Fixed-dose subcutaneous reslizumab did not effectively reduce exacerbation frequency in patients with both uncontrolled asthma and increased blood eosinophil count, nor did it reduce the daily oral corticosteroid (OCS) maintenance dose in patients with severe, OCS-dependent eosinophilic asthma, according to research published in Lancet Respiratory Medicine.
Researchers conducted 2 randomized, double-blind, placebo-controlled, phase 3 clinical trials in order to examine the safety and efficacy of subcutaneous, fixed-dose reslizumab injection (110 mg) in patients with both uncontrolled asthma and increased blood eosinophils.
The first study (ClinicalTrials.gov Identifier: NCT02452190) was an asthma exacerbation study and included a 2-week screening period, a 3-week run-in period, a 52-week treatment period, and 12 weeks of follow-up. The second study (ClinicalTrials.gov Identifier: NCT02501629) was a corticosteroid sparing study and included a 2-week screening period, a period of up to 10 weeks for OCS dose optimization, a 2-week run-in period, a 24-week treatment period, and 8 weeks of follow-up.
Participants in study 1 were randomly assigned 1:1 to receive either subcutaneous reslizumab 110 mg or placebo. The investigators stratified randomization by age (12 to <18 years and ≥18 years) and blood eosinophil count at screening (300 to <400 cells/μL and ≥400 cells/ μL). Participants in study 2 were also randomly assigned 1:1 to receive either the treatment drug or placebo; however, randomization was stratified by the optimized average daily OCS dose (>10 mg or ≤10 mg) and age (12 to <18 years and ≥18 years).
Between August 2015 and October 2016, 1159 patients were recruited for study 1. Of these, 468 patients were enrolled; 232 were assigned to placebo and 236 to treatment. Between September 2015 and December 2016, 273 patients were recruited for study 2; 177 of whom were assigned to either placebo (n=89) or treatment (n=88). Both demographic and baseline disease characteristics were similar across the treatment groups.
In study 1, clinical asthma exacerbation frequency did not significantly differ over 52 weeks between the 2 groups in the intention-to-treat (ITT) population (rate ratio [RR], 0.79; 95% CI, 0.56-1.12). The investigators found that fixed-dose subcutaneous reslizumab therapy reduced the frequency of clinical asthma exacerbations compared with placebo in a subgroup of patients with eosinophil counts of >400 cells/μL (RR, 0.64; 95% CI, 0.43-0.95); this was not demonstrated in individuals with eosinophil counts between 300 cells/μL and <400 cells/μL.
Change from baseline in prebronchodilator forced expiratory volume in 1 second at 52 weeks was larger in the treatment group compared with the placebo group. Improvements in the treatment group were noted rapidly — at 2 weeks — and were maintained over 52 weeks. Increases from baseline at week 52 were larger in the treatment group in both eosinophil subgroups. There were no meaningful differences in the results of other prespecified subgroup analyses and the ITT analyses for key secondary outcomes.
In study 2, no statistically significant difference was noted between the treatment and placebo groups across the 5-level categorized percentage reductions in OCS dose during weeks 20 to 24 compared with baseline (end of the optimization phase; odds ratio 1.23; 95% CI, 0.70-2.16). The results of the per-protocol sensitivity analysis were similar to results of the primary ITT analysis, with no notable differences discerned between treatment and placebo across subgroup analyses.
The analysis of the primary efficacy outcome did not meet the criteria for statistical significance; therefore, secondary effect outcomes were not interpreted inferentially. No significant differences were noted in the secondary efficacy analyses for the ITT population.
Both studies saw decreased blood eosinophil counts across treatment groups between baseline and the first visit. These counts remained below baseline until the end of treatment.
Across both studies, the incidence of adverse events was similar across treatment groups, and the most common adverse events were viral upper respiratory tract infection, asthma, and allergic rhinitis. The most common serious adverse event across both studies was asthma.
Several limitations were noted for both studies, including low patient numbers across subgroups, the use of a multiple testing procedure, and the inclusion of patients with a lower blood eosinophil count, which likely weakened the researchers’ ability to demonstrate treatment effect in either study.
“The results…suggest that the lower dose and lower systemic reslizumab concentrations associated with fixed-dose subcutaneous reslizumab, compared with intravenous reslizumab, might not be sufficient to provide robust reductions in exacerbation frequency in patients with uncontrolled asthma and increased blood eosinophil counts,” the researchers concluded. “The use of higher, weight-based doses of subcutaneous reslizumab should be assessed in future studies.”
Disclosure: This clinical trial was supported by Teva Branded Pharmaceutical Products R&D. Please see the original reference for a full list of authors’ disclosures.
Bernstein JA, Virchow JC, Murphy K, et al. Effect of fixed-dose subcutaneous reslizumab on asthma exacerbations in patients with severe uncontrolled asthma and corticosteroid sparing in patients with oral corticosteroid-dependent asthma: results from two phase 3, randomised, double-blind, placebo-controlled trials [published online February 14, 2020]. Lancet Respir Med. doi:10.1016/S2213-2600(19)30372-8