Pirtobrutinib Mechanism of Action in CLL and SLL

Catherine Callaghan Coombs, MD, an assistant professor of medicine in the Division of Hematology at the University of North Carolina School of Medicine, discusses the mechanism of action of pirtobrutinib (LOXO-305) in chronic lymphocytic leukemia and small lymphocytic leukemia.

According to Coombs, pirtobrutinib is a non-covalent BTK inhibitor, meaning it binds to the same target ibrutinib (Imbruvica) and acalabrutinib (Calquence) do. However, unlike ibrutinib and acalabrutinib, pirtobrutinib does this in a non-covalent fashion. This means that the activity of pirtobrutinib is independent of the presence of absence of the C481 mutations, which is the most common mechanism of resistance to ibrutinib and acalabrutinib.

In addition to this, pirtobrutinib has a very clean pharmacokinetic profile. According to Coombs, the agent has liner responses based on dosing and is effective at binding above IC90 for all doses above 100 milligrams daily.

0:08 | Pirtobrutinib is a non-covalent BTK inhibitor so it binds the same target as ibrutinib and acalabrutinib. However, it does so in a non-covalent fashion. The advantage of this is that its activity is independent of the presence or absence of the C481 mutations which are the most common mechanism of resistance to ibrutinib and acalabrutinib. The other advantage of the drug is that it has a very clean pharmacokinetic profile with linear responses based on the dosing and it is effective at binding above IC90 for all doses above 100 milligrams daily