MPN Workshop of the Carolinas 2025 | Navtemadlin in myelofibrosis: disease modifying potential & the unique design of the POIESIS trial

Navtemadlin is a very interesting drug. It is, as you said, an MDM2 inhibitor that has gone the farthest in terms of clinical development in MPNs, currently in Phase III. In fact, they already reported a Phase III. They already reported a Phase III of it as a single agent in patients with relapsed or refractory, JAK inhibitor relapsed or refractory, myelofibrosis. And there, the results were just top line were 15% spleen response and 24% symptom response at 24 weeks. While those numbers don’t sound particularly high, it’s important to remember that this was a relapsed/refractory population, not intolerant, but straight up relapsed/refractory. And this was a single agent, right? 

So there is clearly activity and what they’re doing now is a truly unique, remarkably designed trial where it’s really for a suboptimal population, suboptimal responder population. But the difference is that all patients sign consent before ruxolitinib initiation. So then they start ruxolitinib, and they go 18 to 24 weeks. And if they have a suboptimal response at that point for both spleen and symptoms, that’s when they add navtemadlin or placebo. Now this is called the POESIS trial. 

So there is no other trial frankly in the field that has this sort of a design and what is unique about it is that this perhaps I mean of course we need to wait for the results but this I think allows them, allows the sponsor Kartos, to really isolate if you will the suboptimal population because everyone’s sort of starting at the same time point. It’s not like someone’s been on ruxolitinib for three years and someone else has been on ruxolitinib for six months. Everyone is starting at the sort of the same, you know, baseline. And then 18 to 24 weeks later, if they are suboptimal, they are randomizing to navtemadlin or placebo. 

So I think this is a truly unique and perhaps a more precise way of looking at suboptimal response. So really excited to see what that shows. Of course, the downside of doing it this way is that they need lots and lots of patients, because many of those will not be suboptimal, happily, and will not be randomized. So there is that aspect, but otherwise a very exciting trial. 

But getting back to your question on the disease modification piece is, I think, what you asked about. Right. So navtemadlin, again, has, you know, has shown us a number of very, you know, compelling and also somewhat unique correlates. So like other drugs, it has shown reduction in cytokines, the cytokines that really matter, you know, like TNF-alpha, IL-8, you know, things like that – the ones we know are bad. But also, you know, variant allele frequency reduction of the driver mutation, as well as bone marrow fibrosis. But somewhat uniquely to navtemadlin, they have this interesting, intriguing correlation between circulating CD34 cell count, reduction in that, and clinical response, which I’m yet to see with any other drug. So they have that, and then they also have robust reductions in cytokines, bone marrow fibrosis, and driver mutation allele burden.

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