NUCALA- mepolizumab_injection, powder, for solution

Mepolizumab is an IL-5 antagonist (IgG1 kappa). IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Mepolizumab binds to IL-5 with a dissociation constant of 100 pM, inhibiting the bioactivity of IL-5 by blocking its binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface. Inflammation is an important component in the pathogenesis of asthma, CRSwNP, COPD, EGPA, and HES. Multiple cell types (e. , mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e. , histamine, eicosanoids, leukotrienes, cytokines) are involved in inflammation. Mepolizumab, by inhibiting IL-5 signaling, reduces the production and survival of eosinophils; however, the mechanism of mepolizumab action in asthma, CRSwNP, COPD, EGPA, and HES has not been definitively established. The pharmacodynamic response (blood eosinophil reduction) following repeat doses of mepolizumab administered subcutaneously or intravenously was evaluated in adult subjects with asthma and blood eosinophil levels >200 cells/mcL. Subjects received 1 of 4 mepolizumab treatments (administered every 28 days for a total of 3 doses): 12. 5 mg subcutaneous, 125 mg subcutaneous, 250 mg subcutaneous, or 75 mg intravenous. Sixty-six of the 70 randomized subjects completed the trial. Compared with baseline levels, blood eosinophils decreased in a dose‑dependent manner. A reduction in blood eosinophil levels was observed in all treatment groups by Day 3 (48 hours post-dose). On Day 84 (4 weeks post-last dose), the observed geometric mean reduction from baseline in blood eosinophils was 64%, 78%, 84%, and 90% in the 12. 5-mg subcutaneous, 75-mg intravenous, 125-mg subcutaneous, and 250-mg subcutaneous treatment groups, respectively. The model-predicted subcutaneous doses providing 50% and 90% of maximal reduction of blood eosinophils at Day 84 were estimated to be 11 and 99 mg, respectively. These results, along with the clinical efficacy data from the dose-ranging exacerbation DREAM Trial in adult and adolescent subjects with severe asthma supported the evaluation of mepolizumab 75 mg intravenous and 100 mg subcutaneous in the confirmatory severe asthma trials [see Clinical Studies ( 14. 1 The pharmacodynamic response (blood eosinophil reduction) was also evaluated in children aged 6 to 11 years with severe asthma. Following subcutaneous administration of mepolizumab 40 mg every 4 weeks for 52 weeks, blood eosinophils were reduced to a geometric mean count of 48 cells/mcL. This corresponds to a geometric mean reduction from baseline of 85%. The magnitude of reduction in adults, adolescents, and children with severe asthma was observed within 4 weeks of treatment and was maintained throughout the treatment periods. Following subcutaneous administration of NUCALA 100 mg every 4 weeks (for CRSwNP or COPD), or 300 mg every 4 weeks (for EGPA or HES), blood eosinophils were reduced to a similar magnitude to that observed in patients with severe asthma compared to placebo. For adults with CRSwNP, following subcutaneous administration of mepolizumab 100 mg every 4 weeks for 52 weeks, blood eosinophils were reduced to a geometric mean count of 60 cells/mcL. There was a geometric mean reduction of 83% compared with placebo. This magnitude of reduction was observed within 4 weeks of treatment and was maintained throughout the treatment period [see Clinical Studies ( 14. 2 For adults with COPD, following subcutaneous administration of mepolizumab 100 mg every 4 weeks for 52 to 104 weeks, blood eosinophils were reduced to a geometric mean count of 50‑60 cells/mcL. There was a geometric mean reduction of approximately 79% compared with placebo, and this magnitude of reduction was observed within 4 weeks of treatment and was maintained throughout the treatment period [see Clinical Studies ( 14. 3 For adults with EGPA, following subcutaneous administration of mepolizumab 300 mg every 4 weeks for 52 weeks, blood eosinophils were reduced to a geometric mean count of 38 cells/mcL. There was a geometric mean reduction of 83% compared with placebo, and this magnitude of reduction was observed within 4 weeks of treatment [see Clinical Studies ( 14. 4 For adults and pediatric patients aged 12 years and older with HES, following subcutaneous administration of mepolizumab 300 mg every 4 weeks for 32 weeks, blood eosinophils were reduced to a geometric mean count of 70 cells/mcL. There was a geometric mean reduction of 92% compared with placebo [see Clinical Studies ( 14. 