Recent studies have demonstrated that the most promising alternative to dopaminergic treatments resides in the glutamatergic correction of some neuronal degeneration of the substantia nigra, observed in Parkinson’s disease (PD). Several lines of evidence have demonstrated the contribution of certain metabotropic glutamate receptor subtypes to this process, in particular, mGluR4. As a consequence, mGluR4 has been suggested to be a primary target for PD.
A newly optimised mGluR4 PAM series has been discovered, developed and licensed to Prexton Therapeutics, with the objective to generate a clinical candidate for PD. PXT002331 has been identified as the most promising lead compound of the series. This compound has been validated in many systems including all standard rodent models of PD. The development of this compound has been further pursued with a robust validation in MPTP-treated non-human primates, which is the most accurate animal model of PD. It can be noted that this study has been performed with the support of the Michael J. Fox Foundation.
At the end of 2015, regulatory agencies have given the green light for a clinical evaluation of PXT002331 and the first patients are scheduled to be administered in February 2016. The objective of this first trial is to test the tolerability of the compound before engaging a Proof of Concept Study at the beginning of 2017.
CVXL-0069 is a dual A2A/A1 receptor antagonist (A2A antagonists were shown to ameliorate movement control in animal models and L-DOPA treated PD patients). It showed efficacy on haloperidol induced catalepsy, demonstrating in vivo interaction with Dopamine signaling.
CVXL-0069 preliminary results obtained in MPTP-treated macaques with optimal L-DOPA indicates ameliorations of the time course of disability scores.
CVXL-0069 is positioned as best-in-class in the A2A market for early PD patient treatment, and first-in-class as a dual A2A and A1 inhibitor (potential synergistic activity: motor symptom improvement along with cognitive dysfunction treatment).
CVXL-0069 has the potential to cover most of the spectrum of PD-related symptoms (including cognitive impairment).
CVXL-0069 is currently in regulatory preclinical development and was licensed to CleveXel Pharma by Domain Therapeutics’ Specific Purpose Vehicle, Kaldi Pharma (press release).
mGluR3 positive allosteric modulator (PAM) represents a novel promising disease-modifying strategy for neurodegenerative disorders such as Parkinson’s disease. Indeed, mGluR3 activation or potentiation was shown to induce in situ production of GDNF, a clinically validated neurotrophic factor involved in survival and regeneration of dopaminergic neurons.
Domain Therapeutics’ mGluR3 (PAM) program consists of a series of NCEs represented by the lead DT011088. These compounds show nanomolar PAM activity on mGluR3, selectivity over mGluR2 and the other mGluR subtypes and excellent early ADME properties.
Proof of concept was obtained in vitro with DT011088, which was also shown to induce GDNF expression in vitro and in vivo.
This project received the support of the Michael J. Fox Foundation with three successive grants.
A recent publication (Mittal D et al; Cancer Res. 2014) suggests that combining an A2A-antagonist with an anti-PD1 monoclonal antibodies is able to significantly reduce metastatic burden (also demonstrated with anti-CTLA 4 and anti-TIM 3) and prolong survival in animal cancer models. Thanks to its proprietary technology, Domain has identified a novel chemical series of A2A-antagonists distinct from xanthines or furan-heterocycles known to be associated with metabolism issues. This series includes molecules with dual A2A/A1-antagonism property such as CVXL-0069, currently developed by Clevexel for Parkinson disease, as well as selective A2A-antagonists or dual A2A/A2B-antagonists that are positioned for immuno-oncology/oncology treatments. These new A2A-antagonists present clear differentiating points over the standard A2A-antagonists that were initially developed for CNS indications, including reduced brain penetration and A2B blocking activity, shown to reduce tumor growth, angiogenesis and metastasis.
The A2A-antagonist asset is currently managed by Domain Therapeutics’ Specific Purpose Vehicle, Kaldi Pharma (press release).
mGluR2 constitutes an emerging target for many neurodegenerative and neuropsychiatric disorders. Numerous reports have shown that blocking the mGluR2 subtype is able to improve cognitive symptoms and relieve depression in preclinical models.
Based on its expertise in CNS, Domain recently identified a series of mGluR2 NAMs for the treatment of specific non-core symptoms of Parkinson’s disease. The series consists of nanomolar, non-competitive antagonists of mGluR2, with excellent selectivity, PK and eADME profiles, and early proof-of-concept pro-cognitive activity in a rodent model.