(HARBOR) Study to Evaluate Efficacy and Safety of BLU-263 Versus Placebo in Patients With Indolent Systemic Mastocytosis

Key Inclusion Criteria:

All Patients

-1. Patient must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2.

Part 1 and Part 2

2. Patient must have moderate-to-severe symptoms based on minimum mean totalsymptom score (TSS) of the ISM Symptom Assessment Form (ISM-SAF) over the 14-day eligibility screening period.

3. Patient has confirmed diagnosis of ISM, confirmed by Central Pathology Reviewof BM biopsy and central review of B- and C-findings by WHO diagnosticcriteria. Archival biopsy may be used if completed within the past 12 months.

4. Patient must have failed to achieve adequate symptom control for 1 or moreBaseline symptoms, as determined by the Investigator, with at least 2 of thefollowing symptomatic therapies administered: H1 blockers, H2 blockers,proton-pump inhibitors, leukotriene inhibitors, cromolyn sodium,corticosteroids, or omalizumab.

5. Patients must have BSC for ISM symptom management stabilized for at least 14days prior to starting screening procedures.

6. For patients receiving corticosteroids, the dose must be ≤ 20 mg/d prednisoneor equivalent, and the dose must be stable for ≥ 14 days.

Part M

7. Patients must have mMCAS, confirmed by Central Pathology Review of BM biopsy.An archival biopsy may be used if completed within the past 12 months.

8. Patients must have tryptase < 20 ng/mL.

9. Patients must have KIT D816V in peripheral blood (PB) or BM and/or CD25+ Mastcells in BM.

10. Patients must have symptoms consistent with mast cell activation (despite BSC)in at least two organ systems characterized by cutaneous flushing, tachycardia,syncope, hypotension, diarrhea, nausea, vomiting and gastro-intestinalcramping) and serum blood tryptase (sBT) levels above 8 ng/mL OR Severe (Ringand Messmer grading ≥ II, recurrent anaphylaxis, including but not limited tohymenoptera venom, drug or food, regardless of sBT levels.

PK Groups

11. See inclusion criteria for All patients and Part 1/Part 2

12. Accrual may be limited to patients who have specific disease manifestations (ie, GI involvement) or are taking acid-reducing agents to better explore theimpact of these features on PK.

Part S:

-13. Patient has confirmed diagnosis of SSM, confirmed by Central Pathology Review of BM biopsy and central review of B- and C-findings by WHO 2022 diagnostic criteria.

Key Exclusion Criteria:

1. Patient has been diagnosed with any of the following WHO systemic mastocytosis (SM) sub-classifications: cutaneous mastocytosis only, SM with an associatedhematologic neoplasm of non-MC lineage (SM-AHN), aggressive SM, mast cellleukemia, or mast cell sarcoma.

2. Patient has been diagnosed with another myeloproliferative disorder.

3. Patient has organ damage C-findings attributable to SM.

4. Patient has clinically significant, uncontrolled, cardiovascular disease

5. Patient has a QT interval corrected using Fridericia's formula (QTcF) > 480msec.

6. Patient has previously received treatment with any targeted KIT inhibitors.

7. Patient has a history of a primary malignancy that has been diagnosed orrequired therapy within 3 years. The following prior malignancies are notexclusionary: completely resected basal cell and squamous cell skin cancer,curatively treated localized prostate cancer, and completely resected carcinomain situ of any site.

8. Time since any cytoreductive therapy including mastinib and midostaurin shouldbe at least 5 half-lives or 14 days (whichever is longer), and for cladribine,interferon alpha, pegylated interferon, or antibody therapy < 28 days or 5half-lives of the drug (whichever is longer), before beginning the screeningperiod.

• 9.Patient has received radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14 days before beginning the screening period.