Addex Reports that Dipragluant Demonstrated Dose-Dependent mGlu5 Receptor Occupancy in a Non-Human Primate PET Study
• Dose-dependent receptor occupancy correlates with plasma exposure and links to efficacy in non-human primate model of Parkinson’s Disease levodopa-induced dyskinesia
• Data reinforces Phase 2a pharmacological profile of dipraglurant as a potent, selective and brain penetrant mGlu5 negative allosteric modulator
• Similar receptor occupancy study in human subjects to be initiated by July 2013
• Receptor occupancy studies supported by a $1 MM grant from the Michael J. Fox Foundation for Parkinson’s Research
• Program on track to initiate Phase 2a testing in dystonia by July 2013
Geneva, Switzerland, 2 May 2013 – Addex Therapeutics (SIX: ADXN), a leading company pioneering allosteric modulation-based drug discovery and development announced today that dipragluant demonstrated dose-dependent mGlu5 receptor occupancy in a non-human primate positron emission tomography (PET) study. PET is a non-invasive nuclear imaging technique used in drug discovery and development for assessing specific receptor distribution in the brain and has been proven very useful in assessing drug pharmacodynamics and receptor occupancy. The study demonstrated the correlation between the plasma concentration of dipraglurant and occupancy of dipraglurant on mGlu5 receptors in the brain. The results support efficacy data as observed in a preclinical non-human primate model of levodopa-induced dyskinesia and will be used to inform dosing in future clinical studies. In addition, the study results reinforce data seen in the Phase 2a trial supporting dipraglurant as a potent, selective and brain penetrant mGlu5 negative allosteric modulator (NAM). The study was performed by Molecular NeuroImaging (MNI) in New Haven, CT, USA and supported by a $1 MM grant from the Michael J. Fox Foundation for Parkinson’s Research.
“The results of the study are in line with previous reports on mGlu5 receptor occupancy studies and are consistent with the preclinical pharmacology data gathered so far with dipraglurant,” stated Gilles Tamagnan, Ph.D., Vice President Chemistry and Translational Science at MNI. “We look forward to the next phase of the study; investigating receptor occupancy in human volunteers and Parkinson’s patients.”
The non-human primate PET study measured the mGlu5 receptor occupancy after bolus/i.v. infusion of dipraglurant followed by administration of 18F-FPEB, a high-quality, high affinity, high specificity mGlu5 PET tracer. The treatment comprised 4 different dose levels of dipraglurant (4.34, 1.52, 0.6 and 0.2 mg/kg) and two baseline PET scans. Dynamic PET images were acquired for 2 hours and plasma samples were drawn during the PET scan and analysed for drug levels. The results demonstrated that dipraglurant penetrates the blood-brain barrier and dose-dependently blocks the binding of 18F-FPEB. The dissociation constant (KD) was determined to be 0.82 mg/kg and at the highest dose nearly complete blockade of the receptor was achieved (81% RO). The receptor occupancy data combined with the dipraglurant plasma concentration was used to analyse the previously reported data obtained in the non-human primate model of Parkinson’s disease Levodopa induced dyskinesia (PD-LID). There was a clear and direct relationship between mGlu5 receptor occupancy and efficacy as demonstrated by decreasing dyskinesia in the MPTP-PD-LID model. This invaluable information relating the receptor occupancy to the therapeutic dose is a step forward in the understanding of the pharmacology of dipraglurant and will be translated into dose selection for the future clinical development of dipraglurant.
“This was an important study in further understanding the pharmacology of dipraglurant,” said Graham Dixon, Ph.D., Chief Scientific Officer of Addex Therapeutic. “These results as well as results from the PET receptor occupancy study in humans will continue to better our understanding of how dipraglurant is targeting mGlu5. With top line data from the dystonia trial expected by the end of 2013, the data from all of these studies, taken as a whole, will place us in a strong position to make data-driven decisions on the further clinical development of dipraglurant in PD-LID, rare dystonias as well as other potential therapeutic indications.”
Dipraglurant is an oral, small molecule allosteric modulator that inhibits selectively the metabotropic glutamate receptor 5 (mGlu5), 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. Data from a recent Phase 2a show 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 appears to reduce dystonia severity in addition to chorea, the two major LID components. In a 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 include 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.
