Addex Therapeutics, a leading organization pioneering allosteric modulation-based drug discovery and development, has reported 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 II 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.
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.
Activation of 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.