Pridopidine

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Pridopidine
Pridopidine.svg
Identifiers
CAS number 346688-38-8 YesY
PubChem 9795739
ChemSpider 7971505
UNII HD4TW8S2VK YesY
KEGG D09953
Jmol-3D images Image 1
Properties
Molecular formula C15H23NO2S
Molar mass 281.41 g mol−1
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 YesY (verify) (what is: YesY/N?)
Infobox references

Pridopidine (Huntexil, formerly ACR16) is an experimental drug candidate belonging to a class of agents known as dopidines, which act as dopaminergic stabilizers in the central nervous system. These compounds may counteract the effects of excessive or insufficient dopaminergic transmission,[1][2] and are therefore under investigation for application in neurological and psychiatric disorders characterized by altered dopaminergic transmission, such as Huntington's disease (HD).

Pridopidine is in late-stage development by NeuroSearch A/S, Ballerup, Denmark as a treatment for HD. In April 2010, NeuroSearch announced results from the largest European phase 3 study in HD carried out to date (MermaiHD). The MermaiHD study examined the effects of pridopidine in patients with HD and the results showed after six months of treatment, pridopidine improved total motor symptoms, although the primary endpoint of the study was not met. Pridopidine was well tolerated and had an adverse event profile similar to placebo.[3]

The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have both indicated they will not issue approval for pridopidine to be used in human patients on the basis of the MermaiHD and HART trials, and a further, positive phase 3 trial is required for approval.[4][5]

Dopidines[edit]

Dopidines, a new class of pharmaceutical compounds, act as dopaminergic stabilizers, enhancing or counteracting dopaminergic effects in the central nervous system.[1][2] They have a dual mechanism of action, displaying functional antagonism of subcortical dopamine type 2 (D2) receptors, as well as strengthening of cortical glutamate and dopamine transmission.[6] Dopidines are, therefore, able to regulate both hypoactive and hyperactive functioning in areas of the brain that receive dopaminergic input (i.e. cortical and subcortical regions). This potential ability to restore the cortical–subcortical circuitry to normal suggests dopidines may have the potential to improve symptoms associated with several neurological and psychiatric disorders, including HD.

Pharmacology[edit]

In vitro studies demonstrate pridopidine exerts its effects by functional antagonism of D2 receptors. However, pridopidine possesses a number of characteristics[1][2][6][7] that differentiate it from traditional D2 receptor antagonists (agents that block receptor responses).

  • Lower affinity for D2 receptors than traditional D2 ligands[8]
  • Preferential binding to activated D2 (D2high) receptors (i.e. dopamine-bound D2 receptors)[8]
  • Rapid dissociation (fast ‘off-rate’) from D2 receptors
  • D2 receptor antagonism that is surmountable by dopamine
  • Rapid recovery of D2-receptor-mediated responses after washout[1][2][6][7]

Pridopidine is less likely to produce extrapyramidal symptoms, such as akinesia (inability to initiate movement) and akathisia (inability to remain motionless), than dopamine antagonists (such as antipsychotics).[9] Furthermore, pridopidine displays no detectable intrinsic activity,[9][10] differentiating it from D2 receptor agonists and partial agonists (agents that stimulate receptor responses). Pridopidine, therefore, differs from D2 receptor antagonists, agonists and partial agonists.[6]

As a dopaminergic stabilizer, pridopidine can be considered to be a dual-acting agent, displaying functional antagonism of subcortical dopaminergic transmission and strengthening of cortical glutamate transmission.

Clinical development[edit]

The MermaiHD study[edit]

In 2009, NeuroSearch completed the largest European HD trial to date, the Multinational EuRopean Multicentre ACR16 study In Huntington’s Disease (MermaiHD) study.

This six-month, phase 3, randomized, double-blind, placebo-controlled trial recruited patients from Austria, Belgium, France, Germany, Italy, Portugal, Spain and the UK, and compared two different pridopidine dose regimens with placebo. Patients were randomly allocated to receive pridopidine (45 mg once daily or 45 mg twice daily) or placebo. During weeks 1–4, patients received once-daily treatment (as a morning dose). Thereafter, patients took two doses (one morning and one afternoon dose) until the end of the treatment period. The study had a target recruitment of 420 patients; recruitment was finalized in April 2009 with 437 patients enrolled.[14]

The purpose of the study was to assess the effects of pridopidine on a specific subset of HD motor symptoms defined in the modified motor score (mMS).[14] The mMS comprises 10 items relating to voluntary motor function from the Unified Huntington’s Disease Rating Scale Total Motor Score (UHDRS—TMS).[14] Other study endpoints included the UHDRS—TMS, submotor items, cognitive function, behaviour and symptoms of depression and anxiety.