5 Following subcutaneous dosing in adult subjects with asthma, mepolizumab exhibited approximately dose‑proportional pharmacokinetics over a dose range of 12. 5 to 250 mg. The pharmacokinetic properties of mepolizumab observed in subjects with CRSwNP (adults), COPD (adults), EGPA (adults), or HES (adults and adolescents) were similar to the pharmacokinetic properties observed in subjects with severe asthma (adults and adolescents). Subcutaneous administration of mepolizumab 300 mg had approximately 3 times the systemic exposure of mepolizumab 100 mg. Absorption Following 100-mg subcutaneous administration in the upper arm of adult and adolescent subjects with asthma, the bioavailability of mepolizumab was estimated to be approximately 80%. Following repeat subcutaneous administration once every 4 weeks, there was approximately a 2-fold accumulation at steady state. Distribution The population central volume of distribution of mepolizumab in adult subjects with asthma is estimated to be 3. 6 L for a 70-kg individual. Elimination Following subcutaneous administration of mepolizumab in adult subjects with asthma, the mean terminal half-life (t 1/2 Metabolism: Specific Populations Racial Groups and Male and Female Patients: Age: Pediatric Patients: Patients with Renal Impairment: Patients with Hepatic Impairment: Drug Interaction Studies No formal drug interaction studies have been conducted with mepolizumab. In population pharmacokinetics analyses of Phase 3 studies, there was no evidence of an effect of commonly coadministered small molecule drugs on mepolizumab exposure. The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of NUCALA or of other mepolizumab products. In adult and adolescent patients with severe asthma receiving NUCALA 100 mg, 15/260 (6%) had detectable anti-mepolizumab antibodies. Neutralizing antibodies were detected in 1 patient with asthma receiving NUCALA 100 mg. Anti-mepolizumab antibodies slightly increased (approximately 20%) the clearance of mepolizumab. There was no evidence of a correlation between anti-mepolizumab antibody titers and change in eosinophil level. The clinical relevance of the presence of anti-mepolizumab antibodies is not known. In the clinical trial of children aged 6 to 11 years with severe asthma receiving NUCALA 40 or 100 mg, 2/35 (6%) had detectable anti-mepolizumab antibodies during the initial short phase of the trial. No children had detectable anti-mepolizumab antibodies during the long phase of the trial. In patients receiving NUCALA 100 mg over 52 weeks for CRSwNP or over 52 to 104 weeks for COPD, 6/196 (3%) and 35/999 (4%) had detectable anti-mepolizumab antibodies, respectively. In patients receiving NUCALA 300 mg over 52 weeks for EGPA or over 32 weeks for HES, 1/68 (<2%) and 1/53 (2%) had detectable anti-mepolizumab antibodies, respectively. No neutralizing antibodies were detected in any of these patients. Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of NUCALA is unknown. The reported frequency of anti-mepolizumab antibodies may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentration. The data reflect the percentage of patients whose test results were positive for antibodies to mepolizumab in specific assays.

NUCALA is an interleukin-5 (IL-5) antagonist monoclonal antibody (IgG1 kappa) indicated for: 1. 5 Limitations of use: 1. 3 NUCALA is indicated for the add-on maintenance treatment of adult and pediatric patients aged 6 years and older with severe asthma and with an eosinophilic phenotype [see Use in Specific Populations ( 8. 1 Limitations of Use NUCALA is not indicated for the relief of acute bronchospasm or status asthmaticus [see Warnings and Precautions ( 5. 2 NUCALA is indicated for the add-on maintenance treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in adult patients aged 18 years and older with inadequate response to nasal corticosteroids. NUCALA is indicated for the add-on maintenance treatment of adult patients with inadequately controlled chronic obstructive pulmonary disease (COPD) and an eosinophilic phenotype. Limitations of Use NUCALA is not indicated for the relief of acute bronchospasm [see Warnings and Precautions ( 5. NUCALA is indicated for the treatment of adult patients with eosinophilic granulomatosis with polyangiitis (EGPA). NUCALA is indicated for the treatment of adult and pediatric patients aged 12 years and older with hypereosinophilic syndrome (HES) for greater than or equal to 6 months without an identifiable non-hematologic secondary cause.

