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Eosinophilic Granulomatosis with Polyangiitis

Recent research efforts aimed at curing Eosinophilic Granulomatosis with Polyangiitis.

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Eosinophilic Granulomatosis with Polyangiitis

Overview

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare immune-mediated vasculitis—an inflammation of small and medium blood vessels—associated with asthma, high levels of eosinophils (a type of white blood cell), and inflammatory or granulomatous injury that can affect the lungs, sinuses, nerves, skin, heart, kidneys, and other organs. It is classified among antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides, although only a subset of patients has detectable ANCA antibodies. EGPA usually develops in adults and can be serious or life-threatening when it damages major organs, but modern treatment has substantially improved outcomes. Evidence-based EGPA guideline (pubmed.ncbi.nlm.nih.gov)

Care aims to induce remission, prevent relapses, preserve organ function, and minimize the cumulative harms of glucocorticoids (steroids). For organ- or life-threatening disease, current guidance supports glucocorticoids combined with cyclophosphamide or rituximab; for relapsing or refractory non–organ-threatening EGPA, mepolizumab, an antibody that blocks interleukin-5 (IL-5), is recommended. Benralizumab, which depletes eosinophils by targeting the IL-5 receptor, became FDA-approved for adults with EGPA on September 17, 2024. These treatments control disease but are not established cures. EULAR recommendations FDA Fasenra label (pubmed.ncbi.nlm.nih.gov)

Scope of Recent Research (2020–present)

Research activity since 2020 has been meaningful but remains constrained by EGPA’s rarity and biological diversity. The dominant questions are how best to suppress eosinophil-driven type 2 inflammation, how to treat the more vasculitic ANCA-associated form, how to taper steroids safely, and how to match therapy to a patient’s organ involvement and immune profile. The field has delivered new targeted options and more precise disease measurement, but it is not yet close to a therapy that permanently resets the underlying disease process. Evidence-based EGPA guideline Molecular pathogenesis review (pubmed.ncbi.nlm.nih.gov)

Major Breakthroughs and Emerging Therapies

The clearest advance has been stronger targeting of the eosinophil/IL-5 pathway. In the phase 3 MANDARA trial, 140 adults with relapsing or refractory EGPA received either benralizumab or mepolizumab for 52 weeks. Remission at both weeks 36 and 48 occurred in 58% of benralizumab-treated participants and 56% of mepolizumab-treated participants, establishing benralizumab as noninferior, though not superior, to mepolizumab. Complete withdrawal of oral glucocorticoids during weeks 48–52 occurred in 41% and 26%, respectively. MANDARA trial (nejm.org)

This is clinically important because benralizumab induces near-complete eosinophil depletion, whereas mepolizumab neutralizes IL-5 itself. However, neither approach is curative: substantial numbers of participants did not meet remission criteria, and the trial was conducted in relapsing or refractory disease rather than in patients with immediately life-threatening manifestations. Real-world European data likewise support steroid-sparing benefit from mepolizumab, while showing that relapse and incomplete response remain common. MANDARA trial European mepolizumab cohort (nejm.org)

B-cell-directed therapy has had a more cautionary recent result. In the phase 3 REOVAS trial, rituximab plus glucocorticoids was not superior to conventional remission-induction treatment with glucocorticoids alone or glucocorticoids plus cyclophosphamide: remission by day 180 occurred in 63.5% versus 60.4% of participants. This does not rule out a role for rituximab in selected severe or ANCA-positive patients, but it argues against viewing B-cell depletion as a universal path to cure. REOVAS rituximab trial (pubmed.ncbi.nlm.nih.gov)

The next wave aims beyond direct eosinophil depletion. Depemokimab is a long-acting anti-IL-5 antibody being tested against mepolizumab, while tezepelumab blocks thymic stromal lymphopoietin (TSLP), an upstream epithelial “alarmin” that can initiate several inflammatory pathways. NS-229 is an oral, selective Janus kinase 1 (JAK1) inhibitor intended to dampen cytokine signaling across T cells, B cells, and eosinophils. These approaches are disease-control strategies rather than gene, RNA, or cell therapies; no human gene-editing or cell-replacement treatment has yet demonstrated a cure for EGPA. OCEAN depemokimab trial NS-229 development program (gsk-studyregister.com)

Clinical Trials and Experimental Approaches

The phase 3 OCEAN trial, sponsored by GSK, is comparing depemokimab with mepolizumab in 163 adults with relapsing or refractory EGPA receiving standard care. It uses remission with a Birmingham Vasculitis Activity Score (BVAS) of zero and prednisone or prednisolone of 4 mg/day or less as a central outcome. In GSK’s July 8, 2026 update, the trial was listed as active but not recruiting, with no clinical publication or results summary available. OCEAN depemokimab trial (gsk-studyregister.com)

