MPN Workshop of the Carolinas 2025 | Telomerase inhibition in MPNs: ongoing investigations of imetelstat in myelofibrosis

So I’m going to be talking about imetelstat primarily, which is a telomerase inhibitor, first in class, small molecule inhibitor of telomerase, which is upregulated in malignant stem cells and only transiently in normal stem cells. So it really provides an opportunity to target the malignant clone, which is really the theme of, I would say, drug development right now in myelofibrosis. And I will review sort of the clinical development pathway that started with the Phase I study demonstrating not only improvements in blood counts, which we see with a number of different agents, but really changes both bone marrow histopathologically and molecularly, suggesting that the drug really does target the malignant stem cell. There is some debate, I would say, about its actual mechanism of action. But at the end of the day, there’s really an overwhelming amount of data, particularly from the Phase II randomized study, two different doses, intravenously administered every three weeks in JAK inhibitor failure patients with myelofibrosis that in fact does hit telomerase, reduces and changes biomarkers of both disease burden and telomerase activity, suggesting an on-target disease modifying approach. That, at least in that Phase II study, demonstrated survival benefit in a patient population that does not do well. So that really inspired the ongoing randomized Phase III study comparing Imetelstat to best available therapy, excluding JAK inhibitors in patients who are JAK inhibitor refractory with myelofibrosis. 

So right now it’s not approved in myelofibrosis or in MPNs at all. It’s approved in lower-risk transfusion-dependent MDS patients with an anemia improving endpoint in those patients, which is interesting because we are evaluating it in the sort of the advanced end of the spectrum of disease in myelofibrosis with a survival endpoint. I will point out though that 25% of patients in the Phase II study did have a clinical improvement in anemia, sometimes overlooked because the survival benefit was really what caught the attention in myelofibrosis. So it’s approved in a related disease with ineffective erythropoiesis, but right now the focus in clinical development, at least in MPNs, is in the myelofibrosis relapsed/refractory state.

So you know I don’t know that we have a great biomarker, predictive biomarker, for imetelstat at this point, I mean it is part of the ongoing studies. Whether telomerase activity itself would be a good predictor, whether there’s a molecular profile that would necessarily be a predictor, so I don’t know that we have that information. Right now the Phase III the registration study is a single agent in the relapsed/refractory setting, but perhaps, and we’re going to start to look at more data as it matures, combining it earlier on with the JAK inhibitor, which there is preclinical rationale for may be better. So maybe a combination strategy, which a lot of therapies are moving towards, may be the more appropriate patient population.

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