Clinical Research Directory

DECIPHERING AND TARGETING VEXAS

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome (1/4,000 males aged \>50) is a paradigmatic age-onset acquired, severe, autoinflammatory hematological disease due to clonal dominance of hematopoietic cells bearing a somatic mutation in the UBA1 (ubiquitin-activating enzyme 1) gene. VEXAS presents with treatment-refractory systemic myeloid-driven inflammatory manifestations and hematologic abnormalities, hence the poor prognosis. Current available therapies are poorly effective and burdened by debilitating side effects. VEXAS mutations inactivate cytoplasmic UBA1-driven ubiquitination, impairing protein clearance and triggering stress responses. By innovative base-editing (patent PCTIB2024060412), the investigators generated new in vitro and in vivo models that, along with comprehensive phenotyping of VEXAS patients, disclosed progressive inflammatory poisoning of healthy hematopoiesis and resilience to inflammation of UBA1-mutant hematopoietic stem/progenitor cells (HSPC) as key mechanisms of inflammation and clonal dominance. Deciphering these mechanisms might reveal predictive markers, actionable targets, and inform drug repurposing or novel therapies. The investigators hypothesize that cell-intrinsic and -extrinsic mechanisms triggered by altered UBA1 function are targetable drivers linking inflammation and clonal dominance. The research plan is designed to investigate, both in vitro and in BM and peripheral hematopoietic cells from VEXAS patients, the key pathogenic mechanisms sustaining inflammation and clonal dominance in VEXAS syndrome. Patients with VEXAS syndrome, defined by the presence of pathogenic mutations in the UBA1 gene identified in hematopoietic cells isolated from the peripheral blood of individuals with systemic autoinflammatory disease, will be included in the study population. The study will also enroll healthy control subjects, matched as closely as possible for age and sex, with no history of inflammatory or hematologic disorders. The dissection of mechanisms underlying the interplay between inflammation and clonal dominance will be fundamental to identify novel therapeutic strategies against disease progression that would enable the treatment of VEXAS patients at early disease stages, improving prognosis and life expectancy. Moreover, establishing robust genotype-to-phenotype correlations in patients may inform the design of personalized therapeutic options. The obtained results may inform the design of new therapeutic strategies against this cureless disease. Overall, in this observational monocentric study the investigators will use retrospective samples collected from 2020 to 2026 to conduct cytokine profiling and comprehensive omics-based characterization (transcriptomics, proteomics, metabolomics) on peripheral blood-derived monocytes/neutrophils and bone marrow (BM) hematopoietic cells.

Pacritinib in Vacuoles, E1 Ubiqutin-activating Enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) Syndrome

VEXAS (vacuoles, E1 ubiqutin-activating enzyme, X-linked, autoinflammatory, somatic syndrome) is a recently described disorder with severe hematologic and rheumatologic manifestations caused by somatic variants in the ubiquitin- activating enzyme gene, UBA1, that is acquired in hematopoietic progenitor cells. Patients are often debilitated by autoinflammatory symptoms and there is currently no standard of care available. There is a clinically unmet need for better therapies in VEXAS Syndrome. There have been no prospective clinical trials of JAK-I in VEXAS syndrome. The investigators hypothesize that pacritinib, as a JAK2/IRAK1 inhibitor with a manageable safety profile in myelofibrosis patients with thrombocytopenia, will improve the autoinflammatory and hematologic manifestations of VEXAS syndrome with a tolerable toxicity profile. The investigators propose a single arm, pilot Phase 1 study evaluating the safety and tolerability of pacritinib in patients with VEXAS syndrome with an initial safety run-in phase of 6 patients treated with pacritinib 200mg twice daily (BID) on days 1-28 of a continuous 28 day cycle. If no more than 1 patient experiences a dose-limiting toxicity (DLT), the investigators will enroll an expansion cohort to gain additional toxicity and efficacy data, for a total enrollment of 15 patients. If more than 1 patient experiences a DLT during the safety run-in phase, the investigators will decrease the dose to 100 mg BID, and if no more than 1 of 6 patients experiences a DLT, the investigators will complete the expansion cohort as above for up to a total enrollment of 15 patients. If more than 1 patient experiences a DLT at 100 mg BID, the investigators will discontinue the study. Patients will be treated for up to 12 cycles.

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

This trial is to assess the effectiveness and safety of pacritinib in patients with VEXAS (i.e., Vacuoles in myeloid progenitors, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory manifestations, and somatic) syndrome. 78 participants will be enrolled, randomized to either pacritinib dose A, pacritinib dose B + placebo, or placebo. Randomization will be stratified by prescribed GC dose on the day of randomization.

HRQoL and Financial Toxicity in Patients With VEXAS Syndrome

This multicenter cross-sectional observational study aims to describe health-related quality of life (HRQoL) and symptom profiles of patients with VEXAS syndrome.