At EHA2025, Dr John Mascarenas (Icahn School of Medicine at Mount Sinai, New York City, NY, USA) presented early-phase data on INCA33989, a first-in-class mutant CALR-targeted monoclonal antibody in essential thrombocythemia (ET). This late-breaking abstract addresses a gap in ET management – especially for patients with CALR mutations who often fail or cannot tolerate current therapies like hydroxyurea, anagrelide or interferon. INCA33989 demonstrated an 80% platelet normalization rate, no dose-limiting toxicities, and early signs of disease modification, including reductions in mutant CALR variant allele fraction and changes in bone marrow and stem cell compartments. As dose expansion continues, this promising therapy may represent a paradigm shift in the treatment of ET – not just controlling blood counts, but targeting the disease at its root.
The late-breaking abstract, ‘INCA33989 IS A NOVEL, FIRST IN CLASS, MUTANT CALRETICULIN-SPECIFIC MONOCLONAL ANTIBODY THAT DEMONSTRATES SAFETY AND EFFICACY IN PATIENTS WITH ESSENTIAL THROMBOCYTHEMIA (ET)’ (LB4002) was presented at the European Hematology Association (EHA) 2025 Congress from June 12-15th in Milan, Italy.
Chapters
0.28.78: Rationale, clinical unmet needs for patients with essential thrombocythemia, and why INCA33989 is different from existing therapies
1:21.09: Methodology and study design of INCA33989-101 (NCT05936359) and -102 (NCT06034002)
3:17.47: Results and conclusions from the data so far
6:46.27: The future, ongoing trials and next steps
Transcript
I’m John Mascarenas from the Icahn School of Medicine at Mount Sinai in New York City, NY, USA. And today, we’ll be talking about the, novel mutant CAL R antibody, INCA33989, which was presented as a late-breaking abstract at EHA in Milan, based on the ET, the essential thrombocythemia, cohort. I think this is an important study because there’s still unmet needs in ET.
Rationale, clinical unmet needs for patients with essential thrombocythemia, and why INCA33989 is different from existing therapies
ET, of course, is a myeloproliferative neoplasm associated with thrombosis and haemorrhage and progression to myelofibrosis. And right now, for mutant CAL R disease, it is approximately 25-30% of these patients.
We are using hydroxyurea, anagrelide and interferon, and many patients end up either failing due to toxicity issues, not being responsive, losing response to these agents or can’t tolerate them, in some cases. So there is a need for therapies.
This case is what I would argue is a disease-modifying therapy, to alter the natural history and progression of disease, not just to control the platelet counts. And I think that’s what really makes this study really, exciting. So there is unmet need. I think this drug INCA33989, fits that unmet need.
Methodology and study design of INCA33989-101 (NCT05936359) and -102 (NCT06034002)
So in terms of the study itself, I will point out it was two studies, actually, a US-based study and then an ex-US-based study. The data was combined and presented as one study in patients with mutant CAL R. So that was a criteria, who had essential thrombocythemia WHO diagnosed, with at least one prior line of therapy and had a platelet count greater than 450,000. And they could be on cytoreductive therapy therapy like hydroxyurea and anagrelide to get onto the ET cohort.
So what we’re not talking about is the myelofibrosis. That will be presented in the latter part of 2025. This is just the ET cohort.
And these patients were screened and then enrolled into this unblinded phase I study that was dose escalation, from 24mg dose cohort all the way up to 2,500mg looking for toxicity and identifying dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) in this study with this agent that’s infused every two weeks.
And the agent INCA33989 is a monoclonal antibody to mutant CAL R, which is expressed on the surface of the cell in complex to the thrombopoietin receptor, and this is super selective to binding that complex, internalizing that complex and turning off aberrant JAK-STAT signaling, ultimately leading to apoptosis of mutant CAL R cells specifically.
And this was shown very elegantly, by Dr Rice and colleagues in preclinical modeling with this antibody, both primary cells and murine modeling. We sought to replicate this in humans with the disease, first looking at safety and then ultimately by modified, response criteria, efficacy from count control and really exciting correlative markers that I’ll describe, looking at the potential for disease modification.
