Addex Dipraglurant Shows Highly Statistically Significant Anti-Dyskinetic Effects Following Additional Analysis of Data from the PD-LID Phase II Proof of Concept
Additional analysis underlines the potential significant therapeutic benefit of dipraglurant to patients with Parkinson’s disease.
Geneva, Switzerland, 11 January 2016 – Addex Therapeutics (SIX: ADXN), a leading company pioneering allosteric modulation-based drug discovery and development, announced today 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.
“This additional analysis further strengthens our conviction that dipraglurant has the potential to provide significant therapeutic benefit to Parkinson’s disease patients that are suffering from debilitating levodopa-induced dyskinesia”, said Sonia Poli, Chief Scientific Officer of Addex.” We now plan to engage the FDA in a dialogue regarding the future development of dipraglurant in PD-LID with the objective of starting a phase III pivotal trial around year end.”
“We are delighted by the outcome of this additional independent review and the recently achieved orphan drug status for dipraglurant in PD-LID,” said Tim Dyer, Chief Executive Officer of Addex. “We now look forward to the results from the ongoing receptor occupancy clinical trial, feedback from the FDA on our development plans in PD-LID and starting the Phase II proof of concept in focal cervical dystonia, as we execute the Addex turnaround.”
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. Dipraglurant has received FDA orphan drug designation for levodopa-induced dyskinesia associated with Parkinson’s disease and is currently in preparation to enter a phase III pivotal clinical trial, which includes an ongoing mGluR5 receptor occupancy clinical study that is expected to report by the end of Q1 2016.
About Levodopa-Induced Dyskinesia Associated with Parkinson’s Disease
Levodopa-Induced dyskinesia’s (LID) are involuntary movements that appear after 3-5 years of treatment with dopamine replacement therapies. They may affect any body area e.g. face, trunk, limbs. Patients suffering from LID commonly present with irregular migrating contractions or twisting and writhing due to dystonia, chorea, however other forms of abnormal movements have also been observed; peak-dose levodopa-induced dyskinesia is the most common form and is associated with peak plasma levels of levodopa. Symptoms of LID are serious and can restrict the dosing of levodopa which may result in inadequate control of Parkinsonian symptoms. In addition to the impact on quality of life associated with uncontrollable involuntary movements, patients with LID are easily fatigued, present a risk of injury to themselves as well as caregivers, and suffer pain due to dystonia.
About Addex Therapeutics
Addex Therapeutics (www.addextherapeutics.com) 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 II 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 and TrKB PAM for neurodegenerative disorders and mGluR7NAM for psychosomatic 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.
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