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    CVXL-0107: A CLINICALLY SAFE AND EFFECTIVE, NON-DOPAMINERGIC TREATMENT, FOR WEARING-OFF PARKINSON PATIENTS

    CVXL-0107 is a potent in-vitro and in-vivo glutamate release inhibitor. It significantly alleviated dyskinesia and extended duration of anti-parkinsonian action of levodopa, in the MPTP-lesioned monkey model of PD, and proved clinical safety on 110 volunteers/patients .

    CVXL-0107 clinically demonstrated (early phase IIa) symptomatic improvements on UPDRS motor scores, non-L-DOPA sensitive symptoms and dyskinesia during “On” time.

    CVXL-0107 entered a placebo-controlled phase IIa in December 2015 to confirm its efficacy in combination with optimal dose of levodopa on motor symptoms of Parkinson's disease (PD).

    CVXL-0107 was licensed to Clevexel Pharma by Domain Therapeutics in 2015.

    mGluR4 PAM as a promising treatment for Parkinson’s disease

    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, PXT002331entered a Phase I clinical evaluation concluded in September 2016. Results showed that the mGluR4 PAM candidate is safe and well tolerated at doses above those producing effects in PD preclinical models. On the basis of these data, a Proof of Concept Study is planned at the beginning of 2017.

    CVXL-0069: A DUAL A2A/A1-ANTAGONIST FOR THE TREATMENT OF SYMPTOMATIC AND COGNITIVE DEFICITS OF PARKINSON PATIENTS

    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).

    ADENOSINE RECEPTOR ANTAGONISTS FOR IMMUNO-ONCOLOGY

    Adenosine is a purine nucleoside which is produced under metabolic stress conditions to limit inflammation and immune responses. Many cancers are known to produce and sustain high concentrations of adenosine that, once in the tumor microenvironment, will exert various immunomodulatory effects via adenosine receptors (A1, A2A, A2B and A3) expressed on various immune cells.

    One of the consequences of this adenosine receptor activation will be a reduced ability of the immune system to attack the tumor. Indeed, cancer-produced adenosine will act as a protective shield preventing the natural immune response.

    Adenosine receptor antagonists are small molecules that can block this anti-immune response. Such agents have been shown previously to increase responses of standard immune checkpoint inhibitors (such as anti-PD1 or anti-CTLA4) in preclinical animal models of cancers.

    At Domain, we have discovered a unique chemical series of adenosine receptor antagonists that will be co-developed with Merck in immuno-oncology.

    MGLUR3 PAM PROGRAM FOR PARKINSON DISEASE

    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 has discovered and optimized a novel chemical series of NCEs showing strong mGluR3 PAM activity. Members of that series demonstrated proof of concept activities in multiple preclinical tests. This project received the support of the Michael J. Fox Foundation with three successive grants.

    This mGluR3 PAM series is now developed by Mavalon Therapeutics, an asset-centric company created by Domain Therapeutics and Medicxi in 2016.