Addex Reports Statistically Significant Positive Interim Data for Dipraglurant in Healthy Volunteer mGlu5 Receptor Occupancy Trial

Addex Reports Statistically Significant Positive Interim Data for Dipraglurant in Healthy Volunteer mGlu5 Receptor Occupancy Trial

Geneva, Switzerland, 17 December 2015 – Addex Therapeutics (SIX: ADXN), a leading company pioneering allosteric modulation-based drug discovery and development, announced today positive interim data for dipraglurant in an mGlu5 receptor occupancy study in healthy volunteers. The study is being conducted under the direction of lead investigator Dean F. Wong, MD, PhD, of the Departments of Radiology, Psychiatry and Neuroscience at Johns Hopkins University. The trial is 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. 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). 

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
  • 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.

"Management of dyskinesia is a research priority for our Foundation," said Jamie Eberling, PhD, MJFF Senior Associate Director of Research Programs. "And Addex is making strides toward a therapy to alleviate this side effect and improve quality of life for people living with Parkinson’s disease.”

“These interim results are very promising as they indicate that dipraglurant is able to reverse dyskinesia in PD-LID patients at low levels of receptor occupancy” said Sonia Poli, PhD, Chief Scientific Officer of Addex. “The good tolerability of dipraglurant and these data together with the data obtained in the non-human primate model suggest that a higher dose should be used in the Phase III trial which will potentially demonstrate even stronger anti-dyskinetic effects than those seen in the Phase IIa study.”

"We are very excited by these data which are an important part of our preparations to move dipraglurant into a Phase III pivotal trial for PD-LID," said Tim Dyer, Chief Executive Officer of Addex. "The support of MJFF demonstrates the promise of dipraglurant as a potential treatment for Parkinson’s disease levodopa-induced dyskinesia.”

About the Trial Design
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: 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 will be 300 mg; 2) 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 three to four hours before the second post-dose scan. The maximum dose to be given will be 600 mg (300mg twice). Refer to Identifier: NCT02447640.

About Dipraglurant 
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), with 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.

About The Michael J. Fox Foundation
As the world's largest nonprofit funder of Parkinson's research, The Michael J. Fox Foundation is dedicated to accelerating a cure for Parkinson's disease and improved therapies for those living with the condition today. The Foundation pursues its goals through an aggressively funded, highly targeted research program coupled with active global engagement of scientists, Parkinson's patients, business leaders, clinical trial participants, donors and volunteers. In addition to funding more than $525 million in research to date, the Foundation has fundamentally altered the trajectory of progress toward a cure. Operating at the hub of worldwide Parkinson's research, the Foundation forges groundbreaking collaborations with industry leaders, academic scientists and government research funders; increases the flow of participants into Parkinson's disease clinical trials with its online tool, Fox Trial Finder; promotes Parkinson's awareness through high-profile advocacy, events and outreach; and coordinates the grassroots involvement of thousands of Team Fox members around the world. 

About Addex Therapeutics
Addex Therapeutics ( is a biopharmaceutical company focused on the development of novel, orally available, small molecule allosteric modulators for neurological disorders. Addex lead drug candidate, dipraglurant (mGluR5 negative allosteric modulator or NAM) has successfully completed a phase IIa POC in Parkinson’s disease levodopa-induced dyskinesia (PD-LID), and is being prepared to enter phase III for PD-LID with support from the Michael J. Fox Foundation for Parkinson’s Research (MJFF). In parallel, dipraglurant’s therapeutic use in dystonia is being investigated with support from the Dystonia Medical Research Foundation (DMRF).  Addex second clinical program, ADX71149 (mGluR2 positive allosteric modulator or PAM) is being developed in collaboration with Janssen Pharmaceuticals, Inc for epilepsy. In addition, ADX71441 (GABAB receptor PAM) has received regulatory approval to start phase I and is being investigated for its therapeutic use in Charcot-Marie-Tooth Type 1A disease (CMT1A), alcohol use disorder and nicotine dependence with support from the US CMT Association (CMTA), the US National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the US National Institute on Drug Abuse (NIDA), respectively.  Discovery programs include mGluR4PAM for neurodegenerative diseases, mGluR7NAM for psychosomatic disorders and TrkBPAM for neurodegenerative disorders which are being advanced in collaboration with the Universities of Lausanne and Geneva under the Swiss CTI grant program; and mGluR3PAM which is being advanced in collaboration with Pierre Fabre Pharmaceuticals. Allosteric modulators are an emerging class of small molecule drugs which have the potential to be more specific and confer significant therapeutic advantages over conventional "orthosteric" small molecule or biological drugs.  Addex allosteric modulator drug discovery platform targets receptors and other proteins that are recognized as essential for therapeutic intervention – the Addex pipeline was generated from this pioneering allosteric modulator drug discovery platform.

Press Contacts:
Tim Dyer
Chief Executive Officer
Addex Therapeutics
Telephone: +41 22 884 15 61
Email: PR(at)

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