NS Pharma’s NCT06046222 is a randomized, double-blind, placebo-controlled phase 2 trial of oral NS-229 in relapsing or refractory EGPA. The 28-week treatment period permits background corticosteroids with or without mepolizumab or benralizumab, then evaluates remission during steroid tapering; the registry listed the study as active but not recruiting and did not report results. AstraZeneca’s RACEMATE phase 2 program is testing tezepelumab in EGPA, with publicly available European trial documentation but no published efficacy results. NS-229 phase 2 trial RACEMATE trial record (clinicaltrials.gov)

Methodologies and Scientific Approaches

Clinical research increasingly combines organ-based assessment with immune profiling. Investigators use BVAS and steroid dose to define remission, while measuring eosinophils, ANCA status, lung function, imaging, biopsy findings, and patient-reported manifestations such as asthma, nasal disease, and neuropathy. The 2022 ACR/EULAR classification criteria formalized a weighted approach incorporating eosinophilia, airway disease, nasal polyps, neuropathy, tissue eosinophilic inflammation, hematuria, and ANCA specificity. 2022 ACR/EULAR classification criteria (pubmed.ncbi.nlm.nih.gov)

Biomarker research is seeking ways to identify active disease and treatment-responsive subgroups before irreversible organ damage occurs. Proteomic studies have nominated blood-protein panels including SERPINA3, FGA, AGP1, ITIH3, and SAA1, but these findings need validation in larger, diverse cohorts before they can guide routine care. More recently, single-cell RNA sequencing of airway samples identified interferon-driven inflammation in EGPA that differs from severe eosinophilic asthma, reinforcing the need for disease-specific—not asthma-derived—treatment models. Proteomic biomarker study Airway single-cell study (pubmed.ncbi.nlm.nih.gov)

Leading Institutions and Funding

Major work is organized through international academic and industry networks. The U.S.- and Canada-based Vasculitis Clinical Research Consortium, coordinated through the University of Pennsylvania, reports 18 academic medical centers, more than 1,900 participants across eight vasculitis diseases, and a biospecimen and clinical-data infrastructure supporting EGPA cohorts, biomarker work, and multicenter trials. Its prior NIH support included grant U54AR057319 through NCATS and NIAMS. Vasculitis Clinical Research Consortium (vcrc.rarediseasesnetwork.org)

Industry sponsors have supplied the resources for pivotal targeted-therapy trials, including AstraZeneca for MANDARA and RACEMATE, GSK for OCEAN, and NS Pharma/Nippon Shinyaku for NS-229. Patient-led funding also supports discovery science: the Vasculitis Foundation reports a two-year, $48,000 award to University Hospital of Parma for whole-exome sequencing in EGPA, illustrating investment in genetic susceptibility research even though no single causative gene has been identified. MANDARA trial Vasculitis Foundation researchers (nejm.org)

Strengths, Limitations, and Challenges

A major strength of the recent pipeline is that it has translated a clear biological feature—eosinophilic inflammation—into therapies that increase remission and reduce steroid exposure. Benralizumab’s head-to-head phase 3 performance provides an additional approved option, and emerging agents test whether longer dosing intervals or broader cytokine blockade can improve convenience and response. MANDARA trial FDA Fasenra label (nejm.org)

The central limitations are heterogeneity, small trial populations, incomplete remission, relapse, and uncertainty about how to treat severe vasculitic disease affecting the heart, kidneys, nerves, or lungs. Trials of biologics often exclude organ-threatening disease, limiting direct applicability to the highest-risk patients. JAK inhibition may broaden immune control but also requires careful safety evaluation because it affects multiple cytokine pathways. The available evidence therefore supports an inference that current therapies suppress important drivers of EGPA without reliably eliminating the underlying tendency to disease. OCEAN depemokimab trial REOVAS rituximab trial NS-229 phase 2 trial (gsk-studyregister.com)

Outlook and Future Directions

As of October 14, 2026, an EGPA cure is not imminent, but the therapeutic landscape is improving from broad immunosuppression toward tailored, steroid-sparing immune control. The key milestones to watch are results from OCEAN, RACEMATE, and NS-229; confirmation that biomarker-defined subgroups predict benefit; and trials that safely include patients with severe organ involvement. A durable cure would likely require both deeper understanding of EGPA’s distinct eosinophilic and ANCA-associated disease mechanisms and proof that treatment can maintain medication-free remission without progressive organ damage. OCEAN depemokimab trial Proteomic biomarker study Evidence-based EGPA guideline (gsk-studyregister.com)

References

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