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 some 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 optimized mGluR4 PAM series has been discovered, developed and licensed to Prexton Therapeutics, an asset centric company dedicated to the objective to nominate and further develop a clinical candidate for PD. PXT002331 has been identified as the most promising lead compound of the series (Charvin et al, 2017). 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. This study has been performed with the support of the Michael J. Fox Foundation.
In 2016, Prexton successfully led PTX002331 (Foliglurax) through a Clinical Phase I demonstrating its safety, tolerance and excellent pharmacokinetic profile. Mid-2017, Prexton was the first company to initiate a Phase II with a mGluR4 PAM, across six countries in Europe (study NCT03162874, AMBLED). The objectives of the trial are to assess the safety and tolerability of Foliglurax, and its efficacy in reducing motor complications of Levodopa therapy in subjects with PD experiencing end-of-dose wearing off and Levodopa-Induced dyskinesia. In March 2018, Prexton was acquired by Lundbeck (press release).
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).
Tumor microenvironment is characterized by specific pro-tumorigenic features among which, i) an anatomic structure responsible of a low delivery of anticancer drugs, ii) the abnormal histology promoting the metastatic cell extravasation and stimulating metastatic dissemination throughout the body, iii) a poorly functionality responsible of hypoxic immunosuppressive environment. SGL10060 is a recombinant protein, mutant version of the Semaphorin3a (Sema3a), discovered by an academic group from Torino University, Italy.
Sema3a is a natural ligand of PlexinA4 and Neuropilin 1, two receptors inducing respectively a tumor suppressor- and a protumorigenic-activity. SGL10060 was designed to specifically activate PlexinA4 and to be more stable than the natural Sema3a. This candidate is protected by strong IP.
In 2017, Domain Therapeutics incorporated SeaGull, an asset-centric company dedicated to move forward SGL10060, as a first-in-class candidate, through pre-IND studies up to clinical proof of concept.
In 2014, a publication (Mittal D et al; Cancer Res. 2014) suggests that combining an A2A-antagonist with an anti-PD1 monoclonal antibody is able to significantly reduce metastatic burden (also demonstrated with anti-CTLA 4 and anti-TIM 3) and to extend survival in animal cancer models. Thanks to its expertise in adenosine pharmacology, Domain Therapeutics has identified a novel chemical series of A2A-antagonists distinct from xanthines or furan-heterocycles, and presenting clear differentiating points over the standard A2A-antagonists initially developed for CNS indications.
In early 2017, Domain Therapeutics entered into a license and collaboration agreement with Merck to develop A2A antagonists in immuno-oncology (press release).
mGluR3 positive allosteric modulator (PAM) represents a novel promising disease-modifying strategy for neurodegenerative disorders such as Parkinson’s disease (PD). 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.
This project received the support of the Michael J. Fox Foundation with three successive grants.
In 2016, Domain Therapeutics and Medicxi incorporated Mavalon Therapeutics, an asset centric company focused on the development of Domain’s mGluR3 PAM for the treatment of PD (press release).
Active compounds targeting membrane receptors essentially binds to extracellular or intracellular part of the targeted proteins. Domain Therapeutics identified a technology from Strasbourg University aiming at designing peptides able to interfere with the transmembrane domain of receptors. Such compounds constitute a brand-new family of modulators with unique features.
In 2015, Domain Therapeutics participated to incorporate PeptiMimesis, a NewCo entity fully dedicated to exploit transmembrane peptide technology in oncology and CNS and supported by seed and non-dilutive funds (press release).
mGluR3 receptor was shown to be involved in multiple tumorigenic processes in different tumor types. In 2012, the correlation between the expression of mGluR3 and the MGMT-mediated resistance to temozolomide in glioblastoma stem cells was established (Ciceroni & al, Cell Death & Differentiation). The article showed the capacity of mGluR3 antagonists to potentiate the temozolomide effects both in vitro and in vivo.
Moreover, in the clinic such paradigm was also confirmed by a better responsiveness to temozolomide treatment and an extended survival in patients holding a low expressing mGluR3-glioblastoma vs a high expressing mGluR3-glioblastoma.
Based on its expertise on metabotropic glutamate receptors, Domain Therapeutics has developed two series of mGluR3 NAMs currently at the lead stage.
Group III metabotropic glutamate receptors mediate important neuroprotective and anti-inflammatory effects. mGluR4 is expressed in dendritic cells and constitutes a strategic target to reverse the release of interleukines responsible of neuroinflammation-associated syndrome such as multiple sclerosis.
Beside its first mGluR4 PAM series for Parkinson’s disease, Domain Therapeutics has discovered and is moving forward a second series compounds, independent from the first one, with nanomolar mGluR4 PAM potency, good PK profile and solid patent protection as a new source of candidates for autoimmune-disease.
Following the signature with 5 French TTOs of an innovative commercial and scientific partnership to accelerate drug development, Domain Therapeutics has incorporated from the SATT Conectus an NPFF antagonist program for the treatment of pain. NPFF pathway is involved in the development of opioid-induced hyperalgesia which can be blocked by the treatment with specific small molecule antagonists.
Initial proof-of-concept in multiple pain animal models have been generated with the NPFF antagonists developed by Domain Therapeutics. The program is currently at the lead stage.
Immune checkpoint (ICP) modulators (PD1, PDL1, CTLA4) constitute a groundbreaking approach in the field of anticancer therapies but more and more evidences highlight mechanisms of resistance contributing to limit the efficacy of ICP treatments in the clinic.
Domain Therapeutics owns and is developing a series of proprietary hit-to-lead stage small molecules against an undisclosed GPCR target involved in immunosuppressive mechanism of resistance against ICP modulators. It was already demonstrated that the combination of such GPCR antagonists with ICP inhibitors is able to restore anticancer efficacy in different animal tumor models (melanoma and colorectal cancer).