After six months of treatment, patients who received pridopidine 45 mg twice daily showed significant improvements in motor function, as measured by the UHDRS-TMS, compared with placebo. For the mMS, which was the primary endpoint of the study, a strong trend in treatment effect was seen, although statistical significance was not reached. Pridopidine was also very well tolerated, had an adverse event profile similar to placebo and gave no indication of treatment-associated worsening of symptoms.[3]

The MermaiHD study – open-label extension[edit]

Patients who completed the six-month, randomized phase of the MermaiHD study could choose to enter the MermaiHD open-label extension study and receive pridopidine 45 mg twice daily for six months. In total, 357 patients were enrolled into the MermaiHD open-label extension study and of these, 305 patients completed the entire 12-month treatment period.[15]

The objective of this study was to evaluate the long-term safety and tolerability profile of pridopidine and to collect efficacy data after a 12-month treatment period to support the safety evaluation. Safety and tolerability assessments included the incidence and severity of adverse events, routine laboratory parameters, vital signs and electrocardiogram measurements.[15]

Results from the MermaiHD open-label extension study showed treatment with pridopidine for up to 12 months (up to 45 mg twice daily for the first six months; 45 mg twice daily for the last six months) was well tolerated and demonstrated a good safety profile.[3][15]

The HART study[edit]

In October 2010, NeuroSearch reported results from their three-month, phase 2b, randomized, double-blind, placebo-controlled study carried out in Canada and the USA – Huntington’s disease ACR16 Randomized Trial (HART). This study was conducted in 28 centres and enrolled a total of 227 patients, who were randomly allocated to receive pridopidine 10 mg, 22.5 mg or 45 mg twice daily) or placebo.[14][16] During weeks 1–4, patients received once-daily treatment (as a morning dose). Thereafter, patients took two treatment doses (one morning and one afternoon dose) until the end of the treatment period. Study endpoints were the same as those for the MermaiHD study.

Results from the HART study were consistent with findings from the larger MermaiHD study. After 12 weeks of treatment with pridopidine 45 mg twice daily, total motor function significantly improved, as measured by the UHDRS–TMS. The primary endpoint, improvement in the mMS, was not met.[16]

In both studies, the effects on the UHDRS–TMS and the mMS were driven by significant improvements in motor symptoms such as gait and balance, and hand movements, deemed by the authors to be "clinically relevant". However, the magnitude of the improvements was small. Pridopdiine demonstrated a favourable tolerability and safety profile, including no observations of treatment-related disadvantages in terms of worsening of other disease signs or symptoms.[15][16]

Compassionate use programme and open-ended, open-label study[edit]

To meet requests from patients and healthcare professionals for continued treatment with pridopidine, NeuroSearch has established a compassionate use programme in Europe to ensure continued access to pridopidine for patients who have completed treatment in the MermaiHD open-label extension study. The programme is active in all of the eight European countries where the MermaiHD study was conducted.

NeuroSearch has initiated an open-ended, open-label clinical study in the USA and Canada, called the Open HART study. In this study, all patients who have completed treatment in the HART study are offered the chance to restart treatment with pridopidine until either marketing approval has been obtained in the countries in question, or the drug's development is discontinued. The first patients were enrolled in March 2011.[3]

Regulatory agency advice[edit]

The results of the MermaiHD and HART trials were presented to the American and European regulatory agencies: the FDA in March 2011 and EMA in May, 2011. Both agencies indicated insufficient evidence had been produced to allow approval in human patients, and a further phase 3 trial would be required for approval.[4][5]

See also[edit]

References[edit]

