Biologic Therapy for Eosinophilic Granulomatosis With Polyangiitis: Building the Therapeutic Armamentarium

Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome, has now drawn attention with the publication of results from several clinical trials. The main targets of eosinophilic inflammation — interleukin (IL)-5 and T-helper-2 cells — cause a constellation of symptoms including asthma, sinusitis, eosinophilia, and necrotizing vasculitis.^1,2

For years, oral glucocorticoids were considered first-line therapy for patients with EGPA. However, these agents did not completely ameliorate symptoms and were linked to numerous adverse events.³ Emerging data show that certain biologics may produce enduring results, often defined as remission (score of 0 on the Birmingham Vasculitis Activity Score [BVAS]), less reliance on oral glucocorticoids, and reduction in flares.⁴

First Biologic for EGPA

Evidence now suggests that mepolizumab, a monoclonal antibody that targets IL-5, may help patients achieve EGPA remission. In one of the first randomized, placebo-controlled, multisite trials, a team of investigators led by Michael Wechsler, MD, professor of medicine and director of the Cohen Family Asthma Institute at National Jewish Health in Denver, Colorado, randomly assigned 68 study participants to receive mepolizumab and an equal amount to receive placebo (ClinicalTrials.gov Identifier: NCT02020889).⁵

The 2 primary end points were accrued weeks of remission (0 on the BVAS) over a 52-week period according to categorical quantification and the percentage of patients in remission at both week 36 and 48. ⁵   Secondary end points included time to first relapse and mean daily glucocorticoid dose (during weeks 48 through 52).⁵

Patients treated with mepolizumab had more accrued weeks of remission than those in the placebo group (≥24 accrued weeks achieved by 28% vs 3% of patients, respectively; odds ratio [OR], 5.91; 95% CI, 2.68-13.03; P <.001).⁵ Those treated with mepolizumab vs placebo had lower daily doses of prednisolone or prednisone during weeks 48 through 52 (44% vs 7%, respectively; OR, 0.20; 95% CI, 0.09-0.41; P <.001). More participants in the mepolizumab group vs the placebo group had remission at both week 36 and 48 (32% vs 3%; OR, 16.74; 95% CI, 3.61-77.56; P <.001). In the mepolizumab group, the annualized relapse rate was 1.14 vs 2.27 in the placebo group (rate ratio, 0.50; 95% CI, 0.36-0.70; P <.001). Overall adverse events were similar in both groups.⁵

---

---

Two years after results of the phase 3 study were published, researchers conducted a post hoc analysis to determine the clinical benefit of mepolizumab.³ Clinical benefit was defined as remission (BVAS=0) plus an oral glucocorticoid dose ≤4 mg/d or ≤7.5 mg/d during the study treatment period and ≥50% reduction in average dose of oral glucocorticoid during weeks 48 to 52. Clinical benefit was evaluated in all patients. More than half of patients treated with mepolizumab (53%) had achieved remission vs 19% of patients receiving placebo.³

“Clinicians can come to understand that there are many different outcomes that one can look at in deciding if a therapy is effective,” explained Dr Wechsler. “For instance, not only is it important to achieve remission but also to reduce corticosteroids or not have relapses. For any of these reasons, mepolizumab was effective in EGPA.”

Therapeutic Candidates in the Drug Pipeline

Beyond mepolizumab, other biologic agents have been studied for the treatment of EGPA, including reslizumab, benralizumab, rituximab, and omalizumab. Though the evidence is growing, limited data exist to support their use as pharmacotherapy for EGPA.⁷

A phase 2, open-label study of reslizumab, a monoclonal antibody with the same anti IL-5 target as mepolizumab, is underway.⁸ In addition to intravenous reslizumab, participants will also receive standard therapy for EGPA, including oral steroids such as prednisone.

Benralizumab, which targets the IL-5 receptor and elicits a natural killer cell-mediated antibody-dependent response against eosinophils, is being studied in a phase 3 trial.^7,9 The 52-week study will assess the efficacy and safety of benralizumab compared to mepolizumab.

---

Click Here for PDF

---

Mixed Signals With an Older Biologic

The chimeric anti-CD20 monoclonal antibody rituximab has been studied in patients with EGPA to determine if it can reduce their need for steroids. In a study of 69 patients conducted by Teixeira and colleagues from the Vasculitis and Lupus Clinic, Addenbrooke’s Hospital, Cambridge, United Kingdom, 76.8% of those treated with rituximab had a full or partial response to therapy at 6 months, 82.8% at 12 months, and 93.2% at 24 months.¹⁰ However, by 24 months, 54% of the patients had experienced relapse, mostly due to asthma. During 24 months, 16% of patients experienced ≥1 severe infection.

