Addex Announces the Publication of Positive Data on the Efficacy of mGluR4 Positive Allosteric Modulator in Parkinson’s Disease Pre-Clinical Models
- Seminal Research Provides Greater Insight into the Role of Selective mGluR4 Modulation on Motor Symptoms
Geneva, Switzerland, 16 July 2012 – Addex Therapeutics (SIX:ADXN), a leading company pioneering allosteric modulation-based oral small molecule drug discovery and development, announced today the publication of positive pre-clinical efficacy data on its novel, highly selective oral small molecule positive allosteric modulator (PAM) of metabotropic glutamate receptor 4 (mGluR4), and its role in Parkinson’s disease. The results were published in the Journal of Pharmacology and Experimental Therapeutics (JPET) on 11 July 2012 as DOI:10.1124/jpet.112.196063. The researchers report the discovery of ADX88178, a novel, potent, brain penetrant and selective mGluR4 PAM, with drug-like properties, to explore the therapeutic potential of mGluR4 modulation in disease models. The research was conducted in collaboration with Merck & Co.
“There continues to be a significant need for new approaches to treat Parkinson’s disease. Research shows that increasing mGluR4 activity could normalize the aberrant synaptic transmission resulting from dopamine depletion and restore normal activity in the brain circuits that control movement,” explained Dr. Graham Dixon, Chief Scientific Officer at Addex. “The allosteric modulation approach enables modulation of mGluR4 with exquisite selectivity and our research provides compelling evidence and validation for mGluR4 activation for the treatment of Parkinson’s disease and a host of other indications through a non-dopaminergic approach.”
The publication entitled, “A potent and selective mGluR4 positive allosteric modulator improves movement in rodent models of Parkinson's disease” reported that ADX88178, an mGluR4 selective, potent, orally available and brain penetrant small molecule, has the potential to ameliorate the Parkinsonian symptoms as shown in two rodent models of dopamine depletion. ADX88178 was found to enhance glutamate-mediated activation of human and rat mGluR4 with EC50 values of 3.5 and 9.1 nM respectively. ADX88178 is a potent allosteric modulator of mGluR4 that shows excellent selectivity against other metabotropic glutamate receptors. Oral administration of ADX88178 in rats was associated with high bioavailability and was able to readily penetrate into the brain. ADX88178 was shown to reverse haloperidol-induced catalepsy in rats at 3 and 10 mg/kg. More importantly, the combination of ADX88178 (3, 10 and 30 mg/kg, p.o.) with a low dose of L-DOPA enabled a robust, dose-dependent reversal of the forelimb akinesia deficit induced to a bilateral 6-OHDA lesion of the striatum in rats. Similar synergistic effect was also demonstrated with Dopamine D2 agonist, Quinpirole. In addition, co-administration of ADX88178 (10 mg/kg, p.o.) did not worsen dyskinesia induced by L-DOPA in rats subjected to a unilateral 6-OHDA lesion of the medial forebrain bundle. This is consistent with an L-DOPA sparing action that may prove to be therapeutically useful for the management of motor symptoms of PD. ADX88178 is an invaluable proof of concept candidate in that it appears to be the most potent of the mGluR4 PAM molecules reported to date, and also has a greater window of selectivity against mGluRs, as well as other non-GPCR targets.