1 NUCALA is for subcutaneous use only, and should be injected into the upper arm, thigh, or abdomen [see Dosage and Administration ( 2. Recommended Dosage of NUCALA a Indication Adults Pediatric Patients Severe asthma 100 mg every 4 weeks 12 to 17 years of age: 6 to 11 years of age: Chronic rhinosinusitis with nasal polyps 100 mg every 4 weeks Not applicable Chronic obstructive pulmonary disease 100 mg every 4 weeks Not applicable Eosinophilic granulomatosis with polyangiitis 300 mg a Not applicable Hypereosinophilic syndrome 300 mg a 12 to 17 years of age: a NUCALA for injection should be reconstituted and administered by a healthcare professional. In line with clinical practice, monitoring of patients after administration of biologic agents is recommended [see Warnings and Precautions ( 5. 1 Reconstitution Instructions 1. Note: Do not shake the reconstituted solution during the procedure as this may lead to product foaming or precipitation. Reconstitution is typically complete within 5 minutes after the Sterile Water for Injection has been added, but it may take additional time. Administration of 100 mg Dose 1. Administration of 40 mg Dose 1. Each vial of NUCALA for injection should be used for a single patient, and any remainder of the contents should be discarded. NUCALA injection is intended for use under the guidance of a healthcare provider. The 100 mg/mL prefilled autoinjector and 100 mg/mL prefilled syringe are only for use in adults and adolescents aged 12 years and older. A patient may self-inject, or the patient caregiver may administer NUCALA injection 100 mg/mL subcutaneously after the healthcare provider determines it is appropriate. The 40 mg/0. 4 mL prefilled syringe is only for use in children aged 6 to 11 years and must be administered by the healthcare provider or the patient caregiver. The patient caregiver may administer NUCALA injection 40 mg/0. 4 mL subcutaneously after the healthcare provider determines it is appropriate. Provide proper training in subcutaneous injection technique and on the preparation and administration of NUCALA injection prior to use [see Instructions for Use] 1.

The following adverse reactions are described in greater detail in other sections: [see Warnings and Precautions ( 5. 1 [see Warnings and Precautions ( 5. 3 Most common adverse reactions (incidence >=5%): 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Adult and Adolescent Patients Aged 12 Years and Older with Severe Asthma A total of 1,327 patients with severe asthma were evaluated in 3 randomized, placebo-controlled, multicenter trials of 24 to 52 weeks’ duration (Severe Asthma Trials DREAM, MENSA, and SIRIUS). Of these, 1,192 had a history of 2 or more exacerbations in the year prior to enrollment despite regular use of high-dose ICS plus additional controller(s) (Severe Asthma Trials DREAM and MENSA), and 135 patients required daily oral corticosteroids (OCS) in addition to regular use of high-dose ICS plus additional controller(s) to maintain asthma control (Severe Asthma Trial SIRIUS). All patients had markers of eosinophilic airway inflammation [see Clinical Studies ( 14. 1 The incidence of adverse reactions in the first 24 weeks of treatment in the 2 confirmatory efficacy and safety trials MENSA and SIRIUS with NUCALA 100 mg is shown in Table 2 Table 2. Adverse Reactions with NUCALA with >=3% Incidence and More Common than Placebo in Patients with Severe Asthma (MENSA and SIRIUS) Adverse Reaction NUCALA (Mepolizumab 100 mg Subcutaneous) (n = 263) % Placebo (n = 257) % Headache 19 18 Injection site reaction 8 3 Back pain 5 4 Fatigue 5 4 Influenza 3 2 Urinary tract infection 3 2 Abdominal pain upper 3 2 Pruritus 3 2 Eczema 3 <1 Muscle spasms 3 <1 52-Week Trial: Table 2 Systemic Reactions, including Hypersensitivity Reactions: Injection Site Reactions: Long-Term Safety: Adverse Reactions in Pediatric Patients Aged 6 to 11 Years