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Welcome to this week's bonus episode of Blood Podcast, your source for innovative ideas and cutting edge information. In this episode, Associate Editor Dr. Jason Gottlieb discusses the Review series on the new Wave of targeted therapeutics for NPNS with authors Dr. Anne Mullally, Dr. Marina Kremenskaya, and Dr. Stefan Constantinescu.
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Dr.
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Today we welcome Blood's audience to a bonus edition of its podcast series. My name is Jason Gottlieb and I'm an Associate Editor for Blood. Today's podcast is offered in conjunction with the journal's review series entitled the New Wave of targeted therapeutics and MPNs. At the 2025 annual ASH meeting, Drs. Rodick Skoda and Reuben Mesa were honored with the Ernest Beutler Lectern Prize for their seminal basic science and clinical research contributions to the myeloplature of neoplasms. In their Torded Force lectures, they highlighted the 20 year journey of laboratory and clinical trial collaborations that were foundational to translating genetic and mechanistic insights into the development and approval of JAK inhibitors. Over almost two decades, the MPN community has generally fleshed out the clinical profiles of JAK inhibitors, although some important knowledge gaps remain, I think today's guests would agree that there is palpable excitement about the current therapeutic landscape being an inflection point in the pipeline of MPN drugs. This is the impetus for the current Review series. Joining me on today's podcast to discuss these developments are the authors of the three articles in the review series. They include Dr. Stefan Catantonescu from the University Catholic de Louvain's De Douve Institute in Brussels, as well as the Ludwig Institute for Cancer Research in Brussels in Oxford. Together with William Fenshanker and Christian Piquet, they authored a review on next generation JAK inhibitors, the treatment of MPNs. Next we have Dr. Ann Mulally from the Stanford University School of Medicine and the Stanford Cancer Institute, who with Gabriel Salzman, wrote the piece of novel strategies targeting mutant chirreticlin in essential thrombocythemia and myelofibrosis. Lastly, Dr. Marina Kryminskaya joins us today from the Icahn School of Medicine at Mount Sinai. With Helena Ginsberg and Ronald Hoffman, they authored the article Modulators of the Hepcitin Pathway in Polycythemia vera and other MPNs. With this background, I'd like to extend a warm welcome to our podcast participants and use this opportunity to thank you all for your contributions to the series and today's podcast.
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Thank you, Jason. Thanks so much for having us thank you, Jason.
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It was a pleasure.
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You're very welcome. And Stefan, how about we kick off today's conversation with you? So my first question is whether you can provide for the audience some major takeaway points about the sheer mechanism of action of the currently approved JAK inhibitors, especially as it relates to selectivity and what is the unmet clinical need such that we need next generation JAK inhibitors.
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The currently approved JAK inhibitors are type 1 inhibitors, meaning that they bind to the active kinase domain of the mutated JAK2 and of the wild type JAK2, of course. And classical one is the ruxolitinib inhibitor, which is both a JAK2 and a JAK1 inhibitor. So it's not selective only for JAK2. We have fedratinib, which is a more selective JAK2 inhibitor, but it also inhibits FRIT3 and RET pacritinib, which prefers JAK2 and it also inhibits IREC1 and recently approved momelotinib, which inhibits again, both JAK1 and JAK2 and also active in receptor one. So they are all inhibitors that inhibit the kinase domain of jak2. So they are not specific for the mutated jak2 or for jak2 activated by calr or mutated mpl. And the major clinical need is to really target the clone that is carrying the phenotypic driver mutant, the phenotypic driver mutation in mpn. So there is a major need for that to spare the side effects of inhibiting JAK2 that is important for hematopoiesis and for immune response.
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Thank you, Stefan. Anne, let me pivot to you. Can you summarize what we know about the biology of mutant Calor and why does it lend itself to being an attractive target in MPNs?
