Elenestinib for ISM in Phase 2/3 HARBOR Trial with Mariana C. Castells, MD, PhD

Patients with indolent systemic mastocytosis (ISM) have long relied on symptom management rather than disease-modifying treatments. Now, emerging therapies targeting a key genetic mutation that drives abnormal mast cell growth are reshaping the treatment landscape, offering new hope for improved outcomes.

In May 2023, the US Food and Drug Administration (FDA) approved avapritinib (AYVAKIT) for the treatment of adults with ISM, marking the first medicine designed to target KIT D816V, the primary underlying cause of the disease, and relieve the mast cell symptom burden.

The ongoing randomized, double-blind, placebo-controlled, Phase 2/3 HARBOR trial is evaluating the efficacy and safety of oral elenestinib, a highly selective KIT D816V inhibitor with minimal brain penetration, for patients with ISM with symptoms inadequately controlled by best supportive care. Results from part 1 of the trial supported the tolerability and pharmacokinetics of once-daily dosing of elenestinib.

At the 2025 American Academy of Allergy, Asthma, and Immunology (AAAAI)/World Allergy Organization (WAO) Joint Congress, Mariana C. Castells, MD, PhD, director of the drug hypersensitivity and drug desensitization center and the mastocytosis center at Brigham & Women’s Hospital, spoke with HCPLive on what’s missing from the current treatment landscape, the potential implications of elenestinib, and part 2 of the ongoing Phase 2/3 trial.

This transcript has been edited for clarity.

From your clinical perspective, what’s missing from the current treatment landscape in ISM?

Essentially, what's missing is a medication that could take care of the mast cell burden. For example, the number of mast cells in the tissues, and also the activation of those mast cells. There are two components of mastocytosis. One is that the patients have too many mast cells in the skin. For example, they have a specific rash called urticaria pigmentosa or cutaneous mastocytosis. That’s also in children, which is an unmet need. We have no medication to get rid of those lesions.

Then, there is also the burden of those symptoms. Mast cells are cells of the immune system that have a lot of mediators, starting with tryptase, histamine, prostaglandins, and leukotrienes. They release those mediators, and those mediators go to the tissues and produce symptoms, including itching, flushing, abdominal bloating, pain, diarrhea, and brain fog. A lot of those symptoms, including fatigue, diminish the patient’s quality of life. We have up to now used antihistamines and medications directed towards symptom control, and we find that this might not be sufficient for two reasons.

One is that patients are on polypharmacy, so we need many antihistamines and other medications to block the effects of leukotrienes, prostaglandins, and so forth. On the other hand, those do not address the central problem and those medications may have side effects. They do not address the central problem of having too many mast cells, so the disease progresses and continues.

What are the mechanisms of action and clinical relevance of elenestinib for the treatment of ISM?

Elenestinib is part of the new generation of medications called tyrosine kinase inhibitors (TKIs). It doesn't cross the blood-brain barrier, and it addresses the KIT mutation which is a protein on the surface of the mast cells at the origin of mastocytosis in about 95% of the patients. It’s a targeted small molecule that addresses or targets this D816V-mutant KIT protein on top of the mutated mast cells, and that makes the muscles die. The important and interesting thing about this next generation is it doesn't cross the blood-brain barrier, so it doesn't have potential side effects on the central nervous system.

Based on the HARBOR trial, what stands out to you in terms of symptom improvement, biomarker changes, and drug safety?

We only have the first part, we haven't gone to part two of the elenestinib trial. In that first part, we have seen that the patients have a pretty significant improvement in the total symptom score (TSS). All the symptoms in all the organ systems seem to decrease in potentially a very significant way, whether it's the skin itching and flushing, the abdominal bloating, pain, and diarrhea, as well as the brain symptoms. That is quite significant and then we don't potentially have any other brain side effects that could happen with first generation of TKIs.

How vast are the implications of these data, and what could they mean for the treatment of patients with ISM in the near future?

We never dreamed of targeted medications for mastocytosis patients. It's a rare disease, and for a very long time, for the first 40 years of having a good understanding of its biology, we treated it symptomatically. We have now a tremendous opportunity to treat it in a way that is targeted, and it will make a significant and dramatic impact on the quality of life of those patients.

Castells reports relevant disclosures with Blueprint Medicines, Cogent Biosciences, and Telios Pharmaceuticals.

References

1. Castells M, Livideanu CB, Hermine O, et al. HARBOR: An Ongoing Phase 2/3 Study of Elenestinib in Patients With Indolent Systemic Mastocytosis. Presented at: 2025 AAAAI/WAO Joint Congress, February 28-March 3. Abstract 533

2. FDA approves AYVAKIT® (avapritinib) as the first and only treatment for indolent systemic mastocytosis. Blueprint Medicines Corp. May 22, 2023. Accessed March 3, 2025. https://ir.blueprintmedicines.com/news-releases/news-release-details/fda-approves-ayvakitr-avapritinib-first-and-only-treatment.