Fasenra Drug Information

Clinical Studies in Patients with Asthma

The efficacy of FASENRA for the add-on maintenance treatment of severe asthma and with an eosinophilic phenotype was evaluated in two randomized, double-blind, parallel-group, placebo-controlled, exacerbation trials, SIROCCO (NCT01928771) and CALIMA (NCT01914757), for 48 and 56 weeks in duration, respectively. Furthermore, the effects of FASENRA in the reduction of oral corticosteroid use and effect on lung function were evaluated in clinical trials, ZONDA (NCT02075255) and a 12-week lung function trial (NCT02322775), respectively. SIROCCO and CALIMA were randomized, double-blind, parallel-group, placebo-controlled, exacerbation trials in patients 12 years of age and older, and 48 and 56 weeks in duration, respectively.

The trials randomized a total of 2,510 patients. Patients were required to have a history of 2 or more asthma exacerbations requiring oral or systemic corticosteroid treatment in the past 12 months, Asthma Control Questionnaire-6 (ACQ‑6) score of 1.5 or more at screening, and reduced lung function at baseline despite regular treatment with high dose ICS (SIROCCO) or with medium or high dose ICS (CALIMA) plus a long-acting beta agonist (LABA) with or without oral corticosteroids (OCS) and additional asthma controller medications. Patients were stratified by geography, age, and blood eosinophils count (≥300 cells/μL or <300 cells/μL).

All patients continued their background asthma therapy throughout the duration of the trials. ZONDA was a randomized, double-blind, parallel-group, OCS reduction trial in 220 adult patients with asthma. Patients were required treatment with daily OCS (7.5 to 40 mg per day) in addition to regular use of high-dose ICS and LABA with or without additional controller(s).

The trial included an 8‑week run-in period during which the OCS was titrated to the minimum effective dose without losing asthma control. For the purposes of the OCS dose titration, asthma control was assessed by the investigator based on a patient’s FEV 1, peak expiratory flow, nighttime awakenings, short-acting bronchodilator rescue medication use or any other symptoms that would require an increase in OCS dose. Baseline median OCS dose was similar across all treatment groups.

Patients were required to have blood eosinophil counts greater than or equal to 150 cells/μL and a history of at least one exacerbation in the past 12 months. Table 3. Demographics and Baseline Characteristics of Asthma 3 3 3 Exacerbations The primary endpoint for SIROCCO and CALIMA was the rate of asthma exacerbations in patients with baseline blood eosinophil counts of greater than or equal to 300 cells/μL who were taking high‑dose ICS and LABA.

Asthma exacerbation was defined as a worsening of asthma requiring use of oral/systemic corticosteroids for at least 3 days, and/or emergency department visits requiring use of oral/systemic corticosteroids and/or hospitalization. For patients on maintenance oral corticosteroids, an asthma exacerbation requiring oral corticosteroids was defined as a temporary increase in stable oral/systemic corticosteroids for at least 3 days or a single depo-injectable dose of corticosteroids. In SIROCCO, 35% of patients receiving FASENRA experienced an asthma exacerbation compared to 51% on placebo.

In CALIMA, 40% of patients receiving FASENRA experienced an asthma exacerbation compared to 51% on placebo (Table 4). Table 4. The time to first exacerbation was longer for the patients receiving FASENRA compared with placebo in SIROCCO ( Figure 2 ).

Similar findings were seen in CALIMA. Figure 2. Kaplan-Meier Cumulative Incidence Curves for Time to First Exacerbation, SIROCCO Subgroup analyses from SIROCCO and CALIMA identified patients with a higher prior exacerbation history and baseline blood eosinophil count as potential predictors of improved treatment response.

Reductions in exacerbation rates were observed irrespective of baseline peripheral eosinophil counts; however, patients with a baseline blood eosinophil count ≥300 cells/μL showed a numerically greater response than those with counts <300 cells/μL. In both trials, patients with a history of 3 or more exacerbations within the 12 months prior to FASENRA randomization showed a numerically greater exacerbation response than those with fewer prior exacerbations. Oral Corticosteroid Reduction ZONDA evaluated the effect of FASENRA on reducing the use of maintenance oral corticosteroids in adult patients with asthma.