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The biology of mutant CALOR is really super fascinating. And these mutations, recurrent mutations in the calverticulin gene, were discovered a little over 10 years ago now. And these are somatic mutations that are acquired in the hematopoietic stem cell. And they are indel mutations. So insertions and or deletions, and that basically result in a frame shift and generate an alternate reading frame that translates a novel C terminal peptide to the mutant calverticulin protein. And what's really interesting is that regardless of what mutation occurs at the DNA level, and there have been more than 100 mutations described now, they all encode this shared C terminal peptide. And obviously that makes this very attractive in terms of a therapeutic target. What makes it even more attractive is that this mutant C terminus is expressed on the cell surface. So calreticoline is normally an E or chaperone protein and it binds several receptors including the thrombopoietin receptor mpl. In the case of the mutant Cal reticulin, it binds MPL intracellularly in the endoplasmic reticulum, but then it retains this binding interaction with it so it does not release it. It retains this sort of pathogenic binding interaction. The complex traffics to the cell surface and the mutant C terminal peptide of the mutant color protein is exposed on the cell surface. That's what makes it especially attractive as a therapeutic target.
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Thank you. Ann and Marina, let me get to you. Can you discuss how iron homeostasis is perturbed in MPNs and what is the therapeutic rationale for using stimulators and or antagonists of the hepcidin pathway in these diseases?
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So first, as a reminder, hepcidin is the central negative regulator of iron trafficking and when hepcidin levels are high it binds to ferroportin, an iron transporting channel, resulting in its internalization and degradation preventing iron egress which leads to decreased iron availability. Normally when systemic iron supply is low, anemia occurs, but severe iron deficiency can also compromise the function of non air fluid cells, causing diminished muscle and cardiac function as well as cognitive deficit and other known effects of iron deficiency. Now to get back to polycytomaevira. The hallmark of PV is of course erythrocytosis and most PV patients also have severe iron deficiency which is often made worse by repeated phlebotomies, which is the mainstay of PV treatment. Interestingly, PV rifoiesis is much less sensitive to iron deficiencies and the severity of iron deficiency observed in many PV patients would be expected to cause severe anemia in non PV patients. And so what has been observed in recent years is that PV patients have decreased hepcidin levels if you compare it to patients with secondary forms of cytosis with similar degrees of increase in hematocrit levels. And these findings led to the idea that potentially reducing hepcidin levels in PV patients would lead to continued iron availability for persistent erythropoiesis that is seen in PV and that using hypcidin agonists would enable hematocrit control in PV patients and possibly correct the non hematologic consequences of iron deficiency. Now, on the other end of the spectrum, hepcidin pathway is also playing a role in development of anemia in patients with myelofibrosis. Hepcidin levels are high due to highly inflammatory state that patients with myelofibrosis have. And as a result iron availability is actually restricted, contributing to anemia at least partially. And therefore agents that could potentially decrease hepcidin levels would be used to treat anemia that is seen in myelofibrosis. And multiple drugs that are either currently available or in development are explored in this pathway. So we have both agonists and antagonists of the hepcidin pathway that currently being developed to treat MPNs and and I think it's a pretty exciting area of development.
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Thanks very much, Marina. I think it's very helpful to understand the physiology of the pathway in order to in turn understand why we're using stimulators and antagonists of the hepatic pathway. Thank you for that, Stefan. I was wondering if you can summarize the mechanisms of action on the next generation JAK inhibitors in development and how their design may translate into into greater clonical activity.
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On one hand there are the so called type 2 JAK2 inhibitors which are molecules that target the inactive confirmation of the kinase domain of jak2. They are not selective for the mutant jak2, but they're much stronger. So if you want, they can be compared to what imatinib does for BCR abl. So they find the kinase domain inactive and doesn't allow it to become active. The other group are the allosteric inhibitors which target really the pseudokinase domain of JAK2. They generally bind to the ATP binding site or around in the pseudokinase domain of JAK2 and that allosterically prevents the activation of the kinase domain. And there is one that claims to be JAK to V617F specific and that would really target the clone. The holy grail of all those inhibitors would be to simply eradicate the mutated clone that induces the mpn.
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Thank you Stefan. And Ann, perhaps you can touch on some of the different classes of CALR directed therapies under development and what are some of the maybe potential advantages and disadvantages of each of them.
