ASH 2023 | A Phase I trial of DSP-5336, a novel menin inhibitor, in the treatment of AML

Menin inhibitors are quite the hot topic these days in acute myeloid leukemia. Menin place a key role in the pathogenesis of two types of acute leukemia, NPM1-mutated AML, and remember 50% of normal karyotype AML will have an NPM1 mutation, as well as KMT2A-mutated AML, which is only about 5% but associated with a very poor outcome. Now, some have said, do we really need better therapies for the NPM1-mutated subset of patients with acute myeloid leukemia? Well, I’ll remind you that although these are considered favorable risk, this is favorable risk in the context of a very unfavorable disease such as acute myeloid leukemia, so relapse rates are high. And the data that’s been published by our colleague Ghayas Issa and his colleagues from MD Anderson, suggests that the outcomes of patients with AML with an NPM1 after relapse isn’t very good and we really do need therapeutic options. And I said acute leukemia, because let’s not forget, KMT2A rearrangements are quite common in ALL, and in fact in infant ALL this is the most common rearrangement that we will see, the KMT2A rearrangement.

And so menin inhibitors have been developed that will specifically block the interaction between menin and KMT2A. Now, we have heard at this congress and have seen published now the first-in-class drug revumenib and as well ziftomenib and both of these drugs have shown activity in AML with an NPM1 mutation as well as a KMT2A mutation. But what’s interesting about these two drugs is they are not the same, obviously, and they do have slightly different toxicity profiles, such as revumenib was associated with a higher rate of QT prolongation, whereas ziftomenib we did not see QT prolongation. On the other hand, in the KMT2A-mutated subset of patients, when we treated patients with the recommended Phase II dose of ziftomenib, we saw a high rate of differentiation syndrome and a leukocytosis, and many patients did not complete the first course, which contributed to the low response rates that we saw in the KMT2A-mutated subset. It’s not to say that this drug doesn’t have activity there, ziftomenib is clearly active, leading to the differentiation syndrome, but we need to learn how to mitigate that better and possibly with the addition of chemotherapy. So the point that I’m getting at is that yes, we have two drugs, but they’re not exactly the same. And then finally there has now been data presented with revumenib and ziftomenib that at least suggests that there may be differences in the mechanisms of resistance. So we have seen the data presented with revumenib, showing that many of the patients who developed resistance to revumenib had point mutations leading to missense mutations in the menin protein, whereas we did not see that as frequently, in fact it was in only one of our samples that we saw that with ziftomenib.

So that’s my long winded preamble to what’s this drug? What’s DSP-5336? So this is yet another oral menin inhibitor. And as an investigator on the study, I could tell you this is still in Phase I, it’s in dose-escalation. We are evaluating the use of this drug with and without azoles. At this point in time, we have not seen a clear impact of strong CYP3A4 inhibitors such as the azoles on the pharmacokinetics of 5336 but more work needs to be done. We have seen complete remissions in our dose-escalation, and we do believe we’re getting close to a recommended Phase II dose. In my own personal experience, my patients who have received 5336 have tolerated it remarkably well, with minimal GI toxicity. We’ve seen some differentiation syndrome, but easily managed. I think finally pulling this all together with all of the menin inhibitors, something that we’re going to need to pay close attention to, not only with 5336 but also with revumenib and ziftomenib, is when we use these drugs as single agents, there’s still some element of myelosuppression that we don’t quite understand. We can clear the leukemia, but in some of these patients count recovery doesn’t occur. And so we have to figure out why that is and how to mitigate that, maybe through dose interruptions or dose reductions. But more work needs to be done.

Obviously the hope for the future is, in my mind, treating older patients with AML. Having a single agent, orally bioavailable drug that is well-tolerated is critical, even though those remissions may not be very long. However, really moving the field forward, of course, will be when we start to look at the combinations of revumenib and ziftomenib and the others like 5336 that are coming in combination with chemotherapy, in combination with FlT3 inhibitors and in combination with IDH inhibitors. So it’s a really active area of investigation and we’re all very hopeful that this is going to lead to benefit for our patients with acute myeloid leukemia who have met NPM1 mutations and KMT2A mutations.

Finally, I will say that it appears that these two mutations lead to increase in HOXA9 and MEIS1 expression. And so it may be that other AMls that are being driven by upregulation of HOXA9 and other HOX proteins, such as MEIS1, may actually respond to menin inhibition. And in fact, in our early Phase I study with ziftomenib we saw such a response in a patient who did not have an NPM1 or a KMT2A rearrangement. So we still have a lot to learn about which population and patients will benefit and how best to use the menin inhibitors.