Mepolizumab as the first targeted treatment for eosinophilic granulomatosis with polyangiitis: a review of current evidence and potential place in therapy

Figures & data

Table 1 Evolution of diagnostic criteria for EGPA

Churg and Strauss (1951)^Citation3	Lanham et al (1984)^Citation4	ACR (1990) (≥4 of the following)^5,a	Watts et al (2007) proposed diagnostic algorithm^Citation6
Asthma; eosinophilia; vasculitis; extravascular granulomas; fibrinoid necrosis	Asthma; eosinophilia >1,500 cells/mL; vasculitis with involvement of at least two extrapulmonary organs	Asthma; eosinophilia >10% of total white blood cell count; mononeuropathy or polyneuropathy; pathological alterations to paranasal sinuses; migrating or transient pulmonary infiltrates; biopsy containing a blood vessel with extravascular eosinophils	Signs and symptoms compatible with vasculitis (if histologically proven vasculitis) or characteristic of vasculitis (in absence of histologically proven vasculitis) At least one of the following: histologically proven vasculitis (including necrotizing glomerulonephritis) and/or granulomas; positivity of p-ANCA or c-ANCA; specific investigations suggestive for vasculitis or granulomas; eosinophilia >1,500 cells/mL or >10%; absence of other diagnoses that may explain signs and symptoms, including infections, neoplasms, drug- induced conditions, secondary vasculitis (eg, associated with systemic lupus erythematosus), Behçet’s disease, Takayasu’s arteritis, giant cell arteritis, Kawasaki disease, Henoch–Schönlein purpura, sarcoidosis, and diseases that mimic vasculitis (eg, atrial myxoma) In patients who comply with the aforementioned criteria, the concomitant presence of ACR or Lanham criteria allows the diagnosis of EGPA

Note:

a To be used only in the presence of histologically proven vasculitis.

Abbreviations: ACR, American College of Rheumatology; c-ANCA, cytoplasmic anti-neutrophil cytoplasm antibody; EGPA, eosinophilic granulomatosis with polyangiitis; p-ANCA, perinuclear anti-neutrophil cytoplasm antibody.

Figure 1 Pathophysiology of EGPA.

Abbreviations: ANCA, anti-neutrophil cytoplasm antibody; APC, antigen-presenting cell; CCL-17, chemokine 17; CCL-26, eotaxin-3; EGPA, eosinophilic granulomatosis with polyangiitis; IFN-γ, interferon-γ; ROS, reactive oxygen species; TCR, T-cell receptor.

Table 2 Summary of the main observational studies and RCTs on the use of mepolizumab in EGPA