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As has been alluded to earlier, this is an incredibly exciting time in that we have so many drugs in development now to target mutant calor. And the way we can organize this is to think about those that are already in clinical trials and then those that are in the preclinical stage of development and then also some that are independent of T cell function and T cell activity and those that are dependent on T cell activity. So if we take first of all what the drugs that are in the clinic, thinking about those that do not require T cell function, obviously the main one here is a monoclonal antibody that's targeting mutant calretic line on the cell surface. And this is in phase 1 clinical trials currently. And basically the antibody binds on the surface and then appears to interfere with MPL dimerization. This is an FC silent antibody. And by blocking MPL dimerization, it inhibits, you know, activation of the MPL JAK STAT pathway. And so the advantages of that are that it's obviously very selective because it's binding to the mutant. I think it's likely that it's going to inhibit the proliferation of the cells. And we know from preclinical data that that is the case. What's unclear is whether the cells will undergo apoptosis, how dependent the cells are, you know, on Calverticulin signaling for survival. And currently the drug is administered intravenously every two weeks. And what would happen if you stopped the drug? Would the cells just start reproliferating? So those are some of the sort of up and downsides of that approach. And then the two kind of main T cell dependent, dependent approaches that are in the clinic are first of all, bispecific T cell engagers. So this is where you engineer a bispecific antibody against two targets, one of which is mutant calreticulin on the cell surface and one is against a T cell. And typically that's CD3 to engage and activate T cells. And we have one trial that's open and enrolling and another one soon to open in that space. Again, specificity is going to be high because we have the mutant caloric antibody. There's potential for more potency because now you're bringing T cells to target these mutant caloric expressing cells, potential to actually kill the cell, but with that obviously potential for more toxicity related to activating T cells. And then of course, there's the requirement that the T cells be functional, the endogenous T cells in the patient be functional, because we're engaging the those T cells. And then finally, the last approach that's in the clinic are peptide vaccines. And Dr. Kremenskaya is leading one of these trials at Mount Sinai. And here what you're doing is you're basically taking that C terminal peptide and injecting it as a vaccine to basically activate the endogenous immune response of the patient and giving an adjuvant in combination. I think the upside of that is that it's safe. In fact, there's been one trial that's been completed in Denmark here where 10 patients were enrolled. No toxicity, unfortunately, no clinical responses. So safe. But whether the efficacy with different adjuvants will be different remains something to be determined. I think the major limitation or major thing with the vaccine is the issue of HLA restriction. The idea here is that the patient processes and presents new epitopes that are in the C terminal peptide region and then they're presented to the immune system, seen by T cells, and then T cells are activated and kill the cell. But we know that there are only certain HLA subtypes that are predicted to bind these new epitopes with high affinity. So the patient needs to have that particular HLA subtype in order to be able to process and present the new epitope. Again, it requires a, you know, active T cells, endogenous T cells. So those are the ones that are in the clinic I'll very briefly mention, I won't go into details, the more details are in the article. But in the preclinical realm we have CAR T cells. There's some preclinical data there from the UK and also from Austria looking at CAR T cells to target mutant calreticlin. And the other main approach is antibody drug conjugates. So these are what are called precision antibody drug conjugates where you combine the antibody via a linker to a protein degrader that targets a protein that you think is essential for their survival of the MPN cell. And there are some really nice preclinical data on both of those approaches not yet in the clinic.
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Thank you, Ann. That's a wonderful review of the available therapies that are in pre clinical development or actually in clinical trials right now. Marina, let me come back to you. You've led clinical efforts with the Hepcid and mimetic resveratide and pv, which is in late stage development. Can you provide a 20,000 foot view of its clinical activity based on what the trials were actually looking at the endpoints and where you see such drugs fitting in the PV toolkit?
