ASH 2024 | Phase II RESTORE trial: elritercept as monotherapy & in combination with ruxolitinib in pts with MF

Elritercept is a really fascinating new agent that’s emerging into the MDS and myelofibrosis field. Effectively, it is a TGF-beta superfamily ligand trap. So it’s a bit like luspatacept, but it has extra targets. So it basically targets activin A like luspatacept, but also GDF8 and 11. And so I just want to remind listeners that TGF-beta is really well known as a key factor in the pathogenesis and progression of MPNs. And so if we could target that, it should do what luspatacept does, improve hemoglobin, and more. So it should allow remodeling of the stem cell niche, reduction in fibrosis, etc. And so we’ve been trialing this agent in a study known as the RESTORE study. We’ve completed dose escalation and we fixed our RP2D at 3.75 milligrams per kilogram, the same as in MDS. And in our study, we’ve had treated a cohort of patients that are monotherapy, those patients who were JAK inhibitor ineligible or relapsed, refractory, or in combination with ruxolitinib. And the patients had to have at least eight weeks of ruxolitinib, and most of them had more than 20 weeks. And in fact, the median was 66. And so what we presented at ASH was an update, so 73 patients with this agent and 32 of them at the recommended dose. So what you have to remember when you look at a Phase I/II study is several of the patients will have been treated at what you believe is a suboptimal dose. And so the first thing to say is all the patients we could assess for safety, and there were no new safety signals, a little bit of thrombocytopenia, a little bit of diarrhea. The only thing that was grade three or above was thrombocytopenia. And that occurred in 14 out of 15 patients with any thrombocytopenia of any grade started with subnormal platelet counts. And in the monotherapy arm, most patients had subnormal platelet counts and a third of them had a platelet count of less than 50. So it’s a really heavily pre-treated cohort of patients. So well tolerated and plenty of patients staying on, which is also really important. So three quarters of the patients on the combo arm continue on the study, which is really important and fewer patients on the combo arm but it’s still a third of patients. Then thinking about efficacy so we saw significant numbers of patients having increases in hemoglobin. So at the recommended dose, 50% of patients had an increase in hemoglobin of at least a gram per deciliter and at the sub-recommended dose we had more patients, and 10% of them had an increase of two grams or more. So that’s really quite impressive. And it also occurred in the monotherapy arm. So that tells us that it’s working on disease-related as well as ruxolitinib-related anemia. And the same is also true for transfusion dependence. So at the recommended dose, two-thirds of patients having a reduction of at least 50% in their transfusions and a third achieving transfusion independence, which is very striking. Did we do that at the cost of thrombocytopenia? So one of the slides we showed, we cohorted out the patients baseline platelet count, and we showed that even in the patients whose platelets were less than 50 at the outset, generally there was stability. And for four patients, there was actually an increase in platelet count of 30 times 10 to the 9 per liter for at least 12 weeks. So we could improve both hemoglobin and platelets, which is important as they go together. And again, that’s indicative of an action beyond just erythropoiesis. And then finally, thinking about spleen and symptoms, and we did see benefits in both of those. We had three patients who had SVR35 without a change in their ruxolitinib dose. And one of those patients was actually a monotherapy patient who was recruited at the lowest monotherapy dose. And then for symptoms, we saw quite a significant proportion of patients having a reduction in their symptom score. So two thirds of patients had a reduced symptom score. And when we looked at the balance of symptoms, it was across all of the symptoms that we measure. So we measure seven key symptoms ranging from fatigue, night sweats, to things that might relate to the spleen, like abdominal pain and early satiety. And bone pain also was significantly improved. So I think this is exciting. As listeners will know, this drug is being taken forward as an agent to treat anemia in low, intermediate and very low-risk MDS. And we’re continuing to recruit patients in the RESTORE study. So I think it’s an exciting potential treatment for patients in the future.

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