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Pridopidine

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Not to be confused with Prodipine.

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).

Pridopidine
Identifiers
  • 4-(3-methylsulfonylphenyl)-1-propylpiperidine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.240.998 Edit this at Wikidata
Chemical and physical data
FormulaC15H23NO2S
Molar mass281.41 g·mol−1
3D model (JSmol)
  • CCCN1CCC(CC1)C2=CC(=CC=C2)S(=O)(=O)C
  • InChI=1S/C15H23NO2S/c1-3-9-16-10-7-13(8-11-16)14-5-4-6-15(12-14)19(2,17)18/h4-6,12-13H,3,7-11H2,1-2H3
  • Key:YGKUEOZJFIXDGI-UHFFFAOYSA-N

Mechanism of action

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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-vivo positron emission tomography (PET) imaging studies in rats and human.[12][13]

Potential indications

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Huntington's disease (HD)

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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

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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).

References

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  1. ^ a b Ionescu A, Gradus T, Altman T, Maimon R, Saraf Avraham N, Geva M, et al. (March 2019). "Targeting the Sigma-1 Receptor via Pridopidine Ameliorates Central Features of ALS Pathology in a SOD1G93A Model". Cell Death & Disease. 10 (3): 210. doi:10.1038/s41419-019-1451-2. PMC 6397200. PMID 30824685.
  2. ^ Geva M, Gershoni-Emek N, Naia L, Ly P, Mota S, Rego AC, et al. (November 2021). "Neuroprotection of retinal ganglion cells by the sigma-1 receptor agonist pridopidine in models of experimental glaucoma". Scientific Reports. 11 (1): 21975. Bibcode:2021NatSR..1121975G. doi:10.1038/s41598-021-01077-w. PMC 8578336. PMID 34753986.
  3. ^ Francardo V, Geva M, Bez F, Denis Q, Steiner L, Hayden MR, et al. (April 2019). "Pridopidine Induces Functional Neurorestoration Via the Sigma-1 Receptor in a Mouse Model of Parkinson's Disease". Neurotherapeutics. 16 (2): 465–479. doi:10.1007/s13311-018-00699-9. PMC 6554374. PMID 30756361.
  4. ^ Eddings CR, Arbez N, Akimov S, Geva M, Hayden MR, Ross CA (September 2019). "Pridopidine protects neurons from mutant-huntingtin toxicity via the sigma-1 receptor". Neurobiology of Disease. 129: 118–129. doi:10.1016/j.nbd.2019.05.009. PMC 6996243. PMID 31108174.
  5. ^ Smith-Dijak AI, Nassrallah WB, Zhang LY, Geva M, Hayden MR, Raymond LA (2019). "Impairment and Restoration of Homeostatic Plasticity in Cultured Cortical Neurons From a Mouse Model of Huntington Disease". Frontiers in Cellular Neuroscience. 13: 209. doi:10.3389/fncel.2019.00209. PMC 6532531. PMID 31156395.
  6. ^ Naia L, Ly P, Mota SI, Lopes C, Maranga C, Coelho P, et al. (April 2021). "The Sigma-1 Receptor Mediates Pridopidine Rescue of Mitochondrial Function in Huntington Disease Models". Neurotherapeutics. 18 (2): 1017–1038. doi:10.1007/s13311-021-01022-9. PMC 8423985. PMID 33797036.
  7. ^ Ryskamp D, Wu J, Geva M, Kusko R, Grossman I, Hayden M, et al. (January 2017). "The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease". Neurobiology of Disease. 97 (Pt A): 46–59. doi:10.1016/j.nbd.2016.10.006. PMC 5214572. PMID 27818324.
  8. ^ Ryskamp D, Wu L, Wu J, Kim D, Rammes G, Geva M, et al. (April 2019). "Pridopidine stabilizes mushroom spines in mouse models of Alzheimer's disease by acting on the sigma-1 receptor". Neurobiology of Disease. 124: 489–504. doi:10.1016/j.nbd.2018.12.022. PMC 6363865. PMID 30594810.
  9. ^ Shenkman M, Geva M, Gershoni-Emek N, Hayden MR, Lederkremer GZ (July 2021). "Pridopidine reduces mutant huntingtin-induced endoplasmic reticulum stress by modulation of the Sigma-1 receptor". Journal of Neurochemistry. 158 (2): 467–481. doi:10.1111/jnc.15366. PMID 33871049. S2CID 233300408.
  10. ^ Geva M, Kusko R, Soares H, Fowler KD, Birnberg T, Barash S, et al. (September 2016). "Pridopidine activates neuroprotective pathways impaired in Huntington Disease". Human Molecular Genetics. 25 (18): 3975–3987. doi:10.1093/hmg/ddw238. PMC 5291233. PMID 27466197.
  11. ^ Johnston TH, Geva M, Steiner L, Orbach A, Papapetropoulos S, Savola JM, et al. (May 2019). "Pridopidine, a clinic-ready compound, reduces 3,4-dihydroxyphenylalanine-induced dyskinesia in Parkinsonian macaques". Movement Disorders. 34 (5): 708–716. doi:10.1002/mds.27565. PMID 30575996. S2CID 58587757.
  12. ^ Grachev ID, Meyer PM, Becker GA, Bronzel M, Marsteller D, Pastino G, et al. (April 2021). "Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [18F] fluspidine and [18F] fallypride PET study". European Journal of Nuclear Medicine and Molecular Imaging. 48 (4): 1103–1115. doi:10.1007/s00259-020-05030-3. PMC 8041674. PMID 32995944.
  13. ^ Sahlholm K, Sijbesma JW, Maas B, Kwizera C, Marcellino D, Ramakrishnan NK, et al. (September 2015). "Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses". Psychopharmacology. 232 (18): 3443–3453. doi:10.1007/s00213-015-3997-8. PMC 4537502. PMID 26159455.
  14. ^ McColgan P, Tabrizi SJ (January 2018). "Huntington's disease: a clinical review". European Journal of Neurology. 25 (1): 24–34. doi:10.1111/ene.13413. PMID 28817209. S2CID 24764480.
  15. ^ "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. PMID 8458085. S2CID 802885.
  16. ^ 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. PMID 8684382. S2CID 45982731.
  17. ^ "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.
  18. ^ a b Asla MM, Nawar AA, Abdelsalam A, Elsayed E, Rizk MA, Hussein MA, et al. (January 2022). "The Efficacy and Safety of Pridopidine on Treatment of Patients with Huntington's Disease: A Systematic Review and Meta-Analysis". Movement Disorders Clinical Practice. 9 (1): 20–30. doi:10.1002/mdc3.13357. PMC 8721839. PMID 35005061.
  19. ^ a b Verma A (2021-07-25). "Clinical Manifestation and Management of Amyotrophic Lateral Sclerosis". In Araki T (ed.). Amyotrophic Lateral Sclerosis. Exon Publications. pp. 1–14. doi:10.36255/exonpublications.amyotrophiclateralsclerosis.management.2021. ISBN 978-0-645-00177-8. PMID 34473441. S2CID 237727438.
  20. ^ "Sean M. Healey & AMG Center for ALS at Mass General launches first ALS Platform Trial with 5 promising drugs". Massachusetts General Hospital. Retrieved 2021-12-06.
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