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Absolutely. Respiratide is the first agent that led the field of Hepcit and agonists as a potential treatment option for PB patients. So respiratide is a hip site in memetic and as I mentioned earlier, it's believed that hippocytin levels are low in patients with bb. And so the idea is to use hepcidin agonists such as Rosatide to restrict the amount of iron that's available for refroesis and therefore control hematocrit that way. And this was the idea behind using Rosfortide as a treatment for pv. So I want to mention that it was very remarkable to see this approach as it ended up being very effective. As first patients were treated in the phase two trial, it was very rewriting to see that it resulted in hematocrit control in basically all patients. And we don't often see those kinds of effects with new drugs. So the results of the phase three verified trial were presented recently. And in this trial, patients with PV that were heavily phlebotomy dependent were randomized to either receive placebo or Rosfertide, and then they were evaluated for their continued need for phlebotomy phlebotomies. And so those patients that were treated with respiratory had significantly reduced their need for therapeutic phlebotomies compared to those patients that were treated with placebo. And if we look at the specific number, 77% versus 33% of patients had clinical responses. In addition, what I think was also very important for patients is that those patients that were treated with Rosfertide showed improvement in their symptoms as assessed through patient reported outcome tools such as promis, Fatigue Score or Myelofibrosis Symptom Assessment Form. And these are validated tools to assess patient symptom intensity in patients with MPNs. And then, of course, following respiratory success, there are other agents that are also targeting hepcidin pathway to treat polycythemia vera that are in earliest stages of development. And some of the early results have been presented recently, and they also look promising. I think if these hepcidin agents, all of them or some of them, become available eventually as standard of care, it does provide us with additional tools to treat polycythemia vera. And the different possibilities, I think, are for those patients that have truly low risk PV and are really being treated with phlebotomies alone. I think this potentially could replace the need for phlebotomies. And why would this be important? For some patients, phlebotomies are difficult, whether physically because it's time consuming, because they have difficult venous access, because of anxiety and such. So it gives them another option. And hopefully, as shown by the verified trial, it will also improve some of the symptoms that patients with thalassythema vera have that may be related to iron deficiency. And in addition, those patients that are on cytoreductive therapies, such as interferons or ruxolitinib or hydroxyurea Addition of this drug for those patients that still require phlebotomies could result in in them feeling better and potentially allow the opportunity to reduce the dose of the cytoreductive agent. They would still derive the benefit of potentially disease modification from these agents, but would have less side effects. So I think there are many possibilities if these drugs become available.
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Great. Thank you so much, Marina and Stefan, I'm going to come back to you. And looking forward, what do you see as the greatest challenges and opportunities with the new JAK inhibitors that you've talked about?
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We know that in the classical JAK inhibitor therapies, patients become resistant to them and also some high risk mutations are selected, such as EZH2, SXL1 and RAS. It's going to be very important to see for the type 2 inhibitors once we see if they're efficacious, if they have the same kind of problem now with the mutant specific inhibitors, we, we would hope to either decrease massively the allele burden that is an ultra deep molecular response, because if we just decrease it to a certain level, we know from other therapies that even low level of allele frequency can still induce disease. So we have to have a massive response. And then there is the issue that the confirmation of the JAK2V617F resembles a little bit the confirmation JAK2 assumes in the interferon gamma receptor complex. So there may be some issues with immunosuppression that we have to be aware of. But overall I think there are very exciting times coming for this field and I think I'm looking forward for the clinical results of all these inhibitors.
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Thank you, Stefan. And it's a similar question, and that is what do you consider some of the outstanding biologic and clinical questions that need to be addressed with these new CALR directed therapies are emerging.
