A Randomized, Double‐Blind, Controlled Phase II Study of Foliglurax in Parkinson's Disease

Abstract

Background: Agents targeting the metabotropic glutamate receptor 4 have emerged as a potentially attractive new class of drugs for the treatment of Parkinson's disease (PD). Objective: The objective of this study was to evaluate the efficacy and safety of foliglurax in reducing off time and dyskinesia in patients with PD. Methods: This was a 28-day, multicenter, randomized, placebo-controlled, double-blind clinical trial of foliglurax 10 and 30 mg as adjunct to levodopa in 157 randomly assigned patients with PD and motor complications.Results: Although dose-dependent decreases in daily awake off time were apparent following treatment with foliglurax, the change from baseline to day 28 in off time (primary endpoint) and dyskinesia (secondary endpoint) did not improve significantly compared with placebo for either foliglurax dose. Treatment with foliglurax was generally safe, and there were no relevant safety signals.Conclusions: There was no evidence in this study that foliglurax has efficacy in improving levodopainduced motor complications in PD.

Metabotropic Glutamate Receptor 4 (mGlu4) Positive Allosteric Modulators Lack Efficacy in Rat and Marmoset Models of L-DOPA-Induced Dyskinesia

“…We found no evidence in support of these pharmacological agents having any impact either on already established LID or on the development of de novo LID. These data are in line with the recent failure of foliglurax to demonstrate efficacy in phase II clinical trials of LID [ 21 ]. They add to an increasing body of evidence arguing against mGlu 4 PAMs having any meaningful impact as future therapeutics in the fight against LID, while nevertheless supporting the translational potential of the rat and primate models of LID as test beds for future antidyskinetic agents.…”

“…The recent failure of foliglurax to reduce LID in phase II clinical trials [ 21 ], highlights the need for further studies exploring the anti-dyskinetic effects of mGlu 4 modulators. To shed light on these discordant findings on the antidyskinetic potential of targeting mGlu 4 receptors, and to gather further insight into whether the pre-clinical dyskinesia models have good translational potential in the drug discovery pipeline, we investigated the efficacy of mGlu 4 receptor PAMs in both a rodent and a non-human primate model of LID.…”

Newly Approved and Investigational Drugs for Motor Symptom Control in Parkinson's Disease

“…Among them, foligrulax is a mGluR4 agonist that has been shown to be beneficial in the treatment of LID in animal models [ 196 , 197 ]. On the other hand, a recent Phase 2 trial enrolling 157 individuals with PD did not demonstrate any improvement in OFF time or UDysRS scores by the end of 28 days with foliglurax 10 mg or 30 mg compared to placebo (NCT03162874) (Table 4 ) [ 198 – 200 ]. Given the negative results, the manufacturer has decided to terminate this development program.…”

Off-time Treatment Options for Parkinson’s Disease

“…A negative Phase II trial has recently halted the development of Foliglurax, a positive allosteric modulator of the mGlu4R, for the treatment of patients with PD with MF [ 66 ].…”