Addex Therapeutics, a leading company pioneering allosteric modulation-based drug discovery and development, has achieved a positive Proof of Concept for its lead metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulator (PAM) compound series in a validated rodent model for multiple sclerosis (MS).
MS is a chronic inflammatory demyelinating auto-immune disease that affects the central nervous system (CNS), leading to serious disability.
"We are very excited that this promising Addex mGluR4 PAM series may offer a differentiated approach to treating MS," said Professor Ursula Grohmann, of University of Perugia, Italy, in whose laboratories one of these studies was performed. "These data confirm our previous observations, using an mGluR4 PAM tool compound called PHCCC, which demonstrated efficacy in the industry standard neuroinflammation model of MS, the Relapsing-Remitting Experimental Allergic Encephalomyelitis (RR-EAE) model. In this study, the mGluR4 PAM worked by promoting regulatory T-cell (Treg) formation and reversing pro-inflammatory T-cell release. Therefore, we believe that positive modulation of mGluR4 could potentially stop the destruction of myelin in MS in a robust and durable manner."
Addex lead chemical series is a highly selective orally available mGluR4 PAM and shows good pharmacokinetic properties for potential once-daily dosing. When administered once a day for 3 weeks at 10, 30 and 60 mg/kg sc, Addex mGluR4 PAM demonstrated a dose-dependent, statistically significant reduction in paralysis (clinical score) and the relapse rate in the RR-EAE model of MS in mice. The presentation of these data is being planned for a major international conference.
"Current MS therapies are primarily focused on reinstating motor function after an inflammatory attack, preventing new attacks, and preventing or treating disability and symptoms, such as spasticity. In addition, most of these therapies are primarily based on immunomodulatory strategies, and have serious compliance-limiting side effects", noted Graham Dixon, CSO of Addex Therapeutics. "We believe a well-tolerated, oral mGluR4 PAM would represent a major advance in the treatment of MS because of the novel and potentially broader mechanism; having the potential to not only treat symptoms, but slow disease progression and offer neuroprotection. We are now rapidly advancing this lead series towards a clinical candidate and conducting experiments to further elucidate the biological role of mGluR4 PAM in MS."
"Moving the lead compound from this series into full development in 2012 clearly illustrates our strategy of advancing innovative novel selective oral small molecule drug candidates against previously "undruggable" targets" said Bharatt Chowrira, CEO of Addex Therapeutics. "These data along with the recently announced data on the role of the mGluR4 PAMs in Parkinson's disease, the positive Phase 2 data for dipraglurant in Parkinson's disease levodopa-induced dyskinesia, the two Phase 2 clinical trials being conducted by our partner Janssen, and our GABABR PAM program advancing towards an IND filing later this year, demonstrate the power of Addex platform that continues to generate multiple, novel high value product opportunities."
High levels of glutamate are detected in patients with relapsing remitting multiple sclerosis. It has been suggested that glutamate may affect neuroinflammation via modulation of immune cells and/or neuroprotection through mGluR4 signaling. Therefore, pharmacological activation of mGluR4 may represent a novel therapeutic avenue addressing multiple aspects of MS pathology. The mGluR4 belongs to the Group III mGluRs (Class C G-Protein Coupled Receptor) and is negatively coupled to adenylate cyclase via activation of the Gαi/o protein. It is expressed primarily on presynaptic terminals, functioning as an autoreceptor or heteroceptor and its activation leads to decreases in neurotransmitter release from presynaptic terminals. The mGluR4 have unique distribution in key brain regions involved in multiple CNS disorders. In particular, mGluR4 is abundant in striato-pallidal synapses within the basal ganglia circuitry a key area implicated in movement disorders, like Parkinson's disease. In the immune system mGluR4 has been found on dendritic cells (DCs). Emerging data implicate mGluR4 in multiple indications such as multiple sclerosis, Parkinson's disease, anxiety, neuropathic and inflammatory pain, schizophrenia and diabetes.