GENEVA, Switzerland, Oct. 3, 2013 (GLOBE NEWSWIRE) --
Addex Therapeutics (SIX: ADXN), a leading
company pioneering allosteric modulation-based drug discovery and development
announced today 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-foldą0.49 and 0.93-foldą0.35, respectively). Baclofen given
orally twice daily reduced PMP22 mRNA expression at 3mg/kg (0.91-foldą0.25).
ADX71441 did not significantly reduced PMP22 mRNA expression at 1mg/kg (1.48-
foldą0.26) compared to CMT vehicle group (1.6-foldą0.19).
"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).