Addex Reports Positive Preclinical Data for GABA-BR PAM Oral Small Molecule in Overactive Bladder
April 15, 2012 --
GENEVA, SWITZERLAND -- (Marketwire) -- 04/16/12 --
* Program on track for IND filing before end of 2012
* GABA-BR PAM compounds have potential in several major Indications
Addex Therapeutics (SIX: ADXN), a leading organization pioneering allosteric modulation-based drug discovery and development, announced today positive data from studies of its lead GABA-B receptor (GABA-BR) positive allosteric modulator (PAM) oral small molecule in validated disease-relevant preclinical models of overactive bladder (OAB).
"Current treatments for OAB are associated with marginal efficacy and significant side effects, which limits their use in treating the millions of people suffering from this condition," noted Dr. Sonia Poli, Head of Non- Clinical Development at Addex Therapeutics. "We believe that a well tolerated and efficacious oral treatment would represent a major advance in OAB treatment. We are delighted with the efficacy and safety profile of our GABA-B receptor PAM oral small molecules and are rapidly advancing the lead candidate towards a regulatory filing to initiate clinical trials by the end of 2012."
The Addex lead compound (ADX71441), an oral small molecule, with potential for once daily dosing, selectively activating GABA-BR function, was evaluated in female guinea pigs with bladder overactivity. ADX71441 (1 and 3 mg/kg, i.v.) induced a strong increase in inter contraction interval (ICI), a validated measure of bladder muscle control, in the first 15 min post- administration compared to vehicle. The efficacy of ADX71441 was well correlated with its pharmacokinetic properties. ADX71441 also significantly decreased micturition (urination) frequency compared to vehicle at the 1 mg/kg dose.
In an independent mouse diuretic stress-induced model of overactive bladder, administration of ADX71441 dose-dependently normalized urination latencies. ADX71441 also dose-dependently reduced micturition frequency in furosemide- treated animals. The magnitude of the effect in response to 10 mg/kg ADX71441 was similar to those observed in oxybutynin (a commonly prescribed anti- cholinergic medication for OAB) - treated animals. At this dose, however, unlike oxybutynin-treated animals, ADX71441 was well tolerated and had no marked effects on body temperature, locomotor activity or motor coordination.
These data on ADX71441 will be presented at the American Urology Association (AUA) Annual Meeting in Atlanta (May 19-23, 2012).
"We look forward to a regulatory filing for clinical testing for this molecule at the end of this year as we drive forward our strategy of filing one IND per year. These data along with our recent announcement of positive phase 2 data in Parkinson's disease levodopa-induced dyskinesia demonstrate the strength of our pipeline based on allosteric modulator oral small molecule platform and its ability to generate multiple high value novel product opportunities" said Bharatt Chowrira, President and CEO of Addex Therapeutics.
About Overactive Bladder
Approximately 11-16 million U.S. women suffer from overactive bladder, with some estimates claiming an equal number of men suffer from the condition. Patients with an overactive bladder feel a strong and sudden need to urinate, which is usually associated with frequent nocturia (excessive trips to the bathroom in the middle of the night). These symptoms arise due to involuntary contractions of bladder muscle when filling with urine. Current standard of care is inadequate due to limited efficacy and side effects, such as dry mouth, blurred vision, tachycardia, CNS effects, ranging from cognitive impairment to episodes of psychosis, which significantly limit their use.
About GABA-BR Activation
Activation of gamma-aminobutyric acid subtype B (GABA-B) receptor, a Family C class of GPCR, is clinically & commercially validated. Generic GABA-B receptor agonist, baclofen, is marketed for spasticity and some spinal cord injuries, and used for OAB, but is not commonly used due to severe CNS side effects of the drug and rapid clearance. Orthosteric GABA-B receptor agonists have also shown clinical validation in gastroesophageal reflux disease (GERD). Addex' GABA-B receptor PAMs have shown efficacy in multiple preclinical models including: OAB, pain, osteoarthritis pain and anxiety.
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. Addex also is advancing several preclinical programs including: GABA-BR PAM for overactive bladder, pain and other disorders; mGluR4 PAM for Parkinson's, anxiety and other diseases; GLP1R PAM for type 2 diabetes; mGluR2 NAM for treating Alzheimer's disease and depression; and FSHR/LHR NAM for sex hormone dependent tumors & reproductive system disorders. 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.
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, FSHR/LHR, GLP1R, TNFR1, RTK, 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, FSHR/LHR, GLP1R, TNFR1, RTK, 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, FSHR/LHR, GLP1R, TNFR1, RTK, 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, FSHR/LHR, GLP1R, TNFR1, RTK, 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.
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