The primary endpoint was percent reduction from baseline of the final OCS dose during Weeks 24 to 28, while maintaining asthma control (see definition of asthma control in trial description). Compared to placebo, patients receiving FASENRA achieved greater reductions in daily maintenance oral corticosteroid dose, while maintaining asthma control. Only patients with an optimized baseline OCS dose of 12.5 mg or less were eligible to achieve a 100% reduction in OCS dose during the study.

Exacerbations resulting in hospitalization and/or ER visit were also assessed as a secondary endpoint. Lung Function Change from baseline in mean FEV 1 was assessed in SIROCCO, CALIMA, and ZONDA as a secondary endpoint. Compared with placebo, FASENRA provided consistent improvements over time in the mean change from baseline in FEV 1 ( Figure 3 and Table 5 ).

Figure 3. Mean Change from Baseline in Pre-Bronchodilator FEV 1 (L), CALIMA Table 5. Change from Baseline in Mean Pre-Bronchodilator FEV 1 (L) at End of Subgroup analyses also showed greater improvements in FEV 1 in patients with higher baseline blood eosinophil counts and more frequent prior exacerbation history.

The clinical program for FASENRA also included a 12-week, randomized, double-blind, placebo-controlled lung function trial conducted in 211 adult patients with mild to moderate asthma. Patients were treated with placebo or benralizumab 30 mg subcutaneously every 4 weeks for 3 doses. Lung function, as measured by the change from baseline in FEV 1 at Week 12 was improved in the benralizumab treatment group compared to placebo.

Patient Reported Outcomes The ACQ-6 and Standardized Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) were assessed in SIROCCO, CALIMA, and ZONDA. In SIROCCO, the ACQ-6 responder rate for FASENRA was 60% vs 50% placebo odds ratio In CALIMA, the ACQ-6 responder rate for FASENRA was 63% vs 59% placebo odds ratio Similar results were seen in ZONDA. Figure 2 figure_3_change_from_baseline_fev1

Clinical Studies in Patients with Eosinophilic Granulomatosis with Polyangiitis The efficacy of FASENRA for EGPA was evaluated in a randomized, double-blind, active-controlled, noninferiority clinical trial (MANDARA ) of 52‑weeks duration. The trial enrolled a total of 140 adults aged 18 years and older with EGPA. Patients were required to have asthma, eosinophilia (1,000 cells/uL or >10% of leukocytes) and a history of relapsing or refractory disease treated with background prednisolone/prednisone with or without immunosuppressive therapy.

Starting at Week 4, the OCS dose was tapered at the discretion of the investigator. The MANDARA trial was a noninferiority trial and was not designed to assess whether FASENRA was superior to mepolizumab. The pre-specified noninferiority margin was a treatment difference of ‑25%.

The secondary endpoints accrued duration of remission, relapse, OCS reduction and the ACQ‑6 were not included in the pre-specified multiple testing procedure for statistical significance. The demographics and baseline characteristics of patients in MANDARA are provided in Table 6. Table 6.

Demographics and Baseline Characteristics of Patients with EGPA in the MANDARA Remission The primary endpoint in MANDARA was the proportion of patients in remission, defined as Birmingham Vasculitis Activity Score (BVAS)=0 (no active vasculitis) plus prednisolone/prednisone dose ≤4 mg/day, at both Week 36 and Week 48. The BVAS is a clinician-completed tool, that is divided into 9 organ-based systems to assess clinically active vasculitis that would likely require treatment, after exclusion of other causes. As shown in Table 7, FASENRA demonstrated noninferiority to mepolizumab for the primary endpoint of remission and the components of remission.

