10 December 2014
Positive Pre-Clinical Outcome for Rheumatoid Arthritis Drug Candidate Supports Progressing to Next Stage of Development
Proxima Concepts Limited is pleased to announce that it has obtained back the rights from Bone Medical Limited to develop the TNF down-regulating cyclic peptide for treatment of rheumatoid arthritis, discovered using its Mozaic and Lexicon technologies.
Two studies have been conducted to date using the in vivo CAIA (Collagen Antibody-Induced Arthritis, the gold standard murine arthritis model) model for rheumatoid arthritis. In the first study, the lead molecule, Lex5.2b, was more potent than expected, and a high degree of efficacy was observed even at the lowest dose tested. A second study was thus required, testing the molecule at lower doses in order to determine at what level efficacy started to wane. As a result, a clear dose-response relationship has now been demonstrated for the major parameter measured, reduction in footpad swelling – a clear indicator of inflammation. At the optimal dose level, efficacy was equivalent to that seen for the anti-TNF antibodies Enbrel and Humira, administered in a regime closely mimicking that for human treatment. Other parameters, including clinical score and weight loss, also showed changes, although differences were not so clear-cut at the low doses tested.
Professor Peter Brooks of Melbourne University, an international expert in the field of rheumatic diseases, stated "the evidence, both in this, and in the previous study, of an effect leading to significant reduction of inflammation is irrefutable. It is also very encouraging to see a response at a dose which is commercially viable. Proxima has in its possession a potential new therapy which could be very valuable in the treatment of rheumatoid arthritis, working in a manner completely different from current therapies."
In addition to testing the efficacy of Lex5.2b over a range of doses, a variant of this peptide, Lex2.6, was also tested, showing itself to have significant activity according to both clinical score and weight loss, as well as footpad swelling. Proxima plans to conduct additional studies to optimise this peptide. Dr Michael Burnet, Managing Director of Synovo GmbH in Germany, where the studies were conducted, stated "Lex2.6 showed great promise in the study just concluded, and further development of this molecule is very worthwhile."
Lex2.6, like Lex5.2b, has the ability to inhibit secretion of TNF from macrophages, and this has been described in a paper shortly to be published in the journal Molecules, co-authored by Dr Roger New and Professor Marc Feldmann, of the Kennedy Institute of Rheumatology (Oxford University). This action of these molecules also makes them ideal candidates for treatment of other disorders where over-production of TNF is a factor – for example Crohn's Disease, bacterial septicaemia, and certain types of cancer. Other diseases where TNF may play a role include multiple sclerosis, diabetes, malaria, meningitis, ischaemic reperfusion injury and adult respiratory distress syndrome.
The peptides Lex5.2b and 2.6 are small molecules and resistant to the action of serine proteases, so there is reason for optimism that these peptides will be available after administration via the oral route. In preliminary studies carried out, blood levels of peptide were measured after oral dosing, and work is progressing to optimise a formulation which will afford high bioavailability to these molecules.
Dr Roger New, CSO and Co-Founder of Proxima Concepts Limited, said "it is very encouraging that this latest study has continued to give positive results, which justify going to the next stage in development work to take these molecules to the clinic. Having two different candidates in the pipeline increases the chances of success."