About mGlu5 Inhibition
There is an increasing body of evidence that mGlu5 inhibition may be a valuable new strategy for treating a number of important diseases and conditions, such as Parkinson's disease, Parkinson’s disease levodopa-induced dyskinesia (PD-LID), anxiety, depression, pain, tardive dyskinesia, dystonia, addiction, autism and Fragile X syndrome. With regards to Parkinson’s disease, recent clinical and preclinical evidence suggest that mGlu5 inhibition may have an effect on parkinsonian motor symptoms as well as dyskinesia. MGlu5 is found in regions of the brain considered to be key control points in the neuronal movement circuits affected by abnormal signaling by the neurotransmitter glutamate in Parkinson’s disease. Perturbations in glutamate signaling (along with disruptions in dopaminergic signaling) are believed to be an underlying cause of movement disorders like Parkinson's disease. As such, inhibiting mGlu5 could act to re-establish normal movement via a non-dopaminergic mechanism. Separately, preclinical findings also suggest that mGlu5 inhibitors may be neuroprotective and may, therefore, hold potential as disease modifying agents that can slow or prevent progression of Parkinson’s disease.
Dystonia is a movement disorder that causes the muscles to contract and spasm involuntarily, according to the Dystonia Medical Research Foundation. The involuntary muscle contractions force the body into repetitive and often twisting movements as well as awkward, irregular postures. There are approximately 13 forms of dystonia, and dozens of diseases and conditions include dystonia as a major symptom. Dystonia may affect a single body area or be generalized throughout multiple muscle groups. Dystonia affects men, women, and children of all ages and backgrounds. Estimates suggest that no less than 300,000 people in North America are affected. Dystonia causes varying degrees of disability and pain, from mild to severe. There is presently no cure, and, although many drugs are utilized to try to treat dystonia, the leading treatment is botox injections and many patients are left with inadequate efficacy. Dipraglurant has been shown to effectively reduce dystonia in both a clinical study and preclinical models of Parkinson’s disease levodopa-induced dyskinesia (PD-LID). The neurophysiology of different forms of dystonia is thought to be similar and recent preclinical data in dystonia - suggesting that dipraglurant may also work for non-parkinsonian forms of dystonia.
About Addex Therapeutics
Addex Therapeutics (www.addextherapeutics.com) is a development stage company focused on advancing innovative oral small molecules against rare diseases utilizing its pioneering allosteric modulation-based drug discovery platform. The Company’s two lead products are being investigated in Phase 2 clinical testing: dipraglurant (dipraglurant, an mGlu5 negative allosteric modulator or NAM) is being developed by Addex to treat Parkinson’s disease levodopa-induced dyskinesia (PD-LID) and rare forms of dystonia; and ADX71149 (mGlu2 positive allosteric modulator or PAM) is being developed in collaboration with Janssen Pharmaceuticals, Inc. to treat both schizophrenia and anxiety as seen in patients suffering from major depressive disorder. Addex is also advancing several preclinical programs including: GABA-BR positive allosteric modulator (PAM) for Charcot-Marie-Tooth (type 1a) disease, spasticity in patients with multiple sclerosis (MS), pain, overactive bladder and other disorders; and mGlu4 PAM for MS, Parkinson’s disease, anxiety and other diseases. 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. The Company uses its proprietary discovery platform to target receptors and other proteins that are recognized as essential for the therapeutic modulation of important diseases with unmet medical needs.
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Disclaimer: The foregoing release may contain forward-looking statements that can be identified by terminology such as "not approvable", "continue", "believes", "believe", "will", "remained open to exploring", "would", "could", or similar expressions, or by express or implied discussions regarding Addex Therapeutics, formerly known as, Addex Pharmaceuticals, its business, the potential approval of its products by regulatory authorities, or regarding potential future revenues from such products. Such forward-looking statements reflect the current views of Addex Therapeutics regarding future events, future economic performance or prospects, and, by their very nature, involve inherent risks and uncertainties, both general and specific, whether known or unknown, and/or any other factor that may materially differ from the plans, objectives, expectations, estimates and intentions expressed or implied in such forward-looking statements. Such may in particular cause actual results with allosteric modulators of mGlu2, mGlu4, mGlu5, GABA-BR or other therapeutic targets to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that allosteric modulators of mGlu2, mGlu4, mGlu5, GABA-BR or other therapeutics targets will be approved for sale in any market or by any regulatory authority. Nor can there be any guarantee that allosteric modulators of mGlu2, mGlu4, mGlu5, GABA-BR or other therapeutic targets will achieve any particular levels of revenue (if any) in the future. In particular, management’s expectations regarding allosteric modulators of mGlu2, mGlu4, mGlu5, GABA-BR or other therapeutic targets could be affected by, among other things, unexpected actions by our partners, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; competition in general; government, industry and general public pricing pressures; the company’s ability to obtain or maintain patent or other proprietary intellectual property protection. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Addex Therapeutics is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise, except as may be required by applicable laws.