Foliglurax

Foliglurax is a positive allosteric modulator that enhances signalling of the mGlu4 receptor in response to endogenous glutamate. In the basal ganglia, mGlu4 is located presynaptically at the striatopallidal and corticostriatal synapses of the indirect motor pathway, where its activation reduces GABA and glutamate release and helps rebalance circuits thrown into disarray by dopamine loss in Parkinson's disease. Medicinal-chemistry work identified foliglurax as a potent, brain-penetrant compound in a series of mGlu4 positive allosteric modulators with antiparkinsonian activity in animal models ^[1], and a related mGlu4 modulator was shown to alleviate parkinsonism in primates, strengthening the translational rationale ^[2].

In the clinic, the phase 2 AMBLED study evaluated foliglurax at 10 and 30 mg as an adjunct to levodopa in patients with Parkinson's disease and motor complications. Although dose-dependent decreases in daily awake off time were apparent, neither the change in off time, the primary endpoint, nor dyskinesia, a secondary endpoint, improved significantly compared with placebo, and the trial was considered negative despite a generally favourable safety profile ^[3]. The result led Lundbeck to discontinue development, but foliglurax remains an important reference for the mGlu4 approach and for the broader effort to treat Parkinson's disease without adding dopaminergic load ^[1][3]. It illustrates both the appeal and the difficulty of group III metabotropic strategies in movement disorders.

In the phase 2 AMBLED trial foliglurax was generally safe with no relevant safety signals at the doses tested. Its allosteric, activity-dependent mechanism was designed to avoid overstimulation of the target. As an investigational compound whose development was discontinued, it is not approved and its long-term human safety is not established.

Foliglurax was discovered and advanced by the Swiss biotech Prexton Therapeutics as PXT002331, representing one of the first mGlu4 positive allosteric modulators to reach clinical testing for Parkinson's disease. Lundbeck acquired Prexton in 2018 largely on the strength of the program. After the AMBLED phase 2 study failed to meet its primary endpoint in 2020, Lundbeck discontinued development, though the compound remains widely cited in the mGlu4 literature.

Foliglurax is regarded as the flagship clinical example of the mGlu4 positive allosteric modulator strategy for Parkinson's disease and a key data point on the feasibility of non-dopaminergic motor therapy. Its negative pivotal result tempered expectations for the approach but did not eliminate interest in group III metabotropic targets. It is known within movement-disorder and metabotropic glutamate research communities rather than as a consumer compound.