Next Steps for INCA33989 Focus on Dosing, Delivery, and Safety: John Mascarenhas, MD

During the final part of an interview conducted after the European Hematology Association 2025 Congress, John Mascarenhas, MD, of the Icahn School of Medicine at Mount Sinai, outlines next steps following the INCA33989-101 (NCT05936359) and -102 (NCT06034002) trials. Given differences in calreticulin (CAL-R) mutation responses and the limitations of biweekly intravenous delivery, these steps include optimizing INCA33989 dosing and scheduling in patients with essential thrombocythemia (ET).

Mascarenhas concludes by emphasizing INCA33989's strong safety profile and early signs of disease modification, with upcoming myelofibrosis (MF) data expected to further demonstrate its potential.

Watch parts 1 and 2 to learn more about INCA33989 and both phase 1 trials.

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

Transcript

Could you elaborate on the next steps following the INCA33989-101 and -102 trials? How do you see this therapy ultimately fitting into the essential thrombocythemia (ET) treatment landscape?

The next steps are ongoing. Expanding some dose cohorts in ET to get a sense of optimal dosing of such an antibody. There are some nuances, which I didn't mention, which is there may be a differential in response between a type one CAL-R mutation, which is a 52-base pair deletion, vs a type 2, which is a 5-base pair insertion. Some of that might be overcome by dosing strategies, so we have some stuff to learn.

It is [an] intravenous drug delivered every 2 weeks. That's probably not feasible for many [patients with] ET. Another obvious question is, does it really need to be given every 2 weeks? Can it be given less frequently? We need to explore scheduling of the drug, so there's still a lot of work to be done to optimize, I would say, the delivery of what appears to be [a] very safe drug. We need to work on that. That's really the ongoing part from the ET population.

We will present the MF [myelofibrosis] data, which I'm really looking forward to, because MF is obviously another MPN [myeloproliferative neoplasm] with a more aggressive disease course and represents an unmet need, as well. Whether this drug could have this type of safety and efficacy in MF would really be exciting, as well. I'm just generally excited by this approach.

Of course, there are other companies that are developing bispecific T-cell–engaging mutant CAL-R approaches, as well as Incyte. I think the theme of targeting mutant CAL-R is going to blossom in the next few years. This is obviously the first publicly-released data set that really encourages, I think, the research community to pursue this type of approach.

But what I really think is the take-home message here is [that INCA33989 is] super clean, very well tolerated, and already signals clinical and biomarker activity, suggesting disease modification. A lot more to be done, but [it's] an exciting start.