BETA - What is a BTK inhibitor and how is this drug class used to treat chronic lymphocytic leukemia?

What is a BTK inhibitor and how is this drug class used to treat chronic lymphocytic leukemia? So BTK inhibitor stands for Bruton Styrocyne Kinase Inhibitor. And what it is, these are small molecule inhibitors of Bruton Styrocyne Kinase. Bruton Styrocyne Kinase is a step that's downstream from the B cell receptor. It's a step in the B cell receptor pathway. And this can be blocked by drugs called BTK inhibitors. BTK inhibitors can be divided into two types. We have covalent BTK inhibitors and we have non-covalent BTK inhibitors. The first covalent BTK inhibitor that was approved was Ibrutinib. Subsequent to that, we had A-cala Brutonib and Xana Brutonib approved for CLL. These work very well. They have shown survival advantage for patients with CLL and they are very well tolerated. The reason that we had the second generation or next generation covalent BTK inhibitors, A-cala Brutonib and Xana Brutonib, is because it's not that Ibrutonib wasn't good enough. It worked very well, but it was associated with certain side effects, especially effects on the heart. It caused atrial fibrillation and there was high incidence of bleeding. That led to the development of the second generation covalent BTK inhibitors, which were more specific for the target, BTK target. Most kinases have off-target effects. That means they bind to other areas also, which lead to the side effects. So these were developed, the next generation were developed to have more sensitivity for the BTK and had lesser of those off-target effects. We have had head-to-head studies between Ibrutonib and A-cala Brutonib in the Elevate RR study, which showed that the side effect profile for A-cala Brutonib was better. Then we had head-to-head between Ibrutonib and Xana Brutonib in the Alpine study, which showed again showed the side effect profile of Xana Brutonib to be better. Now the second type of BTK inhibitor is the non-covalent BTK inhibitor, of which we have Pertro Brutonib as the FDA approved agent, which was approved in December of 2023. For now it's approved for patients who have relapsed on a covalent BTK inhibitor and a BCL2 inhibitor. And Pertro Brutonib is very well tolerated, very minimal cardiac effect, low incidence of bleeding, so very well tolerated agent. BTK inhibitors have been probably the biggest advance in the field of CLL in the last 15 years. BTK inhibitors essentially target the switch of life in the cancer cells and it basically flips the switch off. CLL cells need that switch to be turned on to survive. So if you flip the switch off, the cells die. Very simple. Now the cancer is getting smarter. As it gets exposed to the drug, the cancer realized, hey, this is not good for me. So as a way to hide against that targeting, when you take a pill that turns that switch off, the cancer cells began to think of ways that we can escape from that. And what happened was we realized that the cancer cells were changing the switch from this way to this way. So that was called a mutation. So essentially the cancer cells were mutating, not randomly, but in a very smart manner. And they said, OK, fine, if you're going to turn the switch off this way, I will change the shape of my switch. So now you have nowhere to attach to and turn the switch off. So that was the first challenge we faced a few years ago. So we were like, OK, fine, if the cancer can get smart, can we get smarter? And that's what happened. So we went from the first generation of drugs, which were only targeting the switch in one way, to the second generation of drugs, which are targeting the switch in another manner. And then the first generation of drugs, when it got to the switch, it just kept attaching to the switch and then never came off. We found out that that would be good to turn the switch off. But then over time, the cancer cells get used to it. So then the other next generation of drugs don't attach and stay attached. They come off and they attach again. So it's an on-off mechanism. So this is what we call covalent PTK inhibitors, which is the first generation drugs. And the second generation is called the non-covalent PTK inhibitors. So that's been a very remarkable advance in the field. So now patients who were taking the first drug and the cancer became resistant and the disease starts to come back, we can employ the next generation of drugs, which would essentially do the same thing, but target the switch at another site. Now the cancer got smart again. So then they said, OK, fine, we're just going to change this direction too. So now the second generation of drugs don't have anywhere to wind. So the first generation is now useless. Second generation is useless. So we were like, OK, fine, if the cancer can get smarter, so can we. We're smarter than the cancer. And so in the next generation of drugs, which are what we are currently studying in different clinical trials and they're looking very promising, we basically take the entire switch out along with the wiring. So that's the next step. Those are called BTK degraders. So we just take the whole thing out. So it doesn't matter where the mutation is. In theory, it should work. So that's what we are working on actively right now. So we're in the third generation of drugs. So as the cancer keeps getting smarter, we keep evolving and our technology keeps getting better and better.