Addex Therapeutics, a leading company pioneering allosteric modulation-based drug discovery and development, 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.

"Levodopa-induced dyskinesia can be debilitating in its own right and can impact the use of medications to treat Parkinson's motor symptoms," said Jamie Eberling, PhD, MJFF director of Research Programs. "A therapy, such as dipraglurant, to control this side effect would have a great impact on the lives of many living with this disease."

"We are very pleased with the quality of the data provided by the group of Dr Wong", said Sonia Poli, chief scientific officer of Addex. "The results are robust and will guide the further development of dipraglurant"

"The completion of this study represents an important milestone in the development of dipraglurant", said Tim Dyer, chief executive officer of Addex. "We are looking forward to moving dipraglurant into a phase III pivotal trial for PD-LID."

The study is an open label, non-randomized, PET study investigating mGluR5 occupancy after single or double oral dosing of ADX48621 in 16 healthy subjects using [18F]-FPEB. The study consists of two parts: 1) A receptor occupancy dose curve was obtained by using an adaptive design. Subjects underwent two [18F]-FPEB PET imaging sessions at baseline and after treatment with one dose of ADX48621. The second scan was taken at Tmax for ADX48621 (one hour post dose). The initial dose was 100 mg as this has been proven to be efficacious in a phase IIA study in Parkinson's patients. The maximum dose given was 300 mg. 2) The time course of receptor occupancy was studied for the 300 mg dose. Four subjects received a single daily dose of ADX48621 on two separate days and underwent three [18F]-FPEB PET imaging sessions: a baseline scan and two post-dose scans. Subjects were given ADX48621 one hour before the first post-dose scan. The second dose was given approximately three to four hours before the second post-dose scan. The maximum daily dose given was 600 mg (300mg twice).

Dipraglurant is an oral, small molecule allosteric modulator that inhibits selectively the metabotropic glutamate receptor 5 (mGluR5), a Class C G-Protein Coupled Receptor (GPCR).It has the potential to be used in combination with levodopa or dopamine agonists or as a standalone treatment for Parkinson's disease levodopa-induced dyskinesia (PD-LID), motor and non-motor symptoms of Parkinson's disease and other movement disorders. In a double-blind, placebo-controlled, US and European phase II study in PD-LID, data showed that dipraglurant met the primary objective of the study by exhibiting a good safety and tolerability profile. Dipraglurant also demonstrated a statistically significant reduction in LID severity with both 50 and 100 mg doses. Dipraglurant reduced dystonia severity in addition to chorea, the two major LID components. Efficacy was measured using the modified Abnormal Involuntary Movement Scale and patient diaries documenting "off-time" (impaired voluntary movement), "on-time" (with or without dyskinesia) and sleep. Additional endpoints include the Unified Parkinson's Disease Rating Scale, the Clinical and Patient Global Impression of Changes scales, and an evaluation of the patient's mood using the Hospital Anxiety and Depression Scale. The trial was supported by a grant from The Michael J. Fox Foundation for Parkinson's Research.