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Phase 3 Study of Reslizumab in Patients With Poorly Controlled Asthma: Effects Across a Broad Range of Eosinophil Counts
Chest, Volume 150, Issue 4, October 2016, Pages 799 - 810
IL-5, a mediator of eosinophil activity, is an important potential treatment target in patients with uncontrolled asthma. The efficacy of reslizumab, a humanized anti-human IL-5 monoclonal antibody, has been characterized in patients with blood eosinophils ≥ 400 cells/μL. This study further characterizes the efficacy and safety of reslizumab in patients with poorly-controlled asthma, particularly those with eosinophils < 400 cells/μL.
Patients were randomly assigned to intravenous reslizumab 3.0 mg/kg or placebo once every 4 weeks for 16 weeks. The primary end point was the change in FEV1 from baseline to week 16. Secondary measures included Asthma Control Questionnaire-7 (ACQ-7) scores, use of short-acting β-agonists (SABAs), and FVC.
Four hundred ninety-two patients received ≥ 1 dose of placebo (n = 97) or reslizumab (n = 395). In the overall population, mean FEV1 change from baseline to week 16 was not significantly different between reslizumab and placebo, and no significant relationship was detected between treatment, baseline blood eosinophils and change in FEV1. In the subgroup of patients with baseline eosinophils < 400 cells/μL, patients treated with reslizumab showed no significant improvement in FEV1 compared with those receiving placebo. In the subgroup with eosinophils ≥ 400 cells/μL, however, treatment with reslizumab was associated with much larger improvements in FEV1, ACQ-7, rescue SABA use, and FVC compared with the placebo group. Reslizumab was well tolerated, with fewer overall adverse events compared with placebo (55% vs 73%).
Reslizumab was well tolerated in patients with inadequately controlled asthma. Clinically meaningful effects on lung function and symptom control were not seen in patients unselected for baseline eosinophils.
Key Words: asthma, eosinophil, phase 3, reslizumab.
Abbreviations: ACQ - Asthma Control Questionnaire, ADA - anti-drug antibody, AE - adverse event, FAS - full analysis set, ICS - inhaled corticosteroid, LABA - long-acting β-agonist, LS - least squares, SABA - short-acting β-agonist.
FOR EDITORIAL COMMENT SEE PAGE 766
Asthma is a heterogeneous disease with multiple phenotypes reflecting varying molecular, pathologic, and physiologic processes.1 and 2 Several asthma phenotypes are characterized by elevated eosinophil levels in the lung, blood, and sputum.2 and 3 Eosinophils play an important role in promoting and sustaining airway inflammation, airway wall thickening, ﬁbrosis, and angiogenesis.4 Increased blood and sputum eosinophil counts have been correlated with increased asthma severity and are independent risk factors for asthma exacerbations.5 and 6
IL-5 is a key cytokine involved in the maturation, recruitment, and activation of eosinophils.7 Specific effects of IL-5 on eosinophils include inducing terminal maturation, prolonging cell survival by delaying apoptosis, increasing endothelial adhesion, and enhancing effector function.4 and 7 Thus, abrogation of IL-5 activity represents a potentially important strategy for reducing eosinophil-mediated inflammation in asthma.8
Reslizumab is a humanized anti-IL-5 monoclonal (IgG4/κ) antibody that binds circulating IL-5 with high affinity and prevents binding of IL-5 to its receptor.9 Reslizumab has been shown to reduce blood and sputum eosinophils, improve pulmonary function, and reduce asthma exacerbations in patients with elevated sputum eosinophils or blood eosinophil counts ≥ 400 cells/μL.10, 11, 12, and 13 The current study was conducted in a population with asthma unselected for baseline blood eosinophil counts to determine the impact of baseline eosinophil level on efficacy and to help identify the patient population most likely to benefit clinically from reslizumab.
