Naveen Pemmaraju, MD: John, you’ve had a leading role in multiple of the novel agents that I want to pick your brain about. Can you give us the latest updates on what’s going on with the Imetelstat program, as well as the MDM2 inhibitors, which have multiple drugs?

John Mascarenhas, MD: Imetelstat is a telomerase inhibitor. It’s an intravenous drug that’s given every 3 weeks and it targets an enzyme, telomerase, which is important for adding telomere repeats to the ends of chromosomes. It is an enzyme that’s upregulated in malignant stem cell populations and only transiently so in normal stem cell populations it provides a therapeutic window. In poisoning this enzyme, you can induce death in those stem cells, and there’s a lot of great preclinical data that’s been published that would suggest that you can have a depleting effect on those malignant stem cell populations while sparing the normal. That’s what we’re trying to do with these therapies. We have phase 2 data for imetelstat in the IMbark study, demonstrating a relapsed/refractory ruxolitinib [Jakafi]-treated patient population, very advanced population, what appears to be a survival benefit when looking at overall survival at a dose of 9.4 milligrams per kilogram every 3 weeks when compared to a lower dose of 4.7 milligrams per kilogram every 3 weeks. If you think back about numerous retrospective studies, the median survival of patients who fail ruxolitinib is akin to having metastatic cell malignancy; it’s about a year, maybe 14 months, and here we’re talking about maybe 30 months of median survival in this prospective study. I think that got a lot of attention. The study correlated on-target activity, so biomarkers that demonstrated on-target engagement. Those pharmacodynamic markers were also tied in nicely to the clinical items of spleen, symptom, and survival. It told a nice story, but that story is incomplete. The impact on that study is the randomized phase 3 study. It’s ongoing, enrolling globally, and it’s taking a patient population that’s refractory to ruxolitinib and randomizing them to imetelstat given at the 9.4 milligram per kilogram arm or best available therapy, which excludes a JAK [Janus kinase] inhibitor. The primary end point of this trial is overall survival, which is exciting, and it’s unique, but it will only be truly exciting if it hits that end point, and that’s what we need to wait for. That’s an exciting study. I think it approaches our field in a different way.

A stem cell-depleting therapy with the potential to improve survival, not so much the focus of spleen reduction, maybe not so much the focus of symptom improvement, which is not unimportant. To that point, there are now early studies that are ongoing, which is natural, to take imetelstat and start combining it with ruxolitinib earlier on into these. So, addressing spleen, symptom, and this preclinical data that suggests that there’s synergy between the 2 drugs in the lab. That’s still yet to be seen as it translates now into the clinic. The MDM2 inhibition part is also exciting. Initially with idasanutlin, which is an MDM2 inhibitor, the ability to induce deep responses in polycythemia vera, including molecular responses that were rapid. There’s a terrific amount of preclinical data that supports taking this class of drugs into MPNs [myeloproliferative neoplasms] in general and, of course, it’s been investigated in AML [acute myeloid leukemia]. The drug that’s furthest along that deserves some discussion is navtemadlin, KRT-232. That’s a selective MDM2 inhibitor, and it has shown activity as a single agent monotherapy after ruxolitinib discontinuation, both in terms of spleen, symptom, and reduction in driver allele burden and bone marrow fibrosis reduction. This drug is also in phase 3 testing called the BOREAS study, which is a randomized phase 3 study that evaluates navtemadlin against best available therapy in patients who have discontinued ruxolitinib. The drug is also in clinical investigation as a combination partner with ruxolitinib, which is the cornerstone of all these combination approaches. We’re anxiously waiting to see if we can get those kind of results that we saw in the earlier phase studies. So deep molecular responses, fibrosis reduction, and hopefully something that translates to improvement in survival.

Naveen Pemmaraju, MD: That’s wonderful. Steve, as I turn to you, just in general, we’ve mentioned a lot of the novel agents. We’ve mentioned some of the combinations, the 3 that are furthest along, which is JAK inhibitor combined with BET [bromodomain and extraterminal] inhibitor, Bcl-xL [B-cell lymphoma-extra large], and PI3 [phosphoinositide 3] kinase. What about some of these other newer agents, perhaps XPO1 [exportin 1] inhibition and some of these other combinations? What should we be on the lookout for, and particularly, with regards to novel toxicities? What has your attention in that space?

Stephen Oh, MD, PhD: I’m going to start by coming back to hepcidin if that’s OK?

Naveen Pemmaraju, MD: The new theme of our field.

