A study to assess the effectiveness and safety of pacritinib in patients with VEXAS syndrome (PAXIS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Sobi Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

29 Apr 2025 → ongoing

Decision date (initial)

2025-04-07

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Sobi, Inc. USA

External identifiers

EU CT number

2024-516347-41-00

WHO UTN

U1111-1312-0076

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Pharmacodynamic, Efficacy, Therapy, Safety, Pharmacokinetic

To evaluate the efficacy of two dose levels of pacritinib compared to placebo during the double-blind treatment period in participants with VEXAS (i.e., Vacuoles in myeloid progenitors, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory manifestations, and somatic) syndrome

Secondary objectives 5

1. 1. To evaluate hematologic improvement (HI) in participants with VEXAS syndrome treated with two dose levels of pacritinib compared to placebo during the double-blind treatment period
2. 2. To evaluate change in quality of life (QOL) in participants with VEXAS syndrome treated with two dose levels of pacritinib compared to placebo during the double-blind treatment period
3. 3. To evaluate pharmacokinetics (PK) of pacritinib in participants with VEXAS syndrome treated with two dose levels of pacritinib during the double-blind treatment period
4. 4. To evaluate pharmacodynamics (PD) of inflammatory markers in participants with VEXAS syndrome treated with two dose levels of pacritinib compared to placebo during the double-blind treatment period
5. 5. To evaluate safety and tolerability in participants with VEXAS syndrome treated with two dose levels of pacritinib compared to placebo during the double-blind treatment period

Conditions and MedDRA coding

VEXAS Syndrome

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

Qualified researchers may request access to patient level data and related study documents. Patient level data will be anonymized and study documents, if applicable will be redacted to protect the privacy of trial participants. Further details on Sponsor's data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.sobi.com/en/policies

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Age ≥18 years at the time of signing the informed consent form (ICF).
2. 11. Willingness and ability of the participant to comply with protocol requirements, including but not limited to: completing in-person trial visits, completing training in the use of the Prednisone / Prednisolone Dose Diary and recording daily prednisone / prednisolone use in the diary, undergoing trial-related procedures, and completing patient-reported outcome (PRO) assessments.
3. 12. Provision of signed informed consent
4. 2. Documented evidence of a pathogenic or likely pathogenic mutation at methionine-41 (M41) or neighboring splice site mutation (c.118-1, c.118-2) position in UBA1 based on myeloid NGS, droplet digital polymerase chain reaction (ddPCR), or Sanger sequencing in peripheral blood or bone marrow samples.
5. 3. 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). Note: Other inflammatory signs may be considered for enrollment at the discretion of the Investigator with Medical Monitor approval provided that these signs have been previously demonstrated to be GCresponsive (i.e., resolve after administration of or escalation in GC therapy).
6. 4. Receiving ongoing GC therapy (with prednisone or prednisolone) for ≥4 consecutive weeks leading up to enrollment for the treatment of VEXAS syndrome
7. 5. Prednisone or prednisolone baseline dose of 15-45 mg/day that has been stable for ≥10 days prior to enrollment.
8. 6. Karnofsky Performance Status ≥50%
9. 7. Adequate organ function, meeting all the following criteria within 30 days prior to (CrCl) ≥30 mL/min based on the Cockcroft-Gault formula; d. Absolute neutrophil count ≥500/μL; e. Prothrombin time (PT) or international normalized raenrollment: a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN); b. Total bilirubin ≤4 × ULN (≤8 × ULN in the setting of Gilbert’s syndrome); c. Creatinine clearancetio (INR) ≤1.5 × ULN (unless prolonged due to therapeutic anticoagulation); f. Partial thromboplastic time (PTT) or activated PTT ≤1.5 × ULN (unless prolonged due to therapeutic anticoagulation); g. Platelet count ≥25 × 10^9/L (value must be obtained in the absence of platelet transfusion in the prior 7 days); h. Peripheral blasts <5%
10. 9. 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.
11. 10. 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
12. 8. 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 re‑evaluated.

