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). FASENRA administered once every 4 weeks for the first 3 doses, and then every 4 or 8 weeks thereafter as add-on to background treatment was evaluated compared to placebo.

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.

The baseline median OCS dose was 10 mg (range: 8 to 40 mg) for all 3 treatment groups (placebo, FASENRA every 4 weeks, and FASENRA every 4 weeks for the first 3 doses, and then once every 8 weeks). While 2 dosing regimens were studied in SIROCCO, CALIMA, and ZONDA, the recommended dosing regimen is 30 mg FASENRA administered every 4 weeks for the first 3 doses, then every 8 weeks thereafter . Table 3. Demographics and Baseline Characteristics of Asthma Trials Total Population SIROCCO (N=1204) CALIMA (N=1306) ZONDA (N=220) Mean age (yr) 49 49 51 Female (%) 66 62 61 White (%) 73 84 93 Duration of asthma, median (yr) 15 16 12 Never smoked (%) 80 78 79 Mean baseline FEV 1 pre-bronchodilator (L) 1.67 1.76 1.85 Mean baseline % predicted FEV 1 57 58 60 Mean post-SABA FEV 1 /FVC (%) 66 65 62 Mean baseline eosinophil count (cells/μL) 472 472 575 Mean number of exacerbations in previous year 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. Rate of Exacerbations, SIROCCO and CALIMA (ITT Population) Baseline blood eosinophil counts of greater than or equal to 300 cells/μL and taking high-dose ICS. Trial Treatment Exacerbations per year Rate Difference Rate Ratio (95% CI) All exacerbations SIROCCO FASENRA FASENRA 30 mg administered every 4 weeks for the first 3 doses, and every 8 weeks thereafter. (n=267) 0.74 -0.78 0.49 Placebo (n=267) 1.52 -- -- CALIMA FASENRA (n=239) 0.73 -0.29 0.72 Placebo (n=248) 1.01 -- -- Exacerbations requiring hospitalization/emergency room visit SIROCCO FASENRA (n=267) 0.09 -0.16 0.37 Placebo (n=267) 0.25 -- -- CALIMA FASENRA (n=239) 0.12 0.02 1.23 Placebo (n=248) 0.10 -- -- Exacerbations requiring hospitalization SIROCCO FASENRA (n=267) 0.07 -0.07 0.48 Placebo (n=267) 0.14 -- -- CALIMA FASENRA (n=239) 0.07 0.02 1.48 Placebo (n=248) 0.05 -- -- ITT=Intention to treat 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. The median percent reduction in daily OCS dose from baseline was 75% in patients receiving FASENRA (95% CI: 60, 88) compared to 25% in patients receiving placebo (95% CI: 0, 33). Reductions of 50% or higher in the OCS dose were observed in 48 (66%) patients receiving FASENRA compared to those receiving placebo 28 (37%). The proportion of patients with a mean final dose less than or equal to 5 mg at Weeks 24 to 28 was 59% for FASENRA and 33% for placebo (odds ratio 2.74, 95% CI: 1.41, 5.31). 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. Of those patients, 52% (22 of 42) receiving FASENRA and 19% (8 of 42) on placebo achieved a 100% reduction in OCS dose.

Exacerbations resulting in hospitalization and/or ER visit were also assessed as a secondary endpoint. In this 28-week trial, patients receiving FASENRA had 1 event while those on placebo had 14 events (annualized rate 0.02 and 0.32, respectively; rate ratio of 0.07, 95% CI: 0.01, 0.63). 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 Trial Week 48 in SIROCCO, Week 56 in CALIMA, Week 28 in ZONDA. Trial Difference from Placebo in Mean Change from Pre-Bronchodilator Baseline FEV 1 (L) (95% CI) SIROCCO 0.159 CALIMA 0.116 ZONDA 0.112 (-0.033, 0.258) 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. The responder rate for both measures was defined as improvement in score of 0.5 or more as threshold at the end of SIROCCO, CALIMA, and ZONDA (48, 56, and 28 weeks, respectively). In SIROCCO, the ACQ-6 responder rate for FASENRA was 60% vs 50% placebo (odds ratio 1.55; 95% CI: 1.09, 2.19). In CALIMA, the ACQ-6 responder rate for FASENRA was 63% vs 59% placebo (odds ratio 1.16; 95% CI: 0.80, 1.68). In SIROCCO, the responder rate for AQLQ(S)+12 for FASENRA was 57% vs 49% placebo (odds ratio 1.42; 95% CI: 0.99, 2.02), and in CALIMA, 60% FASENRA vs 59% placebo (odds ratio of 1.03; 95% CI: 0.70,1.51). 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. Patients were randomized to receive FASENRA 30 mg administered subcutaneously every 4 weeks or mepolizumab 300 mg administered subcutaneously every 4 weeks in addition to continued background 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 Trial MANDARA (N=140) Mean age (years) 52 Female (%) 60 White (%) 79 Asian (%) 12 Other (%) 4 Hispanic or Latino (%) 3 Time since diagnosis of EGPA, years, mean (SD)