  1. ^ a b c d Seeman P, Tokita K, Matsumoto M, Matsuo A, Sasamata M, Miyata K (October 2009). "The dopaminergic stabilizer ASP2314/ACR16 selectively interacts with D2(High) receptors". Synapse 63 (10): 930–4. doi:10.1002/syn.20663. PMID 19588469. 
  2. ^ a b c d Rung JP, Rung E, Helgeson L, et al. (June 2008). "Effects of (-)-OSU6162 and ACR16 on motor activity in rats, indicating a unique mechanism of dopaminergic stabilization". Journal of Neural Transmission 115 (6): 899–908. doi:10.1007/s00702-008-0038-3. PMID 18351286. 
  3. ^ a b c d "NeuroSearch A/S announces the results of additional assessment and analysis of data from the Phase III MermaiHD study with Huntexil® in Huntington's disease" (Press release). NeuroSearch. 28 April 2010. Retrieved 2010-04-28. 
  4. ^ a b "NeuroSearch press releases (dated 23.03.2011 and 24.05.2011)". NeuroSearch. Retrieved 11 December 2011. 
  5. ^ a b "Huntexil update: EMA asks for further trial". HDBuzz. Retrieved 11 December 2011. 
  6. ^ a b c d e f g Ponten, H.; Kullingsjö, J.; Lagerkvist, S.; Martin, P.; Pettersson, F.; Sonesson, C.; Waters, S.; Waters, N. (2003-11-19) [2000-12-22]. "In vivo pharmacology of the dopaminergic stabilizer pridopidine". European Journal of Pharmacology. 644 (1-3) (1–3): 88–95. doi:10.1016/j.ejphar.2010.07.023. PMID 20667452. 
  7. ^ a b Dyhring T; Nielsen EØ; Sonesson C; et al. (February 2010). "The dopaminergic stabilizers pridopidine (ACR16) and (-)-OSU6162 display dopamine D(2) receptor antagonism and fast receptor dissociation properties". European Journal of Pharmacology 628 (1–3): 19–26. doi:10.1016/j.ejphar.2009.11.025. PMID 19919834. 
  8. ^ a b Pettersson, F; Pontén, H; Waters N; Waters S; Sonesson C (March 2010). "Synthesis and Evaluation of a Set of 4-Phenylpiperidines and 4-Phenylpiperazines as D2 Receptor Ligands and the Discovery of the Dopaminergic Stabilizer 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine (Pridopidine; ACR16)". Journal of Medicinal Chemistry 53 (6): 2510–2520. doi:10.1021/jm901689v. PMID 20155917. 
  9. ^ a b c Natesan S; Svensson KA; Reckless GE; et al. (August 2006). "The dopamine stabilizers (S)-(-)-(3-methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-methanesulfonylphenyl)-1-propyl-piperidine (ACR16) show high in vivo D2 receptor occupancy, antipsychotic-like efficacy, and low potential for motor side effects in the rat". The Journal of Pharmacology and Experimental Therapeutics 318 (2): 810–8. doi:10.1124/jpet.106.102905. PMID 16648369. 
  10. ^ Tadori Y; Forbes RA; McQuade RD; Kikuchi T (November 2008). "Characterization of aripiprazole partial agonist activity at human dopamine D3 receptors". European Journal of Pharmacology 597 (1–3): 27–33. doi:10.1016/j.ejphar.2008.09.008. PMID 18831971. 
  11. ^ Rung JP, Carlsson A, Markinhuhta KR, Carlsson ML (June 2005). "The dopaminergic stabilizers (-)-OSU6162 and ACR16 reverse (+)-MK-801-induced social withdrawal in rats". Progress in Neuro-psychopharmacology & Biological Psychiatry 29 (5): 833–9. doi:10.1016/j.pnpbp.2005.03.003. PMID 15913873. 
  12. ^ Nilsson M; Carlsson A; Markinhuhta KR; et al. (July 2004). "The dopaminergic stabiliser ACR16 counteracts the behavioural primitivization induced by the NMDA receptor antagonist MK-801 in mice: implications for cognition". Progress in Neuro-psychopharmacology & Biological Psychiatry 28 (4): 677–85. doi:10.1016/j.pnpbp.2004.05.004. PMID 15276693. 
  13. ^ Pettersson F, Waters N, Waters ES, Carlsson A, Sonesson C (November 7, 2002). "The development of a new class of dopamine stabilizers". Society for Neuroscience Annual Conference. Orlando, FL. 
  14. ^ a b c d Tedroff, J.; Krogh, P. Lindskov; Buusman, A.; Rembratt, Å. (2010). "Poster 20: Pridopidine (ACR16) in Huntington's Disease: An Update on the MermaiHD and HART Studies". Neurotherapeutics 7: 144. doi:10.1016/j.nurt.2009.10.004. 
  15. ^ a b c d "NeuroSearch announces results from an open-label safety extension to the Phase III MermaiHD study of Huntexil® in patients with Huntington's disease" (Press release). NeuroSearch. 15 September 2010. Retrieved 2010-09-15. 
  16. ^ a b c "The HART study with Huntexil® shows significant effect on total motor function in patients with Huntington's disease although it did not meet the primary endpoint after 12 weeks of treatment" (Press release). NeuroSearch. 14 October 2010. Retrieved 2010-10-14.