Exclusion criteria 24

1. 1. Prior allogenic hematopoietic stem cell transplant (allo-HSCT) or solid organ transplant (other than corneal).
2. 10. 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/L. Participants with MGUS may enroll.
3. 11. Systemic treatment with a strong CYP3A4 inhibitor or inducer within 5 half-lives prior to enrollment
4. 12. Significant recent bleeding history defined as National Cancer Institute CTCAE Grade ≥2 within 3 months prior to enrollment, unless precipitated by an inciting event (e.g., surgery or trauma).
5. 13. History of clinically significant cardiovascular disease, including: a.Severe cardiac event (CTCAE Grade ≥3) within 3 months prior to enrollment b.Heart failure resulting in limitations during ordinary activity.
6. 14. 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.
7. 15. Any condition known to significantly interfere with absorption, distribution, metabolism, or excretion of oral drugs in the opinion of the Investigator.
8. 16. Moderate or severe hepatic impairment that meets criteria for Child-Pugh Class B or C , or active viral hepatitis, including: a) Active hepatitis B virus (HBV) infection: participants with positive hepatitis B surface antigen (HBsAg) are excluded. Participants with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before enrollment. Participants who are hepatitis B PCR positive will be excluded. b) Active hepatitis C virus (HCV) infection: participants who are positive for HCV antibody are eligible if PCR is negative for HCV RNA. PCR testing is only required if HCV antibody testing is positive.
9. 17. Uncontrolled human immunodeficiency virus (HIV) off antiretrovirals, or on antiretrovirals with detectable viral load. Note: Participants with a known history of HIV must have viral load assessed for eligibility and must be on a stable antiretroviral regimen that can be administered concurrent with pacritinib.
10. 18. Positive Quantiferon (or other interferon gamma release assay) during Screening. Note: participants with indeterminant Quantiferon results may enroll.
11. 19. Known history of disseminated mycobacterial infection.
12. 2. 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.
13. 20. 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.
14. 22. Any unstable disease, intercurrent illness, abnormality, or event (i.e., psychiatric episode, adverse social situation) that could compromise participant safety or affect the conduct of the trial, in the judgment of the Investigator.
15. 23.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.
16. 24. Known hypersensitivity to pacritinib or any of the following inactive ingredients: microcrystalline cellulose, polyethylene glycol, and magnesium stearate.
17. 25. Persons committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
18. 3. More than one prior admission to an intensive care unit due to a VEXAS Syndrome flare within the prior 6 months
19. 4. Received ≥9 units of RBC transfusion in the 90 days prior to enrollment
20. 5. Known concurrent myelodysplastic syndrome (MDS) requiring antineoplastic treatment (e.g., HMAs), 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
21. 6. 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.
22. 7. Exposure to HMAs (e.g., azacitidine, decitabine) within 6 months prior to enrollment, or exposure to HMAs for more than 6 cycles at any time. Note: a cycle refers to a dosing period of approximately 28 days.
23. 8. Exposure to the following agents within the following timeframe prior to enrollment a.Anti-CD20 agents (e.g.ay, rituximab): 180 days b.Anti-IL-23 agents (e.g., ustekinumab): 90 days c.Anti-TNFα agents except for etanercept (e.g., infliximab): 60 days d.Canakinumab: 60 ds e.Intravenous anti-IL-6 agents: 42 days f.Subcutaneous anti-IL-6 agents: 28 days g.Anti-IL-17 agents (e.g., secukinumab): 28 days h.Anti-integrins (e.g., vedolizumab): 60 days i.Intravenous immunoglobulin: 28 days j.Omalizumab: 28 days k. Danazol, immunomodulatory imide drugs (IMiDs), luspatercept, or thrombopoietin receptor agonists: 28 days l.Cytotoxic chemotherapy: 28 days m.Etanercept: 21 days n.Oral JAK inhibitors: 14 days o.Anti-IL-1 agents except for canakinumab: 14 days p.Any other non-GC anti-inflammatory therapy (e.g., mycophenolate, azathioprine, cyclosporine, sulfasalazine, methotrexate): 14 days or 5 half lives, whichever is longer. Note: Participants on erythropoiesis stimulating agents (ESAs) at the time of informed consent may continue to receive ESAs during Screening and on trial, but new ESA use is not permitted during this 28-day period or on trial.
24. 9. Exposure to anti-platelet therapy with the exception of low-dose aspirin (≤100 mg daily) within 28 days prior to enrollment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1. The primary endpoint is Overall Clinical Response (OCR), defined as achieving Clinical Response or better at any time during the double-blind treatment period.

Secondary endpoints 8

1. 1. Best Response (Clinical Biochemical Response, Clinical Response, Partial Clinical Response, Stable Disease, or Non-response) during the double-blind treatment period. Note that Stringent Clinical Biochemical Response is not applicable during the double-blind treatment period (i.e., by Week 24) based on the fixed GC taper schedule
2. 2. Number of flare-free days with GC dose <10 mg during the double-blind treatment period.
3. 3. Hematologic Improvement – Erythroid (HI-E) at any time during the double-blind treatment period among participants with baseline hemoglobin <10 g/dL, per modified International Working Group (IWG) criteria.
4. 4. Hematologic Improvement – Platelets (HI-P) at any time during the double-blind treatment period among participants with baseline platelet count <100 × 10^9/L, per modified IWG criteria.
5. 5. Change in health-related QOL as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) short forms (fatigue, physical function, sleep disturbance), 36-Item Short Form Health Survey (SF-36), and the Patient Global Impression of Change (PGIC).
6. 6. PK of pacritinib.
7. 7. PD inflammatory biomarkers (CRP, erythrocyte sedimentation rate [ESR][where available], ferritin)
8. 8. Safety and tolerability, assessed by adverse events (AEs), laboratory tests, electrocardiogram (ECG) results, and vital signs will be assessed throughout the double-blind and open-label treatment periods.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Sobi Inc.

Sponsor organisation

Sobi Inc.

Address

77 4th Avenue Floor 3

City

Waltham

Postcode

02451-7567

Country

United States

Scientific contact point

Organisation

Sobi Inc.

Contact name

Medical Information

Public contact point

Organisation

Sobi Inc.

Contact name

Medical Information

Third parties 8

Locations

4 EU/EEA countries · 19 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 37 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications