INCA033989 Shows Potential as a Targeted Approach for Myelofibrosis With Mutant Calreticulin: Claire Harrison, MD

The American Journal of Managed Care^® (AJMC^®) recently spoke with Claire Harrison, MD, following the European Hematology Association 2026 Congress last month, where she presented findings from her abstract, “Mutant Calreticulin–Specific Monoclonal Antibody, INCA033989, is Well Tolerated and Achieves Robust Spleen, Anemia, and Molecular Responses in Patients (PTS) With Myelofibrosis (MF).”

In the interview, Harrison, the study’s lead author, discussed the rationale for targeting mutant calreticulin in myelofibrosis with INCA033989, an Fc-silent monoclonal antibody designed to recognize the abnormal protein complex expressed on affected cells. She highlighted early clinical data demonstrating spleen volume reductions, symptom improvements, anemia responses, reductions in variant allele frequency (VAF), and biological changes suggesting the therapy may target the underlying disease biology.

Harrison noted that responses were observed across calreticulin mutation types and among patients with additional mutations, with minimal toxicity reported to date. She concluded by describing INCA033989 as a potential “step change” in myelofibrosis treatment and emphasized the significance of upcoming phase 3 studies.

This transcript has been lightly edited for clarity.

AJMC: To start, why did you choose to target patients with myelofibrosis who have mutant calreticulin, and what sets it apart from other monoclonal antibodies?

Harrison: In myeloproliferative neoplasms, we haven't really used antibody-based therapy ever before, so this is our first go at an antibody-based therapy. We target the immune system, maybe with interferon, tweaking it up, ruxolitinib, dampening it down. But the thing is that mutant calreticulin is present in around a third of our patients with myelofibrosis. These patients have a unique phenotype. First of all, they tend to be more anemic and not respond so well to standard therapies. While the Janus kinase [JAK] inhibitors do work for them, they don't work as well as they do for patients with other mutations. Broadly speaking, the JAK inhibitors, anyway, are not mutation-targeted.

Just a word about the really exquisite beauty of the calreticulin mutation. We have this mutation, and it generates a novel sequence on the end of the protein. The calreticulin proteins are involved in calcium signaling and protein folding inside the cells, but the mutant calreticulin binds to the thrombopoietin receptor, MPL, and then is trafficked out to the cell surface, so it's tagged on the surface. There's the mutant calreticulin waggling around on the surface of these cells that have got the mutation in them. It's like a perfect immune target.

INCA033989 is an Fc-silent monoclonal antibody that binds to the mutant calreticulin when it's complexed to the thrombopoietin receptor. We've been running these studies in patients with myelofibrosis because there's significant unmet need there. We know that our current therapies don't work well for myelofibrosis patients with calreticulin and that there are no therapies that specifically target this mutation, so it’s a perfect opportunity.

AJMC: Could you summarize the responses observed with INCA033989 and what they suggest about the treatment's mechanism of action?

Harrison: In myelofibrosis, we've been studying several different cohorts of patients with INCA033989. It's given as a drip or an infusion over about 30 minutes, roughly every 2 weeks. First of all, we recruited patients who were resistant, intolerant, or refractory to JAK inhibitors, and we treated them with monotherapy. There was also a cohort of similar patients already on a JAK inhibitor but with residual disease. Amongst those patients who got the drug as a monotherapy (I'm going to be talking about 3 cohorts of patients), this last cohort of patients were patients who had never seen a JAK inhibitor because they weren't really eligible for one, maybe because they had too much anemia or maybe because they already had skin cancer, for example. You've got these 3 nice cohorts of patients, and the age range of patients is up to 82, so very reflective of our patient population.

You asked about spleen responses, so we classically measure spleen response using MRI, and we look at the spleen volume. Typically in the first-line setting, we’re looking for a spleen volume reduction [SVR] of 35%, and in the second-line setting, maybe 25%. But you also have to be really careful about when you take the baseline spleen measurement. In studies where we've switched between JAK inhibitors, we've always washed patients out of a JAK inhibitor, typically for 2 weeks, then done the baseline spleen, then started the patient on the treatment.

With INCA033989, we just did a baseline spleen measurement. If the patient was on a JAK inhibitor, they were on one, so likely what happened to those patients was we took the baseline, the spleen went up, and then it started to come down. We just need to remember that when we talk about the results. For the second-line patients receiving a monotherapy, about a third of them got a 25% SVR, and about 1 in 5, or 20%, got an SVR35. So, it could well be more than that, bearing in mind the spleen going up and down when you wash out a JAK inhibitor.

