iwMDS 2025 | Novel targets in MDS: telomerase inhibition, the SELECT-MDS-1 trial, PK agonists, & more

Hetty Carraway

Hi everyone, my name is Dr Hetty Carraway. I work at the Cleveland Clinic in Cleveland, Ohio.

Amy DeZern

And I’m Amy DeZern from Baltimore, Maryland, where I work at Johns Hopkins. And we’ve just ended a lovely session of novel therapeutics and targets in myelodysplastic syndrome. We started with Dr Valeria Santini speaking about telomerase inhibition, which I was really interested in. What did you think?

Hetty Carraway

I agree. I thought she did a fantastic job reviewing kind of the importance of imetelstat in our patients with low-risk MDS that are highly transfusion dependent. And she kind of walked us through some of the questions that we have in terms of the biomarkers that may not be entirely relevant with those inhibitors. And I thought that was a nice kind of foray also into your talk about the importance of having a biomarker. Your question was specific to her as well about what are we going to use as a biomarker if any and it sounded like her thoughts were that we don’t quite have one yet for her for imetelstat.

Amy DeZern

I think what’s interesting is there’s no question the drug works right it’s been approved it raises the hemoglobin in patients who’ve previously remained transfusion dependent we know that from the IMERGE trial and even though it is listed or labeled as a telomerase inhibitor. There’s no question that it’s an on-target effect, but it’s not clear that that’s the mechanism through which the hemoglobin is raised. And so I think we just really need to see some more studies to better understand how it’s actually working. And that may show us which patients it’s more suitable for and in a way be a biomarker. But I do think she was clear that there’s really no role for measuring telomerase length a priori. So we’ll have to figure something else out.

Hetty Carraway

Yeah, it sounds like she’s working hard on that.

Amy DeZern

For sure.

Hetty Carraway

And tell me a little bit or highlights for the group about your study and your talk about Rara.

Amy DeZern

So we did speak about retinoids specific to the SelectMDS1 trial, which unfortunately was not a trial that ended up with a positive result as the combination of tamibarotene with azacitidine compared to azacitidine alone had very similar CR rates. But there were some pearls in the data. For one thing, back to the earlier point, it was a biomarker study with a peripheral blood-based assay that was done a priori for eligibility, and it accrued really quite efficiently. We saw that the toxicity was manageable, though a little bit more myelosuppressive, especially more anemia than we had anticipated. But interestingly enough, in the patients who were transfusion-dependent at baseline, the combination with tamibarotene and azacitidine led to more transfusion independence compared to azacitidine alone, which kind of begs the question if retinoids would have a role in lower risk MDS. I think we’re going to find out if, you know, there’s another retinoid out there in a combination trial from China with dicitamine that may be published very soon to see what the path forward could be for those other drugs, but certainly very interesting.

Hetty Carraway

Definitely.

Amy DeZern

You want to tell us sort of what you talked about, thinking of other ways to alleviate anemia?

Hetty Carraway

Yeah, I had the good fortune of talking about luspatercept, of course, which is FDA approved for our patients that are transfusion dependent. And we highlighted some of the benefits in the TGF beta pathway for inhibition, including luspatercept as well as elritercept. Both of them seem to be quite effective and have really nice response rates. And the durability seems to be really encouraging, and luspatercept does evidence by meeting some of the secondary endpoints of the study that was presented by Garcia Manero at ASH this past year. And equally important is the elritercept data that also shows really encouraging response rates and really nice durability. So I think there’ll be some really interesting questions that emerge with what are the patient populations that benefit from both of these? Are there subsets or is it really everybody? And, you know, some of the benefits with the elritercept is really that it’s both early and late stages that it has an impact in terms of the erythropoiesis. And so if that really changes things or impacts how patients do and gosh, that would be really exciting to see improvements in both platelets and neutrophils as well as hemoglobin. So I’m excited about that data.

Amy DeZern

One thing that I thought was interesting also about elritercept is it may have some other benefits in terms of metabolism, cardiac function, immune system. I think it remains to be seen. That sort of led to a spirited debate at the end of how soon is too soon to start therapy or what level of depth of hemoglobin do you wait until to start. With the ELEMENT trial starting a bit earlier at hemoglobin around nine and a half. And I think that maybe on either side of the pond, there’s a little bit different approach of what the appropriate hemoglobin threshold is, but we’re definitely going to learn more.

Hetty Carraway

Yeah, I actually liked the debate. I’m really glad that people are pushing forward to say these agents are well tolerated. And if we have patients that are symptomatic and not meeting criteria of transfusion dependence, why couldn’t we start therapy earlier and hopefully improve their quality of life and also potentially the duration of some response and or benefit to them. These diagnoses are really tough on our patient population. And as you well know, many of our patients are elderly and have many comorbidities. And if these agents have an impact on comorbidities like cardiovascular disease, that hopefully can, that is important, A, for us to measure and B, important for our patients if there’s benefit.

Amy DeZern

And I think it’s sort of merged a number of themes that we’ve heard today and led to the fourth talk in this session with Dr Zeiden’s data on PK agonists and then the Matterhorn trial and roxadustat. What endpoints we’re going to measure, what makes a trial successful if it’s designed correctly, but he alluded to the fact that he believed that the drug was still very useful. What did you think about some of that Matterhorn data?

Hetty Carraway

Yeah, so the roxadustat study looks really interesting to me, especially with the subset analysis that then was done in the post hoc setting where they looked at transfusion independence along with a rise in hemoglobin. And gosh, I wish that was pre-specified rather than post hoc. And so it really does highlight the fact that setting up the study from the beginning is really important to get that right because perhaps this drug may not move forward as a result of not including some of those those right endpoints in the upfront setting. I hope we’ll be able to somehow have access to that drug or resurrect it because it sounds like it has activity. The other things he ended up talking about was the pyruvate kinase pathway which seems to have some huge strides in the thalassemia space currently and probably another area of investigation for us to pursue in the future.

Amy DeZern

Well and he has a next generation of that as well looking in a two-way study. So maybe some data we’ll see in the relative near term. But I think a lot of fun discussions on novel agents and targets and hopefully just other ways we can find to treat our MDS patients.

Hetty Carraway

Yeah, hoping for the best and looking to the future.

Amy DeZern

Sounds good.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.