EHA 2026 | Targeting mutant CALR in MF and ET: the therapeutic potential of INCA33989

I would say it’s our first real mutation or biomarker-directed therapeutic in myelofibrosis where mutant CALR, as we now know, is aberrantly expressed on the surface of stem cells and the clonal cells. It’s not on normal cells. It is targetable by an antibody. Insight brilliantly developed an Fc-silent antibody that selectively targets the complex of mutant CALR with the TIPO receptor. And at least pre-clinically, it would suggest that it internalizes that complex and you abrogate JAK-STAT signaling. So it all goes back to stopping JAK-STAT signaling. And what we saw pre-clinically was a very active compound. What we’ve seen clinically, both in MF and ET, that our CALR mutant, whether it’s type 1, type 2, or non-type 1, type 2, is first and foremost, a very, very safe drug. So we don’t see toxicity. I would argue probably one of the safest things that we’ve used in this context of these diseases. So it doesn’t really pose a tolerability issue, which of course is great. And we’ve dose ramped up from 24 milligrams all the way now to 3,500 milligrams. And we’ve never hit an MTD. So we know that the antibody can be given. Right now, it’s every two weeks infusion. And what we’re seeing clinically is in ET, which is much cleaner, very clear normalization of platelet count. So not dipping down and missing the mark, but you actually normalize it. And what I think is most exciting as someone who’s interested in developing therapeutics and the science that drives it is the fact that they’ve documented in the study reduction in mutant CALR-bearing hematopoietic and stem and progenitor cells. So it’s not just reducing the whole blood bath. It’s actually going after the compartment that matters the most, the disease-initiating cells. We see reduction in CALR mutant megakaryocytes in the bone marrow after treatment, and then increase in normal wild-type megakaryocytes. So we’re changing hematopoiesis. So I actually think we’re on the cusp of seeing fundamental changes in the biology and probably the outcomes of these patients. We need to refine it a little bit more. They’re developing a subcutaneous administration of the drug ultimately probably less frequent than every two weeks we have to you know figure out some of the kinks of how to how to choose which patients you know would be ideal for a Phase III study but but it’s the kind of therapeutic where I could see it being used across the board if you have a mutant CALR driven disease the antibody would make a lot of sense now whether we can improve upon it with you know different different antibodies that might bind to different parts of CALR or or BiTEs you know that’s the subject of ongoing clinical investigation but INCA033989 has clearly demonstrated that you can safely administer this targeted therapeutic and really exact pretty rapid and significant effects both in ET and myelofibrosis.

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