Technology for the treatment of neurodegenerative diseases

Selection Patent

Due to the age of the patent, it was decided at the end of the 2020 to maintain the rights only in Europa (France and United Kingdom) waiting for the filing of a worldwide selection patent in US which has been done at the beginning of 2024. Such a strategy will enable to rejuvenated the assets of the R&D and certainly increase the intellectual property of Alzex being of newly protected technology.

The choice of a selection patent relies on important chemical and biological improvements of the original family of drugs with the discovery of a particular sub-family of prodrugs: such prodrugs present the same biological assets than the original molecules but benefit from strong improvement without any geno and cardiotoxicity often observed with the first family.

Currently, positive proof of concept and severe selection process allow Alzex to hold 3 lead molecules in its portfolio. These drug candidates are new chemical entities which have been successfully tested on animals (Irwin test) before entering in the preclinical phase: discriminating genotoxicity and cardiotoxicity trials are favorable which allows the continuation of the preclinical studies to prepare the launching of phase 1 trials.

These preclinical trials are of the utmost importance as they are go/no-go milestones. So far, our best drug candidate displays very good in vitro ADMET properties (appendix 1) and all indicators are on green to continue the preclinical phase.

The synthesis of the best prodrug has been already optimized starting from simple and accessible products and reagents. The 12 steps synthesis allows an overall 20% yield starting from commercial meta-anisidine (20 $/ton), it is free to operate and the last steps are protected by the parent patent. Nonetheless the synthesis has still to be reworked in view of the future GMP preparation.

Concerning the 3 lead molecules and particularly the best one named VFP-015, both detailed synthesis description, analytical data and current biological trials results have been be included in the recent provisional patent application. In our labs both in Canada and France, we are in the process of establishing final formulations delivery system ready to be included in the Regulatory Functional Plan and be part of a submission for requesting authorization of animal and human toxicology-and clinical trials.

The regulatory development of our best lead molecule will be completed and enriched by some parallel testing of active adjuvants which could be capable to reinforce the power of our lead (symptomatic action) due to their antioxidative and anti-inflammatory synergetic activities.

Prodrug Scope Extension

Furthermore, thanks to previous research work, the French team has developed selective carriers by optimizing the Bodor dihydropyridines mimicking NADH into more suitable structures. Current specific carriers targeting Brain Pharmaceuticals have been designed in order to optimize the BBB Crossing by improving the physicochemical properties (stability, toxicity, solubility...) of API derived prodrugs (galantamine, leucettamine, INDY...).

The advantages of this Chemical Delivery System are their easy chemical access associated with large optimization facilities and their selectivity for brain release due to the targeted enzymatic oxidative cleavage. Such a strategy implies the knowledge of the biological targets and the choice of promising pharmaceuticals; it could be extended to most brain diseases which require crossing of the BBB, e.g. Parkinson, depression, cancer...

Some preliminary results will lead to the filing of a provisional patent application in the next future in order to protect further studies.

Biological Data

Selected from some drug/prodrug couples, 3 lead candidates have been identified which displays favorable ADME properties and no risks of geno and cardiotoxicity (Ames, micronucleus or hErg assays). Irwin test on rats showed us that these compounds are highly potent by per os administration with an expected central effect at very low doses. (table 1).

So, new couples of drug/prodrug were prepared monitoring their in vitro activity against AChE. Among them, 2 couples showed a better selectivity than VFP-011 regarding the ratio of their activities (Table 1). They were consequently evaluated in Irwin tests in the same conditions than VFP-011.

The obtained results indicate that the best lead candidates VFP-013 and VFP-015, administered per os on rats induced dose-dependent central effect (long-lasting tremor with hypothermia) associated with very slight signs of peripheral effects for the highest administered doses. Moreover, the preliminary in vitro toxicity evaluation of VFP-013 and VFP-015 were performed. For both compounds, no mutagenic potential (Ames and micronucleus assays) and no cardiotoxicity (hErg and Nav 1.5 IC50 assays) were detected.