Study Design and Patients
This was a randomized, double-blind, placebo-controlled, phase 3 trial conducted at 66 study locations across the United States (NCT01508936). Eligible patients were 18 to 65 years with asthma (Asthma Control Questionnaire [ACQ]-7 score ≥ 1.5) inadequately controlled by at least a medium-dose inhaled corticosteroid (ICS) at screening (fluticasone propionate ≥ 440 μg/day, or equivalent). Other permitted baseline medications included long-acting β-agonists (LABAs), leukotriene-receptor antagonists, 5-lipoxengase inhibitors, or cromolyn, provided the regimen was stable for 30 days before screening and not expected to change throughout the study; maintenance oral corticosteroids were not allowed. Patients were required to demonstrate airway reversibility (≥ 12% to short-acting β-agonist [SABA]) at screening. The population did not select for patients based on blood eosinophil counts, and there was no limit on FEV1 for entry. Exclusion criteria are outlined in e-Appendix 1. The study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice Guidelines and was approved by local ethics review committees (e-Table 1). All patients provided written informed consent.
Study Procedures and Assessments
The study consisted of a 3-week screening period, a 16-week double-blind treatment period, and a 12-week follow-up period. Patients were randomly assigned (4:1) to reslizumab 3.0 mg/kg or placebo given intravenously once every 4 weeks during the treatment period (total of 4 doses), stratified by the occurrence of exacerbations in the 12 months before screening (yes/no). Patients were to refrain from using SABAs for 6 h and LABAs for 12 h before study visits. The first visit during the treatment period (week 0) was the baseline visit, followed by visits at weeks 4, 8, 12, and 16. During visits, treatment efficacy was assessed by spirometric measures of pulmonary function; safety was evaluated at specified time points throughout the study. Patients were discontinued from treatment for asthma exacerbations requiring systemic corticosteroids.
End Points and Outcome Measures
The primary end point was the change in FEV1 from baseline to week 16. Secondary end points included ACQ-7 score14; rescue (SABA) use within the previous 3 days (assessed using 3-day recall at scheduled visits); FVC; and blood eosinophils (standard complete blood count). ACQ-6 (excludes lung function domain) was analyzed post hoc. Safety was evaluated by adverse events (AEs), coded using the Medical Dictionary for Regulatory Activities v15.0. Blood samples were collected for antidrug antibodies (ADAs) determination at baseline, weeks 8 and 16 (end of therapy or at early withdrawal), and at follow-up, and analyzed by Teva Biopharmaceuticals (Rockville, MD) using a validated homogeneous solution-based bridging enzyme-linked immunosorbent assay.15 and 16 All cut-point calculations were performed according to recommended statistical methods.17 and 18
Unless otherwise stated, efficacy analyses were based on the full analysis set (FAS), including all patients treated with ≥ 1 dose of study drug. Results from patients using concomitant medication (including oral or systemic corticosteroids or addition of an LABA or a long-acting antimuscarinic agent if not taken at baseline) within 7 days preceding a scheduled visit that could significantly confound interpretation of the efficacy parameters were excluded from the FAS. A blind data review meeting was conducted before the database lock to determine the exclusion of affected, individual pulmonary function tests, ACQ, and SABA assessments. Sensitivity analyses without data exclusion are presented in e-Appendix 2.
The primary efficacy variable was FEV1 at week 16. The primary end point was analyzed using a linear regression model with model effects including treatment (reslizumab or placebo), blood eosinophils at baseline, and the interaction of treatment and eosinophils. The interaction was tested at the significance level 0.10 using the FAS. A secondary analysis was performed for the primary variable for patients included in the FEV1 subpopulation (all patients in the FAS with % predicted FEV1 < 85% at baseline) using the same linear regression analysis described above. Change in FEV1 by discrete blood eosinophil thresholds was prespecified; a post hoc analysis of FEV1, FVC, and ACQ-7 stratified by eosinophil quartile categories was also performed. Secondary variables, including change in FEV1 from baseline to planned time points, were analyzed using a mixed effects model for repeated measures. Analyses of secondary variables are further described in e-Appendix 3.
A total of 869 patients were screened; 98 were randomly assigned to placebo and 398 to reslizumab (Fig 1); 492 (> 99%) received ≥ 1 dose of study drug and were included in the FAS (4 patients withdrew before taking any study drug). A total of 82 patients (84%) treated with placebo and 340 patients (85%) treated with reslizumab completed treatment. The most common reason for withdrawal or study discontinuation was an AE (12% placebo, 8% reslizumab).
