EHA 2025 | Safety & efficacy of INCA33989, a mutCALR-specific monoclonal antibody, in essential thrombocythemia

Today for the Late Breaking Abstract we presented the initial results of 989, which is a monoclonal antibody to mutant CALR TIPO receptor complex. This is a treatment in development that is supported by preclinical modeling demonstrating selective targeting of mutant CALR hematopoietic stem cells and the ability to deplete that pool and potentially change the course of disease. So the preclinical data looked very good. 

We took it into the clinic in a dose escalation Phase I study starting at 24 milligrams infused every two weeks all the way up to 2,500 milligrams. This was really a very large global effort so there was really two studies in, one in the US and then one outside the US combined data set demonstrating most importantly safety, very well tolerated drug, very few events that were significant that were attributed to the antibody. There was one thrombotic event, visceral venous thrombosis, when a patient was treated at a low dose in a patient with risk factors for thrombosis including a history of thrombosis, so unlikely related to the drug. So patients tolerated the drug very well. We saw lipase increase that was mostly grade one and two, unexplained with no clinical or radiographic consequences. So we were very happy with the safety and tolerability. In fact, we did not have a DLT, nor did we achieve a maximally tolerated dose. 

When looking at efficacy, we saw very rapid and durable reductions in normalization of the platelet count without thrombocytopenia. And then we looked at the biomarkers of disease modification, including reduction in mutant CALR VAF. And we did this through single cell RNA sequencing demonstrating that in the, by immunophenotyping, in the hematopoietic stem cell and myeloid erythroid lineage cells, significant reduction in mutant VAF was seen, and this was also correlated with clinical responses. Additionally, in the bone marrow, we saw a reduction in mutant CALR staining megakaryocytes with an increase in normal megakaryocytes, suggesting shifting to normal hematopoiesis. So in two compartments, biomarker evidence of disease modification correlating with clinical activity, reduction and normalization of platelet counts. 

I would say this is probably one of the most exciting abstracts, I’m biased, that I’ve seen recently because it’s rare to have a Phase I study with such well tolerated and early clinical activity, both at a clinical and biomarker level. It’s paramount that we continue to follow these patients out. It’s paramount that we expand probably several dose levels to really look at efficacy and ultimately create a clinical development pathway forward for mutant CALR ET. At the same time, we’re also evaluating patients in these studies for myelofibrosis, mutant CALR myelofibrosis. The data set will likely be shown at upcoming meetings too. So very exciting times for immune therapy which is I would say novel for this disease type.

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