Clinical Summary: 

• Design/Population: The phase 1 INCA033989-101 and INCA033989-102 studies evaluated the mutant CALR-specific monoclonal antibody INCA033989 as monotherapy or in combination with ruxolitinib in patients with CALR-mutant myelofibrosis who were JAK inhibitor–intolerant, relapsed or refractory, ineligible for JAK inhibitor therapy, or had a suboptimal response to ruxolitinib.
• Key Outcomes: INCA033989 produced clinically meaningful spleen, symptom, and anemia responses as both monotherapy and combination therapy, accompanied by reductions in mutant CALR variant allele frequency and mutant CALR-positive cell populations. The therapy demonstrated a favorable safety profile, with no dose-limiting toxicities or maximum tolerated dose identified.
• Clinical Relevance: These findings provide early evidence that mutant CALR-directed therapy may modify disease biology while improving clinical outcomes, supporting the planned phase 3 development of INCA033989 in myelofibrosis.

Claire Harrison, MD, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom, discusses updated results from a phase 1 study evaluating INCA033989, a first-in-class monoclonal antibody targeting mutant calreticulin in patients with CALR-mutant myelofibrosis. The studies enrolled patients across multiple treatment settings, including those who were JAK inhibitor naïve, relapsed or refractory, intolerant to JAK inhibitors, or receiving combination therapy with ruxolitinib.

In addition to improvements in conventional clinical end points, INCA033989 demonstrated molecular activity through reductions in mutant CALR allele burden and circulating mutant cell populations, supporting its potential as a disease-modifying therapy. These results, together with the favorable safety profile, provide the rationale for ongoing phase 3 development in patients with CALR-mutant myelofibrosis.

Dr Harrison presented these results at the European Hematology Association (EHA) Congress in Stockholm, Sweden.

Transcript:

Hi, my name is Claire Harrison. I'm a Professor of Hematology at Guy's Hospital in London, UK.

I'm going to talk to you about a study that I presented at the EHA meeting in Stockholm with the mutant CALR-specific monoclonal antibody INCA033989, which I'll call 989 as a shorthand, and the responses in the latest data cut in patients with myelofibrosis (MF). 

Just as a reminder about 989 and CALR mutations, calreticulin mutations, which are seen in around 30% of patients with ET and MF, have a very unique biology. The mutant CALR is packaged in the Golgi body and associated with the thrombopoietin receptor MPL, and then expressed on the cell surface. It's only the mutant CALR that is expressed on the surface in that way, and it's only expressed on the surface of cells with the mutation. Therefore, it's a very attractive mutation-specific marker.

INCA033989 is an Fc-silent monoclonal antibody that targets mutant CALR in complex with MPL. The data that we showed at the Stockholm meeting were in patients with myelofibrosis. We've now treated quite a large cohort of patients: overall, 83 patients with monotherapy and around 20 additional patients with the combination of 989 and ruxolitinib. Within the monotherapy cohort, there were also 21 patients, out of the total of 83, who hadn't previously received a JAK inhibitor because they were ineligible.So, we've now got data across the spectrum of JAK inhibitor–naïve patients, JAK inhibitor–relapsed, refractory or intolerant patients, and combination.

In the monotherapy cohort, patients were treated up to the age of 80 and now have exposure extending to well over 800 days. Thinking about our classical myelofibrosis end points, these are, of course, spleen reduction. It's important, when you see these data, to remember that we were doing baseline spleen scans often while patients were still on a JAK inhibitor. Then we took them off the JAK inhibitor and gave them 989.So, the spleen is probably smaller because they were on the JAK inhibitor beforehand.

We saw good spleen responses in both the upfront monotherapy and second-line settings, regardless of mutation type. In the second-line setting, we often think about a 25% reduction in spleen volume, and overall just over half of patients achieved that. Almost 40% of patients achieved an SVR35, which is really the field gold standard in the upfront setting. If you think about the JAK inhibitor–ineligible, or first-line, patients, SVR35 was achieved by 47% of patients overall, which compares quite nicely with some of the newer combination trials we've been looking at. Symptom improvement was also good with this agent, reflecting its tolerability. Overall, just over half of patients achieved a 50% reduction in symptom burden.

Now I want to talk about some of the other end points, which to me indicate that this is a very novel agent that is probably modifying the disease, and I'm super excited by these results. First of all, we saw robust and durable improvements in anemia in patients who were anemic at baseline or not, and whether they had previously received a JAK inhibitor or not. Thinking about the highest bar, the patients with transfusion dependency, there were 6 of them, and 3 had a major response, meaning they became transfusion independent. We also saw reductions in blast cells and in mutant-positive circulating hematopoietic progenitor cells, and these were striking reductions. 

We went on to measure whole-blood CALR VAF, and around 89% of patients had some reduction in VAF, while 12.3% achieved at least a 25% reduction as their best response. If you look at circulating peripheral blood mononuclear cells and specifically at the mutation, we saw even deeper responses. Here, 81% of patients achieved at least a 25% reduction.

What I'm also super excited about is what we're seeing in the bone marrow of these patients. Because you can stain mutant CALR on the surface of megakaryocytes, we're seeing reductions in mutant megakaryocytes, the return of mutation-negative megakaryocytes, reductions in fibrosis in about 40% of patients, and overall the bone marrow actually looks more normal. We also saw increases in erythroid progenitors as determined by CD71. 

All of this is accompanied by a drug that is really well tolerated. Eighty-four percent of patients receiving monotherapy remain on treatment, now approaching almost 3 years, and about three-quarters of patients remain on combination therapy. Those combination patients generally had a much higher disease burden. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. We did see some toxicity in terms of cytopenias, but these generally occurred in patients who already had cytopenias.

These data, I think, support the disease-modifying potential of INCA033989 and the initiation of a phase 3 program. Also at EHA, we presented translational data and data in patients with ET, so I'd urge you to take a look at those as well.

Source: 

Harrison C, Gupta V, Al-Ali HK, et al. Mutant calreticulin–specific monoclonal antibody, INCA033989, is well tolerated and achieves robust spleen, anemia, and molecular responses in patients (pts) with myelofibrosis (MF). Presented at EHA 2026 Congress; June 11-14, 2026; Stockholm, Sweden. Abstract EHA-2822.