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
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
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."
About CMT1A
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.
About GABABR
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.
Tim Dyer
Chief Financial Officer
Addex Therapeutics
+41 22 884 15 61
PR@addextherapeutics.com
Disclaimer: The foregoing release may contain forward-looking
statements that can be identified by terminology such as "not
approvable", "continue", "believes", "believe", "will", "remained
open to exploring", "would", "could", or similar expressions, or by
express or implied discussions regarding Addex Therapeutics,
formerly known as, Addex Pharmaceuticals, its business, the
potential approval of its products by regulatory authorities, or
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implied in such forward-looking statements. Such may in particular
cause actual results with allosteric modulators of mGlu2, mGlu4,
mGlu5, GABA-BR or other therapeutic targets to be materially
different from any future results, performance or achievements
expressed or implied by such statements. There can be no guarantee
that allosteric modulators of mGlu2, mGlu4, mGlu5, GABA-BR or other
therapeutics targets will be approved for sale in any market or by
any regulatory authority. Nor can there be any guarantee that
allosteric modulators of mGlu2, mGlu4, mGlu5, GABA-BR or other
therapeutic targets will achieve any particular levels of revenue
(if any) in the future. In particular, management's expectations
regarding allosteric modulators of mGlu2, mGlu4, mGlu5, GABA-BR or
other therapeutic targets could be affected by, among other things,
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or delays or government regulation generally; unexpected clinical
trial results, including unexpected new clinical data and
unexpected additional analysis of existing clinical data;
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Should one or more of these risks or uncertainties materialize, or
should underlying assumptions prove incorrect, actual results may
vary materially from those anticipated, believed, estimated or
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press release as of this date and does not undertake any obligation
to update any forward-looking statements contained in this press
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Posted: January 2013
