ASH 2021 | Phase Ib trial of ianalumab plus ibrutinib for CLL

We have a very exciting study that’s looking at the addition of an anti-BAFF receptor antibody called VAY736 to ibrutinib. And the really neat thing about this study is it’s really looking at clearing out residual disease and getting people to discontinue ibrutinib. So we all know what a benefit ibrutinib has been for CLL patients. You know, it’s really disease-altering for so many people. The drawback is it inhibits B-cell receptor signaling and changes the biology of the CLL cells, but it doesn’t just eliminate all the CLL and you don’t get these minimum residual disease-undetectable remissions very often, or they occur after many, many years on treatment. So that’s very different than the chemoimmunotherapy or venetoclax anti-CD20 experience. And so when you take a drug really long-term, like multiple years, it increases the risk for chronic physical toxicities. And then also there’s financial toxicity and psychosocial burden of having to take continuous oral therapies for treatment of CLL. So the idea to add a second agent for people with CLL taking ibrutinib who are doing well with it, tolerating it, to see if you can reduce the residual disease burden and then stop therapy is kind of what the overall goal of what we’re trying to achieve is. The drug is really fantastic. It’s a very active anti-BAFF receptor antibody. And the neat thing about this is that it does actually not only targets the CLL B-cells for destruction, but it also blocks BAFF receptor signaling in the CLL cells. It’s a blocking antibody, too, and BAFF receptor signaling is active even during ibrutinib treatment. It is probably the targeting that is the bulk of the mechanism, but it’s neat that it has two.
And the goal of this study, it’s a Phase Ib with expansion cohorts. So the main goal is, of course, to find the safe and recommended dose for continued study of VAY736 in combination with ibrutinib, but it’s enrolling patients who were trying to eliminate residual disease with the ultimate goal of getting them to stop taking ibrutinib. So there’s that benefit to patients that they achieve this response. And the study enrolled two groups of patients taking ibrutinib. Either those that have been taking it for at least a year without a complete remission or those with molecular resistance as indicated by BTK or PLCG2 mutation, because those are really people that have something to gain from the strategy of adding something. We did identify the safe dose. That’s kind of the biologically recommended dose for continued study. The treatment plan is for either, so for six cycles of infusions, the cycle is 28 days with doses being given days one and 15. So approximately six months of every two week or so antibody infusions. And then there’s an option for two additional cycles if people don’t achieve that remission. And then kind of response is assessed and people who have very deep remissions will stop taking treatment. So we had a recommended dose based not only on safety, we had no dose-limiting toxicities as you might expect with an antibody like this, but also on some of the things like receptor occupancy. And there’s now an expansion. So some of the data we’re presenting at this meeting is from the expansion cohorts. And we have two, one for people that didn’t achieve a complete remission and those with molecular resistance. So it’s just very exciting to see how active this antibody is. It’s extremely well tolerated. And I think this idea to give ibrutinib, reduce the disease burden, and then use something like VAY736 to kind of remove the residual disease to stop therapy is a good strategy, and this antibody is a perfect choice for this because it’s very active and very well tolerated and it’s novel compared to the anti-CD20s, the target’s really novel.