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Clinical Trials

Date: 2016-01-11

Type of information: Results

phase: 2a

Announcement: results

Company: Addex Therapeutics (Switzerland)

Product: dipraglurant

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: Parkinson's disease levodopa-induced dyskinesia (PD-LID)

Therapeutic area: Neurodegenerative diseases - CNS diseases

Country: USA, Europe

Trial details:

In the double-blind, placebo-controlled study conducted in the US and Europe, the primary objective was to demonstrate safety and tolerability in PD-LID patients. In addition, the trial was designed to evaluate exploratory efficacy as a secondary objective. Efficacy was measured using the modified Abnormal Involuntary Movement Scale (mAIMS), patient diaries documenting \"off-time\" (impaired voluntary movement), \"on-time\" (with or without dyskinesia) and sleep. Additional endpoints included the Unified Parkinson\'s Disease Rating Scale (UPDRS), the Clinician & Patient Global Impression of Change (CGIC & PGIC), and an evaluation of the patients\' mood using the Hospital Anxiety & Depression Score. The trial was supported by a grant from The Michael J. Fox Foundation for Parkinson's Research.
A total of 76 male and female patients (dipraglurant, n = 52; placebo, n = 24) with moderate or severe PD-LID were randomized into the study. Patients followed a dose-titration regimen, receiving 50mg doses from Day 1 to Day 14 and then 100mg from Day 14 until Day 28.

Latest news:

* On January 11, 2016, Addex Therapeutics announced that dipraglurant shows a statistically significant anti-dyskinetic effect, over the total treatment duration of 28 days, following additional analysis of the previously reported data from the Parkinson's disease levodopa-induced dyskinesia Phase II proof of concept (POC) clinical trial. As part of preparing the Phase III development plan, the statistical analysis of the Phase II POC study (ADX48621-201) was reviewed and audited under the supervision of Professor Dr Philippe Lehert, PhD, (Faculty of Medicine, the University of Melbourne, Australia and Faculty of Economics, UCL Mons, Louvain, Belgium). In the study, the primary efficacy variable was the area under the curve from 0 to 3 hours of the modified Abnormal Involuntary Movement Scale (mAIMS) measured at the end of treatment on Day 28 (dipraglurant 100 mg/placebo), on Day 14 (dipraglurant 100 mg/placebo) and at first dose on Day 1 (dipraglurant 50 mg/placebo). The effect of dipraglurant was assessed by a Linear Mixed Model in adjusting for baseline and supportive analyses were also conducted to adjust for country effects. Out of 76 patients in the trial, the intent to treat sample was constituted by 52 patients (dipraglurant) and 24 patients (placebo). The two groups were comparable at baseline (mAIMS value of 9.95). For the three post-baseline visits, a reduction in mAIMS mean value was observed in the dipraglurant treatment group with a mean benefit of -2.08 (p<0.001) compared with placebo over 28 days. The dipraglurant benefit was stronger when country and center heterogeneity was included, the effect reached a value of -2.11 (p<0.0001). For sensitivity purposes, the significance of the dipraglurant effect, compared to placebo, was tested with an Analysis of Covariance (ANCOVA) on mAIMS values adjusted for baseline, considering country as a fixed effect. This analysis confirmed a statistically significant effect with a mean decrease of mAIMs of -1.35 (p=0.026) compared with placebo over 28 days. Addex Therapeutics plans to engage discussions with the FDA with the objective of starting a phase III pivotal trial around year end. 

* On March 21, 2013,  Addex Therapeutics has announced that François Tison, M.D.-Ph.D., Professor at the University of Bordeaux, on behalf of the ADX48621-201 Study Group, presented the positive data obtained from a Phase 2a proof-of-concept trial of dipraglurant (ADX48621) in Parkinson's patients with levodopa-induced dyskinesia (PD-LID) in an oral presentation at the AAN conference on 20th March 2013. Professor Tison reported that the study met the primary objectives of safety and tolerability at both 50 and 100mg doses; supporting further clinical testing in this patient population. In addition, dipraglurant demonstrated positive anti-dyskinetic effect measured by observer evaluated mAIMS, patient reported diary data and patient and clinician global impression of change scales. Further, there was no negative effect on Parkinsonism and the data suggested that dipraglurant provided a beneficial effect on motor fluctuation. Addex has previously reported top-line results from this study last year. The Phase 2a study was supported by a $900,000 grant from The Michael J. Fox Foundation for Parkinson's Research. The recent $1,000,000 grant by this foundation will be used to help fund continued human clinical testing of dipraglurant for the treatment of PD-LID. "We continue to be engaged in partnering discussions with a number of global players who we believe have the expertise and capability to fully exploit dipraglurant and expect to have a deal completed sometime this year," said Bharatt Chowrira, Ph.D., Chief Executive Officer of Addex Therapeutic. "While we continue to advance this compound for PD-LID we will also initiate parallel clinical efforts for a rare form of dystonia. We expect to initiate a Phase 2 study in dystonia and report data by the end of 2013. Completion of the PD-LID clinical work as well as the dystonia study will bring significant value to our dipraglurant franchise."
* On June 18, 2012, Addex Therapeutics, a Swiss company pioneering allosteric modulation-based drug discovery and development, has announced that positive data from a recently completed Phase 2a study with dipraglurant in Parkinson's disease patients with levodopa-induced dyskinesia will be presented at the Movement Disorder Society's 16th International Congress of Parkinson's Disease and Movement Disorders, June 17-21 in Dublin, Ireland.
As previously reported, all key objectives were achieved in the Phase 2a study of dipragluarant in Parkinson's disease levodopa-induced dyskinesia (PD-LID). The data show that dipraglurant met the primary objective of the study by exhibiting a good safety and tolerability profile.
Dipraglurant also demonstrated statistically significant reduction in levodopa-induced dyskinesia severity with both 50mg and 100mg doses. Dipraglurant appears to reduce dystonia severity in addition to chorea, the two major LID components. 
The presentation is entitled "Safety, tolerability and anti-dyskinetic efficacy of dipraglurant, a novel mGluR5 negative allosteric modulator in Parkinson's disease (PD) patients with levodopa-induced dyskinesia (LID)" by Prof. Francois Tison of the Centre Hospitalier Universitaire de Bordeaux, France.
Addex is currently seeking a partner to advance dipraglurant into Phase IIb for PD-LID and other indications.