Patient disposition (all patients).
At baseline, the treatment groups were comparable with respect to demographic and asthma characteristics (Table 1). Similar proportions in each group reported experiencing an asthma exacerbation during the 12 months before study entry (Table 1). Eosinophils ≥ 400 cells/μL were observed in 20% of patients at baseline, and were distributed similarly between treatment groups.
Baseline Patient and Disease Characteristics
|Characteristic||Placebo (n = 98)||Reslizumab 3.0 mg/kg (n = 398)|
|Mean age, y||45.1||44.9|
|Sex, No. (%)|
|Female||54 (55)||261 (66)|
|Male||44 (45)||137 (34)|
|Race, No. (%)|
|White||73 (74)||260 (65)|
|Black||21 (21)||113 (28)|
|Asian||2 (2)||10 (3)|
|BMI, mean, kg/m2||31.6||32.3|
|Years since diagnosis, mean||25.8||26.2|
|ICS use at enrollment, mean, μg/d||627.8||615.7|
|Exacerbation within previous 12 mo, No. (%)||37 (38)||166 (42)|
|ACQ score, mean||2.564||2.558|
|Airway reversibility, %||24.2||26.0|
|FEV1, mean, L||2.180||2.101|
|FEV1, % predicted||66.5||66.8|
|Rescue medication use, mean inhalations/previous 3 d||2.0||1.9|
|Blood eosinophils, mean (range), cells/μL||277 (0-1,288)||281 (0-1,584)|
|Treated with LABA, %||80 (82)||307 (77)|
ACQ = Asthma Control Questionnaire; ICS = inhaled corticosteroid; LABA = long-acting β-agonist.
Mean change in FEV1 from baseline to week 16 was 255 mL (reslizumab group) and 187 mL (placebo group), with a between-group difference of 68 mL (SE, ± 49.5; P = .17) (Fig 2, Table 2). A positive relationship was observed between baseline blood eosinophils and change from baseline in FEV1 for reslizumab (slope, 0.0229) with a negative relationship observed for placebo (slope, –0.2778) based on linear regression; however, the interaction between treatment and the relationship between baseline eosinophils and FEV1 did not achieve statistical significance (slope difference, 0.3; SE, ± 0.26; P = .24) (Fig 3). A sensitivity analysis using all FEV1 measurements without data exclusions for concomitant medication violations was consistent with the primary analysis using the FAS (slope difference, 0.31; SE, ± 0.26; P = .23). A sensitivity analysis based on an ostensibly less well-controlled subpopulation based on lower baseline lung function (% predicted FEV1 ≤ 85% at baseline) did not alter this relationship significantly (slope difference, 0.3215; SE, ± 0.2643; P = .22).
LS mean (± SE) change from baseline to each visit in FEV1 by treatment group (full analysis set). LS = least squares.
Change From Baseline to Week 16 for Efficacy Variables by Baseline Eosinophil Count
|Efficacy Variable||Overall Population||Baseline Eosinophils < 400 cells/μL||Baseline Eosinophils ≥ 400 cells/μL|
|Placebo||Reslizumab, 3.0 mg/kg||Placebo||Reslizumab, 3.0 mg/kg||Placebo||Reslizumab, 3.0 mg/kg|
|Baseline mean ± SE||2.172 ± 0.0643||2.098 ± 0.0350||2.182 ± 0.0746||2.068 ± 0.0372||2.153 ± 0.1392||2.224 ± 0.0928|
|Mean change from baseline ± SE||0.187 ± 0.0446||0.255 ± 0.0232||0.215 ± 0.0484||0.247 ± 0.0255||0.002 ± 0.1216||0.272 ± 0.0557|
|Treatment effect change ± SE||0.068 ± 0.0495||0.033 ± 0.0539||0.270 ± 0.1320|
|95% CI||–0.030 to 0.165||–0.073 to 0.139||0.008 to 0.532|
|Baseline mean ± SE||3.209 ± 0.0924||3.041 ± 0.0481||3.217 ± 0.1095||2.973 ± 0.0513||3.206 ± 0.1757||3.321 ± 0.1234|
