What underlies a successful drug development programme?

Drug development is a long, expensive and risky process. The target is fixed at the beginning so it is vital to have good evidence that the target is relevant and plays a causal role in human disease. The case studies below highlight the importance of good target validation.

An unusual patient hinted at a new target for anti-coagulation without off-target bleeding

The coagulation cascade is complex and as research has progressed there has still been great difficulty in developing drugs that prevent clotting without the unwanted side effects.

An unusual patient revealed a hopeful therapy. A clotting screen after a head injury revealed that the patient appeared to have blood that was unable to clot, however, the patient recovered from a haematoma without intervention. Studies showed that the patient had developed an antibody for thrombin. The crystallised structure of the complex revealed the binding site, unique to thrombin. This data has given investors great confidence that a synthetic version of this antibody could successfully prevent blood clotting without unwanted bleeding. An antibody has been designed and is currently being assessed in clinical trials to prove the concept.

Strong clinical relevance from gene mapping studies for PCSK9

PCSK9 is a target of focus for a number of pharmaceutical companies in the treatment of hypercholesterolemia. The target has been well validated by gain and loss of function mutations correlating with LDL levels and disease risk, gene mapping in a family with familial hypercholesterolemia and the identification of a healthy woman with no PCSK9 and low levels of LDL. These data indicated that the target was clinically relevant and gave an insight into safety, making PCSK9 attractive for development and investment. Two monoclonal antibodies, alirocumab and evolocumab have been recently approved for the treatment of hypercholesterolemia.

Is CRP causal or associative of disease?

Researchers have debated whether C reactive protein (CRP), an inflammatory biomarker, is a causal factor in the development of atherosclerosis. Observational studies showed an association between elevated plasma CRP levels and cardiovascular events, leading to it being suggested by many as a potential therapeutic target. Compounding risk factors make it difficult to investigate causality. CRP has different biological roles across species, making it challenging to use animal models to elucidate the role of CRP in humans. More recently however, Mendelian randomisation studies showed that while there is an association it is unlikely that CRP plays a causative role in atherosclerosis. Therefore it is unlikely to be an attractive target for the prevention of atherosclerosis.