Clinical Implications and Positioning of Imetelstat in Lower-Risk MDS


Closing remarks on the overall clinical implications of imetelstat data, and patient populations that could benefit the most from it.

Dr. Michael Savona: I think several open questions will remain, and I would be also interested to kind of take your perspective on this, Mike, that we did not discuss the Commands trial in detail. You alluded to it, but the Commands basically showed for the first time ever that we have a drug that improves transfusion independency rate over ESA in the frontline setting. That was a higher rate, 60% compared to 30%. The patient population were both ringed sideroblasts plus positive and negative, which means potentially that also those Luspatercept could become the first line treatment. It's an exciting year for lower risk MDS. But how do you think about the sequencing of the drugs with two positive trials? The first two positive trials, I think when you look at the field 25 years with less than five positive trials in MDS, you have two positive randomized phase three trials in one year. Very exciting. The field is starting to change quickly. How do you see I guess the sequencing of therapies in the upcoming year?

Dr. Michael Savona: I'm kind of like you. I think I used to have this slide that I'd show of a snail on a racetrack illustrating the paucity of new development in MDS. We've got 727 approved in intermediate and higher risk MDS in the last couple years and Luspatercept. Now Luspatercept kind of with a pending expanding indication. Now imetelstat. So it is an exciting time and the questions that are going to then move to the forefront is how you actually sequence these things. I think that much like in CML when we deal with TKIs, well, what's the TKI? Well, if someone has a problem with recurrent pleural effusions, you may want to avoid dasatinib. If someone has chronic pancreatitis, you don't give them Nilotinib. Even though those are low risk complications, you certainly have a lower threshold to develop those things if you have a background of that comorbidity. I think in the same way you know when you approach patients with low MDS I don't think ESAs are going away. They're frankly a lot cheaper and kind of ensconced in part of the standard of care. Will they be supplanted by Luspatercept? Maybe in some patients but probably not most. I think that going back to my CML analogy, I think there are patients who are particularly fatigued and really can't take to be pushed down anymore. Maybe Luspatercept is not their first drug they should try. Maybe they would be better off with imetelstat beforehand. Those are kind of questions that we have yet to answer. I'll just remind everyone that in addition to these approvals, there's a variety of new therapies that are focused on the microenvironment and altering the immune landscape. Because we think that the pro-inflammatory milieu of early MDS, the increased danger associated molecular patterns, the pyroptosis or necroptosis that occurs, and a feedforward system leads to the generation of further clones in the progression of MDS. And we think there's probably a role for treating this and also going after high risk chip clones or CCUs. Those are things that are really exciting to me. We're still kind of early with a lot of these agents. But that's where I think low risk MDS is going to get really exciting from a tertiary prevention standpoint, where we'll be able to identify CHIP is common. 30% of 70-year-olds have chip. But maybe we'll be able to figure of those 30%, what are the 10% of those patients who are actually at a 50% risk of developing MDS by the pattern of mutations they have. The VAF or the mutations. And that's only going to happen with greater prospective study, which is ongoing. But it basically changes our capacity to treating the disease after it's happened, to really preventing it from ever getting worse. That's where a lot of my excitement is.

Dr. Amer Zeidan: I think I shared a lot of these thoughts, Mike. It's actually very interesting. You mentioned some of the newer kind of agents looking at the inflammasome and inflammation and immune modulation. Actually, one of the oral presentations in EM looked at the immune impact of the imetelstat. Kind of a common theme in MDS I think where we kind of have active drugs, but we don't fully understand the mechanism of action. We have seen this with Lenalidomide, with HMAs, probably with imetelstat. I think trying to understand the full mechanism of action of these drugs is going to help us both to identify bio-predictors. How can we select patients in advance rather than trial and error of what causes the patient to become transition dependent or not? But also it's going to help us to kind of design rational approaches to combine drugs. Because you mentioned sequencing as one of the most important areas I think of research. I think the other important area in lower risk MDS is the combinations. Can we combine some of those active agents to not only increase the rate of transfusion independency, but also increase the durability and potentially even start to aim more ambitiously. Why should we settle just for transfusion dependence? Can we completely resolve the anemia? Why would I aim to get a hemoglobin of 11 or 11 and a half? This is still anemia. This still has downside aspects to it. If I have very active drugs which are safe, can't we just completely resolve the anemia? Can we go to hemoglobin of 13 and get the patients to feel better and hopefully live longer? Can we shoot for overall survival? I think there are many aspects that are very exciting for us in terms of the sequencing, in terms of the combinations, in terms of the novel agents. But most importantly, disease modification and kind of moving away from this paradigm of just fixing the anemia and kind of starting to go more ambitiously for overall survival improvement, which has been always a boogeyman in lower risk MDS. Maybe we can start to look there. So thank you so much, Mike. This was a very exciting discussion. I think the audience can easily feel the level of excitement in our discussion about this drug and the other evolving drugs. We thank the audience for watching this targeted oncology discussion. We hope you found this discussion to be informative and valuable to the treatment of your patients with lower risk MDs. Thank you so much, Mike.

Dr. Michael Savona: Thank you. It was a pleasure.

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