|Mean change from baseline ± SE||0.236 ± 0.0506||0.247 ± 0.0263||0.256 ± 0.0537||0.248 ± 0.0283||0.055 ± 0.1449||0.230 ± 0.0681|
|Treatment effect change ± SE||0.012 ± 0.0560||–0.009 ± 0.0598||0.175 ± 0.1571|
|95% CI||–0.098 to 0.122||–0.126 to 0.109||–0.137 to 0.487|
|Baseline mean ± SE||2.574 ± 0.0698||2.559 ± 0.0353||2.564 ± 0.0778||2.574 ± 0.0390||2.677 ± 0.1692||2.501 ± 0.0839|
|Mean change from baseline ± SE||–0.648 ± 0.0878||–0.844 ± 0.0453||–0.714 ± 0.0954||–0.836 ± 0.0499||–0.368 ± 0.2407||–0.858 ± 0.1105|
|Treatment effect change ± SE||–0.195 ± 0.0974||–0.122 ± 0.1065||–0.490 ± 0.2616|
|95% CI||–0.387 to –0.004||–0.332 to 0.087||–1.010 to 0.030|
|SABA use, puffs/day|
|Baseline mean ± SE||2.0 ± 0.19||1.9 ± 0.09||2.0 ± 0.21||1.9 ± 0.10||2.2 ± 0.44||1.9 ± 0.21|
|Mean change from baseline ± SE||–0.4 ± 0.19||–0.3 ± 0.10||–0.4 ± 0.21||–0.2 ± 0.11||–0.1 ± 0.43||–0.8 ± 0.19|
|Treatment effect change ± SE||0.063 ± 0.2050||0.216 ± 0.2300||–0.708 ± 0.4587|
|95% CI||–0.340 to 0.466||–0.236 to 0.668||–1.619 to 0.204|
a Negative changes in ACQ indicate improved asthma control. The minimal clinically important difference for ACQ is 0.5 units.
Mean change from baseline expressed as least squares mean with associated SE. SABA = short-acting β-agonist. See Table 1 legend for expansion of other abbreviation.
Change in FEV1 (wk 16) vs baseline eosinophils: linear regression model (full analysis set).
This study was not adequately powered to test the efficacy of reslizumab across multiple eosinophil subgroups. Keeping this design limitation in mind, we determined that 80% of the study population had a blood eosinophil count of < 400 cells/μL at randomization. The difference in change in FEV1 from baseline to week 16 between the reslizumab (n = 275) and placebo treatment (n = 68) groups in the subgroup with eosinophils < 400 cells/μL was 33 mL (P = .54). The difference in change in FEV1 in patients with eosinophils ≥ 400/μL between the reslizumab (n = 69) and placebo (n = 13) groups was 270 mL (P = .04) (Figs 4A and 4B, Table 2). The magnitude of the treatment difference in this subgroup appears to have been primarily influenced by a near complete lack of response in the small number of patients treated with placebo. Analysis of the FEV1 treatment effect in patients with < 400 cells/μL across a range of cutoffs did not show a meaningful trend (Fig 4B). A sensitivity analysis without data exclusion for concomitant medication violations was consistent with the primary analysis (e-Table 2). A post hoc analysis of FEV1 by baseline eosinophil quartiles (Fig 4C) was performed; no effect was observed at very low eosinophil counts, with positive changes in FEV1 observed only for the upper quartiles.
A–C, Effect on FEV1 at wk 16 by change from baseline in patients with eosinophils ≥ 400 cells/μL and < 400 cells/μL (A), treatment difference vs placebo by baseline eosinophil strata (full analysis set) (B), and treatment difference vs placebo by additional baseline eosinophil quartiles (C). *P = .0436 for reslizumab vs placebo, not adjusted to control for multiplicity. Error bars are SE of least squares mean (A) or SE of mean difference between reslizumab and placebo (B, C).