History of ≥1 confirmed relapse in past 2 years (%) 79 Refractory

disease (%) 60 Baseline oral corticosteroid Prednisone or prednisolone equivalent. daily dose, mg, median (range) 10 (5 - 40) Baseline BVAS, median (range) 0 (0 – 18) BVAS=0 (%) 52 Receiving immunosuppressive therapy Azathioprine, methotrexate, mycophenolic acid. (%) 36 ANCA positive Anti-neutrophil cytoplasmic antibody (ANCA) positive historically or at screening. (%) 29 Biopsy Evidence of Eosinophilic Vasculitis/Inflammation (%) 38 SD=Standard deviation; BVAS=Birmingham vasculitis activity score. 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 Trial Remission (OCS≤4 mg/day + BVAS=0) OCS≤4 mg/day BVAS=0 FASENRA FASENRA 30 mg administered subcutaneously every 4 weeks. N=70 Mepo Mepolizumab (Mepo) 300 mg administered subcutaneously every 4 weeks. N=70 FASENRA N=70 Mepo N=70 FASENRA N=70 Mepo N=70 Patients in remission at both Weeks 36 and 48 Patients, n (%) Model adjusted percentages. 41 40 43 41 58 59 Differences in remission rate (%) (95% CI) 2.7 -- 4.1 -- -1.2 -- (-13, 18) Noninferiority margin -25% with 2.5% 1 sided significance level.

Since the lower bound of the 95% CI for the treatment difference was >-25%, effectiveness of FASENRA was demonstrated to be noninferior to the effectiveness of mepolizumab. -- (-11, 19) -- (-13, 11) -- N=Number of patients in analysis. 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 1.4, 95% CI: 0.75, 2.5). Results for accrued duration of remission are shown in Table 8. The proportion of patients achieving remission within the first 24 weeks of treatment and remaining in remission through Week 52 was 42% for FASENRA and 37% for mepolizumab (difference in responder rate 5.5%, 95% CI: -9.3, 20). This result was not statistically significant as there was no pre-specified multiple testing procedure.

Table 8. Accrued Duration of Remission in Patients with EGPA in the MANDARA Trial Remission (OCS≤4 mg/day + BVAS=0) OCS≤4 mg/day BVAS=0 FASENRA FASENRA 30 mg administered subcutaneously every 4 weeks. N=70 Mepo Mepolizumab (Mepo) 300 mg administered subcutaneously every 4 weeks. N=70 FASENRA N=70 Mepo N=70 FASENRA N=70 Mepo N=70 Accrued duration over 52 weeks Not included in the pre-specified multiple testing procedure for statistical significance., n (%) 0 weeks Did not achieve remission at any point. >0 to <12 weeks 12 to <24 weeks 24 to <36 weeks ≥36 weeks 9 12 8 21 20 15 10 8 19 18 9 10 9 19 23 12 12 8 18 20 0 0 2 6 62 0 2 2 7 59 Odds ratio An odds ratio >1 favors FASENRA. This result was not statistically significant as there was no pre-specified multiple testing procedure. (95% CI) 1.4 -- -- 1.4 -- -- 1.5 -- -- N=Number of patients in analysis.

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 0.98 (95% CI: 0.53, 1.8). 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 1.0, 95% CI: 0.56, 1.9). The types of relapse were consistent for patients receiving FASENRA or mepolizumab. Oral Corticosteroid Reduction During Weeks 48 to 52, a 100% reduction in the OCS dose was observed in 41% of patients receiving FASENRA compared to 26% of those receiving mepolizumab (difference 16%, 95% CI: 0.67, 31). During Weeks 48 to 52, reductions of 50% or higher were observed in 86% of patients receiving FASENRA compared to 74% of those receiving mepolizumab (difference 12%, 95% CI: -0.57, 25). 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 -6.2%, 95% CI: -19, 6.2).

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 Trial NATRON (N=133) Mean age (years) 48 Female (%) 62 Race White (%) 76 Asian (%) 18 Black or African American (%) 3 Other (%) 3 Ethnicity Hispanic or Latino (%) 2 Time since diagnosis of HES, years, mean (SD)

Absolute blood eosinophil count (cells/µL) at screening, median

Based on central laboratory results. 1,100 SD=Standard deviation 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: 0.35; 95% CI: 0.18, 0.69; 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 Trial FASENRA FASENRA 30 mg administered every 4 weeks. (N=67) Placebo (N=66) Proportion of patients who experienced a HES flare Patients with ≥1 HES flare or who withdrew from study Any patients who withdrew from the study without having flared (placebo, n=2; FASENRA, n=2) are included in the analysis as if they had flared., n (%) 15 30 Odds ratio An odds or rate ratio <1 favors FASENRA. (95% CI) 0.31 -- CMH p-value Analysis stratified by region. 0.003 -- Frequency of HES flares Patients with 0 flares, n (%) 54 38 Patients with 1 flare, n (%) 13 20 Patients with 2 flares, n (%) 0 8 Patients with ≥3 flares, n (%) 0 0 Comparison (FASENRA versus placebo) Analyzed with a negative binomial model. Rate/year 0.41 1.23 Rate ratio (95% CI) 0.34 -- p-value 0.0008 -- CMH=Cochran-Mantel-Haenszel, N=Number of patients in analysis. 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 24 was -8.6 (95% CI: -10.6, -6.6; baseline mean 54.3) in the FASENRA group and -3.9 (95% CI: ‑6.0, ‑1.8; baseline mean 55.9) in the placebo group. figure_4_saphnelo