First author, journal, year	Trial	Aim	Design, study groups	Inclusion/exclusion criteria	Outcome measure	Main results	Conclusion	Strengths/limitations/notes
Wechsler, NEJM, 2017^Citation81	Double-blind RCT to investigate the efficacy and safety of mepolizumab in the treatment of EGPA in subjects receiving SOC therapy	To investigate the efficacy and safety of mepolizumab vs placebo as add-on therapy in relapsing or refractory EGPA	Multicenter (31 sites), double- blind RCT (1:1 mepolizumab 300 mg SC vs placebo)	Incl: >18 years, relapsing or refractory EGPA, stable dose GC (≥7.5 to ≤50.0 mg/day, ± additional immunosuppressive therapy). Excl: GPA, microscopic polyangiitis, organ- threatening or life-threatening EGPA within 3 months before screening	Two primary efficacy endpoints: total accrued weeks of remission and proportion of pts who had remission at both weeks 36 and 48. Secondary endpoints: proportion of pts who had remission within the first 24 weeks and continued to have remission until week 52; time to first relapse; proportions of pts with an average GC dose of 0 mg/day, of 0–4 mg/day, of 4–7.5 mg/day and of >7.5 mg/day during weeks 48–52	136 pts included. Two primary endpoints met. Mepolizumab led to more accrued weeks of remission than placebo (28% vs 3% of pts had ≥24 weeks of accrued remission; P,0.001) and a higher % of pts in remission at both weeks 36 and 48 (32% vs 3%, P,0.001). Remission did not occur in 47% of pts in mepolizumab group vs 81% in placebo group. The annualized relapse rate was 1.14 in the mepolizumab group vs 2.27 in the placebo group (P,0.001). 44% of pts in the mepolizumab group vs 7% in the placebo group had an average GC dose ≤4 mg/day during weeks 48–52 (P,0.001)	Approximately half the pts (53%) with relapsing or refractory EGPA treated with mepolizumab had clinically relevant improvements in the rates of remission and relapse, which allowed for reduced GC use. This suggests that not all pts have the same benefit from mepolizumab	This is the first RCT conducted to evaluate the efficacy of mepolizumab in relapsing or refractory EGPA. These results contributed to FDA approval of mepolizumab in EGPA
Moosig, Ann Intern Med, 2011^Citation43	Phase 2, single- center open-label, prospective trial to evaluate the efficacy and safety of mepolizumab for pts with refractory or relapsing CSS (MEPOCHUSS)	To evaluate mepolizumab for remission induction in relapsing and refractory EGPA	Single-center, phase 2, uncontrolled trial. Design: after stopping immunosuppressant therapy, pts received mepolizumab (9 monthly infusions, 750 mg IV) and then switched to methotrexate 0.3 mg/kg per week for maintenance	Incl: active refractory or relapsing active EGPA (BVAS >3) despite treatment with immunosuppressants + GC ≥12.5 mg/dL	Primary endpoint: remission at week 32 (BVAS =0 and GC dose <7.5 mg/day). Further outcome measures: BVAS, Vasculitis Damage Index, Disease Extent Index, GC dose, eosinophil counts, adverse events	Out of 10 pts, 8 reached the primary endpoint. The daily GC dose was reduced in all pts (median 19 mg at baseline vs 4 mg at week 32; P=0.006). After switching to methotrexate maintenance therapy, 2 major relapses and 5 minor relapses occurred over a median follow-up of 10 months	Mepolizumab allowed GC reduction over the course of the disease in most pts, with no relapses during the active 9-month treatment phase. The safety profile of mepolizumab was good	In the study by Herrmann et al,^Citation80 in 9 out of 10 pts from the original cohort an extended follow-up of 22 months was performed. At the end of follow-up, 3 out of 9 pts were still in remission. During follow-up, another 4 relapses occurred. ECP levels correlated more strongly with the BVAS (P,0.0001) than eosinophil counts (P,0.0001)
Kim, J Allergy Clin Immunol, 2010^Citation82	Mepolizumab as a steroid-sparing treatment option in CSS	To assess whether mepolizumab safely decreases EGPA disease activity and allows GC tapering	Open-label pilot study. Treatment phase: mepolizumab (4 monthly 750 mg IV doses); GC dose tapering began 2 weeks after the initial infusion and continued every 2 weeks. Subsequent washout phase (4 weeks) and safety monitoring phase (20 weeks)	Incl: EGPA (ACR criteria) in stable dose ≥10 mg prednisone (or equivalent) daily. Adjunct therapies at stable dose. Excl: non-EGPA hypereosinophilic syndrome, GPA	Primary outcome: assessment of adverse events and lowest prednisone dose achieved at the end of the treatment phase	Out of 7 pts, none showed severe adverse events. Mean dose of prednisone was 12.9 mg/day at baseline and 4.6 mg/day at week 16 (P=0.0001). Mean GC dose at washout phase (week 24) was 5 mg/day (61% decrease compared to baseline, P=0.02) and at study end (week 40) 15 mg/day. Other clinical markers of activity (FEV < PEF, FeNO, BVAS, ^Citation1 CRP, ESR) did not change significantly	Mepolizumab effectively allowed GC tapering. On cessation of mepolizumab, EGPA manifestation recurred, necessitating steroid bursts

Abbreviations: ACR, American College of Rheumatology; BVAS, Birmingham Vasculitis Activity Score; CRP, C-reactive protein; CSS, Churg–Strauss syndrome; ECP, eosinophil cationic protein; EGPA, eosinophilic granulomatosis with polyangiitis; ESR, erythrocyte sedimentation rate; Excl, exclusion criteria; FDA, Food and Drug Administration; FeNO, fraction of exhaled nitric oxide; FEV₁, forced expiratory volume in 1 second; GC, glucocorticoid; GPA, granulomatosis with polyangiitis; Incl, inclusion criteria; IV, intravenous; PEF, peak expiratory flow; pts, patients; RCT, randomized controlled trial; SC, subcutaneous; SOC, standard of care.

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