Developmental Clinical Studies: Inhibition of C-reactive protein for treatment of cardiovascular & inflammatory diseases

C-reactive protein (CRP), a normal trace constituent of the blood, increases in concentration dramatically following most types of injury, infection or inflammation. We have discovered that human CRP can make such injury worse and have demonstrated it in animal models of heart attack and stroke. There is compelling clinical evidence that CRP has the same damaging effect in human diseases and that its inhibition will make a major contribution to management of a wide range of conditions. We therefore designed a family of new small molecule drugs, called bis(phosphocholine)-alkanes, which inhibit the adverse effects of CRP and are efficacious in animal models. We now propose to develop the optimal drug, bis(phosphocholine) octane, for clinical testing. The required development steps, for which funding is sought, are pharmaceutical manufacture of the drug, pre-clinical testing, toxicology and formulation to comply with regulatory requirements, and first into man studies, in healthy adult volunteers. This programme will provide a medicine which complies with the ethical and regulatory requirements for clinical testing in patients admitted to hospital with a first heart attack who are receiving all other state of the art treatment. We have detailed plans for this trial but do not seek funding for it now. The rigorous regulation of drug development means that the work now needed cannot be conducted in academic institutions but only in pharmaceutical companies or contract research organisations, which specialise in drug manufacture and testing. We shall therefore outsource to selected commercial companies, the production, pre-clinical testing and first into man studies of the drug. Success will critically depend on using the best companies and on very effective project management. We are fortunate that one of the co-applicants, Dr Chris Swain, has a long track record of successful experience in drug development in industry and as an independent consultant. He will be supported throughout by other external consultants specialised in each of the different development tasks, through the services of Advocates Ltd, a leading consultancy firm in this field which advises UCL Business PLC, the technology transfer arm of UCL. Several large pharmaceutical companies and also some investors in pharma company creation are very keen to see our initial clinical results. Positive findings leading to prompt commercialisation and a licensed new medicine will culminate 40 years of continuous MRC support for the research of Professor Pepys, the lead applicant.

We propose to develop the C-reactive protein (CRP) inhibitor drug, bis(phosphocholine)-octane (1,8-bis[{[(trimethylammonium)ethoxy]phosphinyl}-oxy]octane), BPC8, to enable a first phase IIa proof of concept study in patients with acute myocardial infarction treated by primary percutaneous coronary intervention. BPC8 is an optimised version of bis(phosphocholine) hexane (BPC6), the first CRP inhibitor drug. We designed this new small molecule chemical entity and showed that it is well tolerated and efficacious in animals. CRP is the classical human acute phase protein, the circulating concentration of which rises from normal values of 1 mg/l to as much as 500 mg/l in the major acute phase responses associated with most serious infections, inflammatory and tissue damaging disorders. CRP binds to ligands exposed on damaged and dead cells, and then activates complement. The powerful chemotactic, opsonic, cytolytic, pro inflammatory and tissue damaging effects of complement kill cells which would otherwise have survived the primary pathology. We have demonstrated that human CRP significantly exacerbates ischaemic tissue damage via a complement dependent mechanism in rat models of acute myocardial infarction, cardiac ischaemia reperfusion injury and ischaemic stroke. BPC6 completely abrogates this pathogenic effect of human CRP and BPC8 will be even more potent. Compelling observational and epidemiological evidence is consistent with a pathogenic role of CRP after human acute myocardial infarction and high acute phase CRP concentrations are also likely to contribute to tissue damage in a wide variety of other traumatic, inflammatory, infective and neoplastic conditions. Targeting human CRP is therefore a valid therapeutic strategy and our patents covering CRP as a target for phosphocholine drugs and our novel bis(phosphocholine) alkane compounds themselves have been granted or are in condition for allowance. Our work on CRP has received continuous MRC Programme Grant funding since 1975 enabling our many contributions, including establishing the universal use of CRP as a clinical analyte, producing the WHO International Reference Standard for CRP Immunoassay (84/506), and solving the 3D structure of CRP alone and in combination with small molecule ligands. Combined with our comprehensive expertise in CRP, the development programme will be managed by Dr Chris Swain, Cambridge MedChem Consulting, who during his long career at Merck led pre-clinical development of the novel NK1 antagonist drug, Emend, through to commercialisation. Supporting consultancy throughout the CMC, pre clinical, regulatory and clinical programmes will be provided by the firm of Advocates Ltd.