The regulatory authorities in the Netherlands have approved the Addex Therapeutics' clinical trial application (CTA) to initiate a phase 1 study of ADX71441, a GABA-B receptor positive allosteric modulator (PAM).  The company plans to initiate clinical testing at the Centre of Human Drug Research in Leiden, in the first half of 2013 and expects to deliver top-line safety, pharmacokinetic and biomarker data by year end.  

Addex previously announced achievement of positive Proof of Concept for ADX71441 in a validated pre-clinical model of Charcot-Marie-Tooth 1A (CMT1A) neuropathy as well as a number of other disease indications.  The Company plans to move quickly to phase 2a testing of ADX71441 for the treatment of CMT1A, an orphan disease, in 2014.  The CTA was submitted to the authorities in March 2013.

"We are delighted to receive this approval for ADX71441 and to be able to initiate clinical development of this exciting molecule," said Sonia Poli, vice president, Translational Sciences and Project Leader for the ADX71441 programme at Addex.  "We believe the speed at which the Dutch authorities approved the CTA attests to the quality of our preclinical data and related material.  We plan to seek orphan drug designation for this compound in the treatment of CMT1A and attempt to take advantage of a rapid development and regulatory path to market."

ADX71441 is a potent, selective, orally available small molecule that is brain penetrant and shows good pharmacokinetic properties for once-daily dosing. Activation of gamma-aminobutyric acid subtype B (GABA-B) receptor, a Family C class of GPCR, is clinically and commercially validated in several indications including spasticity, overactive bladder (OAB), spinal cord injuries and gastroesophageal reflux disease. However, generic GABA-B receptor agonists are not commonly used in certain disorders due to compliance-limiting drug side effects, receptor sensitization, rebound effect and rapid clearance. An oral once-daily small molecule activator of GABA-B receptor without the issues associated with the current GABA-BR agonists could dramatically change the treatment paradigm for a number of diseases.  Allosteric modulation is ideally suited to overcome such limitations of an agonist. ADX71441 has shown efficacy in multiple preclinical models including: CMT1A, OAB, pain, obsessive-compulsive disorder, alcohol binge drinking and anxiety.  The United States Patent and Trademark Office recently granted Addex a composition of matter patent covering ADX71441 and other GABA-B receptor PAMs. The claims of the issued patent also cover pharmaceutical composition and method of treatment using such GABA-BR PAMs.

"This is an important accomplishment for the company as we continue to execute on our strategy to focus on the clinical development of novel compounds to treat orphan diseases," said Graham Dixon, chief scientific officer at Addex. "With this CTA approval, our pipeline consists of four phase 2 programmes, one phase 1 programme and one preclinical programme which we hope to advance to phase 1 testing by the end of next year.  This robust pipeline represents multiple, strong value drivers which we believe have the potential to generate significant shareholder value."

CMT1A is a rare (1:5,000) hereditary motor and sensory demyelinating peripheral neuropathy (also known as Hereditary Motor and Sensory Neuropathy, HMSN) which is caused by an intrachromosomal duplication and consecutive toxic overexpression of the PMP22 gene on chromosome 17. CMT1A is one of the most common inherited peripheral nerve-related disorders, which is passed down through families in an autosomal dominant fashion. CMT1A disease becomes evident in young adulthood and slowly progresses with distally pronounced muscle weakness and numbness. Pain can range from mild to severe. The disease can be highly debilitating, including being wheelchair bound, and is often accompanied by severe cases of neurological pain. There is no known cure for this incapacitating disease.  Data obtained with ADX71441 and a GABA-BR agonist seems to suggest that positive modulation of the GABA-B receptor could lower toxic PMP22 overexpression and potentially delay the progression of the disease and offer a unique therapeutic opportunity for CMT1A patients.

Addex Therapeutics is a development stage company focused on advancing innovative oral small molecules against rare diseases utilizing its pioneering allosteric modulation-based drug discovery platform.