MANDARA: Benralizumab Proves Noninferiority to Mepolizumab for EGPA

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The MANDARA trial results, published in NEJM, show benralizumab's noninferiority to mepolizumab in eosinophilic granulomatosis with polyangiitis, with potential for oral glucocorticoid discontinuation.

Michael Wechsler, MD | Credit: National Jewish Health

Michael Wechsler, MD
Credit: National Jewish Health

The publication of full trial results from the MANDARA trial further underlines the potential of benralizumab (Fasenra) in the ability to help adult patients achieve remission of relapsing or refractory eosinophilic granulomatosis with polyangiitis.

Presented as a late-breaking trial at the American College of Rheumatology 2023 annual meeting, full results from the study published The New England Journal of Medicine provide the community with further insight into the comparative effects of e benralizumab and mepolizumab (Nucala) in the management of eosinophilic granulomatosis with polyangiitis.1

“Future studies are also necessary to determine whether eosinophil depletion in patients with [eosinophilic granulomatosis with polyangiitis] is associated with complete discontinuation of oral glucocorticoid treatment,” wrote investigators.1 “However, the results of this trial and the previous trial suggest that complete discontinuation of oral glucocorticoids may now be an achievable treatment goal during receipt of eosinophil-targeted drugs.”

Questions surrounding the comparative benefit-risk profiles of biologic medicines in management of eosinophilic granulomatosis with polyangiitis have been held by pulmonologists and allergists since the US Food and Drug Administration granted benralizumab an Orphan Drug Designation for treatment in November 2018, less than 1 year after mepolizumab became the first therapy in agency history to receive approval the disease in late 2017 based on the EGPA Mepolizumab study. Billed by AstraZeneca as the first head-to-head trial of biologics to treat eosinophilic granulomatosis with polyangiitis, the phase 3 MANDARA study was launched in 2019 with the intent of assessing the noninferiority of benralizumab relative to mepolizumab in eosinophilic granulomatosis with polyangiitis.1,2,3,4

Designed as a 52-week, multicenter, double-blind, randomized, active-controlled noninferiority trial, MANDARA enrolled adult patients with relapsing or refractory eosinophilic granulomatosis with polyangiitis from 50 sites in 9 countries and randomized them in a 1:1 ratio to receive benralizumab (30 mg) or mepolizumab (300 mg) subcutaneously every 4 weeks for 52 weeks. In the trial, relapsing or refractory disease was defined as a history of relapsing or refractory disease despite therapy with oral glucocorticoids at a dose of 7.5 to 50.0 mg of prednisolone per day or equivalent, with or without stable immunosuppressive therapy.1

Per trial protocol, patients were required to maintain stable dosing f of oral glucocorticoids between baseline and week 4. After week 4, oral glucocorticoid dose was tapered in accordance with standard practice based on Birmingham Vasculitis Activity Score.1

The primary outcome of interest for the trial was the achievement of remission at weeks 36 and 48, with a prespecified noninferiority margin of -25 percentage points. Investigators defined remission as a BVAS score of 0 and an oral glucocorticoid steroid dose less than or equal to 4 mg per day. The trial included multiple secondary outcomes of interest, such as accrued duration of remission, time to first relapse, oral glucocorticoid use, eosinophil count, and safety.1

In total, 140 patients underwent randomization in the study, with 70 assigned to each treatment arm. The overall cohort had a mean age of 52.3 (Standard Deviation [SD], 14.1) years, 60% were female, and a mean time since diagnosis of 5.16 (SD, 5.64) years, and 77% were using a dose of 12 mg or more of oral glucocorticoids per day.1

Upon analysis, results indicated the adjusted percentage of patients with remission at weeks 36 and 48 was 59% among the benralizumab arm and 56% among the mepolizumab arm (difference, 3 percentage points; 95% Confidence interval [CI], -13 to 18; P = .73for superiority). Investigators underlined this result demonstrates noninferiority, but not superiority, of benralizumab to mepolizumab.1

Analysis of secondary outcomes of interest revealed the duration of remission and the time to first relapse were similar in both treatment groups. Investigators pointed out the complete withdrawal of oral glucocorticoids during weeks 48 through 52 was observed among 41% of the benralizumab arm compared to 26% of those receiving mepolizumab. Additionally, investigators called attention to apparent reductions in blood eosinophil count from baseline to week 52, with reductions from 306.0 (SD, 225.0) to 32.4 (SD, 40.8) μL in the benralizumab group and 384.9 (SD, 563.6) to 71.8 (SD, 54.4) in the mepolizumab group.1

Analysis of safety outcomes revealed adverse events were reported among 90% of those receiving benralizumab and 96% of those receiving mepolizumab. The most common adverse events were COVID-19 (benralizumab: 21%; mepolizumab: 27%),headache (benralizumab: 17%; mepolizumab: 16%), and arthralgia (benralizumab: 17%; mepolizumab: 11%). Further analysis suggested serious adverse events were reported in 6% of the benralizumab group and 13% of the mepolizumab group.1

In their 2023 announcement of topline results, AstraZeneca pointed out mepolizumab is currently the only approved treatment for eosinophilic granulomatosis with polyangiitis, but MANDARA data would be shared with regulatory agencies and they intend to continue explore benralizumab’s potential beyond asthma.4

“The positive MANDARA trial results are exciting because patients with eosinophilic granulomatosis with polyangiitis today have limited treatment options but face crippling symptoms, which can even be fatal if not treated,” said principal investigator Michael Wechsler, director of The Cohen Family Asthma Institute at Jewish National Health, in a statement from AstraZeneca announcing topline results of the trial.4 “This trial demonstrates that a biologic medicine given in a single monthly injection could help patients achieve remission rates comparable to the current standard of care, adding to the importance of benralizumab as a potential treatment option for eosinophilic granulomatosis with polyangiitis.”

References:

  1. Wechsler ME, Nair P, Terrier B, et al. Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis. N Engl J Med. Published online February 23, 2024. doi:10.1056/NEJMoa2311155
  2. Office of the Commissioner. FDA approves first drug for eosinophilic granulomatosis with polyangiitis, a rare disease formerly known as the Churg-strauss syndrome. U.S. Food and Drug Administration. December 12, 2017. Accessed February 23, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-eosinophilic-granulomatosis-polyangiitis-rare-disease-formerly-known-churg.
  3. AstraZeneca. US FDA grants Fasenra Orphan Drug Designation for Eosinophilic Granulomatosis with Polyangiitis. AstraZeneca Media Centre. November 26, 2018. Accessed February 23, 2024. https://www.astrazeneca.com/media-centre/press-releases/2018/us-fda-grants-fasenra-orphan-drug-designation-for-eosinophilic-granulomatosis-with-polyangiitis-26112018.html.
  4. AstraZeneca. Fasenra met the primary endpoint in the MANDARA Phase III trial in eosinophilic granulomatosis with polyangiitis (EGPA). AstraZeneca Media Centre. September 11, 2023. Accessed February 23, 2024. https://www.astrazeneca.com/media-centre/press-releases/2023/fasenra-phase-iii-egpa-trial-met-primary-endpoint.html.
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