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Pharmacological Management of Huntington’s Disease
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Sonia Sharma, Sushant Sharma, Shallina Gupta
Pridopidine is a new drug used to reduce involuntary movement in HD but its mechanism of action is not known till now (Dyhring et al., 2010). This drug is also known as “dopaminergic stabilizer” from the observation of animal studies where it increased locomotor activity (Ponten et al., 2010; Rung et al., 2005, 2008; Seeman et al., 2009). Sahlholm et al. (2013) suggested that pridopidine acts by sigma-1 receptors and this negate the “dopaminergic stabilizer” hypothesis.
Micronutrients for Improved Management of Huntington’s Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
In a randomized, double blind, placebo-controlled trial involving multicenter from 32 European countries, the efficacy of pridopidine, a dopaminergic stabilizer, was evaluated on motor function in patients with HD. The results showed that this drug did not affect non-motor endpoints, but some improvements in motor function were detected.175 The drug at the dose of 90 mg/day was considered safe. A similar study with pridopidine was performed utilizing outpatient’s neurological clinics at 27 sites in the USA and Canada on HD patients receiving 20 mg (N = 56), 45 mg (N = 55), 90 mg (N = 58), or placebo (N = 58) for a period of 12 weeks. The results showed that pridopidine treatment at a dose of 90 mg/day may improve some motor functions.176
Emerging drugs for the treatment of L-DOPA-induced dyskinesia: an update
Published in Expert Opinion on Emerging Drugs, 2020
Sohaila AlShimemeri, Susan H Fox, Naomi P Visanji
Pridopidine is a small molecule with a complex pharmacology exhibiting high affinity to sigma-1-receptor, as well as acting on multiple other receptors including adrenergic α2 C, dopamine D3, and serotoninergic 5-HT1A and lower affinity to dopamine D2, muscarinic M2, histamine H3, alpha2 receptors, and other serotoninergic receptors including 5-HT2A, and 5-HT7 [136]. Interestingly, using an Artificial Intelligence-based approach (IBM Watson), we previously found that pridopidine ranked in the top 1.6% of 3527 candidate compounds based on predicted anti-dyskinetic efficacy [137]. Originally developed for Huntington’s disease, pridopidine has been shown to reduce hyperactivity in models of elevated dopaminergic or decreased glutamatergic neurotransmission including in 6-OHDA-lesioned rats treated with L-DOPA [138]. Furthermore, we have recently shown that pridopidine can significantly reduce LID without affecting the antiparkinsonian benefit of L-Dopa in MPTP macaques [114]. Pridopidine is thought to exert its effect on reducing LID through a combination of effects at sigma‐1, adrenergic α2C and serotoninergic 5-HT1A receptors [114]. A phase II RDPCT to assess the safety and effectiveness of two doses of pridopidine, compared to placebo, in 135 PD patients with LID for 14 weeks is currently recruiting (NCT03922711) [139].
Emerging therapeutics in Huntington’s disease
Published in Expert Opinion on Emerging Drugs, 2021
Another large ongoing Phase 3 trial in HD, the PROOF- HD trial (NCT04556656) is examining the long-term effects of pridopidine over 65 weeks in patients with early HD. The primary outcome measure of the trial is change over 65 weeks in functional status as measured by the Unified Huntington Disease Rating Scale (UHDRS) – Total Functional Capacity (TFC). PROOF- HD plans to enroll 480 participants across 60 centers in the US, Canada and Europe [62]. Pridopidine is a potent and selective Sigma-1 receptor agonist and may be neuroprotective against mHTT in HD [63]. The Sigma- 1 receptor (S1R) regulates protein folding and degradation and is involved in several potential neuroprotective pathways including calcium homeostasis, neurotrophic factor secretion, neuronal plasticity, oxidative stress, and mitochondrial function. Initial investigation of pridopidine in HD focused on symptomatic therapy to improve motor symptoms through a potential mechanism involving dopamine modulation. MermaiHD and HART, both phase 3 trials, did not show a significant improvement in their primary outcome, the UHDRS modified motor score [64–66]. PRIDE-HD dosed patients with pridopidine up to 112.5 mg daily for 26 weeks but did not demonstrate a significant improvement in UHDRS Total Motor Scores [67]. Nonetheless, these large long-term trials demonstrated that pridopidine is very well tolerated over long period of time. With new insight into pridopidine’s high affinity S1R target, PRIDE-HD was extended to 52 weeks with Total Functional Capacity (TFC) as a primary endpoint. A post hoc analysis of patients with TFC between 7 and 13 showed that pridopidine 45 mg BID lessened TFC decline by 0.87 points over 52 weeks compared to placebo [68]. An open label extension of HART also suggested stabilization of TFC at 48 and 60 months with pridopine 45 mg BID [69]. These observations and data from prior trials have led to and informed the study design for the PROOF-HD trial.
Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders
Published in Expert Opinion on Drug Discovery, 2021
Taken together, these observations demonstrate that pridopidine has neuroprotective properties in preclinical models of neurodegeneration through S1R activation. It supports the idea that pridopidine is an attractive drug for the treatment of neurodegenerative disorders. These observations also further confirm that S1R activity is beneficial in different neurodegenerative processes.