VEXAS Syndrome Clinical Trials

• Documented evidence of a pathogenic mutation at methionine-41 (M41) or neighboring splice site mutation (c.118-1, c.118-2) position in UBA1 mutation based on myeloid next-generation sequencing (NGS) droplet digital polymerase chain reaction (ddPCR), or Sanger sequencing in peripheral blood or bone marrow samples.

• Current or documented evidence of past inflammatory involvement within 6 months prior to enrollment of at least one of the following organ systems by VEXAS syndrome: cutaneous (e.g., neutrophilic dermatosis, cutaneous vasculitis), vasculature (e.g., vasculitis), musculoskeletal (e.g., chondritis, arthritis), ocular (e.g., uveitis, scleritis), periorbital (e.g. periorbital edema), genitourinary (e.g., epididymitis), or pulmonary (e.g., alveolitis).

• Receiving ongoing GC therapy (stable prednisone or prednisolone dose of 15-45 mg/day) leading up to enrollment.

• Karnofsky Performance Status ≥50%

• Adequate organ function, meeting all the following criteria within 30 days prior to enrollment:

‣ Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN)

⁃ Total bilirubin ≤4 × ULN (≤8 × ULN in the setting of Gilbert's syndrome)

⁃ Creatinine clearance (CrCl) ≥30 mL/min based on the Cockcroft-Gault formula

⁃ Absolute neutrophil count ≥500/μL

⁃ Prothrombin time (PT) or international normalized ratio (INR) ≤1.5 × ULN (unless prolonged due to therapeutic anticoagulation)

⁃ Partial thromboplastic time (PTT) or activated PTT ≤1.5 × ULN (unless prolonged due to therapeutic anticoagulation)

⁃ Platelet count ≥25 × 10\^9/L (value must be obtained in the absence of platelet transfusion in the prior 7 days)

⁃ Peripheral blasts \<5%

• QT corrected by the Fridericia method (QTcF) ≤450 msec in males or ≤470 msec in females. Participants with QRS prolongation \>100 msec may enroll if their QTcF is ≤480 msec. If QTcF is thought to be prolonged due to a modifiable factor (e.g., medication / electrolyte abnormality), QTcF may be reevaluated.

• Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test within 30 days prior to enrollment and a negative urine pregnancy test on Day 1 prior to randomization and dosing.

• WOCBP and male participants must agree to use a highly effective method of contraception starting at the first dose of trial therapy through 30 days after the last dose of trial therapy.