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I think there are so many really important and interesting questions. I think similar to what Stefan outlined for the DAK2 inhibitors. The major thing we've been looking for in the MPN field is clonal selectivity and disease modification. And that's also true with respect to mutant Chir reticulum. So I think the big question is how well would these drugs do that, be clonally selective and specifically how well will they target the MPN disease propagating stem cell that harbors the Calreticola mutation? I think there'll be interesting things to work out around those approaches that require functional T cells, whether there will be differences in terms of patients with ET versus myelofibrosis where we know that there are differences in the functionality of the T cell in those diseases. Whether that will become important I think will also be very interesting. And a similar issue to what Stephan I outlined for JAK2 is the issue of clonal complexity. What will happen if you have additional mutations? Will it be different if those additional mutations are in the same cell as the calverticulin mutation versus mutations that are in a separate clone, a parallel independent clone? Will they potentially be selected for under the therapeutic pressure of mutant color targeting, for example? This could be be something that would be relevant in myelofibrosis. And then I think there'll be interesting questions around mechanisms of escape, you know, therapeutic resistance. What will be the role of the soluble secreted mutant CALOR potentially acting as a decoy? Will that be relevant at all? And will there be new mechanisms of sort of immune escape and therapeutic resistance that will start to see. So a really fascinating time to be working in this field. Field. And I'm incredibly optimistic that these therapies will have a substantial impact on our ability to treat patients with these diseases.
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Maybe just a follow up question for you, Ann and Stefan, and that is we typically of course use these therapies in individuals that have more advanced disease or have been treated with at least one prior line of therapy. Do you see that if they do have substantive anticlonal effects, kind of a creep toward their use toward low risk patients, or trying to basically knock out the clonal driver, so you're somehow modifying progression or somehow modifying natural course, disease, disease, you know, modifying potential.
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So for JAK2V617F, for example, I am convinced that if the specific inhibitors would work, they would be frontline for old MPNs and even for chips with the JAK2V617F. And I think that we know that 25% of patients that go to leukemia don't have the JAK2V617F. But many people have evidence that it is the paracrine and autocrine storm that the JAK2V617F clone induces that favors another clone to progress. So I think if you would extinguish all the bad signaling that the mutant Jak 2 would do, I think it's going to be very, very effective. And I wouldn't wait for the patient to resist Ruxo to move it to a better inhibitor.
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I completely agree with Stefan. So I've always been an advocate that earlier intervention makes a lot of sense in these diseases. I think what we have been lacking up until now is clonally selective therapies that could target selectively the cells that harbor either the JAK2 or mutation of the cavarticulin mutation. I think it makes a lot of sense if, if we have safe clonally selective therapies that they're introduced earlier in the course of the disease to dampen down all this chronic inflammation that Stefan alluded to and to intervene before we have genetic and clonal evolution when it becomes much more challenging to target the disease with just a single MPN specific targeting drug.
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Great. Thank you, Stefan and Ann and Rita, let me ask you perhaps the final question of the podcast, and that is again, what do you, when looking forward, think about how targeting the hepcitin pathways is going to be integrated into the care of PV and MF patients? We talk about stimulators of the hepcidin pathway in the context of resveratide, but maybe you can also touch on antagonists and how you see such drugs being used.
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The way that the antagonists are being developed right now for myelofibrosis is that we're hoping that it will have a bigger effect on anemia. As we all know, anemia is a major problem for basically all myelofibrosis patients during the course of their disease. And all the agents that we have tried so far to target anemia have had various levels of success, but not very high. And so the hope is that we know that hipside and inflammatory milieu that we see in myelofibrosis results in an increased hepcidin levels. And then this is at least one of the ways that patients with myelofibrosis develop anemia. So if we can target this particular pathway to improve anemia in these patients, I think it would be a very successful tool for treating myelofibrosis patients, especially similarly to what we've talked about before, as we first start with these agents as monotherapy in later stage patients and then move on with combinations targeting different pathways together, hopefully we would have more of a therapeutic effect. Of course, you know, my hope is that as we develop more of these clonal specifically targeting therapy and really eliminate the disease, then perhaps we don't need the drugs that treat anemia specifically. But I think for now we're looking at anything that will be useful for our patients. So that's my hope.
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Thank you, Marina. And with that, I'd like to conclude today's wonderful discussion with Stefan and Marina and I'd like to thank them for their work on the series on podcast and for their contributions to the MPN field. We appreciate Blood's audience for listening to our conversation today and hope you will join us on future podcasts.
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Thank you for listening to this bonus episode of the Blood podcast. To read these articles, visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.