Inclusion Criteria:

Participants are eligible to be included in the study only if all of the following criteria apply:

• ≥ 18 years of age and ≥ the age required for independent consent according to local law at the time of signing the informed consent.

• Participant or legal guardian, when applicable, provides signed informed consent to participate in the study.

• Must meet inclusion criteria for either Cohort 1, 2, or 3.

• Participants with a prior “not detected” KIT D816V test result (limit of detection [LOD] ≤ 0.03%) in PB and/or BM aspirate may be included if:

  • No more than 1 prior result of “not detected” was obtained using a high-sensitivity assay (LOD ≤ 0.03%) and

  • Baseline serum tryptase level is elevated, defined as ≥ 11.4 ng/mL.

Cohort 1 (SMAC) Must meet inclusion criteria for either SMAC-A or SMAC-B:

SMAC-A

• Documented anaphylaxis due to Hymenoptera venom with cardiovascular symptoms (must include one or more of the following: syncope, hypotension, or tachycardia)

• Documented anaphylaxis without known trigger(s) or allergen(s) warranting hospitalization, emergency room visit, and/or epinephrine (inclusive of nasal, intramuscular, and/or intravenous use) with cardiovascular symptoms (must include one or more of the following: syncope, hypotension, or tachycardia).

SMAC-B

• Episodic or recurrent signs and symptoms consistent with mast cell activation without known triggers or allergens in at least 2 of the following organ systems: skin (pruritus, urticaria, flushing, or angioedema), respiratory/naso-ocular (wheezing-bronchospasm, conjunctival injection, nasal congestion, or stridor), gastrointestinal tract (diarrhea, nausea, vomiting, or gastrointestinal cramping), or cardiovascular (tachycardia, syncope, or hypotension). Episodic signs or symptoms are defined as symptoms or reactions that occur in distinct, separate episodes with clear onsets and resolutions separated by periods of minimal or no symptoms for at least 6 weeks.

• Any clinical response on one or more optimally dosed therapies intended to mitigate mast cell mediators, as determined by the Investigator.

Cohort 2 (select, non-malignant diseases with suspected clonal mast cell involvement) Confirmed, known diagnosis of one of the following criteria:

• Either hypermobile Ehlers-Danlos syndrome (hEDS) (based on 2017 international diagnostic criteria) or documented history of hypermobility spectrum disorder.

• Postural orthostatic tachycardia syndrome with one or more systemic symptoms (eg, anxiety, fatigue, resting or nocturnal paroxysmal tachycardia, acrocyanosis, chest pain, nausea, bloating, constipation, diarrhea, abdominal pain, headaches, difficulty concentrating, syncope, or cutaneous flushing).

• Early onset (≤ 50 years old) osteoporosis or osteopenia.

Cohort 3 (CMML or MDS/MPN-NOS)

• Documented diagnosis of one of the following, according to World Health Organization 5th edition criteria: CMML or MDS/MPN-NOS.

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

• Participants previously diagnosed with any of the following:

  • Monoclonal mast cell activation syndrome with a known KIT mutation.

  • Cutaneous mastocytosis only (ie, no documentation of systemic mast cell disease via bone marrow biopsy)

  • Any subtype of systemic mastocytosis

  • Mast cell sarcoma.

• Current or previous treatment (including investigational treatments) with selective KIT D816V inhibitors.

• Any prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator’s or Sponsor’s opinion, could affect the safety of the participant or impair the assessment of study results.

• Unwilling or unable to comply with required scheduled visits, laboratory tests, or other study procedures and study restrictions.

• Cohort 2 only: Osteopenia or osteoporosis attributed to known genetic, endocrine, nutritional, or other medical conditions.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 7/18/2025. Questions regarding updates should be directed to the study team contact.