Addex ADX71441 Dose Dependently Reduced PMP22 Expression Comparable to Baclofen in a Pre-Clinical Transgenic Model of Charcot-Marie-Tooth 1A Disease

Addex Therapeutics, a leading company pioneering allosteric modulation-based drug discovery and development have announced that ADX71441 dose dependently reduced PMP22 expression comparable to baclofen in a preclinical transgenic model of Charcot-Marie-Tooth 1A disease (CMT1A).

ADX71441 was studied in the transgenic CMT1A rat model which displays a 1.6-fold PMP22 overexpression (mRNA level) and exhibits clinical abnormalities, such as reduced nerve conduction velocity and lower grip strength that closely mimic findings in CMT1A patients. In a 5 day comparative study with baclofen, a dose-response was successfully established for orally administered ADX71441. ADX71441 given orally once daily significantly reduced PMP22 mRNA expression at 3 mg/kg and 6 mg/kg (0.98-fold±0.49 and 0.93-fold±0.35, respectively). Baclofen given orally twice daily reduced PMP22 mRNA expression at 3mg/kg (0.91-fold±0.25). ADX71441 did not significantly reduced PMP22 mRNA expression at 1mg/kg (1.48-fold±0.26) compared to CMT vehicle group (1.6-fold±0.19).

"These findings in the CMT1A transgenic rat model which show that ADX71441 has comparable efficacy to Baclofen are very promising," Professor Michael Sereda, of the Max-Planck Institute of Experimental Medicine, Göttingen, Germany, in whose laboratories the study was performed. "These results are consistent with previous reported data which suggest that intraperitoneal application of ADX71441 could lower toxic PMP22 overexpression and potentially delay the progression of the disease. Oral application of ADX71441 may therefore offer a unique therapeutic opportunity for CMT1A patients."

About Charcot Marie Tooth Disease Type 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.

About GABA-B Activation and ADX71441
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. ADX71441 is a potent selective positive allosteric modulator (PAM) which potentiates GABA responses at the GABA-B receptor. ADX71441 is a novel, first-in-class, oral, small molecules that has demonstrated excellent preclinical efficacy and tolerability in several rodent models of pain, anxiety, addiction and overactive bladder (OAB) and have also proven efficacy in a genetic model of Charcot-Marie-Tooth Type 1A disease (CMT1A). ADX71441 differs from the generic drug baclofen in that it is a positive allosteric modulator rather than an orthosteric agonist at the GABA-B receptor. ADX71441 only acts when the natural ligand (GABA) activates the receptor, and therefore respecting the physiological cycle of activation. It has been proposed that PAMs produce less adverse effects and lead to less tolerance than direct agonists (May and Christopoulos 2003; Langmead and Christopoulos 2006; Perdona et al. 2011; Urwyler 2011; Gjoni et al., 2008; Ahnaou et al).