Phase 1 Trials Assess Safety, Dosing of CAL-R Antibody for Essential Thrombocythemia: John Mascarenhas, MD

In part 1 of an interview conducted after the European Hematology Association 2025 Congress in Milan, John Mascarenhas, MD, director of the Center of Excellence for Blood Cancers and Myeloid Disorders and professor of medicine at the Icahn School of Medicine at Mount Sinai, provides background on INCA33989 and the phase 1 INCA33989-101 and -102 studies.

He presented these data, as summarized in the abstract titled, “INCA33989 is a Novel, First in Class, Mutant Calreticulin-Specific Monoclonal Antibody That Demonstrates Safety and Efficacy in Patients With Essential Thrombocythemia (ET),” during the meeting's late-breaking oral session on June 15.

This transcript was lightly edited; captions were auto-generated.

Transcript

To start, could you describe what INCA33989 is and how it works?

[INCA33]989 is an antibody specifically and selectively directed towards the mutant CAL-R [calreticulin] protein that's expressed on the surface of hematopoietic stem progenitor cells and myeloid-derived lineage cells in combination with the thrombopoietin receptor. It's a very, I think, clever and simple way of tagging those cells selectively.

What's really interesting about the antibody is [that] it's a humanized antibody. It lacks an Fc-engaging portion, so it actually does not engage the immune system. What it does is it binds to the complex of the thrombopoietin receptor and the mutant CAL-R protein, which is expressed on the surface of the cells. It internalizes that complex and turns off the aberrant JAK/STAT signaling pathway that maintains the cell viability and survival, thereby inducing apoptosis in preclinical models.

It really looks like a really selective and clean immunotherapeutic approach to treating CAL-R-mutant MPN [myeloproliferative neoplasm] without the potential toxicity of immune activation.

Why is targeting mutant CAL-R considered a promising approach for treating essential thrombocythemia (ET)?

Myeloproliferative neoplasms are hematopoietic stem cell–derived clonal hematologic malignancies that are chronic but progressive. They have a lot of symptom burden, a lot of morbidity, and can progress to myelofibrosis [MF], or acute myeloid leukemia, and can limit life.

There are 3 main driver mutations: JAK2 V617F, about 50 to 60% of patients with ET, essential thrombocythemia, and primary myelofibrosis. Then, about 25% to 30% of patients have a mutant CAL-R driver mutation, both in ET and myelofibrosis. Then, there's about 5% of patients who have an MPL, which is a thrombopoietin receptor mutation.

There are 10% of patients who are triple negative. Those patients tend to do very poorly, and there's probably alternative mechanisms that activate the JAK/STAT signaling pathway, which is the central theme among these driver mutations.

But the mutant CAL-R is very interesting because, unlike JAK2 V617F, which is a tyrosine kinase that's mutated inside the cell, the mutant CAL-R is actually expressed on the surface of the cell in combination with the thrombopoietin receptors. That aberrant complex signals through JAK/STAT, which causes the phenomenon of the overproduction of platelets, cytokines, inflammation, symptoms, splenomegaly, fibrosis, and progressive disease.

Knowing that information, which, obviously, [it] took many years to get that far. So, 2013 is when mutant CAL-R was first identified by Jyoti Nangalia, MBBS, PhD. There's been a successive number of studies that have delineated the mechanism [by] which mutant CAL-R induces hyperactive JAK-STAT signaling, and then identifying that it's aberrantly expressed on the surface of the cells, and then developing therapies.

Incyte was really at the forefront of developing [INCA33]989, which is this antibody to mutant CAL-R, with the hopes that we could more selectively target the disease at the highest level, at the mutant CAL-R protein-expressing malignant cells.

With that in mind, can you describe the primary objectives of the phase 1 INCA33989-101 and -102 studies? What methods were used to evaluate the treatment?

I think this is one of the most elegant translational studies that we've seen in a long time, where the preclinical modeling informed that this antibody, [INCA33]989, would induce apoptosis and potentially transform the disease process in culture and in animal models.

With any first-in-human phase 1 study, we had to first test the drug in a dose escalation [and] dose finding study, which is what [INCA33989-]101 and [INCA33989-]102 were. [INCA33989-]101 and [INCA33989-]102 really just signified the fact that there were 2 trials being run at the same time. [INCA33989-]101 was outside the US, so basically Asia and Europe, and then [INCA33989-]102 was the US.

The 2 trials were running simultaneously. We started at low doses, 24 mg of this antibody in cohorts of 3. Then, [the] dose escalated all the way up to 2500 mg. Dose escalation [was used] to try to identify any dose-limiting toxicities, to identify the maximally tolerated dose, [and] ultimately the recommended phase 2 dose.

What's really, I think, fun about this study is it was evaluating the drug in [patients with] ET, which is what we're going to discuss today, but there's also a study going on that we'll present probably at ASH [American Society of Hematology Annual Meeting], evaluating the drug in [patients with] MF, both as a monotherapy [and] in combination with ruxolitinib.

You can see the application of this agent across mutant CAL-R disease types. It's not specific for one subtype, or at this point, one subtype of MPN. To me, that's really exciting. It's really a molecularly driven therapeutic with an immune-based approach.