Benralizumab noninferior to mepolizumab for relapsing, refractory EGPA

Benralizumab compares favourably with mepolizumab for inducing remission in adult patients with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA), as shown in the results of the head-to-head phase III MANDARA trial.

Remission rates at weeks 36 and 48 were 59 percent with benralizumab and 56 percent with mepolizumab (difference, 3 percentage points, 95 percent confidence interval [CI], –13 to 18), establishing the noninferiority but not superiority of benralizumab. [N Engl J Med 2024;390:911-921]

Secondary endpoints

The accrued duration of remission (odds ratio, 1.36, 95 percent CI, 0.75–2.48) and the time to first relapse (hazard ratio for relapse, 0.98, 95 percent CI, 0.53–1.82) did not significantly differ between the two treatment arms.

Notably, more than 70 percent of the patients in each treatment arm were able to reduce their oral glucocorticoid dose by least 50 percent, with 41 percent of patients on benralizumab and 26 percent of those on mepolizumab achieving complete glucocorticoid withdrawal during weeks 48 through 52.

“[The above finding] suggests that treatment of EGPA with benralizumab or mepolizumab may help to reduce dependency on oral glucocorticoids and reduce related morbidity,” according to the investigators.

Finally, the mean blood eosinophil count decreased in the two treatment arms: from 306.0/μL at baseline to 32.4/μL at week 52 with benralizumab and from 384.9/μL to 71.8/μL, respectively, with mepolizumab.

Safety

“Both benralizumab and mepolizumab had acceptable side-effect profiles in this trial, with few serious adverse events (AEs) and no new safety signals,” the investigators noted.

AEs occurred in 90 percent of patients in the benralizumab arm and in 96 percent of those in the mepolizumab arm, with none leading to treatment discontinuation. The most common AEs were COVID-19 (21 percent and 27 percent), headache (17 percent and 16 percent), and arthralgia (17 percent and 11 percent). The rates of serious AEs were 6 percent with benralizumab and 13 percent with mepolizumab, with no deaths recorded in either treatment arm.

“The safety profile of benralizumab did not show any meaningful difference with that of mepolizumab and was similar to the safety profile that had previously been observed in trials involving patients with severe eosinophilic asthma, as well as in real-world analyses of benralizumab in patients with EGPA,” the investigators said. [Lancet Respir Med 2022;10:47-58; J Allergy Clin Immunol Pract 2021;9:4381-4392.e4; Ann Rheum Dis 2023;82:1580-1586; Lancet Rheumatol 2023;5:e707-e715]

Likewise, mepolizumab had a safety profile that was consistent with that observed in the earlier placebo-controlled trial, they added. [N Engl J Med 2017;376:1921-1932]

The role of eosinophils

Both benralizumab and mepolizumab are monoclonal antibodies. While benralizumab targets the interleukin-5 receptor, mepolizumab binds to interleukin-5 and is the first targeted therapy approved for EGPA. These drugs, as the investigators pointed out, highlight a new approach to EGPA treatment, that is targeting eosinophils.

“[MANDARA suggests] that targeting eosinophils as a therapeutic strategy in EGPA can lead to a high percentage of patients with remission and a low percentage having relapse despite substantial reductions in the use of oral glucocorticoids, providing further evidence of the critical role of eosinophils in the pathophysiological processes underlying EGPA,” the investigators said.

“However, although anti–interleukin-5 and anti–interleukin-5Rα drugs primarily target eosinophils, they also have effects on other immune cells, such as mast cells and basophils,” they added. [J Allergy Clin Immunol 2010;125:1344-1353.e2]

MANDARA

The study included 140 adults (mean age 52.3 years, 60 percent women) with relapsing or refractory EGPA who were receiving standard care. These patients were randomly assigned to receive either benralizumab 30 mg (n=70) or mepolizumab 300 mg (n=70), administered subcutaneously every 4 weeks for 52 weeks.

Compared with the pivotal mepolizumab trial, MANDARA had a higher percentage of patients who received mepolizumab and had remission and were able to completely discontinue oral glucocorticoids, the investigators noted. [N Engl J Med 2017;376:1921-1932]

Such difference, they said, may be attributed to the differences in trial design, with MANDARA being an active-comparator trial and the previous trial being placebo-controlled. Moreover, in the years between the trials, physicians have become better experienced at using therapies that target eosinophils, with the aim of eliminating the need for oral glucocorticoids. [Arthritis Rheumatol 2021;73:1366-1383; Ann Rheum Dis 2024;83:30-47]

“Thus, in the current trial, physicians may have had more confidence in tapering oral glucocorticoids. The possibly lower percentage of patients who had relapse in the current trial may partly reflect the effect of social distancing and isolation measures during the COVID-19 pandemic, which has previously been shown to be associated with a reduced frequency of asthma exacerbations,” the investigators said. [BMJ Open Respir Res 2021;8:e000758-e000758]