Addex Therapeutics announced the results of the mGlu5 receptor occupancy study with dipraglurant in healthy volunteers. The study was conducted under the direction of lead investigator professor of neurology, Dean F. Wong, MD, PhD of the Departments of Radiology, Psychiatry and Neuroscience at Johns Hopkins University.
The trial was designed to study brain mGlu5 receptor occupancy by positron emission tomography (PET) following dosing of dipraglurant in healthy subjects and to assess the relationship between dipraglurant plasma concentration and brain mGlu5 receptor occupancy as well as the time course of the receptor occupancy. The Michael J. Fox Foundation for Parkinson's Research (MJFF) provided funding for the trial.
Dipraglurant is a novel small molecule inhibitor of the metabotropic glutamate receptor 5 (mGluR5) that has successfully completed phase II proof-of-concept testing in Parkinson's disease (PD) patients suffering from debilitating levodopa-induced dyskinesia (LID).
Twelve healthy subjects were recruited in the trial. Four subjects were assigned to each of the following dose group: 100, 200 and 300 mg. PET scans were recorded one hour post-dosing. The four subjects in the 300 mg dose group had a second PET scan recorded three hours post-dosing to study the time course of the mGlu5 receptor occupancy by dipraglurant.
The average receptor occupancy measured during 90 min was proportional to the administered dose: 100 mg: 27 per cent; 200 mg: 44.4 per cent; 300 mg: 53.5 per cent.
More importantly, the receptor occupancy data was very well correlated with the plasma concentration and allowed a clear definition of the target plasma concentration range to obtain 50-70 per cent receptor occupancy, a range previously determined to be optimal for a robust anti-dyskinetic effect. The time course evaluation of receptor occupancy showed the plasma pharmacokinetics of dipraglurant reflect the kinetics of receptor occupancy at the effector site, i.e., dipraglurant is cleared from the receptor, according to its plasma pharmacokinetics.
Only two subjects in the highest dose group (300 mg) reported mild AEs (euphoria, lightheadedness, blurred vision), which are consistent with the safety profile known for dipraglurant. All AEs were short-lived, transient and resolved spontaneously. There were no AEs reported by the other study participants. Overall dipraglurant was safe and well tolerated.
