Parkinson’s disease is the second most common neurodegenerative disease and remains incurable. Levodopa is the gold standard but over-time patients develop episodes where the PD symptoms return or worsen (OFF time). A prolonged Levodopa treatment induces dyskinesia (levodopa-induced dyskinesia (LID)) which is one of the most important clinical unmet need for Parkinson’s disease.
DT095435 is a drug candidate targeting metabotropic glutamate receptors mGluR4/7/8. It is a potential best-in-class treatment for the reduction of motor complications of Levodopa therapy and dyskinesia in Parkinson’s Disease.
mGluR 4/7/8 PAM
High neurotransmitter release in the basal ganglia is involved in core motor symptoms of Parkinson’s disease (PD), as well as the development of L-DOPA-induced dyskinesia (LID). Due to their presynaptic localization, metabotropic glutamate receptors mGluR4 can normalize neurotransmitter release. This explains the pro-motor and anti-dyskinetic activity of foliglurax, a selective mGluR4 Positive Allosteric Modulator (PAM), which was evaluated in Phase II trial for PD. mGluR7 and mGluR8, the two other group III mGluR subtypes, share similar strategic localization within the basal ganglia with mGluR4. Parallel activation of the three subtypes is expected to improve the control of the motor symptoms of PD, including the L-DOPA-induced dyskinesia (LID).
We discovered a chemical series of group III mGluR positive allosteric modulators potentiating not only mGluR4, but also mGluR7 and mGluR8. DT095435 was nominated as a pan group III mGluR PAM development candidate to enter regulatory studies. It was evaluated in the MPTP-non-human primate model for LID where it showed robust anti-dyskinetic activity.