with Severe Asthma The safety data for NUCALA is based upon 1 open-label clinical trial that enrolled 36 patients with severe asthma aged 6 to 11 years. Patients received 40 mg (for those weighing <40 kg) or 100 mg (for those weighing >=40 kg) of NUCALA administered subcutaneously once every 4 weeks. Patients received NUCALA for 12 weeks (initial short phase). After a treatment interruption of 8 weeks, 30 patients received NUCALA for a further 52 weeks (long phase). The adverse reaction profile for patients aged 6 to 11 years was similar to that observed in patients aged 12 years and older. Adverse Reactions in Adult Patients with Chronic Rhinosinusitis with Nasal Polyps A total of 407 patients with CRSwNP were evaluated in 1 randomized, placebo-controlled, multicenter, 52-week treatment trial. Patients received NUCALA 100 mg or placebo subcutaneously once every 4 weeks. Patients had recurrent CRSwNP with a history of prior surgery and were on nasal corticosteroids for at least 8 weeks prior to screening [see Clinical Studies ( 14. 2 Table 3 Table 3. Adverse Reactions with NUCALA with >=3% Incidence and More Common than Placebo in Patients with Chronic Rhinosinusitis with Nasal Polyps Adverse Reaction NUCALA (Mepolizumab 100 mg Subcutaneous) (n = 206) % Placebo (n = 201) % Oropharyngeal pain 8 5 Arthralgia 6 2 Abdominal pain upper 3 2 Diarrhea 3 2 Pyrexia 3 2 Nasal dryness 3 <1 Rash 3 <1 Systemic Reactions, including Hypersensitivity Reactions: Injection Site Reactions: Adverse Reactions in Adults with Chronic Obstructive Pulmonary Disease The safety data below reflects the safety of NUCALA in adults with inadequately controlled COPD and an eosinophilic phenotype. NUCALA was evaluated in a pooled safety population that consisted of 2089 patients with COPD in 3 randomized, placebo-controlled, multicenter trials of 52 to 104 weeks duration, including MATINEE and METREX [see Clinical Studies ( 14. 3 Table 4 Table 4. Adverse Reactions with NUCALA with >=3% Incidence and More Common than Placebo in Patients with Chronic Obstructive Pulmonary Disease in a Pooled Safety Population (MATINEE, METREX, and Trial 3) Adverse Reaction NUCALA (Mepolizumab 100 mg Subcutaneous) (n = 1043) % Placebo (n = 1046) % Back pain 7 6 Diarrhea 5 4 Cough 5 4 Oropharyngeal pain 4 2 Urinary tract infection 4 3 Pain in extremity 4 3 Herpes Zoster: Adverse Reactions in Patients with Eosinophilic Granulomatosis with Polyangiitis A total of 136 patients with EGPA were evaluated in 1 randomized, placebo-controlled, multicenter, 52-week treatment trial. Patients received 300 mg of NUCALA or placebo subcutaneously once every 4 weeks. Patients enrolled had a diagnosis of EGPA for at least 6 months prior to enrollment with a history of relapsing or refractory disease and were on a stable dosage of oral prednisolone or prednisone of greater than or equal to 7. 5 mg/day (but not greater than 50 mg/day) for at least 4 weeks prior to enrollment [see Clinical Studies ( 14. 4 Systemic Reactions, including Hypersensitivity Reactions: Injection Site Reactions: Adverse Reactions in Adult and Adolescent Patients with Hypereosinophilic Syndrome A total of 108 adult and adolescent patients aged 12 years and older with HES were evaluated in a randomized, placebo‑controlled, multicenter, 32-week treatment trial. Patients with non-hematologic secondary HES or FIP1L1‑PDGFRalpha kinase-positive HES were excluded from the trial. Patients must have been on a stable dose of background HES therapy for the 4 weeks prior to randomization [see Clinical Studies ( 14. 5 Systemic Reactions, including Hypersensitivity Reactions: Injection Site Reactions: In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during post-approval use of NUCALA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to NUCALA or a combination of these factors. Immune System Disorders Hypersensitivity reactions, including anaphylaxis.

