Does benralizumab improve outcomes in patients with severe asthma who are receiving long-term systemic glucocorticoids?

The addition of the monoclonal antibody benralizumab reduced the median dose of prednisone from 10 mg to 5 mg, and resulted in a small decrease in serious exacerbations in one of the active treatment groups but not the other. Although this drug has not yet been approved by the US Food and Drug Administration, a similar drug, omalizumab (Zolair), is currently priced at approximately $1000 per month in the United States and $750 in Canada. It is unclear whether the modest benefits are worth the drug's high cost. (LOE = 1b)

Nair P, Wenzel S, Rabe KF, et al, for the ZONDA Trial Investigators. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med 2017;376(25):2448-2458.  [PMID:28530840]

Randomized controlled trial (double-blinded)

Industry

Concealed

Outpatient (any)

Benralizumab is a human monoclonal antibody against the interleukin-5 receptor that gives it anti-inflammatory properties. This trial enrolled patients with severe asthma and an elevated blood eosinophil count who were taking a moderate-dose to high-dose inhaled steroid, a long-acting beta-agonist, and a daily dose of an oral steroid for at least 6 months. They initially recruited 369 patients, of whom 220 ultimately met the eligibility criteria after a run-in period during which their oral glucocorticoid dose was reduced to the minimum effective dose and at least 70% compliance with their current medications was ensured. These 220 were then randomized to receive either (1) benralizumab 30 mg by subcutaneous injection every 4 weeks for 28 weeks, (2) benralizumab 30 mg subcutaneously every 4 weeks for 3 months, and then every 8 weeks for the remaining 16 weeks, or (3) placebo injection every 4 weeks. All patients underwent a concerted effort during the 28-week study period to reduce their oral steroid dose, and the primary outcome was how much the steroid could be reduced. Groups were balanced at the start of the study, and analysis was by intention to treat. The mean age of participants was 50 years, with a median prednisone dose of 10 mg at baseline, and a forced expiratory volume in 1 second of approximately 60% of predicted. Asthma exacerbations were defined as requiring an increase in the steroid dose for 3 or more days, a visit to the emergency department (ED), or hospitalization. Patients in both of the active treatment groups saw a statistically significant reduction in the median daily oral dose of prednisone—from 10 mg to 5 mg—compared with no change in the placebo group. Approximately half the patients in the active treatment group were able to discontinue using their steroid. Patients in the active treatment groups were less likely to have any asthma exacerbation during the study period (17% to 19% vs 39%; P = .001; number needed to treat = 5 over 28 weeks). The annualized rate of exacerbations was lower for the active treatment groups (0.55 for benralizumab every 8 weeks, 0.82 for benralizumab every 4 weeks, 1.80 for placebo; P = .003). More serious exacerbations (resulting in a visit to the ED or hospitalization) were slightly less likely for the group dosed every 8 weeks (0.02 vs 0.32; P = 0.02), but not the group dosed every 4 weeks. There were small improvements in quality of life scores, but they were not clinically significant (eg, 0.45 points on a 12-point scale). Adverse events were similar between groups. In their article, the authors overemphasize the more dramatic-sounding relative reductions rather than the absolute reductions for all outcomes, something that the editors of the journal should not have tolerated.