Pridopidine (also known as 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
Names
IUPAC name
4-(3-(Methylsulfonyl)phenyl)-1-propylpiperidine
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.240.998
KEGG
UNII
  • 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 ☒N
    Key: YGKUEOZJFIXDGI-UHFFFAOYSA-N ☒N
  • InChI=1/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-UHFFFAOYAQ
  • CS(C1=CC=CC(C2CCN(CCC)CC2)=C1)(=O)=O
Properties
C15H23NO2S
Molar mass 281.41 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

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][11] 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.[12] 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.[13][14]

Pridopidine for 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.[15] 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.[16]

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.[17][18]

In the phase 2, dose finding PRIDE-HD trial, pridopidine 45 mg bid showed a beneficial effect maintaining functional capacity at one year, as measured by the Unified Huntington’s Disease Rating Scale (UHDRS) Total Functional Capacity (TFC).[19] The TFC scale assesses the patient’s ability to perform daily activities. It is a widely validated and regulatory accepted scale to measure clinical disease stage and progression.[17] Pridopidine’s effect on TFC is potentially durable for up to 5 years.[20]

Human PET imaging studies show that pridopidine dose of 45 mg bid (the clinically relevant dose) has selective and robust target engagement of the S1R in the human brain.[13] Extensive safety data indicate this dose has a favorable safety and tolerability profile.

PROOF-HD (Pridopidine’s Outcome On Function in HD) is a global, multicenter, randomized, double-blind placebo-controlled Phase 3 trial evaluating  the effect of pridopidine 45 mg taken twice daily on TFC in patients with early-stage HD (PROOF-HD trial, NCT04556656). This study is ongoing. 499 early HD patients have been enrolled across 59 sites in North America and Europe. Topline data for the PROOF-HD trial are expected by the end of Q1 2023.

Pridopidine for ALS

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 the booklosing the ability to speak, eat, move and eventually breathe.[21]

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 [21]−,[22] 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

