EHA 2019 | Zanubrutinib and acalabrutinib for CLL: potential alternatives to ibrutinib?

We’re now, you know, ibrutinib is a very effective drug, but there are now kind of next generation BTK inhibitors. Two different types, actually.

There are the kind that are covalent binders like ibrutinib is and there are two prominent ones there, acalabrutinib and

We’re now, you know, ibrutinib is a very effective drug, but there are now kind of next generation BTK inhibitors. Two different types, actually.

There are the kind that are covalent binders like ibrutinib is and there are two prominent ones there, acalabrutinib and zanubrutinib. Acalabrutinib has actually been approved but not in CLL. It’s approved for mantle cell. And zanubrutinib has not been approved yet. It’s a little bit farther behind in development, but in registration trials right now for potential approval.

Both of these drugs have the putative advantage of possibly producing less side effects. And the reason for that is they’re both very potent inhibitors of BTK, which is what we want. But some of the other kinases that are inhibited to some extent by ibrutinib, which are thought to be responsible for some of the side effects of ibrutinib, such as the bleeding, such as the atrial fibrillation. These drugs have higher IC50s against those kinases.

So in other words, it takes much higher doses to inhibit those kinases. So there’s a hope that both of them will produce less of some of the side effects like bleeding, like atrial fibrillation.

Efficacy data with both of these drugs in clinical trials looks very promising. I would say at least as good as ibrutinib. It’s going to be hard to prove it’s better when we have, you know, such high response rates with ibrutinib. Although, acalabrutinib does have a head-to-head comparison as does zanubrutinib. There are there slightly different trials. In the acalabrutinib trial, it’s in relapsed refractory high risk patients, so those are with CLL with a 17p deletion or an 11q deletion, who are relapsed are randomly assigned. And that trial has actually reached accrual, but we don’t, we haven’t seen the data yet in terms of the progression-free survival.

The other drug, the zanubrutinib is also in a randomized relapse trial versus ibrutinib, but that’s all comers and the primary endpoint on that trial is actually going to be response. So we will await both of those trials.

There’s also another category of B-cell receptor inhibitors now that are non-covalent binders, and those are much earlier in development. There’s a number of them that are in phase one and the potential advantage of those is that we know from Ohio State data that in patients who develop clinical resistance to ibrutinib, according to their data, as many as 80% of them have a BTK mutation.

So the non-covalent inhibitors, their advantage is that they’re not binding in the same spot. And so they should be effective even in patients who develop a BTK mutation. And certainly preclinically they are effective in that setting as well as against the wild-type BTK.

So they could have as good efficacy as ibrutinib, plus be able to work in patients where ibrutinib is… They become resistant to ibrutinib.

But again, those drugs are much earlier in development. All of them are in Phase I and we will look forward to seeing those results as they become more mature.