The pattern of improvements in other efficacy parameters (ACQ-7, ACQ-6, FVC, and SABA use) at 16 weeks was consistent with that observed for FEV1. Specifically, improvements relative to placebo in the overall population were modest (Table 2), although a greater proportion of patients achieved a clinically meaningful decrease in ACQ-7 score of ≥ 0.5 at week 16 with reslizumab (71%) vs placebo (57%; P = .01). The treatment effect in the subgroup of patients with blood eosinophils < 400 cells/μL was small. In patients with baseline blood eosinophils ≥ 400 cells/μL, increases in these measures were more substantial, although not significant (Figs 5 and 6, Table 2, e-Fig 1, e-Table 3); treatment effects for ACQ-7, FVC, and SABA use were –0.49 units, 175 mL, and –0.71 inhalations, respectively. Similar to FEV1, treatment effects in the ≥ 400 cells/μL subgroup were at least in part accounted for by a low placebo response.
A–C, Effect on FVC at wk 16 by change from baseline in patients with eosinophils ≥ 400 cells/μL and < 400 cells/μL (A), treatment difference vs placebo by baseline eosinophil strata (full analysis set) (B), and treatment difference vs placebo by additional baseline eosinophil quartiles (C). Error bars are SE of least squares mean (A), SE of the difference between reslizumab and placebo (B; treatment difference and corresponding SE are from mixed model repeated measures), or SE of the difference between reslizumab and placebo (C).
A–C, Effect on ACQ-7 at wk 16 by change from baseline in patients with eosinophils ≥ 400 cells/μL and < 400 cells/μL (A), treatment difference vs placebo by baseline eosinophil strata (full analysis set) (B), and treatment difference vs placebo by additional baseline eosinophil quartiles (C). *P = .0643 for reslizumab vs placebo. Error bars are SE of least squares mean (A), SE of the difference between reslizumab and placebo (B; treatment difference and corresponding SE are from mixed model repeated measures), or SE of the difference between reslizumab and placebo (C). ACQ-7 = Asthma Control Questionnaire-7.
A marked decrease in blood eosinophils was observed after the first dose of reslizumab compared with placebo and was maintained during the 16 weeks, consistent with the known mechanism of action of reslizumab (overall treatment difference, –260 cells/μL; P < .0001) (Fig 7). Mean blood eosinophil count began to return toward baseline by the follow-up visit (3 months after the end-of-treatment visit and approximately 4 months after last the reslizumab dose).
Blood eosinophils over time by treatment group (all randomized patients). *The follow-up visit was conducted 12 wks ± 7 days after the end of treatment at wk 16 or early withdrawal. See Figure 2 legend for expansion of abbreviation.
Safety and Tolerability
Reslizumab was generally well tolerated. A smaller proportion of patients treated with reslizumab (55%) experienced ≥ 1 AE compared with those treated with placebo (74%). Similarly, there were fewer AEs considered by the investigator to be treatment-related (7% vs 16%) and fewer discontinuations due to AEs (8% vs 12%) with reslizumab than placebo. The most common discontinuation AE in either group was asthma (reslizumab 5%, placebo 8%); discontinuations were otherwise single-patient events not predominated by any particular system organ class. Equal proportions (16 patients [4%] in the reslizumab group and 4 [4%] in the placebo group) had serious AEs. The most frequent (≥ 3%) AEs in the reslizumab group were asthma, upper respiratory tract infection, and sinusitis (Table 3). A greater percentage of infections were reported in the placebo group (47%) than in the reslizumab group (31%). Two patients in the reslizumab group had anaphylaxis (one event was related to ongoing allergen immunotherapy; one was associated with reslizumab). For the reaction related to reslizumab, symptoms of wheezing, shortness of breath, and flushing occurred shortly after infusion, without hemodynamic compromise. The patient responded to epinephrine, salbutamol, antihistamine, and prednisone at the study site, and subsequently tested ADA-negative. One patient in the reslizumab group had colon cancer (onset day 64), which was not considered treatment-related. No deaths occurred in either treatment group.
