PAXIS: a randomized, double-blind, placebo-controlled, dose finding phase 2 study (part 1) followed by an open-label period (part 2)to assess the efficacy and safety of pacritinib in patients with VEXAS syndrome

Background:

VEXAS syndrome (Vacuoles, E1 ubiquitin-activating enzyme, X-linked, Autoinflammatory, Somatic) is a systemic disorder characterized by an overlap of hematologic and inflammatory clinical features. Its complex inflammatory mechanism creates significant treatment challenges as most immunomodulators fail to control the disease, resulting in a requirement for moderate to high doses of glucocorticoids (GCs). Current data on non-GC treatments for VEXAS syndrome are limited to retrospective studies. Pacritinib, an oral inhibitor of IRAK1, JAK2, and ACVR1, is FDA-approved for myelofibrosis with severe thrombocytopenia (platelets <50 x 109/L) and has emerged as a potential treatment for VEXAS syndrome.

Objectives:

To assess the efficacy and safety of two dose levels of pacritinib versus placebo in patients with VEXAS syndrome (PAXIS study).

Methods:

PAXIS is an international, randomized, multicentre, double-blind, placebo-controlled phase 2 dose finding trial. It is designed to assess pacritinib in adult patients with VEXAS syndrome. Inclusion criteria include documented evidence of past inflammatory involvement and ongoing GCs (prednisone/prednisolone or equivalent) for ≥4 consecutive weeks at a baseline dose of 15-45 mg/day. Previous exposure to non-GC therapies is allowed, but patients must undergo a washout period (variable according to agent type). Exclusion criteria include prior allogeneic hematopoietic stem cell transplantation (allo-HSCT), receiving ≥9 units of red blood cell transfusion in the 90 days prior to enrolment, concurrent myelodysplastic syndrome requiring antineoplastic treatment (hypomethylating agents [HMAs] or allo-HSCT), and exposure to any HMAs in the previous 6 months or exposure to more than 4 cycles of HMAs at any time. The study will consist of a screening period, a double-blind period (up to end of week 24), an open-label period (up to end of week 48), and a 30-day post-end of treatment period (Figure 1). Patients (n=78) will be randomized 1:1:1 to receive pacritinib 200 mg twice daily (BID), pacritinib 100 mg BID, or placebo (26 per arm) and stratified by GC dose (15-25, >25-45 mg). All patients will follow a fixed GC taper based on GC dose at randomization, with tapering allowed only in the absence of a flare.

Results:

The primary endpoint (assessed during the double-blind period) is the proportion of patients who achieve overall clinical response, defined as having a flare-free interval lasting ≥8 weeks following a GC taper, and a GC dose during the flare-free interval of ≤10 mg/day. Secondary endpoints include number of flare free days with GC dose <10 mg/day, hematologic improvement (in platelets and hemoglobin), change in quality of life measures, and safety. Exploratory endpoints include change in symptoms based on the VEXAS-symptom assessment form (VEXAS-SAF), change in disease activity measured by the Clinical Global Impression of Change (CGI-C) and the VEXAS-disease activity index (VEXAS-DAI), change in variant allele frequency (VAF) of UBA1 by next generation sequencing (NGS), and improvement in GC toxicity as measured by the glucocorticoid toxicity index (GTI). Patients who complete the double-blind period or meet early failure criteria at end of week 12 will transition to an open label pacritinib treatment period through end of week 48 to further evaluate long-term safety and efficacy. PAXIS is anticipated to enrol at approximately 35 sites across 8 countries.

Conclusion:

The PAXIS study represents a significant step forward in the treatment of VEXAS syndrome. As the first randomized, double-blind placebo-controlled pharmacotherapy trial for this disease, it has the potential to redefine treatment and address unmet needs of this complex, refractory, and sometimes fatal condition.