Yesterday, on October 29, the US FDA approved asciminib (ABL001, from Novartis) for two subsets of patients with chronic myeloid leukemia (CML), making it the sixth fragment-derived drug to reach the market.
In common with the five other approved fragment-based drugs, asciminib is a cancer therapeutic. Like three of them, it is a kinase inhibitor. But there the resemblance ends. As we discussed at length in 2018, asciminib targets not the hinge region of BCR-ABL1, but an allosteric myristoyl-binding pocket on the protein. This unique mechanism of action provides improved selectivity over conventional kinase inhibitors, which could be part of the reason the drug causes fewer side effects than other BCR-ABL1 inhibitors.
Another advantage of targeting the allosteric pocket is to sidestep resistance. One group for which asciminib was approved is for patients with the BCR-ABL1 T315I mutation, which causes resistance to other approved therapeutics. Combining asciminib with other drugs might prevent resistance from emerging in the first place.
The approval of sotorasib in May was a study in speed, with less than three years spent in the clinic. In contrast, asciminib was first dosed in 2014. Even getting there was far from certain: as Wolfgang Jahnke recounted five years ago, the project started as a grass-roots effort and was halted twice. Imatinib, which targets the hinge region of BCR-ABL1, also faced a fraught journey to the clinic before being approved twenty years ago.
These stories of persistence paid off, and today humanity has a new weapon against CML. And this is just the beginning: a dozen clinical trials with asciminib are either announced or in progress. Practical Fragments wishes to offer everyone involved congratulations, luck, and thanks.