EHA 2026 | Updated data with INCA033989, a mutant CALR-specific mAb, in patients with MPNs

I have the great privilege of presenting the latest update, which is actually only the second update, if you like, of the data with the totally novel therapy INCA33989, which is an Fc silent monoclonal antibody targeting mutant calreticulin. And just for the listeners, just to summarize a little bit about biology and what makes calreticulin a beautiful, perfect biological target. The mutant calreticulin is processed in the cell in the Golgi body and complexed to the thrombopoietin receptor MPL. And then it’s trafficked out to the surface. So it’s only mutant calreticulin that’s expressed on the surface and it’s only expressed in cells that have the mutant. So it’s like a perfect tag for the cancer cell, if you like. So the antibody recognizes the mutant epitope and then it stops the receptor dimerizing and abrogates signaling. And we’ve seen data with ET, but of course myelofibrosis is more difficult and there’s a significant unmet need for patients as well with myelofibrosis. 

In the study, which is quite a complicated study, patients were dose escalated and they also were recruited across different cohorts. So there were patients who were treated with monotherapy, add on to ruxolitinib. And then because the results were so impressive, we’ve also been recruiting patients who’ve never seen a JAK inhibitor and treated them. And so overall, using the conventional myelofibrosis endpoints, we see significant numbers of patients having 35% reduction in spleen volume. And that’s even though the baseline spleen assessment was taken while the patient was on ruxolitinib and then taken off. Symptom response is more than 50% of patients. But what I’m really excited about is that we’re seeing reduction, as we would expect, in mutant calreticulin progenitors. We’re seeing reduction in the allele burden. The bone marrow morphology is normalizing. And we’re seeing reduction of mutant calreticulin expressing megakaryocytes and improvement in fibrosis. And for a phase one study, we still have more than 80% of patients on study. 

Important to emphasize tolerability here. So what we’re seeing is that tolerability is really astonishing, treating patients up to the age of 82, which is amazing. And then beyond that, we’ve got, you know, no dose limiting toxicity and no maximum tolerated dose. So very, very exciting data and plans for phase three studies, which are justified based on the first line and also in the second line setting. 

I definitely think that this therapy is precision medicine personified, if you like, and that it will enable us to potentially move towards more disease modifying therapy. Yes, we can hit traditional endpoints, which I would say would be more JAK inhibitor expected endpoints, spleen and symptoms. But seeing that as well as the normalization of the marrow, I forgot to mention improvement in hemoglobin. So we’re seeing improvements and restoration of normal hemopoiesis. Super exciting. So I think this really is a line in the sand and a mark that we’re moving towards disease modification definitively in myeloproliferative neoplasms now.

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