Adverse Events Occurring in ≥ 3% of Patients in Either Group by Preferred Term (Medical Dictionary for Regulatory Activities 15.0)
|AE||Placebo (n = 97)||Reslizumab (n = 395)|
|Asthma||19 (20)||50 (13)|
|Upper respiratory tract infection||11 (11)||42 (11)|
|Sinusitis||7 (7)||22 (6)|
|Bronchitis||6 (6)||14 (4)|
|Nasopharyngitis||5 (5)||13 (3)|
|Headache||4 (4)||13 (3)|
|Urinary tract infection||10 (3)|
|Allergic rhinitis||3 (3)||9 (2)|
|Influenza||3 (3)||8 (2)|
|Acute sinusitis||3 (3)||6 (2)|
|Back pain||3 (3)||6 (2)|
|Diarrhea||3 (3)||4 (1)|
|Viral gastroenteritis||3 (3)||4 (1)|
|Oropharyngeal pain||3 (3)||4 (1)|
|Nausea||5 (5)||3 (< 1)|
|Arthralgia||4 (4)||3 (< 1)|
|Dizziness||3 (3)||3 (< 1)|
|Contusion||3 (3)||3 (< 1)|
|Dysgeusia||3 (3)||1 (< 1)|
Data are presented as No. (%). AE = adverse event.
Serum chemistry, hematology, urinalysis, physical examination, vital signs, and electrocardiogram did not reveal any clinically meaningful treatment effect with the exception of the expected pharmacological effect of reslizumab (eosinophil reduction with a slight, proportionate impact on total white blood cell counts). Three percent of patients treated with reslizumab tested ADA-positive at screening before drug exposure, and 5% of patients treated with reslizumab were classified as ADA-positive during treatment. Most ADA responses were low titer and transient; only three patients (1%) treated with reslizumab tested positive at ≥ 2 postbaseline assessments. There was no impact of ADA-positive status on the AE profile compared with the overall population, or on eosinophil depletion by reslizumab, consistent with a lack of neutralizing activity.
Reslizumab has previously been demonstrated to improve asthma control and pulmonary function in asthma patients with blood eosinophils ≥ 400 cells/μL who were uncontrolled with ICS and LABA treatment in three large pivotal trials.12 and 13 The current study was designed to explore the effect of reslizumab in a population with asthma unselected for baseline eosinophils. The results demonstrate that, in contrast to the results of prior studies of patients with elevated blood eosinophils, four once-monthly doses of reslizumab 3.0 mg/kg given to patients with inadequately controlled asthma unselected for eosinophil count produced only modest effects on FEV1 compared with placebo (68 mL). The overall group also had small improvements in FVC, ACQ, and SABA use with reslizumab treatment. A positive relationship between baseline eosinophil count and FEV1 improvement was observed in the reslizumab treatment group; however, the interaction between this relationship and treatment was not significant. Secondary analyses showed small improvements in efficacy measures in the subgroup of patients with a blood eosinophil count < 400 cells/μL. In contrast, substantial improvements in FEV1, FVC, ACQ, and SABA use were seen in the subgroup with ≥ 400 cells/μL at baseline.
Interpretation of the results in the ≥ 400 cells/μL subgroup is limited as the study was not designed or statistically powered to specifically test this group of patients. Only 20% of the study population had a blood eosinophil count of ≥ 400 cells/μL at randomization, and only 13 patients treated with placebo met this criterion. The flat response of these 13 patients treated with placebo contributed, in part, to the overall treatment effect in this category. The small observed placebo effect in the subgroup with blood eosinophils ≥ 400 cells/μL may have occurred by chance given the very small sample size; there were no ostensible differences in baseline control measures for patients treated with placebo with blood eosinophils ≥ 400 cells/μL vs patients treated with placebo with eosinophils < 400 cells/μL (data not shown). Efficacy analyses based on eosinophil quartile results, which are more balanced, support that an eosinophilic phenotype is essential to reslizumab efficacy as patients with very low eosinophil counts had no meaningful response. This result is consistent with observations that higher blood eosinophil levels have been shown to be more specific for airway eosinophilia,19 and 20 and are associated with indicators of more severe disease, including low lung function21, 22, and 23 and greater asthma exacerbation risk.6
To date, clinical trials of other anti-IL-5 agents have demonstrated improvements in FEV1 in some studies24 and 25 but not in others.26 and 27 In a recent phase 2 benralizumab study that included patients with a broad range of blood eosinophil counts, the threshold value associated with meaningful lung function improvements was ≥ 300 cells/μL.24 A subgroup analysis of data from a phase 3 study of mepolizumab in refractory eosinophilic asthma showed that the magnitude of improvement in FEV1 with mepolizumab was larger in patients with baseline blood eosinophils ≥ 500 cells/μL vs the overall population (study inclusion ≥ 150 cells/μL at screening or ≥ 300 cells/μL during the previous 12 months; baseline geometric mean blood eosinophils, 280–320 cells/μL).25 The results from these studies suggest that lung function response to an IL-5 inhibitor is influenced by a patient’s baseline blood eosinophil level.