NUCALA is contraindicated in patients with a history of hypersensitivity to mepolizumab or excipients in the formulation [see Warnings and Precautions ( 5. 1 11 History of hypersensitivity to mepolizumab or excipients in the formulation.

Risk Summary The data on pregnancy exposure are insufficient to inform on drug-associated risk. Monoclonal antibodies, such as mepolizumab, are transported across the placenta in a linear fashion as pregnancy progresses; therefore, potential effects on a fetus are likely to be greater during the second and third trimester of pregnancy. In a prenatal and postnatal development study conducted in cynomolgus monkeys, there was no evidence of fetal harm with intravenous administration of mepolizumab throughout pregnancy at doses that produced exposures up to approximately 9 times the exposure at the maximum recommended human dose (MRHD) of 300 mg subcutaneous (see Data) In the U. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk: Data Animal Data: In a fertility, early embryonic, and embryofetal development study, pregnant CD-1 mice received an analogous antibody, which inhibits the activity of murine interleukin-5 (IL-5), at an intravenous dose of 50 mg/kg once per week throughout gestation. The analogous antibody was not teratogenic in mice. Embryofetal development of IL-5en dashdeficient mice has been reported to be generally unaffected relative to wild-type mice. Risk Summary There is no information regarding the presence of mepolizumab in human milk, the effects on the breastfed infant, or the effects on milk production. However, mepolizumab is a humanized monoclonal antibody (IgG1 kappa), and immunoglobulin G (IgG) is present in human milk in small amounts. Mepolizumab was present in the milk of cynomolgus monkeys postpartum following dosing during pregnancy [see Use in Specific Populations ( 8. 1 Severe Asthma The safety and effectiveness of NUCALA for severe asthma, and with an eosinophilic phenotype, have been established in pediatric patients aged 6 years and older. Use of NUCALA in adolescents aged 12 to 17 years is supported by evidence from adequate and well-controlled trials in adults and adolescents. A total of 28 adolescents aged 12 to 17 years with severe asthma were enrolled in the Phase 3 asthma trials. Of these, 25 were enrolled in the 32-week exacerbation trial (MENSA) and had a mean age of 14. Patients had a history of 2 or more exacerbations in the previous year despite regular use of medium- or high-dose ICS plus additional controller(s) with or without OCS and had blood eosinophils of >=150 cells/mcL at screening or >=300 cells/mcL within 12 months prior to enrollment. [See Clinical Studies ( 14. 1 [see Adverse Reactions ( 6. 1 Use of NUCALA in pediatric patients aged 6 to 11 years with severe asthma, and with an eosinophilic phenotype, is supported by evidence from adequate and well-controlled trials in adults and adolescents with additional pharmacokinetic, pharmacodynamic, and safety data in children aged 6 to 11 years. A single open-label clinical trial was conducted in 36 children aged 6 to 11 years (mean age: 8. 6 years, 31% female) with severe asthma. Enrollment criteria were the same as for adolescents in the 32-week exacerbation trial (MENSA). Based upon the pharmacokinetic data from this trial, a subcutaneous dose of 40 mg every 4 weeks was determined to have similar exposure to adults and adolescents administered a subcutaneous dose of 100 mg [ Clinical Pharmacology ( 12. 3 The effectiveness of NUCALA in pediatric patients aged 6 to 11 years is extrapolated from efficacy in adults and adolescents with support from pharmacokinetic analyses showing similar drug exposure levels for 40 mg administered subcutaneously every 4 weeks in children aged 6 to 11 years compared with adults and adolescents [ Clinical Pharmacology ( 12. 3 [see Adverse Reactions ( 6. 