over time this progressive loss of motor function leads to losing the ability to speak, eat, move and eventually breathe.[19]
In 2019, pridopidine was selected by the Sean M. Healey & AMG Center for ALS at the Massachusetts General Hospital as one of the first potential new innovative treatments to be evaluated in the first Platform Trial in ALS [19]−,[20] aimed to accelerate clinical trials in ALS. The first patient in the pridopidine regimen was enrolled in December 2020 (NCT04615923). The study will enroll 160 patients in each regimen with a 3:1 randomization (120 patients to be treated with pridopidine and 40 patients treated with placebo, daily for 24 weeks).
^"A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group". Cell. 72 (6): 971–983. March 1993. doi:10.1016/0092-8674(93)90585-e. hdl:2027.42/30901. PMID8458085. S2CID802885.
^Huntington Study Group (March 1996). "Unified Huntington's Disease Rating Scale: reliability and consistency. Huntington Study Group". Movement Disorders. 11 (2): 136–142. doi:10.1002/mds.870110204. PMID8684382. S2CID45982731.
^"Huntington's Disease"(PDF). Center for Drug Evaluation and Research (CDER). The Voice of the Patient: A series of reports from the FDA’s Patient-Focused Drug Development Initiative. U.S. Food and Drug Administration (FDA). March 2016. Archived from the original(PDF) on 16 March 2022.