Stephen Oh, MD, PhD: We’ve talked a lot about hepcidin. I’m just going to sort of give my further SAGE elaboration. I’ll give my thoughts here.

Naveen Pemmaraju, MD: Excellent.

Stephen Oh, MD, PhD: We know now that pacritinib [Vonjo] hits ACVR1 [activin A receptor type I] and that it reduces hepcidin. We know that momelotinib has some capacity to do that as well. The question remains as to whether it is achievable to further reduce hepcidin and whether that would potentially result in greater anemia benefit. You have agents that are specifically targeted to hepcidin production, and those agents could potentially be utilized alone or in combination with other partners. For instance, you have the ALK2 [activin receptor-like kinase-2] inhibitor, the insight 92a compound, which is a very potent selective inhibitor of ACVR1/ALK2. It’s very early, as far as that study is going, but it does offer that potential to potently reduce hepcidin, and then could potentially be partnered with ruxolitinib as it's being done in that study. In that sense, it is logical to offset some of the detrimental effects of ruxolitinib on anemia. But you could imagine, something like that could be partnered with other JAK inhibitors or other agents as well. That is something that I want to highlight. Also, just keeping in mind that when you think more broadly about regulation of hepcidin production and the anemia, the inflammation, we know that ACVR1 is probably the master regulator of hepcidin production, but inflammatory signaling IL [interleukin]-6. Other cytokine signaling pathways impact hepcidin production as well. While I’m highlighting this very selective potent inhibition of ACVR1/ALK2, it is very conceivable that the profile of some of the existing JAK inhibitors as they relate to JAK1, JAK2, IRAKs [interleukin-1 receptor-associated kinases], things like that, they also may contribute to both hepcidin production and inflammation, more broadly. The other thing I wanted to comment on relates to disease modification and some of these novel agents, including pelabresib. I presented the analysis from the SIMPLIFY-1 study, looking at bone marrow biopsies baseline in 24 weeks. In that study, patients were randomized to momelotinib versus ruxolitinib, and the take-home really is that bone marrow fibrosis changes were observed in a proportion of patients in both arms; it was similar across the 2 arms. There was absolutely no correlation with any clinical outcome from that study. As Dr Mascarenhas pointed out, it’s a very negative results study. That is absolutely true, and that is the take-home point. I want to elaborate to say that I think that is quite clear. It is obviously specific in that analysis to momelotinib and ruxolitinib in that study. I connect that to ... a presentation on pelabresib where he had several potential biomarkers, surrogates, that he tied to the clinical responses that have been observed, one of which was bone marrow fibrosis changes. Then there was the megakaryocyte de-clustering that was mentioned, molecular changes, and things like that. To be completely cautious, we can’t exclude that something like pelabresib or another agent, even if you come back to myelofibrosis changes alone, they may be relevant for clinical outcomes. I think more likely, as suggested by that analysis, you may need to look at other aspects, either the bone marrow morphology, megakaryocytes specifically, or a consolation of surrogates or biomarkers to at least make the case that this is related to clinical outcome and disease modification.

Naveen Pemmaraju, MD: That’s very well said. Ruben?

Ruben Mesa, MD: It’s a good analogy to be the middle step discussion, where what’s really interesting about what John and colleagues presented was that there may be a survival advantage that has a different mechanism.

Naveen Pemmaraju, MD: I see.

Ruben Mesa, MD: Then improving its spleen at symptoms. That’s totally valid. There’s a lot of complex biology going on and what we have found to be very beneficial end points in JAK inhibition will be different with another agent. It’s valid, again, it asks how will you manage the patient in a different story should they also be on a JAK inhibitor, or other pieces? I think the same is true with fibrosis in the setting of JAK inhibition. I’m still not convinced that fibrosis is a particularly helpful marker now that we have a difficulty quantifying it; and 0 to 3 grade is not granular enough to identify a difference or is it just really not the main goal. I had a patient who I took off ruxolitinib this year that had gone on 13 years ago. And what did that 13 years look like as I looked at his chart? Hemoglobin between 9 and 10, fibrosis of 2, platelets of like 110, spleen was palpable, but it was like 5 centimeters. So, it was stable, nothing was perfect, but 13 years of that, with him traveling, not been hospitalized for 13 years, work for part of that time, retired, the 2 kids, a grandchild.

John Mascarenhas, MD: And not transplanted.

Ruben Mesa, MD: And not transplanted. That’s success. But that may look different for different agents. Steve is correct, very relevant for JAK inhibition, and it may show us as well, if we look at combination studies and there is a dramatic difference. We were pretty no, it’s probably the other drug.

Transcript edited for clarity.