One of the biggest challenges of drug discovery is to determine which targets, when perturbed, will have an acceptable efficacy-safety therapeutic window in patients. In fact, the success rate at choosing the right target and developing a safe and effective drug is quite low: less than 10% of drugs that enter Phase I are approved by regulatory authorities (see recent Nature Reviews Drug Discovery article here, Derek Lowe blog here). Most of the failures in Phase II and III are due to lack of efficacy or unexpected toxicity.
Human genetics offers one potential solution to identify new drug targets with an acceptable therapeutic window. A study published this week in Science Translational Medicine (STM) provides genetics support for an established therapeutic target in type 2 diabetes (T2D), glucagon-like peptide-1 receptor, GLP1R (link to STM article here). What is surprising, however, is that human genetics suggests that GLP1R agonists may also protect from coronary heart disease (CHD).
[Disclaimer: I am a Merck/MSD employee. The opinions I am expressing are my own and do not necessarily represent the position of my employer.]
There are three points that I want to make in this blog. First, the STM study provides general support for the model that human genetics is useful to predict efficacy & safety in drug discovery.…