Addex ADX71441 Demonstrates Preclinical Analgesic Effects
Support Potential of ADX71441 to treat Irritable Bowel Syndrome, Interstitial Cystitis and Painful Bladder Syndrome
Geneva, Switzerland, 9 May 2017 – Addex Therapeutics (SIX: ADXN) announced today positive results from multiple preclinical studies of ADX71441, a positive allosteric modulator (PAM) of the gamma-aminobutyric acid subtype B (GABAB) receptor, in models of visceral hyperalgesia. The studies were led by Prof. Jyoti N. Sengupta at the Medical College of Wisconsin, with the support of a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), a division of the US National Institute of Health. The findings strongly support the potential of ADX71441 in treating hyperalgesia in colonic inflammation (colitis) and bladder inflammation (cystitis). Chronic visceral pain syndromes related to the gastrointestinal or urinary tract represent an important unmet medical need as they can significantly impact the patient’s quality of life.
“These data represent an important step forward in the understanding of the role played by GABAB receptors in visceral pain and the potential of ADX71441 in large unmet medical needs, such as irritable bowel syndrome, interstitial cystitis and painful bladder syndrome,” said Sonia Poli, CSO of Addex. “We look forward to continuing our collaboration with Prof Sengupta’s group, and further evaluating the possibility of conducting clinical trials for ADX71441 in these compelling indications.”
The effect of ADX71441 was studied in reliable, reproducible and quantifiable preclinical models of visceral pain, which included behavioral measurements and electrophysiology recordings(1). Visceral motor reflex after colorectal distension (CRD) and urinary bladder distension (UBD) was significantly decreased (p<0.05) following systemic administration of ADX71441 (5, 10 and 50 mg/kg ip). The visceral analgesic effect of ADX71441 did not affect the normal function of the bladder as assessed by cystometry. In electrophysiology experiments, ADX71441 demonstrated significant inhibition of the response of UBD responsive lumbo-sacral (LS) spinal dorsal horn neurons to graded bladder distension. The effect was observed in spinal intact rats, but not in cervical (C1-C2) spinal transected rats. It also produced a moderate decrease in the spontaneous firing of these neurons in spinal intact rats. ADX71441 had no effect on the mechano-transduction properties or the spontaneous firing of UBD-sensitive pelvic nerve afferent (PNA) fibers. The current behavioral experiments to assess pain and the electrophysiology results indicate that ADX71441 produces visceral analgesia in animal models of cystitis and colitis. The results indicate that ADX71441 produces this analgesic effect primarily by acting at the supra-spinal sites without affecting bladder motility.
“We thank the NIDDK for their support and Prof. Sengupta and his team for their dedication to this important research with ADX71441,” commented Tim Dyer, CEO of Addex. “These compelling results are a further example of how we are leveraging our collaborations with leading academic institutions to better understand the potential of the promising candidates in our pipeline.”
(1) Jyoti N. Sengupta Handb Exp Pharmacol. 2009; (194): 31–74
About GABA B receptor
The GABAB receptor is clinically & commercially validated. Generic GABAB receptor agonist, baclofen, is marketed for spasticity and some spinal cord injuries, and French health authorities have approved its use for the treatment of alcoholism. Baclofen is also used off label for a number of other indications including overactive bladder (OAB), but its utility is limited due to variety of side effects and rapid clearance, requiring frequent administration of higher doses.
ADX71441 is a potent selective positive allosteric modulator (PAM) which potentiates GABA responses at the GABAB receptor. ADX71441 is a novel, first-in-class, oral, small molecule that demonstrated excellent preclinical efficacy and tolerability in rodent models of pain, anxiety, OAB, alcohol use disorders, nicotine dependence and in a non-human primate model of cocaine use disorder. ADX71441 has also proven efficacy in a genetic model of Charcot-Marie-Tooth Type 1A disease (CMT1A). ADX71441 has a different molecular mechanism from the generic drug baclofen in that it is a positive allosteric modulator, rather than an orthosteric agonist at the GABAB receptor, with a longer half-life, suitable for once daily administration. ADX71441 only acts when the natural ligand (GABA) activates the receptor, 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.
Addex Therapeutics (www.addextherapeutics.com) is a biopharmaceutical company focused on the development of novel, orally available, small molecule allosteric modulators for neurological disorders. Allosteric modulators are an emerging class of small molecule drugs which have the potential to be more specific and confer significant therapeutic advantages over conventional "orthosteric" small molecule or biological drugs. Addex's allosteric modulator drug discovery platform targets receptors and other proteins that are recognized as essential for therapeutic intervention - the Addex pipeline was generated from this pioneering allosteric modulator drug discovery platform. Addex's lead drug candidate, dipraglurant (mGluR5 negative allosteric modulator or NAM) has successfully completed a Phase 2a POC in Parkinson's disease levodopa-induced dyskinesia (PD-LID), and is being prepared to enter registration trials for PD-LID with support from the Michael J. Fox Foundation for Parkinson's Research (MJFF). In parallel, dipraglurant's therapeutic use in dystonia is being investigated with support from the Dystonia Medical Research Foundation (DMRF). Addex's second clinical program, ADX71149 (mGluR2 positive allosteric modulator or PAM) is being developed in collaboration with Janssen Pharmaceuticals, Inc for epilepsy. In addition, ADX71441 (GABAB receptor PAM) has received regulatory approval to start Phase 1 and is being investigated for its therapeutic use in Charcot-Marie-Tooth Type 1A disease (CMT1A), cocaine and alcohol use disorder and nicotine dependence. Discovery programs include mGluR4PAM, mGluR7NAM, TrkBPAM and mGluR3NAM & PAM.
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