2 The safety and effectiveness in pediatric patients aged younger than 6 years with severe asthma have not been established. Chronic Rhinosinusitis with Nasal Polyps The safety and effectiveness in patients aged younger than 18 years with CRSwNP have not been established. Chronic Obstructive Pulmonary Disease The safety and effectiveness in pediatric patients aged younger than 18 years with COPD have not been established. COPD is largely a disease of adult patients. Eosinophilic Granulomatosis with Polyangiitis The safety and effectiveness in patients aged younger than 18 years with EGPA have not been established. Hypereosinophilic Syndrome The safety and effectiveness of NUCALA for HES have been established in adolescent patients aged 12 years and older. The safety and effectiveness in pediatric patients aged younger than 12 years with HES have not been established. Use of NUCALA for this indication is supported by evidence from an adequate and well-controlled study (NCT02836496) in adults and adolescents and an open-label extension study (NCT03306043). One adolescent received NUCALA during the controlled study and this patient and an additional 3 adolescents received NUCALA during the open-label extension study [see Clinical Studies ( 14. 5 Of the total number of patients treated with NUCALA (n = 4106) for severe asthma, HES, EGPA, CRSwNP, and COPD, 1073 (26%) were 65 years of age and older and 241 (6%) were 75 years of age and older [see Clinical Studies ( 14.

Formal drug interaction trials have not been performed with NUCALA.

OVERDOSAGE
There is no specific treatment for an overdose with mepolizumab. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
NONCLINICAL TOXICOLOGY
Long-term animal studies have not been performed to evaluate the carcinogenic potential of mepolizumab. Published literature using animal models suggests that IL-5 and eosinophils are part of an early inflammatory reaction at the site of tumorigenesis and can promote tumor rejection. However, other reports indicate that eosinophil infiltration into tumors can promote tumor growth. Therefore, the malignancy risk in humans from an antibody to IL-5 such as mepolizumab is unknown. Male and female fertility were unaffected based upon no adverse histopathological findings in the reproductive organs from cynomolgus monkeys receiving mepolizumab for 6 months at intravenous dosages up to 100 mg/kg once every 4 weeks (approximately 20 times the MRHD of 300 mg on an AUC basis). Mating and reproductive performance were unaffected in male and female CD-1 mice receiving an analogous antibody, which inhibits the activity of murine IL-5, at an intravenous dosage of 50 mg/kg once per week.
CLINICAL STUDIES
The asthma development program for NUCALA in patients aged 12 years and older included 3 double-blind, randomized, placebo‑controlled trials: 1 dose-ranging and exacerbation trial (DREAM, NCT01000506) and 2 confirmatory trials (MENSA, NCT01691521 and SIRIUS, NCT01691508). Mepolizumab was administered every 4 weeks in all 3 trials as add-on to background treatment. All patients continued their background asthma therapy throughout the duration of the trials. Dose-Ranging and Exacerbation Trial DREAM was a 52-week dose-ranging and exacerbation-reduction trial in patients with severe asthma with a history of 2 or more exacerbations in the previous year despite regular use of high‑dose ICS plus additional controller(s) with or without OCS. Patients enrolled in this trial were required to have at least 1 of the following 4 pre-specified criteria in the previous 12 months: blood eosinophil count >=300 cells/mcL, sputum eosinophil count >=3%, exhaled nitric oxide concentration >=50 ppb, or deterioration of asthma control after <=25% reduction in regular maintenance ICS/OCS. Three intravenous dosages of mepolizumab (75, 250, and 750 mg) administered once every 4 weeks were evaluated compared with placebo. Results from this trial and the pharmacodynamic study supported the evaluation of mepolizumab 75 mg intravenously and 100 mg subcutaneously in the subsequent trials [see Clinical Pharmacology ( 12. 