BTK Degrader Study Shows Promise for a New Class of CLL Therapies | Alexey Danilov MD PhD | #ASH2024

My name is Alexey Danilov. I'm a director for Early Phase therapeutics and professor in the Department of Hematology at City of Hope. At this conference, we presented, early data on, two different BTK degraders, NX2127 and NX5948. BTK degraders is a novel class of agents. And you probably heard about, BTK inhibitors such as ibrutinib, acalabrutinib and zanubrutinib.

And, BTK degraders are actually different. In a sense, the BTK inhibitors block the activity, the function of the molecule BTK, which, lymphoma cells and CLL cells heavily rely on in their survival and, proliferation, meaning they depend on this particular kinase protein, to make new cells. So BTK inhibitors block the activity or the function of the kinase.

But meanwhile BTK degraders, fully obliterate or, destroy the kinase. And pull it up into pieces by linking it to the cell waste processing machinery. Why is it important? The problem is that, even though BTK inhibitors can work for a very long time, eventually patients develop resistance.

So the BTK protein learns how to adapt to the presence of this molecules. It introduces mutations so that these molecules no longer can bind well, to the kinase. And as a result, CLL cells or lymphoma cells become resistant. So BTK degrades. However, work in on the setting when this when those different types of mutations are present because it doesn't just bind the, functional pocket of the kinase, it destroys it completely.

There are several trials going on. The two BTK degrade that we investigated. And the study that we presented, at this ash NX2127 and NX5948 are currently in phase one clinical trials. And, some of the results will be presented at, this Ash meeting as well.

The data looks really good. The response rate is about 70%, meaning that at least 70% of patients, achieve formal response where their lymph nodes, decrease, where the anemia improves. And they feel better. But, virtually every patient derives, clinical benefit. There are also other BTK degraders in development.

One particularly great is developed by Biogen and I believe it's, BGB 16553. And there is also BTK degrader, developed by AbbVie, ABBV101. And they are also in, clinical trials enrolling patients. Most of these trials, a larger scale there a large international trials. They're open at many sites in the United States, you know, United Kingdom and continental Europe.

That's where, I'm not aware of any other sites outside of these continents but, these are certainly global studies in that sense. Australia, actually as this data is still early, the initial space where they will be used is relapsed refractory. So right now patients who can go on the studies, typically would have progressed on a BTK inhibitor and potentially also on BCL two inhibitor venetoclax.

But certainly there are plans, to introduce, to study this molecules in earlier lines of therapy. So I will say that these are, have a completely new drugs, state of the art technology, which are very different from all the small molecules that we still we have currently, working in the clinic and in general there there have been, very good, tremendous advances in treatment of CLL with very many effective therapies.

And this, is another wonderful option. I have patients who have been on this drugs, successfully treated for about three years now, who have progressed on multiple therapies. So there's some very effective agents. And I would highly recommend to seek out these clinical trials. So there's been quite, quite a lot of new good information at this Ash.

The amplify study results have been presented, which, will solidify the place of a novel, novel doublet acalabrutinib and venetoclax in patients with previously untreated CLL. We are also presenting, early results from a phase one trial of a bispecific antibody epcoritamab in relapsed refractory CLL. This is also completely new mechanism of action, where we attack, the CLL cells.

So but at the same time engage the patient's immune system through, their T-cells specifically to kill the CLL cells. And the results there are also spectacular.