Objective: Objective was to assess the therapeutic potential of our novel mGlu4 positive allosteric modulator (PAM), foliglurax, as an anti-parkinsonian treatment in gold-standard primate models.

Background: Levodopa remains the gold standard treatment for Parkinson’s Disease (PD). However, as the disease progresses, dopaminergic treatments become less effective and produce debilitating side effects, including motor fluctuations and levodopa-induced dyskinesia (LID). Over the past decade, modulation of presynaptic metabotropic glutamate receptor 4 (mGlu4) has been proposed as a promising anti-parkinsonian approach but it has never been demonstrated in primates so far.

Methods: Foliglurax (PXT002331) was tested in three models of MPTP-induced parkinsonism in macaques: early stage, advanced parkinsonism and LID. Brain penetration of the compound has also been assessed using PET imaging in macaques.

Results: Foliglurax demonstrated consistent anti-parkinsonian efficacy in all models. Co-administration of foliglurax and levodopa resulted in a robust and dose-dependent reversal of parkinsonian motor symptoms in macaques. Moreover, foliglurax strongly decreased dyskinesia induced by levodopa, thus having therapeutic efficacy on both aspects: parkinsonian motor symptoms and LID.

Conclusions: This is the first demonstration that a mGlu4 PAM can alleviate the motor symptoms of PD and the motor complications induced by levodopa in primates. Supported by its unique preclinical profile, foliglurax has been the first mGlu4 PAM entering the clinics and is now being tested in a Phase IIa study.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-mglu4-pam-alleviates-motor-symptoms-in-primate-models-of-pd-and-of-lid/