Impact of weight on the efficacy of mepolizumab in patients with severe eosinophilic asthma

Introduction: The prevalence of obesity is rapidly increasing in the United States. Patients with severe asthma, in particular, tend to be above normal weight. Mepolizumab was recently approved as a fixed-dosed treatment of 100 mg SC every 4 weeks for patients with severe eosinophilic asthma. Although mepolizumab exposure can be influenced by bodyweight, the magnitude of the effect was not deemed clinically relevant. In this analysis we have assessed whether the efficacy of mepolizumab is affected by weight. Methods: In this post-hoc analysis we considered two randomized clinical studies (DREAM and MENSA) of mepolizumab (32 – 52 weeks in duration). Patients had ≥2 exacerbations in the prior year and were treated with high dose ICS plus at least one additional controller. The studies included doses of mepolizumab 750, 250, 75 mg IV (DREAM) and 100 mg SC, 75 mg IV (MENSA) compared to placebo administered every 4 weeks. Patients weight ranged from 42 kg to 162 kg. Patients were divided in 4 weight categories: ≤60 kg, > 60 to ≤75 kg, > 75 to ≤90 kg and > 90 kg. Exacerbations were analyzed using separate negative binomial regression models for each weight category with adjustment for baseline covariates. Results: Mepolizumab reduced the rate of exacerbations by approximately 50% relative to placebo regardless of weight category (Table 1). Tab. 1 Placebo N = 346 Mepolizumab 75 mg IV/100 mgSC* N = 538 Mepolizumab All Doses N = 846 ≤60 kg n 57 106 149 Exacerbation rate/year 2.07 1.14 1.00 RR(Mepo/Pbo) - 0.55 0.48 (95% CI) (0.35 – 0.86) (0.31 – 0.72) Percent reduction 45% 52% > 60 kg to ≤75 kg n 119 164 249 Exacerbation rate/year 1.73 0.76 1.00 RR (Mepo/Pbo) - 0.44 0.57 (95% CI) (0.31 – 0.62) (0.42 – 0.78) Percent reduction 56% 43% > 75 kg to ≤90 kg n 97 170 261 Exacerbation rate/year 1.68 1.00 0.90 RR (Mepo/Pbo) - 0.60 0.54 (95% CI) (0.42 – 0.84) (0.39 – 0.73) Percent reduction 41% 47% > 90 kg n 73 98 187 Exacerbation rate/year 2.15 0.94 1.11 RR (Mepo/Pbo) - 0.44 0.51 (95% CI) (0.29 – 0.68) (0.36 – 0.73) Percent reduction 56% 49% RR = Rate ratio; CI = Confidence Interval; Mepo = Mepolizumab; Pbo = Placebo * Only MENSA included 100 mg SC Conclusion: Fixed dosing for a biologic with a positive risk-benefit profile is considered relevant in drug development. In this analysis there were no meaningful differences in the ability of mepolizumab to reduce the rate of exacerbations across the weight categories studied. Funding: GlaxoSmithKline (NCT01000506 [DREAM] and NCT01691521 [MENSA]).