“This is another example of the power of Addex’ platform to identify and develop oral, highly selective, brain penetrant compounds with adequate drug-like properties where others faced “flat” structure-activity relationship (SAR) and a poor developability profile” commented Sylvain Celanire, Head of the mGluR4 program at Addex. “We are excited by these preclinical results and are looking forward to rapidly advancing our lead molecule into the clinic”
The metabotropic glutamate receptor 4 (mGluR4) belongs to the Group III mGluRs (Class C G-Protein Coupled Receptor) and is negatively coupled to adenylate cyclase via activation of the Gαi/o protein. It is expressed primarily on presynaptic terminals, functioning as an autoreceptor or heteroceptor and its activation leads to decreases in transmitter release from presynaptic terminals. MGluR4 is currently receiving much attention based primarily upon its unique distribution in key brain region involved in many CNS disorders. In particular, mGluR4 is abundant in striato-pallidal synapses within the basal ganglia circuitry a key area for motor control. MGluR4 PAM is therefore emerging as a promising target for the treatment of motor (and non motor) symptoms as well as a disease-modifying agent in Parkinson’s disease through a non-dopaminergic approach. In addition to the search for novel drugs that relieve motor symptoms of Parkinsonism, attenuating the ongoing degeneration of nigrostriatal neurons is also of increasing interest. Orthosteric mGluR4 agonist L-AP4 has demonstrated neuroprotective effects in a 6-OHDA rodent model of PD and first discovered allosteric potentiator (-)-PHCCC reduced nigrostriatal degeneration in mice treated with 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP). Those studies provide preclinical evidence suggesting that mGluR4 activators constitute a strong approach not only for symptomatic treatments of PD, but also potentially as disease modifiers.
Emerging data for other therapeutic indications such as anxiety, multiple sclerosis, neuropathic and inflammatory pain, schizophrenia and diabetes make mGluR4 a highly promising target for both CNS and non CNS diseases. In particular, anxiety disorders are among the most prevalent psychiatric disorders in the world, and are co-morbid with Parkinson’s disease. Addex has reported in 2010 that ADX88178 demonstrated oral efficacy in two preclinical rodent models of anxiety: the marble burying test in mice and EPM in mice and rats. The mGluR4-mediated specific effect has been also confirmed in knock-out mice. Therefore, mGluR4 activators may represent a new generation of anxiolytic therapeutics. More recently, mGluR4 PAM PHCCC demonstrated efficacy in a neuroinflammation model, the remitting-relapsing EAE model, by promoting regulatory T-cell (Treg) formation and reverse pro-inflammatory T-cell release. Therefore, positive modulation of mGluR4 could potentially stop the destruction of myelin in MS in a robust and durable manner.
Addex Therapeutics (www.addextherapeutics.com) discovers and develops an emerging class of small molecule drugs, called allosteric modulators, 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 address receptors and other proteins that are recognized as attractive targets for modulation of important diseases with unmet medical needs. The Company's two lead products are being investigated in Phase 2 clinical testing: dipraglurant (ADX48621, an mGluR5 negative allosteric modulator or NAM) is being developed by Addex to treat Parkinson's disease levodopa-induced dyskinesia (PD-LID); and ADX71149 (mGluR2 positive allosteric modulator or PAM) is being developed by our partner Janssen Pharmaceuticals Inc. to treat schizophrenia and anxiety seen in patients suffering from major depressive disorder. Addex also is advancing several preclinical programs including: GABA-BR PAM for overactive bladder, pain and other disorders; mGluR4 PAM for Parkinson's, MS, anxiety and other diseases; GLP1R PAM for type 2 diabetes; and mGluR2 NAM for treating Alzheimer's disease and depression. In addition, Addex has discovery programs to identify allosteric modulators of: receptor tyrosine kinase (RTK) superfamily, including TrkB PAM for treating neurodegenerative diseases (e.g. Alzheimer's, Parkinson's and Huntington's diseases); and TNF receptor superfamily, including TNFR1 NAM for inflammation (e.g. rheumatoid arthritis) and other diseases.
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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 mGluR2, mGluR4, mGluR5, GABABR, GLP1R, TNFR1, TrkB 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 mGluR2, mGluR4, mGluR5, GABABR, GLP1R, TNFR1, TrkB 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 mGluR2, mGluR4, mGluR5, GABABR, GLP1R, TNFR1, TrkB 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 mGluR2, mGluR4, mGluR5, GABABR, GLP1R, TNFR1, TrkB 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.