2 Confirmatory Trials A total of 711 patients with severe asthma were studied in the 2 confirmatory trials (MENSA and SIRIUS). In these 2 trials patients were required to have blood eosinophils of >=150 cells/mcL at screening (within 6 weeks of dosing) or blood eosinophils of >=300 cells/mcL within 12 months of enrollment. The screening blood eosinophils of >=150 cells/mcL criterion was derived from exploratory analyses of data from the DREAM Trial. MENSA was a 32-week placebo‑ and active‑controlled trial in patients with severe asthma with a history of 2 or more exacerbations in the previous year despite regular use of high-dose ICS plus additional controller(s) with or without OCS. Patients received mepolizumab 75 mg intravenously (n = 191), NUCALA 100 mg (n = 194), or placebo (n = 191) once every 4 weeks for 32 weeks. SIRIUS was a 24-week OCS-reduction trial in patients with severe asthma who required daily OCS in addition to regular use of high-dose ICS plus additional controller(s) to maintain asthma control. Patients in the SIRIUS Trial were not required to have a history of exacerbations in the previous year. Patients received NUCALA 100 mg (n = 69) or placebo (n = 66) once every 4 weeks for 24 weeks. The baseline mean OCS use was similar in the 2 treatment groups: 13. 2 mg in the placebo group and 12. 4 mg in the group receiving NUCALA 100 mg. The demographics and baseline characteristics of these 3 trials are provided in Table 5 Table 5. Demographics and Baseline Characteristics of Severe Asthma Trials FEV 1 2 DREAM (N = 616) MENSA (N = 576) SIRIUS (N = 135) Mean age, years 49 50 50 Female, n (%) 387 (63) 328 (57) 74 (55) White, n (%) 554 (90) 450 (78) 128 (95) Duration of asthma, years, mean 19 20 19 Never smoked, n (%) 483 (78) 417 (72) 82 (61) Baseline FEV 1 1. 95 Baseline % predicted FEV 1 60 61 59 Baseline % reversibility 25 27 26 Baseline post-SABA FEV 1 0. 66 Geometric mean eosinophil count at baseline, cells/mcL 250 290 240 Mean number of exacerbations in previous year 3. 1 Exacerbations Efficacy was assessed in DREAM and MENSA using an endpoint of the frequency of exacerbations defined as worsening of asthma requiring use of oral/systemic corticosteroids and/or hospitalization and/or emergency department visits. For patients on maintenance OCS, an exacerbation requiring OCS was defined as the use of oral/systemic corticosteroids at least double the existing dose for at least 3 days. Compared with placebo, patients receiving NUCALA 100 mg or mepolizumab 75 mg intravenously experienced significantly fewer exacerbations. Additionally, compared with placebo, there were fewer exacerbations requiring hospitalization and/or emergency department visits and exacerbations requiring only in-patient hospitalization with NUCALA 100 mg ( Table 6 Table 6. Rate of Exacerbations in Severe Asthma Trials DREAM and MENSA (Intent-to-Treat Population) CI = confidence interval, IV = intravenous, SC = subcutaneous. Trial Treatment Exacerbations per Year Rate Difference Rate Ratio (95% CI) All exacerbations DREAM Placebo (n = 155) 2. 40 Mepolizumab 75 mg IV (n = 153) 1. 69) MENSA Placebo (n = 191) 1. 74 Mepolizumab 75 mg IV (n = 191) 0. 72) NUCALA 100 mg SC (n = 194) 0. 64) Exacerbations requiring hospitalization/emergency room visit DREAM Placebo (n = 155) 0. 43 Mepolizumab 75 mg IV (n = 153) 0. 81) MENSA Placebo (n = 191) 0. 20 Mepolizumab 75 mg IV (n = 191) 0. 41) NUCALA 100 mg SC (n = 194) 0. 83) Exacerbations requiring hospitalization DREAM Placebo (n = 155) 0. 18 Mepolizumab 75 mg IV (n = 153) 0. 33) MENSA Placebo (n = 191) 0. 10 Mepolizumab 75 mg IV (n = 191) 0. 66) NUCALA 100 mg SC (n = 194) 0. 