Beyond the IL-5 Target

In a systematic review of omalizumab, a recombinant humanized IgE monoclonal antibody approved for use in asthma and chronic idiopathic urticaria, the agent was found to improve EGPA in some patients, while it potentially exacerbated the disease in others due to tapering steroids.¹¹ Basta and colleagues from the Bambino Gesù Children’s Hospital in Rome, Italy, cautioned that omalizumab should be used selectively in patients with EGPA until more robust evidence indicates that it does not paradoxically promote EGPA when steroids are reduced.¹¹

A retrospective study of 18 patients (median age, 48.6 years; 88% women) by Zeynep Celebi Sözener, MD, and colleagues from the Department of Chest Diseases,

Division of Allergy and Clinical Immunology, at the Ankara University School of Medicine in Turkey sought to evaluate the clinical effectiveness of omalizumab.¹² Similar to previous omalizumab studies, the results were mixed.

While 55.6% of patients experienced complete recovery, 38.9% had no improvement.¹² Overall, omalizumab showed benefit as a steroid-sparing agent, with the mean dose reduced to 6.28 mg/d, and was associated with reduced asthma exacerbations and hospitalizations.

Why might this biologic with different targets benefit patients with EGPA? “Omalizumab is a target-specific agent, due to its binding to free IgE, it directly inhibits the T2 pathway as a result of decreased IgE receptors on effector cells,” described study coauthor Sevim Bavbek, MD, professor of medicine also from Ankara University.

“Omalizumab eliminates stimulation of eosinophils and prevents these cells from accumulating in tissues, which is the key point for inflammation in EGPA. Given the antiallergic and anti-inflammatory effectiveness of omalizumab, including the reduction of circulating and tissue eosinophils, it is proposed that omalizumab could be used to decrease eosinophilic activity resulting in asthma control in patients with EGPA,” Dr Bavbek noted.

Summary

For patients with EGPA, biologics may offer an alternative to high-dose steroids. By ameliorating asthma symptoms as well as eosinophilic-driven inflammation, biologics may prolong time to relapse and reduce adverse events associated with steroids.

References

1. Furuta S, Iwamoto T, Nakajima H. Update on eosinophilic granulomatosis with polyangiitis. Allergol Int. 2019;68(4):430-436.
2. Faverio P, Bonaiti G, Bini F, Vaghi A, Pesci A. Mepolizumab as the first targeted treatment for eosinophilic granulomatosis with polyangiitis: a review of current evidence and potential place in therapy. Ther Clin Risk Manag. 2018;14:2385-2396.
3. Steinfeld J, Bradford ES, Brown J, et al. Evaluation of clinical benefit from treatment with mepolizumab for patients with eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol. 2019;143(6):2170-2177.
4. Groh M, Pagnoux C, Baldini C, et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA) consensus task force recommendations for evaluation and management. Eur J Intern Med. 2015;26(7):545-553.
5. Wechsler ME, Akuthota P, Jayne D, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med. 2017;376(20):1921-1932.
6. Nucala. Prescribing Information. GlaxoSmithKline LLC; September 2019. Accessed July 22, 2020. https://gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/ Nucala/pdf/NUCALA-PI-PIL-IFU-COMBINED.PDF
7. Caminati M, Menzella F, Guidolin L, Senna G. Targeting eosinophils: severe asthma and beyond. Drugs Context. 2019;8:212587.
8. ClinicalTrials.gov. Reslizumab in the treatment of eosinophilic granulomatosis with polyangiitis (EGPA) study (RITE). NCT02947945. Accessed July 7, 2020. https://clinicaltrials.gov/ct2/show/NCT02947945
9. ClinicalTrials.gov. A study to evaluate if benralizumab compared to mepolizumab may be beneficial in the treatment of eosinophilic granulomatosis with polyangiitis (EGPA) (MANDARA). NCT04157348. Accessed July 7, 2020. https://clinicaltrials.gov/ct2/show/NCT04157348
10. Teixeira V, Mohammad AJ, Jones RB, et al. Efficacy and safety of rituximab in the treatment of eosinophilic granulomatosis with polyangiitis. RMD Open. 2019;5:e000905.
11. Basta F, Mazzuca C, Nucera E, Schiavino D, Afeltra A, Antonelli Incalzi R. Omalizumab in eosinophilic granulomatosis with polyangiitis: friend or foe? A systematic literature review. Clin Exp Rheumatol. 2020;38(suppl 124):214-220.
12. Celebi Sözener Z, Gorgulu B, Mungan D, et al. Omalizumab in the treatment of eosinophilic granulomatosis with polyangiitis (EGPA): single-center experience in 18 cases. World Allergy Organ J. 2018;11(1):39.

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Pulmonology Advisor had no role in this content’s preparation.

Reviewed August 2020