In the JAK-ineligible patients, there were 17 patients who were accessible at week 24. Of those, around 50% had achieved both. So that's pretty good, if you think about what we would see with a JAK inhibitor in the frontline setting. With ruxolitinib in the COMFORT-II study (NCT00934544), which I led from Europe, we saw 28% to 30% of patients achieving this, so we're doing well. Symptom responses were good. Of course, this is an open-label study, but I think that speaks to the tolerability of the drug. At least a third of patients achieved a 50% reduction in their symptom burden.

Then, you asked me about anemia responses. We showed anemia responses in the EHA meeting in 2 cohorts of patients: those who were anemic at baseline and those who were not. Then, we divided them by whether they had never had a JAK inhibitor or had had one in the past. Both those cohorts of patients showed an anemia response, so this can’t just be a washout of a JAK inhibitor, because it’s occurring in some patients who’ve never had a JAK inhibitor. Looking at the toughest cohort of patients with anemia, so the patients who are transfusion-dependent, 4 out of 6 of them, so small numbers, but still 4 out of 6, had a response, and for 3 of them, they became transfusion-independent. That's really interesting.

Then, you asked me about some other biological markers. I mentioned that we don't see any reduction in the quantity of the mutation or the VAF with standard therapies, or we see very modest reductions. In this study, we've been learning a lot about where we measure the JAK2 VAF, in what cell population. In whole blood, we saw that, overall, almost 90% of patients had a reduction, and 1 in 8, or 12.5%, achieved a 25% reduction at any time. But then when we looked in more specific cells, so we looked in mononuclear cells in the peripheral blood in a subset of patients, we saw much deeper responses. We need to learn a bit more about where we're measuring those responses. Just to give you an idea, in some other studies in the past, we've seen a survival benefit for patients with a 20% reduction in VAF.

In addition to spleen symptoms, anemia responses, and the reduction in VAF, there are some other exciting data that we showed. First of all, we saw a reduction in circulating blasts, and then we were also able to look at the number of progenitors or blasts that were calreticulin mutation–positive. We saw them reducing even from 4% almost to zero, so that's suggestive that we’re kind of tackling the basis, the biology, of the disease.

Finally, I always love to see a bit of bone marrow biopsy morphology, because that's how we make the diagnosis. What we've seen is a return toward normal cellularity, a reduction in fibrosis in around 40% of patients. A reduction of mutant-staining megakaryocytes, so we can stain the megakaryocytes for the mutated protein. We also saw an increase in red cell precursors, which is linked to the anemia aspect.

AJMC: Do you see any early signals that could help identify which patients are most likely to benefit from INCA033989, either clinically or based on molecular characteristics?

Harrison: All in all, then, which patients are more likely to benefit? I think I'd be really cautious in overinterpreting the data with regard to that. There are broadly 2 types of calreticulin mutation: type 1, which is a deletion, and type 2, which is an insertion. They are both recognizable by this antibody, but they both have slightly different biological readouts.

Patients with a type 1 mutation have a better prognosis as long as they don't have other mutations, and type 2 tends to have a worse prognosis, but both sets of patients seem to be responding to the antibody; maybe the type 2s needed a higher dose, but they both still did respond. What the biological rationale for that is, we're not sure whether it's about density or the way that the slightly bigger protein for the type 2 mutations is binding, but they definitely seem to be responding.

I think the other thing that's important to talk about is the toxicity. Toxicity seems to be very minor. We didn't reach the maximum tolerated dose, and we didn't see any dose-limiting toxicity. The only thing at the moment is the patients having to come up for an infusion. My patients are all very happy to do that, including a lady well over 80 years old who's on [the] top dose, but there are plans to develop a subcutaneous formulation.

We also saw patients with additional mutations still benefiting, so it looks like the benefit is still good across the piece, but it's really hard to make very strong statements about that without larger numbers of patients. All these patients were treated at slightly different doses because it's a dose escalation study.

AJMC: As this program advances, what are the key next steps for INCA033989 in myelofibrosis, and what should clinicians be watching for as phase 3 trials get underway?

Harrison: I'm super excited to see the development of INCA033989. I think it represents a step change in the type of treatment that we have to offer our patients. I've got patients queuing up to go on this agent.

For me, somebody who presented at EHA 15 years ago with the first results with ruxolitinib, this feels like that kind of moment again. So, it was a nice symmetry for me in that, I think. Watch out for the availability of this, and there are similar other therapies entering testing now, but the phase 3 studies, I think, are going to be super exciting.

We’re also launching studies in essential thrombocythemia; it would be wrong of me not to point that out. It seems to be a super effective agent for those patients, as well. So, watch out for those studies and think about referring patients for them.