A Study to Assess the Effectiveness and Safety of Pacritinib in Patients With VEXAS Syndrome (PAXIS)

Key Inclusion Criteria:

• 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:

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

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

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

4. Absolute neutrophil count ≥500/μL

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

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

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

8. 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.

Key Exclusion Criteria

• Prior allogenic hematopoietic stem cell transplant (allo-HSCT) or solid organ transplant (other than corneal).

• Current use of systemic GCs for conditions other than VEXAS syndrome, which, in the opinion of the Investigator, would interfere with adherence to a GC taper regimen and/or assessment of efficacy.

• More than one prior admission to an intensive care unit due to a VEXAS Syndrome flare within the prior 6 months.

• Received ≥9 units of intensive red blood cell (RBC) transfusions in the 90 days prior to enrollment.

• Known concurrent myelodysplastic syndrome (MDS) requiring antineoplastic treatment, or allo-HSCT, or known high-risk or very high-risk MDS based on the Revised International Prognostic Scoring System (IPSS-R). Participants with MDS who do not meet these criteria may enroll.

• Malignancy within 1 year prior to enrollment with the exception of MDS (per exclusion criterion), curatively treated non-melanoma skin cancer, or curatively treated carcinoma in situ. Participants with pre-malignant hematologic conditions (e.g., monoclonal gammopathy of unknown significance [MGUS], clonal cytopenia of unknown significance) may enroll.

• Exposure to hypomethylating agents (HMA) within 6 months prior to enrollment, or exposure to more than 6 cycles of HMAs at any time.

• Exposure to non-GC anti-inflammatory therapy or hematologic support therapy within protocol defined timeframes prior to enrollment

• Exposure to anti-platelet therapy with the exception of low-dose aspirin (≤100 mg daily) within 28 days prior to enrollment.

• Known concomitant multiple myeloma, or serum M-protein ≥3 g/dL, involved-to uninvolved free light chain (FLC) ratio ≥100, or involved FLC level ≥100 mg/dL. Participants with MGUS may enroll.

• Systemic treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or inducer within 5 half-lives prior to enrollment.

• Significant recent bleeding history defined as National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade ≥2 within 3 months prior to enrollment, unless precipitated by an inciting event.

• History of clinically significant cardiovascular disease, or clinically significant abnormalities in rhythm or conduction during Screening ECG, including:

1. QT corrected by the Fridericia method (QTcF) > 480 msec within 30 days prior to enrollment; if QTcF is thought to be prolonged due to a modifiable factor (e.g., medication / electrolyte abnormality), QTcF may be re-evaluated

2. Severe cardiac event (CTCAE grade ≥3) within 3 months prior to enrollment

3. Heart failure resulting in limitations during ordinary activity.

• Arterial or venous thrombotic or embolic events, including deep vein thrombosis, pulmonary embolism, and cerebrovascular accident (including transient ischemic attacks), within 60 days prior to enrollment.

• Moderate or severe hepatic impairment that meets criteria for Child-Pugh Class B or C, or active viral hepatitis.

• Uncontrolled human immunodeficiency virus (HIV) off antiretrovirals, or on antiretrovirals with detectable viral load.

• Positive Quantiferon (or other interferon gamma release assay) during Screening.

• Known history of disseminated mycobacterial infection.

• Concurrent enrollment in another interventional trial, or treatment with an experimental therapy within 28 days or five half-lives prior to enrollment, whichever is longer.

• Pregnant, intending to become pregnant during the trial, or currently breastfeeding/lactating.

• Participants with any acute, active infection requiring systemic antimicrobial treatment at the time of enrollment. Exceptions are made for prophylactic antibiotics or chronic antibiotic therapy for non-acute conditions.

• Known hypersensitivity to pacritinib or any of the following inactive ingredients: microcrystalline cellulose, polyethylene glycol, and magnesium stearate.