* On March 22, 2012, Addex, that has recently changed its name to Addex Therapeutics, has announced positive top line data from a Phase IIa clinical study of dipraglurant in Parkinson's disease (PD) patients suffering from debilitating levodopa-induced dyskinesia (LID). The data show that dipraglurant met the primary objective of the study by exhibiting a good safety and tolerability profile. Dipraglurant also demonstrated statistically significant reduction in LID severity with both 50mg and 100mg doses. Dipraglurant appears to reduce dystonia severity in addition to chorea, the two major LID components. A full analysis of the data will be presented at a scientific forum in 2012. This first-in-patients study met its primary objective of demonstrating safety and tolerability in patients with PD. There were no significant changes in any safety monitoring parameters and, in particular, no changes in liver function tests were seen in either treatment group. Both the 50mg and 100mg dose levels were well tolerated. The incidence of adverse events was similar in both active and placebo groups (88.5% for dipraglurant versus 75% for placebo). Typical mGluR5-type adverse events (vertigo, visual disturbance, feeling drunk) were seen in less than 10% of patients in the dipraglurant group but were not severe or dose limiting.
Exploratory efficacy data showed an anti-dyskinetic effect on observer evaluated mAIMS and in patient reported diary data. Both the 50mg and 100mg doses of dipraglurant showed a statistically significant reduction in LID. Peak mAIMS was significantly reduced on Day 1 (50mg; p = 0.042) and on Day 14 (100mg; p = 0.038). The targeted magnitude of effect of either a 30% reduction in mAIMS or a 20% separation from placebo was achieved on Days 1, 14 and 28. The magnitude of reduction in mAIMs was maintained for dipraglurant on Day 28 (100mg), but not statistically significant due to an increase in placebo response on that day. Similar results were seen for the area under the curve (AUC) mAIMS evaluation in the total 3 hour post levodopa dosing period, with about a 30% reduction in the dipraglurant group at Days 14 and 28, which was statistically significant at Day 14 (p = 0.042). In a subset of patients with levodopa-induced dystonia, dipraglurant appears to have reduced dystonia severity. The UPDRS Part III (motor scores) performed during mAIMS evaluation, indicated that dipraglurant did not interfere with levodopa efficacy.
Patient-reported, diary data supported the objective, observer-reported mAIMS data, with an increase in daily on-time without dyskinesia up to twice that of placebo; i.e. dipraglurant patients had as much as 70 minutes more on-time without dyskinesia than placebo patients. Furthermore, during Week 4, patients reported a reduction in daily off-time of 50 minutes, suggesting an effect on parkinsonian motor symptoms in addition to the observed reductions in LID. Patients and clinicians tended to favor dipraglurant treatment for dyskinesia with a higher percentage reporting improvement for the dipraglurant group, as measured by the PGIC and CGIC.

* On March 31, 2011, Addex Pharmaceuticals has initiated a Phase IIa clinical trial to evaluate dipraglurant in patients with Parkinson’s disease levodopa-induced dyskinesia (PD-LID), a debilitating movement disorder caused by long-term treatment with levodopa, the gold standard therapy for Parkinson’s disease. The U.S. and European study is supported in part by a grant from the Michael J. Fox Foundation for Parkinson Research. Results are expected to be announced during the first half of 2012.
A longer-acting extended-release formulation of dipraglurant (dipaglurant-ER), is being developed for the treatment of non-Parkinsonian dystonia. Phase I testing of dipraglurant-ER will commence during the second half of 2011. Phase IIa testing of dipraglurant-ER in dystonia patients is scheduled to start in 2012.

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