Due to the sample size and the short duration of the current study, we were not able to perform a meaningful assessment of the impact of blood eosinophil levels on the reduction of asthma exacerbation events by reslizumab (not formally assessed in this study). A reduction in the annual rate of asthma exacerbations by reslizumab 3.0 mg/kg has previously been demonstrated in patients selected for elevated blood eosinophils.12 Furthermore, meaningful reductions in the annual rate of asthma exacerbations have been shown for other anti-IL-5 and antieosinophil mechanisms of action (ie, mepolizumab and benralizumab24 and 25) at blood eosinophil cutoffs as low as ≥ 150 cells/μL.
Reslizumab treatment was well tolerated in this study, with an AE profile typical of patients with inadequately controlled asthma. Overall, the incidence of AEs was less frequent in the reslizumab group than the placebo group, consistent with previous reslizumab studies.10, 11, and 12 AEs resulting in withdrawal from the study were uncommon, occurring with a frequency similar to placebo with no predominant event pattern. There was a single report of anaphylaxis during reslizumab infusion that resolved with treatment at the study site. As the ADA assessment was ultimately negative in this patient, the event may be more consistent with an infusion reaction than true drug hypersensitivity, although an immune-mediated reaction cannot be completely excluded by the negative ADA status. Since the reaction occurred immediately after infusion and was easily managed by the treating physician, the risks from these types of reactions with a biologic can be mitigated when administered by a health-care provider experienced in the recognition and treatment of anaphylaxis.
In conclusion, reslizumab 3.0 mg/kg was well tolerated in patients with asthma inadequately controlled on a medium- to high-dose ICS-based regimen. Reslizumab did not meaningfully improve asthma outcomes, including both lung function and measures of symptom control, in patients with blood eosinophil counts < 400 cells/μL. These findings support an acceptable benefit-risk profile for reslizumab in patients with asthma who have a blood eosinophil threshold of ≥ 400 cells/μL.
Author contributions: J. C., S. W., L. J., J. Z., and M. G. were involved in data generation, analysis, and interpretation of the data and in preparation of critical reviews of the manuscript. J. C. was the primary investigator and had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed to the writing and revising of the manuscript and read and approved the final manuscript.
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: The study was funded by Teva Branded Pharmaceutical Products R&D, Inc. Medical writing assistance, supported financially by Teva Pharmaceuticals, was provided by Victoria A. Robb, PhD, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this article. Dr Corren has been involved in speaker bureau activities for Genentech and Merck and has served on advisory boards for Vectura Pharmaceuticals, Genentech, Novartis and Merck. Dr Weinstein has received research grants from AstraZeneca, and was involved in speaker bureau activities and advisory boards for Teva; these activities were outside of the submitted work. Ms Janka and Dr Garin are employees of Teva and have shareholdings in Teva. Dr Zangrilli is an employee of Teva, and has a patent pending for the use of reslizumab to treat moderate-to-severe asthma.
Role of sponsors: Teva employees were involved in the study design, data collection and analysis, and in the writing of this manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Other contributions: We thank the patients who participated in the trial, as well as investigators and staff at all study sites.
Additional information: The e-Appendixes, e-Tables, and e-Figure can be found in the Supplemental Materials section of the online article.
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a David Geffen School of Medicine at UCLA, Los Angeles, CA
b Allergy and Asthma Specialists Medical Group and Research Center, Huntington Beach, CA
c Teva Pharmaceuticals Inc, Frazer, PA
∗ CORRESPONDENCE TO: Jonathan Corren, MD, 10780 Santa Monica Blvd, Ste 280, Los Angeles, CA 90025
FUNDING/SUPPORT: The study was funded by Teva Branded Pharmaceutical Products R&D, Inc.
© 2016 Published by Elsevier B.V.