Addex Announces Positive Data with ADX71441 in a Pre-Clinical Transgenic Model of Charcot-Marie-Tooth 1A Disease
ADX71441, a novel oral small molecule positive allosteric modulator, on track for Phase 1 clinical testing in the first half of 2013
Geneva, Switzerland, 7 January 2013 - Addex Therapeutics
(SIX:ADXN), a leading company pioneering allosteric
modulation-based drug discovery and development, announced today
achievement of 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
"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 overexpression 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 overexpression (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 (5 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" noted 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 1 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."
CMT1A is a rare hereditary motor and sensory neuropathy (HMSN) which causes demyelination of the peripheral nerves with a consequence of severely and uniformly reduced nerve conduction velocities and consecutive axonal loss. The disease leads to damage or destruction to the myelin sheath covering around nerve fibers. Nerves that stimulate movement, the motor nerves, are most severely affected. The nerves in the legs are affected first and most severely. Similar symptoms may appear in the arms and hands, which may include a claw-like hand. The disease is highly invalidating with cases of accompanying neurological pain and muscle loss. A combination of lower motor neuron-type motor deficits and sensory symptoms are observed: paresis and muscle atrophy develops, with areflexia. The chronic nature of the motor neuropathy will result in foot deformity, hammertoes, very high-arched feet, loss of lower leg muscle, which leads to skinny calves, numbness in the foot or leg, "steppage" gait (feet hit the floor hard when walking), foot drop (inability to hold foot horizontal) and weakness of the hips, legs, or feet. Involvement of the hands may follow as the disease progresses. Signs of sensory system dysfunction are common (70%) and include loss of vibration and joint position sense followed by decreased pain and temperature sensation. Onset of the disease is between age 5 and 25 years, with a prevalence of 1 in 5,000. Charcot-Marie-Tooth is one of the most common inherited nerve-related disorders passed down through families in an autosomal dominant fashion. Charcot-Marie-Tooth disease slowly gets worse. Some parts of the body may become numb, and pain can range from mild to severe. Eventually the disease may cause disability. There are no known cures for this debilitating condition. Duplication of a chromosome 17 fragment harbouring PMP22 (= CMT1A) represents 43% of the total CMT cases, whereas the yield of duplication detection rises to 70% in CMT1. PMP22 is an essential component of myelin expressed in all myelinated fibers in the PNS and is produced by Schwann cells. While PMP22 represents only 2-5% of the amount of peripheral myelin protein in rodents and humans, it is necessary for stabilizing compact myelin. However, PMP22 is not only an essential constituent of myelin, but too much or too little of the protein causes neuropathy, possibly by disturbing Schwann cell growth and differentiation.
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.
Addex Therapeutics (www.addextherapeutics.com) discovers and develops an emerging class of small molecule drugs, called allosteric modulators, which have the potential to be more specific and confer significant therapeutic advantages over conventional "orthosteric" small molecule or biological drugs. The Company uses its proprietary discovery platform to address receptors and other proteins that are recognized as attractive targets for modulation of important diseases with unmet medical needs. The Company's two lead products are being investigated in Phase 2 clinical testing: dipraglurant (ADX48621, an mGlu5 negative allosteric modulator or NAM) is being developed by Addex to treat Parkinson's disease levodopa-induced dyskinesia (PD-LID); and ADX71149 (mGlu2 positive allosteric modulator or PAM) is being developed in collaboration with Janssen Pharmaceuticals Inc. to treat schizophrenia and anxiety seen in patients suffering from major depressive disorder. Addex also is advancing several preclinical programs including: GABA-BR PAM for spasticity in MS, OAB and other disorders; mGlu4 PAM for Parkinson's, MS, anxiety and other diseases. In addition, Addex is applying its proprietary discovery platform to identify highly selective and potent allosteric modulators of a number of both GPCR and non-GPCR targets that are implicated in diseases of significant unmet medical need.
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Posted: January 2013