The first fragment-derived drug approved, vemurafenib, illustrated how quickly FBDD could move: just six years from the start of the program to approval. In contrast, venetoclax is the culmination of a program that has been running for more than two decades; Steve Fesik and his colleagues at Abbott published the X-ray and NMR structure of the protein BCL-xL back in 1996! The original SAR by NMR work was done on this protein, leading to ABT-263, which hits both BCL-xL and BCL-2. Subsequent work revealed that a selective BCL-2 inhibitor might be preferable in some cases, and further medicinal chemistry led to venetoclax.
Clinical results were sufficiently impressive that the drug was given breakthrough status and granted priority review, accelerated approval, and orphan drug designation. The ultimate victory is for the thousands of patients with relapsed CLL who have the 17p deletion on chromosome 17. In the registration trial, 80% of patients showed a partial or complete remission. It is rare to create something that works this well. Congratulations to all who played a role.