This content was current as of the date it was released. In science and medicine, information is constantly changing and may become out-of-date as new data emerge.
At the 2014 European School of Hematology (ESH) meeting in Greece, Dr. Jennifer Brown gave a lecture on second-generation Bruton Tyrosine Kinase inhibitors (BTK inhibitors), specifically on how to improve upon the already strong results achieved with ibrutinib.
Take Away Points:
- The strong response rates with ibrutinib may discourage further research in CLL.
- Ibrutinib, although a potent inhibitor of BTK, is not that specific in the pathways it inhibits.
- Resistance to ibrutinib is often related to a mutation in its binding site, preventing the tight covalent binding.
- Finding a drug that binds differently might overcome that resistance
While at ESH, I interviewed Dr. Brown out of Dana Farber Cancer Institute and Harvard about the lecture she gave on second-generation BTK inhibitors. Dr. Brown discussed some possible areas of interest, specifically:
- More specific drugs that only block BTK (this may help limit the theoretical issue of ibrutinib (for more background click here) inhibit the action of rituximab through blocking ITK as explained by Dr. Burger here.
- Drugs with different adverse effects.
- Drugs with different binding sites or mechanism of actions.
Although CC-292 (AVL-292) has promising characteristics in the lab, its results in clinical trials have been less stellar.
A new kid on the block, BGB-3111 has an open one phase 1 dosing trial accessible here. Way too soon for any data.
ACP-196 has a positive street buzz in its early trials for its excellent safety and efficacy (click here for a list of several open trials), but the data has not yet been made public.
Any list of BTK inhibitors in the “pipeline” is immediately out of date, but here is an article that reviews some candidates.
A couple points of clarification before we get to the interview:
Covalent bonding is a very tight form of chemical binding where the electrons are shared between drug and target, and is not the way most drugs work, but it is the way ibrutinib and most other BTK inhibitors in development work. It was so unusual that the original developers of ibrutinib, before the drug was sold to Pharmacyclics, envisioned it as more of a research molecule than the blockbuster drug that it has become.
When ibrutinib or probably most other BTK inhibitors lose the ability to covalently bind BTK because its specific binding site changes from C-481 to S-481, then the drugs would be predicted to lose their efficacy. Something that binds differently or blocked BTK differently would not have that problem and might work when ibrutinib fails.
Let’s listen to Dr. Brown.
Brian Koffman 5/17/15