MPN Workshop of the Carolinas 2025 | The potential of MDM2 inhibitors in MPNs: past and ongoing studies of navtemadlin

I had the chance to speak about the POIESIS trial at the MPN Carolinas meeting in Charlotte in August 2025. And let me first set the stage by talking about the treatment options that we have for patients with myelofibrosis today. So in United States, we have the option of using one of four different JAK inhibitors, of course, the one that would be most appropriate for our patients. And in different parts of the world, ruxolitinib is perhaps the most commonly used drug outside of the United States, even in the United States for that matter. Now, the good thing about ruxolitinib use in MPNs is that it leads to spleen and symptom responses. On the other hand, most patients fail to achieve the most optimal responses with regards to spleen and symptom responses. So the ones that we truly want are, for example, the spleen volume reduction by 35% or more and symptom score reduction by 50% or more compared to their baseline. So RUX does improve, but it doesn’t lead to the most optimal responses in a majority of patients. And why this is important is because achieving optimal responses correlates with improvement in quality of life, and it also improves the overall survival. RUX perhaps because of its limited disease modifying activity doesn’t lead to these most optimal responses in a majority of patients. 

So therein lies the unmet need which is the need to deliver most optimal responses and perhaps we can do that by the addition of an add-on drug one which has some disease modifying activities to those patients who are achieving suboptimal responses to ruxolitinib. Now, in the field of MPNs and myelofibrosis in particular, we have been trying different pathway targets and to target mechanisms of actions which are completely novel beyond the JAK-STAT pathway. Over the last many years, we have realized that there’s a protein called MDM2, which is overexpressed in myelofibrosis, especially in myelofibrosis CD34-positive cells. These are the same cells which are at the very heart of this disease. They are the ones that are driving the disease at the biological level. And MDM2 overexpression leads to higher CD34 cell count. It drives the driver gene variant early frequency to go higher. It also increases the pro-inflammatory cytokine levels and also bone marrow fibrosis amongst many other things. So good target if we could decrease it. 

And it is in this context that we should talk about navtemadlin, which is a novel p53 potentiating anti-cancer agent, meaning what it does is that it’s an oral potent selective inhibitor of MDM2. By inhibiting MDM2, it actually allows for the restoration of p53 function. In fact, TP53 is a good thing to have. It’s a tumor suppressor protein. So if we can restore its activity, that would be a good thing. And navtemadlin precisely allows for that to be done by inhibiting MDM2. The drug was studied in a few different clinical trials, and the dose that was found to be the optimal dose was actually 240 milligrams given on days one through seven of a 28-day schedule. And that was found in a phase two study, which then led to a study, a phase three study called BOREAS study, in which it was compared against best available therapy in a second line setting in a monotherapy fashion. And there we found that the spleen responses were nearly three times as compared to best available therapy, and symptom responses were twice as compared to best available therapy, not to mention numerous disease-modifying biomarker effects in favor of navtemadlin, which also correlated with clinical findings. So that was with monotherapy. 

But in addition, we have some studies which have used the combination of navtemadlin with ruxolitinib. And the big one that comes in mind, the one that truly drives the phase three study, is a study that was done using navtemadlin as an add-on therapy to patients with myelofibrosis who had suboptimal response to ruxolitinib. There, numerous patients, about 28 patients, for example, were treated and the efficacy is reported on those. They had spleen volumes of about two liters plus. They had a moderate symptom burden. They had been on ruxolitinib on average about a year and a half or so plus. And the drug was found to be, largely speaking, very tolerable. We did see some GI toxicity and hematologic toxicity in line with expectations with what we would find from an MDM2 inhibitor. But patients could, largely speaking, tolerate that. Well, they stayed on the study. And if anything, their hematopoiesis as measured by mean platelets and mean hemoglobin was actually well preserved. What we found in addition there in terms of clinical findings was a spleen response rate of 32% and similarly a symptom response rate of 32%. So these are great numbers and we should keep in mind that these responses are happening on top of the responses that ruxolitinib already had delivered. These responses also happened for patients who had myelofibrosis for a long duration of time or a short duration of time, and these happened for patients who were on RUX at high or low doses. What that tells us is that navtemadlin is truly leading to the additional effects. Perhaps there’s a clinical synergy that’s happening with RUX and navtemadlin. In fact, that was seen in some of the preclinical models. But beyond these clinical responses, we also found variant lead frequencies to go down. Many patients actually also saw fibrosis improvement in terms of pathology reviews that were done at central level. And very importantly, we found CD34 cell counts to decrease, perhaps nearly about 90%. And again, I want to emphasize this is very important because this is what’s driving the disease. 

So with all of this, what we have is a drug which helps to restore TP53 function. It has clinical activity, as we have seen, both with monotherapy and in combination with ruxolitinib for patients with suboptimal responses to RUX alone. And we have data from preclinical studies that show that there might be synergy when used with ruxolitinib. Last but not the least, there’s also a lot of biomarker improvement data from numerous clinical trials that show that we are treating the disease beyond just the symptoms and spleen. So we are improving the variant allele frequencies, we are driving the cytokines down, we are improving the fibrosis, so on and so forth. 

So all of that then leads us to the POESIS study. This is an ongoing phase three randomized double-blinded study of the addition of navtemadlin to ruxolitinib in patients with myelofibrosis who have had a suboptimal response to RUX treatment. So here patients who have been diagnosed with primary or secondary myelofibrosis, intermediate 1, 2, or high-risk myelofibrosis, and have a platelet count of 100 plus, they go on to initially the run-in period, which is where they can treat in with RUX monotherapy. And if and only if they have a suboptimal response, do they go on to the second part or the add-on period, which is the blinded portion of the study. And in that blinded portion, there is the addition in a two-to-one fashion of either navtemadlin or placebo. I want to highlight two or three important points about this study. One is the fact that this is a study that is clinical practicality at its heart. So we are only going to treat those patients with the combination therapy who truly need it, meaning only the ones who have had a suboptimal response are the ones who get the dual therapy. So that clinical practicality is there for sure. The second part is the very unique design. We’ve had numerous phase 3 trials in myelofibrosis, most of which have failed recently, but this one has a unique design and it has the run-in period as well as the add-on period. Once again, it also defines what suboptimal response means. So that is a great thing because we have a predetermined and predefined suboptimal response in this study. And it truly takes in a unique approach to doing clinical trials, where you go in with rux monotherapy and then add on a different therapy, a disease-modifying therapy. And to that, I will say that the POIESIS study will also help us to gather and validate some of the biomarker findings that we have found from monotherapy and combination therapy studies of navtemadlin in myelofibrosis. So it will validate and give us more data on the disease-modifying activity of navtemadlin. We have nearly 250-plus sites that are enrolling in POIESIS, and I encourage that if you have a patient, please consider enrolling to POIESIS and together only is it that we can lead to change in the field of MPNs.

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