  1. 1 2 Ionescu, Ariel; Gradus, Tal; Altman, Topaz; Maimon, Roy; Saraf Avraham, Noi; Geva, Michal; Hayden, Michael; Perlson, Eran (2019-03-01). "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. ISSN 2041-4889. PMC 6397200. PMID 30824685.
  2. ↑ Geva, Michal; Gershoni-Emek, Noga; Naia, Luana; Ly, Philip; Mota, Sandra; Rego, Ana Cristina; Hayden, Michael R.; Levin, Leonard A. (2021-11-09). "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. ISSN 2045-2322. PMC 8578336. PMID 34753986.
  3. ↑ Francardo, Veronica; Geva, Michal; Bez, Francesco; Denis, Quentin; Steiner, Lilach; Hayden, Michael R.; Cenci, M. Angela (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. ISSN 1878-7479. PMC 6554374. PMID 30756361.
  4. ↑ Eddings, Chelsy R.; Arbez, Nicolas; Akimov, Sergey; Geva, Michal; Hayden, Michael R.; Ross, Christopher A. (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. ISSN 1095-953X. PMC 6996243. PMID 31108174.
  5. ↑ Smith-Dijak, Amy I.; Nassrallah, Wissam B.; Zhang, Lily Y. J.; Geva, Michal; Hayden, Michael R.; Raymond, Lynn A. (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. ISSN 1662-5102. PMC 6532531. PMID 31156395.
  6. ↑ Naia, Luana; Ly, Philip; Mota, Sandra I.; Lopes, Carla; Maranga, Carina; Coelho, Patrícia; Gershoni-Emek, Noga; Ankarcrona, Maria; Geva, Michal; Hayden, Michael R.; Rego, A. Cristina (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. ISSN 1878-7479. PMC 8423985. PMID 33797036.
  7. ↑ Ryskamp, Daniel; Wu, Jun; Geva, Michal; Kusko, Rebecca; Grossman, Iris; Hayden, Michael; Bezprozvanny, Ilya (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. ISSN 1095-953X. PMC 5214572. PMID 27818324.
  8. ↑ Ryskamp, Daniel; Wu, Lili; Wu, Jun; Kim, Dabin; Rammes, Gerhard; Geva, Michal; Hayden, Michael; Bezprozvanny, Ilya (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. ISSN 1095-953X. PMC 6363865. PMID 30594810.
  9. ↑ Shenkman, Marina; Geva, Michal; Gershoni-Emek, Noga; Hayden, Michael R.; Lederkremer, Gerardo Z. (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. ISSN 1471-4159. PMID 33871049. S2CID 233300408.
  10. ↑ Geva, Michal; Kusko, Rebecca; Soares, Holly; Fowler, Kevin D.; Birnberg, Tal; Barash, Steve; -Wagner, Avia Merenlender; Fine, Tania; Lysaght, Andrew; Weiner, Brian; Cha, Yoonjeong (2016-07-27). "Pridopidine activates neuroprotective pathways impaired in Huntington Disease". Human Molecular Genetics. 25 (18): 3975–3987. doi:10.1093/hmg/ddw238. ISSN 0964-6906. PMC 5291233. PMID 27466197.
  11. ↑ Geva, Michal; Kusko, Rebecca; Soares, Holly; Fowler, Kevin D.; Birnberg, Tal; Barash, Steve; -Wagner, Avia Merenlender; Fine, Tania; Lysaght, Andrew; Weiner, Brian; Cha, Yoonjeong (2016-09-15). "Pridopidine activates neuroprotective pathways impaired in Huntington Disease". Human Molecular Genetics. 25 (18): 3975–3987. doi:10.1093/hmg/ddw238. ISSN 0964-6906. PMC 5291233. PMID 27466197.
  12. ↑ Johnston, Tom H.; Geva, Michal; Steiner, Lilach; Orbach, Aric; Papapetropoulos, Spyros; Savola, Juha-Matti; Reynolds, Ian J.; Ravenscroft, Paula; Hill, Michael; Fox, Susan H.; Brotchie, Jonathan M. (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. ISSN 1531-8257. PMID 30575996. S2CID 58587757.
  13. 1 2 Grachev, Igor D.; Meyer, Philipp M.; Becker, Georg A.; Bronzel, Marcus; Marsteller, Doug; Pastino, Gina; Voges, Ole; Rabinovich, Laura; Knebel, Helena; Zientek, Franziska; Rullmann, Michael (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. ISSN 1619-7089. PMC 8041674. PMID 32995944.
  14. ↑ Sahlholm, Kristoffer; Sijbesma, Jurgen W. A.; Maas, Bram; Kwizera, Chantal; Marcellino, Daniel; Ramakrishnan, Nisha K.; Dierckx, Rudi A. J. O.; Elsinga, Philip H.; van Waarde, Aren (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. ISSN 0033-3158. PMC 4537502. PMID 26159455.
  15. ↑ McColgan, P.; Tabrizi, S. J. (January 2018). "Huntington's disease: a clinical review". European Journal of Neurology. 25 (1): 24–34. doi:10.1111/ene.13413. ISSN 1468-1331. PMID 28817209. S2CID 24764480.
  16. ↑ "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. 1993-03-26. doi:10.1016/0092-8674(93)90585-e. hdl:2027.42/30901. ISSN 0092-8674. PMID 8458085. S2CID 802885.
  17. 1 2 "Unified Huntington's Disease Rating Scale: reliability and consistency. Huntington Study Group". Movement Disorders. 11 (2): 136–142. March 1996. doi:10.1002/mds.870110204. ISSN 0885-3185. PMID 8684382. S2CID 45982731.
  18. ↑ "The Voice of the Patient" (PDF). (Fda), U. S. F. A. D. A. March 2016.
  19. ↑ McGarry, Andrew; Leinonen, Mika; Kieburtz, Karl; Geva, Michal; Olanow, C. Warren; Hayden, Michael (2020). "Effects of Pridopidine on Functional Capacity in Early-Stage Participants from the PRIDE-HD Study". Journal of Huntington's Disease. 9 (4): 371–380. doi:10.3233/JHD-200440. ISSN 1879-6400. PMC 7836066. PMID 33164941.
  20. ↑ McGarry, Andrew; Auinger, Peggy; Kieburtz, Karl; Geva, Michal; Mehra, Munish; Abler, Victor; Grachev, Igor D.; Gordon, Mark Forrest; Savola, Juha-Matti; Gandhi, Sanjay; Papapetropoulos, Spyridon (2020). "Additional Safety and Exploratory Efficacy Data at 48 and 60 Months from Open-HART, an Open-Label Extension Study of Pridopidine in Huntington Disease". Journal of Huntington's Disease. 9 (2): 173–184. doi:10.3233/JHD-190393. ISSN 1879-6400. PMID 32508327. S2CID 219538544.
  21. 1 2 Ashok Verma, M. D. (2021-07-25). "Clinical Manifestation and Management of Amyotrophic Lateral Sclerosis". Amyotrophic Lateral Sclerosis. Exon Publications. pp. 1–14. doi:10.36255/exonpublications.amyotrophiclateralsclerosis.management.2021. ISBN 9780645001778. PMID 34473441. S2CID 237727438.
  22. ↑ "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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