Development of a drug-candidate: a phosphorus-based dendrimer with anti-inflammatory and immuno-modulatory properties – TREE-DRUG

The regulatory preclinical development of a drug-candidate goes through the following steps:
1) studies of crystallization of the molecule,
2) synthesis of a certified batch of the molecule (in the 500 g to 1 kg range),
3) studies of the physico-chemical and biological stability of the molecule,
4) statutory toxicity studies in two animal species (among which a non-rodent species): acute (a single administration), sub-acute (short term repeated administration) and chronic (long term repeated administrations) toxicity,
5) preliminary studies regarding biodistribution.

These steps have to be performed in GLP («Good Laboratory Practices«) conditions, therefore most of them require to be outsourced to accredited CROs.

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Chronic Inflammatory Diseases (CID) are pathological situations resulting from an inappropriate and uncontrolled response of the immune system either to endogenous stimuli (auto-immunity) or exogenous stimuli (environment). CID include Multiple Sclerosis (the commonest inflammatory neurodegenerative disease among young people in the World with 2 million persons affected), Rheumatoid Arthritis (prevalence between 0.5 and 1% in developed countries) and Alzheimer’s Disease (prevalence around 1%, strong increase scheduled in the coming decades). Moreover, CID are often characterized by an imbalanced Redox metabolism leading to tissue-localized or sometimes systemic oxidative stress. CID dramatically impact the quality of life of patients, they are disabling and finally life-threatening diseases. In general, treatments are based on graduate therapeutic protocols to reduce inflammation, from classical Non-Steroidal Anti-Inflammatory Drugs (NSAID) to more recent bio-engineered recombinant human (rh) proteins. The most of them are monoclonal antibodies targeting inflammatory cytokines and their receptors. Some of them are soluble receptors aimed at neutralizing soluble cytokines. Unfortunately, all are expensive (around 20,000 € / patient / year for long term treatments which only suspend the disease without curing it), they have deleterious secondary effects and therefore present multiple contra-indications, and a significant proportion of patients do not respond to these biological treatments (20% on average, depending on the disease). Finally, although they have proven their efficiency to improve the quality of life of patients, most patients are not getting better, they are just deteriorating at a less rapid rate. In this context, there is a real unmet need for innovating molecules targeting the different aspects of CID.
DENDRI-DRUG is based on our previous findings that a new family of synthetic molecules, namely phosphorus-based dendrimers, have anti-inflammatory and immuno-modulatory properties. More recently, we have discovered that these molecules are also able to interfere with oxidative metabolism. These biological properties are targeted towards the myeloid lineage (monocytes/macrophages and derived cells).
Dendrimers (“tree-like molecules”) are nonlinear polymers whose size and structure are perfectly defined. In particular, we have shown that a phosphorus-based dendrimer capped with Aza-BisPhosphonate surface functions (the so-called dendrimer G1-ABP) dramatically inhibits inflammation and bone resorption in a mouse model of experimental arthritis relevant to Rheumatoid Arthritis. Moreover, we have also proved the concept of the efficacy of dendrimer G1-ABP in mouse model of Experimental Autoimmune Encephalomyelitis (EAE, equivalent to Multiple Sclerosis in animal models).
Interestingly, as dendrimers are very innovative nano-sized molecules but far from the standards of the pharmaceutical industry, we have already gathered preliminary non-clinical data regarding toxicity, tolerance and immuno-safety of the molecule in mouse and non-human primate models.
Taken all together, we handle strong scientific arguments to think that phosphorus-based dendrimer G1-ABP is promising in human healthcare. This drug-candidate is the paradigm of a new family of innovating molecules which could revisit the treatment of some CID. The objective of DENDRI-DRUG is to face the regulatory requirements of the French National Agency for Medicine Safety (ANSM) to bring dendrimer G1-ABP to first-in-man Phase I clinical trial.