Addex Therapeutics, a leading company pioneering allosteric modulation-based drug discovery and development, has reported a positive Proof of Concept for its lead GABA-B receptor (GABA-BR) positive allosteric modulator (PAM) compound, ADX71441, in a validated pre-clinical model of Charcot-Marie-Tooth 1A (CMT1A). 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 with wheel chair-boundness and is often accompanied by severe cases of neurological pain. There is no known cure for this incapacitating disease.

"We are very excited about the promising results obtained with the Addex GABA-BR PAM candidate," said Professor Michael Sereda, of the Max-Planck Institute of Experimental Medicine, Göttingen, Germany, in whose laboratories the study was performed. "Current CMT1A therapies are primarily symptomatic such as physiotherapy and only focus on the manifestations of the disease, while the data obtained with the Addex compound seem to suggest that positive modulation of GABA-B receptor could lower toxic PMP22 over expression and potentially delay the progression of the disease and offer a unique therapeutic opportunity for CMT1A patients.”

ADX71441 is a potent, selective, orally available small molecule that is brain penetrant and shows good pharmacokinetic properties for once-daily dosing. Addex GABA-BR PAM was studied in the transgenic CMT rat model which has 1.6-fold PMP22 over expression (mRNA level) and exhibits clinical abnormalities, such as reduced nerve conduction velocity and lower grip strength that mimic findings in CMT1A patients. Nine week oral therapy of ADX71441 in CMT rats (five weeks every other day at 10 mg/kg followed by 4 weeks at 5 mg/kg every day) down regulated PMP22 mRNA, reduced the amount of hypo-myelinated axons and increased compound muscle action potentials in peripheral nerves when compared to vehicle treated CMT rats. It also prevented grip strength loss in CMT rats compared to wild type rats.

"These data confirm previous observations obtained using a GABA-BR agonist and the GABAB1-/- mice (knock-out mice), which identified the importance of GABA-BR in the inhibition of the proliferation and in the reduction of the synthesis of specific myelin proteins, in particular PMP22," said Sonia Poli, VP Non Clinical Development at Addex. "These and other data further reinforce the central role of GABA-BR in a broad range of important diseases and conditions, including spasticity, Fragile X, autism, pain, anxiety, obsessive-compulsive disorder, overactive bladder and alcohol binge drinking.”

"We are rapidly advancing ADX71441 into clinical development. Phase I clinical testing with this compound is planned for the first half of this year, initially for the treatment of spasticity associated with multiple sclerosis (MS),” said Graham Dixon, CSO at Addex. "These data are very encouraging as they indicate that the compound may also have a therapeutic benefit in treatment of patients with this debilitating rare disease."

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 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: CMT1A, OAB, pain, osteoarthritis pain and anxiety.