Table 7. Remission and Components of Remission in Patients with EGPA in MANDARA Using an alternative remission definition of BVAS=0 plus prednisolone/prednisone ≤7.5 mg/day, consistent efficacy between groups for these endpoints was observed. Accrued Duration of Remission Total accrued duration of remission was similar in FASENRA compared to mepolizumab odds ratio Results for accrued duration of remission are shown in Table 8.

Table 8. Accrued Duration of Remission in Patients with EGPA in the MANDARA Relapse The hazard ratio for time to first relapse (defined as worsening related to vasculitis, asthma, or sino-nasal symptoms requiring an increase in dose of corticosteroids or immunosuppressive therapy or hospitalization) was Relapse was observed in 30% of patients on FASENRA and 30% of patients on mepolizumab. The annualized relapse rate was 0.50 for patients receiving FASENRA versus 0.49 for patients receiving mepolizumab rate ratio The types of relapse were consistent for patients receiving FASENRA or mepolizumab.

These results were not statistically significant as there was no pre‑specified multiple testing procedure. Asthma Control Questionnaire-6 (ACQ-6) ACQ-6 is a 6-item questionnaire that is completed by the patient to measure the adequacy of asthma control and change in asthma control. The ACQ-6 responder rate during Weeks 48 to 52 (defined as a decrease in score of 0.5 or more compared with baseline) was 42% for FASENRA and 48% for mepolizumab difference Clinical Studies in Patients with Hypereosinophilic Syndrome The efficacy of FASENRA was evaluated in a randomized, double-blind, parallel-group, placebo-controlled clinical trial with a treatment duration of 24 weeks, in patients aged 12 years and older (NATRON ).

A total of 133 adult and pediatric patients who had signs or symptoms of HES flare or had experienced at least 2 HES flares within the past 12 months received randomized treatment. At screening, patients had a blood eosinophil count ≥1,000 cells/µL and had been on stable HES therapy (which could include OCS, immunosuppressive/cytotoxic therapy) for at least 4 weeks. Patients with non-hematologic secondary HES (e.g., drug hypersensitivity, parasitic helminth infection, HIV infection, non-hematologic malignancy) or patients who were FIP1L1-PDGFRA kinase-positive were excluded from the study.

Patients were randomized to receive FASENRA 30 mg or placebo administered subcutaneously every 4 weeks while continuing their stable HES therapy. The demographics and baseline characteristics of patients in this trial are provided in Table 9. Table 9.

Demographics and Baseline Characteristics of Patients with HES in the NATRON The efficacy of FASENRA in HES was established based upon time to first HES flare and the proportion of patients who experienced a HES flare during the 24-week treatment period. A HES flare was defined as a HES clinical manifestation or laboratory abnormality that resulted in an increase or addition of OCS of 10 mg/day or more for at least 2 days or, an increase or addition of new cytotoxic and/or immunosuppressive HES therapy or hospitalization. Time to First Flare Over the 24-week treatment period, treatment with FASENRA delayed the time to first HES flare ( Figure 4 ) and resulted in a significant 65% reduction in the risk of first flare versus placebo (HR: p=0.0024).

Figure 4. Kaplan-Meier Curve for Time to First HES Flare in the NATRON Trial Flares Treatment with FASENRA resulted in 52% relative reduction in the proportion of patients who experienced a HES flare and significantly reduced the number of HES flares observed during the treatment period ( Table 10 ). In addition, fewer patients experienced HES flares resulting in an increased use of OCS with FASENRA compared to placebo over the 24‑week treatment period.

Table 10. Overview of HES Flares in the NATRON Fatigue Fatigue-related symptoms and impacts were evaluated using the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a, where the score ranged from 0 to 100 with a higher score indicating greater fatigue. Compared to placebo, treatment with FASENRA resulted in a statistically significant reduction in fatigue-related symptoms and impacts at Week 24 (p=0.0017).

The LS mean absolute change from baseline in PROMIS Fatigue Short Form 7a score at Week baseline mean 54.3 in the FASENRA group and baseline mean 55.9 in the placebo group. figure_4_saphnelo