An mGlu4-Positive Allosteric Modulator Alleviates Parkinsonism in Primates.
Mov Disord.. 2018-09-14; 33(10): 1619-1631
DOI: 10.1002/mds.27462
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1. Mov Disord. 2018 Oct;33(10):1619-1631. doi: 10.1002/mds.27462. Epub 2018 Sep 14.
An mGlu4-Positive Allosteric Modulator Alleviates Parkinsonism in Primates.
Charvin D(1), Di Paolo T(2), Bezard E(3), Gregoire L(2), Takano A(4), Duvey G(1),
Pioli E(3), Halldin C(4), Medori R(1), Conquet F(1).
Author information:
(1)Prexton Therapeutics SA, 1228 Plan-les-Ouates, Geneva, Switzerland.
(2)Neuroscience Research Unit CHU de Québec, CHUL Pavillon and Faculty of
Pharmacy, Laval University, Quebec City, Quebec, Canada.
(3)Motac Neuroscience Ltd, Manchester, United Kingdom.
(4)Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical
Neuroscience, Stockholm, Sweden.
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.
© 2018 International Parkinson and Movement Disorder Society.
DOI: 10.1002/mds.27462
PMID: 30216534