Results and conclusions from the data so far
The conclusions of the data so far are that it’s super safe. We saw no dose limiting toxicity. We ramped up all the way to 2,500mg with this antibody every two weeks. In fact, if you look at the adverse event profile, there was probably about 60% of patients that had adverse events that could be attributable to the agent, and those adverse events were mostly low-grade events that were likely attributable to the disease or alternative causes. There really wasn’t a signal of infusion-related reactions or clear toxicity with this agent. I would make the statement that this is probably one of the best tolerated therapies I’ve seen in the MPN space over 20 years of clinical trials.
We did see asymptomatic transient lipase elevation. Unclear what the significance of that was. There was no radiographic or clinical sequelae associated with pancreatitis. It wasn’t even clearly related temporally to the to the drug itself, and that was really it. We had no thrombocytopenia. So the platelet counts normalizes, I will describe, but we didn’t overshoot. So really very clean safety profile with no maximally tolerated dose observed.
From a efficacy standpoint, about 80% response rate, overall, in terms of normalizing the platelet count and keeping the white count normal. Since we dose escalated, we broke down the results in (24-400mg cohort and then >400mg). And if you look at the efficacy results, you can see that there’s rapid normalization of the platelet counts even more so at 400mg in greater doses and maintaining that normal, platelet count over the study period.
We also saw improvements in many aspects of the disease that will be will be presented at later meetings, like other markers like lactate dehydrogenase (LDH) and we didn’t see anaemia or leukopenia.
We will eventually present data on spleen and symptom changes as well, which was not a significant aspect to get on the study. So from a platelet perspective, it’s clearly an active agent in normalizing the platelet and very safe.
Ultimately, what we saw that I think speaks to the potential for disease modification is three things. One is significant reductions in variant low fraction of mutant CAL R with this therapy, more so at the higher doses, more so with type 1 versus type 2 patients. Type 1 is a 52-bp deletion versus type 2, which is a 5-bp deletion. And then from RNA sequencing of peripheral blood cells from 7 representative patients that were enrolled in the study, we saw a reduction in mutant CAL R expression in the hematopoietic stem cell population by immunophenotype, suggesting that we’re really targeting the the disease initiating cells and reducing the burden of those, cells in the peripheral blood.
And then in the bone marrow reduction in total megakaryocytes driven by reduction in mutant CAL R bearing megakaryocytes with an increase in normal or wild type mutant CAL R wild type CAL R expressing cells. So, two compartments of the of the body demonstrating the potential for disease modification with this antibody early on. Of course, we need to build upon this.
The future, ongoing trials and next steps
So what’s happening in the future?
We’re going to continue to follow these patients, continue to dose them out. We had one patient stop therapy. That’s very unusual in a phase I study, due to thrombosis, abdominal vein thrombosis, which occurred early on in the study at at the lowest dose, 24mg, in a patient who had a lot of risk factors for it.
So we’re gonna continue to treat these patients and follow their Talar Dome Avulsion Fractures (TALAR VAFs) out, and intra-patient dose escalation will continue to occur. And now we are expanding three doses in the phase 1b part of the of the program to look more closely at efficacy and further biomarkers. So you’ll see further presentations later this year and next year and subsequent meetings on efficacy. I think the safety is obvious.
I think we need to work out maybe dosing schedules, maybe explore subcutaneous administration of the drug, but super exciting results for a novel immunotherapeutic approach in essential thrombocythemia with a mutant CAL R specific antibody.
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Disclosure: John Mascarhenas is a consultant for Incyte, Novartis, Disc, BMS, SOBI, Karyopharm, Geron, Galecto, GSK, Kartos, Abbvie, MorphoSys, PharmaEsssentia and Italfarmco Spa.
He has received grant/research support from: Incyte, Novartis, BMS, SOBI, Karyopharm, Geron, Kartos, Abbvie, MorphoSys, PharmaEsssentia, Italfarmco Spa and Disc.
Cite: #EHA25: INCA33989 shows promise as disease-modifying therapy for essential thrombocythemia. touchHAEMATOLOGY. July 17th, 2025
Interviewer/Editor: Sophie Nickelson
This content has been developed independently by Touch Medical Media for touchHAEMATOLOGY. It is not affiliated with the European Hematology Association (EHA). Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.
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