An mGlu4‐Positive Allosteric Modulator Alleviates Parkinsonism in Primates

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