Date: 2016-04-11
Type of information: Results
phase: 1
Announcement: results
Company: Addex Therapeutics (Switzerland) Johns Hopkins University (USA - MD)
Product: dipraglurant (ADX48621)
Action
mechanism: mGluR5 negative allosteric modulator. Dipraglurant is a metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator. The product has the potential to be used in combination with levodopa or dopamine agonists or as a standalone treatment for Parkinson's disease (debilitating levodopa-induced dyskinesia (PD-LID), PD-related motor symptoms, non-motor symptoms of PD and other movement disorders.
Disease: levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) patients
Therapeutic area: Neurodegenerative diseases
Country: USA
Trial
details: The study is an open label, non-randomized, PET study investigating mGluR5 occupancy after single or double oral dosing of ADX48621 in 15 healthy subjects using [18F]-FPEB. The study consists of two parts: A receptor occupancy dose curve will be obtained by using an adaptive design. Subjects will undergo two [18F]-FPEB PET imaging sessions: at baseline and after treatment with one dose of ADX48621. The second scan will be taken at Tmax for ADX48621 (one hour post dose). The initial dose will be 100 mg as this has been proven to be efficacious in a Phase IIA study in Parkinson's patients. The maximum dose given will be 200 mg. The time course of receptor occupancy will be studied for the dose that gives 70 percent receptor occupancy as determined in the first part of the study. Two subjects will receive a single daily dose of ADX48621 on two separate days and undergo three [18F]-FPEB PET imaging sessions: a baseline scan and two post-dose scans. Subjects will be given ADX48621 one hour before the first post-dose scan. The second dose will be given approximately four to six hours before the second post-dose scan. The maximum dose to be given will be 400 mg (200mg twice). (NCT02447640)
Latest
news: * On April 11, 2016, Addex Therapeutics, a Swiss 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. 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%; 200 mg: 44.4%; 300 mg: 53.5%. 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% 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 adverse events (euphoria, lightheadedness, blurred vision), which are consistent with the safety profile known for dipraglurant. All adverse events were short-lived, transient and resolved spontaneously. There were no adverse events reported by the other study participants. Overall dipraglurant was safe and well tolerated. Addex Therapeutics is now looking forward to completing the analysis of the study to define the doses to move dipraglurant into a Phase III pivotal trial for levodopa-induced dyskinesia in Parkinson's disease patients. * On March 15, 2016, Addex Therapeutics announced completion of the mGlu5 receptor occupancy study with dipraglurant in healthy volunteers. PET scan analysis as well as determination of plasma concentration of dipraglurant and genotyping of a specific metabolic pathway is underway. Only two subjects in the highest dose group (300mg) 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 recognized as safe and well tolerated. * On December 17, 2015, Addex Therapeutics announced positive interim data for dipraglurant in an mGlu5 receptor occupancy study in healthy volunteers. The interim data were obtained in eight subjects. Four subjects received a single 100 mg dose of dipraglurant and another four subjects received a single dose of 200 mg. Both doses were well tolerated with no adverse events reported. PET images of [18F]-FPEB were analyzed by the plasma reference graphical method (Logan et al., 1990). The results are as follow: Dipraglurant shows a good and dose dependent brain penetration * On July 22, 2015, Addex Therapeutics announced that enrollment has been initiated and the first subject has been dosed with dipraglurant in a receptor occupancy study in healthy volunteers. The trial is designed to study brain mGluR5 occupancy by positron emission tomography (PET) following dosing of dipraglurant in healthy subjects and to assess the relationship between dipraglurant plasma concentration and brain mGluR5 occupancy. The Michael J. Fox Foundation for Parkinson's Research (MJFF) provided funding for the trial.
The 100 mg dose gives a value of receptor occupancy of 27% ± 9%
The 200 mg dose gives a value of receptor occupancy of 44% ± 23%
A statistically significant difference was observed between the two doses (F=18.35; p<0.001; df=1 by two-way ANOVA) demonstrating a proportional and dose related increase in receptor occupancy. The local ethic committee of the Johns Hopkins Hospital has approved increasing the maximum dose to 300 mg before moving to the second part of the study, which will evaluate the time course of the receptor occupancy. The high variability observed in receptor occupancy for a given dose was correlated to the distribution of plasma concentrations of dipraglurant. Genotyping of a specific metabolic pathway is underway to explain the variability observed. The interim results show that the dose used in the PoC study (100 mg) was engaging the mGlu5 receptor, and that higher doses might be used in the further clinical development of dipraglurant in PD-LID to potentially achieve even stronger anti-dyskinetic effects.
