Zilurgisertib Alone or Combined With Ruxolitinib Well-Tolerated Among Patients With Myelofibrosis

Prithviraj Bose, MD, MD Anderson Cancer Center, Houston, Texas, discussed phase 1/2 results from an ongoing open-label, multicenter, dose-escalation/expansion study that demonstrated zilurgisertib treatment as monotherapy or in combination with ruxolitinib had a favorable tolerance profile among patients with myelofibrosis, where greater hepcidin control over time was observed at higher zilurgisertib doses in both patient groups.

“Preliminary improvements in anemia were observed in non–transfusion-dependent patients during dose escalation, suggesting potential for therapeutic activity,” explained Dr Bose and colleagues.

Results were presented at the 2024 European Hematology Association (EHA) Meeting in Madrid, Spain.

Transcript:

Hi, I'm Prithviraj Bose. I'm a professor in the department of leukemia at MD Anderson Cancer Center in Houston, Texas. I focus on myeloproliferative neoplasms. Today, I'll be talking to you briefly about the presentation I made at the EHA Congress in Madrid this year on the trial of zilurgisertib, an ACVR1/Activin receptor-like kinase-2 (ALK2) inhibitor in patients with myelofibrosis and anemia.

Zilurgisertib is an inhibitor, a potent and selective inhibitor of ACVR1, also known as ALK2. And as is probably familiar to our audience, when you inhibit ACVR1, you down-regulate hepcidin. Downregulating hepcidin makes iron more available to the bone marrow for erythropoiesis with less of it sequestered in the reticuloendothelial system. This is a principle that we have come to accept and acknowledge as playing a part in the anemia responses, for example, to momelotinib or pacritinib.

In this study, there are 3 cohorts: treatment groups A, B, and C. Treatment group A studies zilurgisertib alone. Treatment group B adds it on in patients who are on a stable dose of ruxolitinib. And treatment group C is for Janus kinase (JAK) inhibitor or naive patients who start with both ruxolitinib and zilurgisertib at the same time from the outset.

The results presented thus far, including at EHA, essentially represent the first 2 cohorts, a total of 45 patients, about evenly distributed, 22 in one cohort, 23 in the other cohort. So [there are] really no results yet in the public domain on the treatment naive cohort. We're just talking about the monotherapy cohort (treatment group A) and the add-on cohort (treatment group B).

What was seen in this trial to date, is that 1, the drug is well-tolerated. And 2. the fact that it is hitting its target. We have proof of principle because we have hepcidin levels going down in a dose-dependent fashion. With higher doses of zilurgisertib, you're getting lower hepcidin levels or greater degrees of hepcidin suppression.

Now, coming to the clinical efficacy, what we've seen so far is that in non-transfusion-dependent patients in both cohorts, there's been 2 responders each. So, there's been 2 anemia responders in both cohorts. Thus far, we've not seen transfusion independent responses. [For] the transfusion dependent patients to date, we've not seen documented responses yet. However, like I said, in the anemic patients or non-transfusion dependent patients to be clear, there's been 2 responses in the monotherapy and there's been 2 responses in the add-on cohort.

The trial is ongoing. In particular, like I said, the treatment group C, which is the treatment-naive cohort who start with the combo of ruxolitinib and zilurgisertib from the get-go is certainly accruing as are the others and we look forward to sharing more results in the future. Thank you for listening.

Source:

Bose P, Oh S, Kiladjian JJ, et al. The activin receptor-like kinase-2 inhibitor zilurgisertib (Incb000928) as monotherapy or with ruxolitinib in patients with anemia due to myelofibrosis: Phase 1/2 study results. Presented at the 2024 European Hematology Association (EHA) Meeting. July 13–16, 2024; Madrid, Spain. Abstract P1060