PURPOSE OF THE STUDY:
To compare the safety (SAE) and efficacy of mepolizumab (MEPO), benralizumab (BEN), and dupilumab (DUP) in individuals with severe eosinophilic asthma.
METHODS:
An extensive literature search (January 2000–February 2021) for randomized, parallel, placebo-controlled trials of MEPO, BEN, and DUP or bioequivalent doses was performed. The primary outcome was clinically significant exacerbations and secondary outcomes were prebronchodilator forced expiratory volume (FEV) 1 and Asthma Control Questionnaire (ACQ) scores. Results were stratified by total eosinophil counts (TEC) ≥300 and 150 to 299 cells/μL.
Bayesian meta-analyses allow simultaneous rather than pairwise comparisons of the therapies and a probability-based ranking of their safety and efficacy. Surface under cumulative ranking (SUCRA) assessed the probability of each treatments’ outcome.
RESULTS:
Of 2040 studies screened, 8 were ultimately included in the meta-analysis, 3 of MEPO, 3 of BEN, and 2 of DUP. The 8 studies included a total 6461 patients. The mean age ranged from 48 to 53 years and 57% to 66% of subjects were women. Where reported, only 10% to 27% were people of color. In the group with TEC ≥300, all 3 biologics were significantly better than placebo in reducing exacerbations (DUP risk ratio [RR] 0.32; MEPO RR 0.37; BEN RR 0.49), improving FEV 1 (DUP mean difference (MD) in mL 230; MEPO MD 150; BEN MD 150), and reducing ACQ score (MEPO MD −0.63; DUP MD −0.48; BEN MD −0.32). For ACQ only MEPO was significantly superior to placebo. DUP and MEPO were superior to BEN in improving exacerbations (RR 0.75 for both). In patients with TEC 150 to 299, BEN (RR 0.62) and DUP (RR 0.60) were associated with lower exacerbation rates and BEN was associated with improved FEV 1 (MD 81). MEPO had a similar quantitative improvement that did not meet significance. For the group with TEC ≥300, SUCRA plots showed DUP, most effective for exacerbation rate and improvement in FEV 1, whereas MEPO (30%) and BEN (10%) had lower likelihood of being most effective. In contrast, for ACQ score improvement, MEPO had the highest probability of being most effective. In patients with TEC 150 to 299, BEN had the highest SUCRA value in reducing exacerbations. BEN and MEPO had similar values ranked higher than in improving FEV 1. Overall, MEPO and BEN, but not DUP, were associated with lower odds of an SAE than placebo, with MEPO significantly lower than DUP. Finally, each pairing of outcomes was compared. In the higher TEC group, DUP had the largest benefit in exacerbation or FEV 1. BEN had the largest benefit in the lower TEC group. In the higher TEC group, DUP had the highest SUCRA score for FEV 1 and ACQ score. DUP and MEPO were superior to BEN for exacerbations and ACQ. In both groups, for exacerbations and SAE and FEV 1 and SAE, MEPO and BEN had the largest benefits.
CONCLUSIONS:
With low to moderate certainty of evidence, MEPO, DUP, and BEN were similar in safety and efficacy in patients with severe eosinophilic asthma. Differences in outcomes did not meet clinically important thresholds.
REVIEWER COMMENTS:
Although this meta-analysis was in adults, MEPO (Nucala®, an anti-IL5 monoclonal antibody), BEN (Fasenra®, anti-IL5R), and DUP (Dupixent®, anti-IL4/IL13Rα chain) are all approved for the treatment of asthma in pediatric ages. This comparative study has not been done in children, but there are valuable lessons, nonetheless.
What is the most important outcome? Pulmonary function? Exacerbation rate? ACQ score? Or some combination? If you can answer that question, then what is the best biologic to choose? The point is there is no simple “all or none” answer. In this era of managed care, our initial biologic choice might be limited by insurance coverage. What next if it does not achieve the desired effect? I suggest that the best treatment of any condition is the one that works the best and is best tolerated (including cost). This might require that the provider and patient do their own “ersatz Bayesian analysis.”
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