Research Article
An mGlu4-Positive Allosteric Modulator Alleviates Parkinsonism in Primates
Delphine Charvin PhD,
Therese Di Paolo PhD,
Erwan Bezard PhD,
Laurent Gregoire,
Akihiro Takano PhD,
Guillaume Duvey PhD,
Elsa Pioli PhD,
Christer Halldin PhD,
Rossella Medori MD, PhD,
François Conquet PhD,
Corresponding Author
Delphine Charvin PhD
Prexton Therapeutics SA, 1228 Plan-les-Ouates, Geneva, Switzerland
Correspondence to: Dr. Delphine Charvin, Prexton Therapeutics, 14 Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland; E-mail: [email protected]Search for more papers by this authorTherese Di Paolo PhD
Neuroscience Research Unit CHU de Québec, CHUL Pavillon and Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada
Search for more papers by this authorErwan Bezard PhD
Motac Neuroscience Ltd, Manchester, United Kingdom
Search for more papers by this authorLaurent Gregoire
Neuroscience Research Unit CHU de Québec, CHUL Pavillon and Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada
Search for more papers by this authorAkihiro Takano PhD
Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm, Sweden
Search for more papers by this authorGuillaume Duvey PhD
Prexton Therapeutics SA, 1228 Plan-les-Ouates, Geneva, Switzerland
Search for more papers by this authorElsa Pioli PhD
Motac Neuroscience Ltd, Manchester, United Kingdom
Search for more papers by this authorChrister Halldin PhD
Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm, Sweden
Search for more papers by this authorRossella Medori MD, PhD
Prexton Therapeutics SA, 1228 Plan-les-Ouates, Geneva, Switzerland
Search for more papers by this authorFrançois Conquet PhD
Prexton Therapeutics SA, 1228 Plan-les-Ouates, Geneva, Switzerland
Search for more papers by this authorDelphine Charvin PhD,
Therese Di Paolo PhD,
Erwan Bezard PhD,
Laurent Gregoire,
Akihiro Takano PhD,
Guillaume Duvey PhD,
Elsa Pioli PhD,
Christer Halldin PhD,
Rossella Medori MD, PhD,
François Conquet PhD,
Corresponding Author
Delphine Charvin PhD
Prexton Therapeutics SA, 1228 Plan-les-Ouates, Geneva, Switzerland
Correspondence to: Dr. Delphine Charvin, Prexton Therapeutics, 14 Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland; E-mail: [email protected]Search for more papers by this authorTherese Di Paolo PhD
Neuroscience Research Unit CHU de Québec, CHUL Pavillon and Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada
Search for more papers by this authorErwan Bezard PhD
Motac Neuroscience Ltd, Manchester, United Kingdom
Search for more papers by this authorLaurent Gregoire
Neuroscience Research Unit CHU de Québec, CHUL Pavillon and Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada
Search for more papers by this authorAkihiro Takano PhD
Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm, Sweden
Search for more papers by this authorGuillaume Duvey PhD
Prexton Therapeutics SA, 1228 Plan-les-Ouates, Geneva, Switzerland
Search for more papers by this authorElsa Pioli PhD
Motac Neuroscience Ltd, Manchester, United Kingdom
Search for more papers by this authorChrister Halldin PhD
Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm, Sweden
Search for more papers by this authorRossella Medori MD, PhD
Prexton Therapeutics SA, 1228 Plan-les-Ouates, Geneva, Switzerland
Search for more papers by this authorFrançois Conquet PhD
Prexton Therapeutics SA, 1228 Plan-les-Ouates, Geneva, Switzerland
Search for more papers by this authorFunding agencies: This study was funded by Prexton Therapeutics. Part of this work was supported by a grant from the Michael J. Fox Foundation for Parkinson's Research (grant ID-9243).
Relevant conflicts of interest/financial disclosures: D.C., G.D., R.M., and F.C. are employees of Prexton Therapeutics.
Full financial disclosures and author roles may be found in the online version of this article.
ABSTRACT
Background: Levodopa remains the gold-standard treatment for PD. However, it becomes less effective as the disease progresses and produces debilitating side effects, such as motor fluctuations and l-dopa-induced dyskinesia. Modulation of metabotropic glutamate receptor 4 represents a promising antiparkinsonian approach in combination with l-dopa, but it has not been demonstrated in primates.
Objective: We studied whether a novel positive allosteric modulator of the metabotropic glutamate receptor 4, PXT002331 (foliglurax), could reduce parkinsonism in primate models.
Methods: We assessed the therapeutic potential of PXT002331 in three models of MPTP-induced parkinsonism in macaques. These models represent three different stages of disease evolution: early stage and advanced stage with and without l-dopa-induced dyskinesia.
Results: As an adjunct to l-dopa, PXT002331 induced a robust and dose-dependent reversal of parkinsonian motor symptoms in macaques, including bradykinesia, tremor, posture, and mobility. Moreover, PXT002331 strongly decreased dyskinesia severity, thus having therapeutic efficacy on both parkinsonian motor impairment and l-dopa-induced dyskinesia. PXT002331 brain penetration was also assessed using PET imaging in macaques, and pharmacodynamic analyses support target engagement in the therapeutic effects of PXT002331.
Conclusions: This work provides a demonstration that a positive allosteric modulator of metabotropic glutamate receptor 4 can alleviate the motor symptoms of PD and the motor complications induced by l-dopa in primates. PXT002331 is the first compound of its class to enter phase IIa clinical trials. © 2018 International Parkinson and Movement Disorder Society
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