iwCLL 2025 | Novel BCL2 inhibitors in CLL: sonrotoclax and lisaftoclax

So, you know, so venetoclax is a very important therapeutic advance in CLL and really has been responsible for the development of time-limited targeted therapy regimens in this disease. You know, we know that prior to this, we really only had continuous therapies that were given until progression or intolerance or chemoimmunotherapy regimens, which are really no longer considered appropriate in this disease. And so venetoclax clearly achieves very high rates of complete response and undetectable measurable residual disease, which has been associated with long-term survival outcomes in patients receiving venetoclax-based therapy. 

But a key problem with this agent and with this class to date has been that in many cases, patients simply aren’t exposed to this class of therapy because of feasibility issues. There’s this five-week ramp up that’s required, that requires multiple stat laboratories to be drawn. And although this is something that is frankly very straightforward, it requires that laboratories be drawn towards the end of the day, that you get them in a reliable manner so that you can act upon them and let folks go home. And so this has really limited their use in the community where most patients with CLL are treated. And today, if you have CLL and acquire an initial line of therapy, it’s much more likely that you receive a covalent BTK inhibitor until progression or intolerance. 

And so the talk really focused on efforts to improve upon the feasibility, safety, and efficacy of BCL2 inhibitors in CLL. With venetoclax, for example, there’s the ongoing VENETIAN trial. This is an effort to develop a more simplified TLS mitigation strategy to hopefully improve the feasibility of this agent. If successful, this would have a major impact on patient convenience, feasibility, and potentially uptake. 

I went on to talk about two novel agents. I focused on sonrotoclax and lisaftoclax. Sonrotoclax is a second-generation BCL2 inhibitor, which is significantly more pharmacologically potent, it’s about 14 times more potent than venetoclax. And so a question is whether this will result in additional activity. This, of course, requires randomized data, and we await results of the ongoing celestial Phase III trial to assess this. It has a very short half-life at about four to five hours. And so the question is whether this would impact on safety or TLS risk. And then finally, it is highly selective for BCL2 over other BH3 proteins like BCL-xL or other proteins like BCL-xL. And so this has also the potential to impact on safety as well. We reviewed data from the phase I, phase I/II study, where we saw very high rates of early undetectable measurable residual disease and a favorable safety profile and no TLS across multiple ramp up schedules evaluated with this agent. And again, we await data from the Phase III study. 

And then we also discussed the lisaftoclax program. This is another second-generation BCL2 inhibitor. This is distinct from sonrotoclax. It similarly has a very short half-life at about four to six hours, which again, the hypothesis is that this could impact on safety outcomes or TLS risk. It’s similarly potent to venetoclax. And I reviewed some of the phase I data describing high overall response rates in a very refractory patient population. They’ve taken on a very different sort of development program with lisaftoclax in that they really are relying on this very rapid ramp up without prior debulking in the phase I study. Despite that, they really saw very low acceptable rates of TLS in this highly refractory population, and we await data from the phase III study, which is evaluating an add-on strategy where patients who are on acalabrutinib for at least a year and meet certain characteristics are randomized either to just continued acalabrutinib or the addition of lisaftoclax.

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