91) The time to first exacerbation was longer for the groups receiving NUCALA 100 mg and mepolizumab 75 mg intravenously compared with placebo in MENSA ( Figure 1 Figure 1. Kaplan-Meier Cumulative Incidence Curve for Time to First Exacerbation (MENSA) IV = intravenous, SC = subcutaneous. DREAM data were explored to determine criteria that could identify patients likely to benefit from treatment with NUCALA. The exploratory analysis suggested that baseline blood eosinophil count of >=150 cells/mcL was a potential predictor of treatment benefit. Exploratory analysis of MENSA data also suggested that baseline blood eosinophil count (obtained within 6 weeks of initiation of dosing) of >=150 cells/mcL was a potential predictor of efficacy and showed a trend of greater exacerbation benefit with increasing blood eosinophil count. In MENSA, patients enrolled solely on the basis of the historical blood eosinophil count of >=300 cells/mcL in the previous 12 months, but who had a baseline blood eosinophil count <150 cells/mcL, had virtually no exacerbation benefit following treatment with NUCALA 100 mg compared with placebo. The Asthma Control Questionnaire-5 (ACQ-5) was assessed in Trials DREAM and MENSA, and the St. George’s Respiratory Questionnaire (SGRQ) was assessed in MENSA. In DREAM, the ACQ-5 responder rate (defined as a decrease in score of 0. 5 or more as threshold) for the 75-mg intravenous mepolizumab arm was 47% compared with 50% for placebo with an odds ratio (OR) of 1. 1 (95% confidence interval [CI]: 0. In MENSA, the ACQ-5 responder rate for the treatment arm for NUCALA 100 mg was 57% compared with 45% for placebo with an OR of 1. 8 (95% CI: 1. In MENSA, the SGRQ responder rate (defined as a decrease in score of 4 or more as threshold) for the treatment arm for NUCALA 100 mg was 71% compared with 55% for placebo with an OR of 2. 1 (95% CI: 1. Oral Corticosteroid Reduction Severe Asthma Trial SIRIUS evaluated the effect of NUCALA 100 mg on reducing the use of maintenance OCS. Efficacy was assessed using an endpoint of the percent reduction of OCS dose during Weeks 20 to 24 compared with baseline dose, while maintaining asthma control. Patients were classified according to their change in OCS use during the trial with the following categories: 90% to 100% decrease, 75% to 0% to <50% decrease, and no improvement (i. , no change or any increase or lack of asthma control or withdrawal of treatment). Compared with placebo, patients receiving NUCALA 100 mg achieved greater reductions in daily maintenance OCS dose, while maintaining asthma control. Sixteen (23%) patients in the group receiving NUCALA 100 mg versus 7 (11%) in the placebo group had a 90% to 100% reduction in their OCS dose. Twenty-five (36%) patients in the group receiving NUCALA 100 mg versus 37 (56%) in the placebo group were classified as having no improvement for OCS dose. Additionally, 54% of patients receiving NUCALA 100 mg achieved at least a 50% reduction in the daily prednisone dose compared with 33% of patients receiving placebo (95% CI for difference: 4%, 37%). An exploratory analysis was also performed on the subgroup of 29 patients in SIRIUS who had an average baseline and screening blood eosinophil count <150 cells/mcL. Five (29%) patients in the group receiving NUCALA 100 mg versus 0 (0%) in the placebo group had a 90% to 100% reduction in their dose. Four (24%) patients in the group receiving NUCALA 100 mg versus 8 (67%) in the placebo group were classified as having no improvement for OCS dose. The ACQ and SGRQ were also assessed in SIRIUS and showed results similar to those in MENSA. Lung Function Change from baseline in mean forced expiratory volume in 1 second (FEV 1 Table 7 1 Table 7. Change from Baseline in FEV 1 FEV 1 a b 1 c d 1 Trial Difference from Placebo in Mean Change from Baseline FEV 1 Week 12 Week 24 Weeks 32/52 DREAM a 10 (-87, 108) 5 (-98, 108) 61 (-39, 161) b MENSA c 52 (-30, 134) 76 (-6, 159) 98 (11, 184) d SIRIUS c 56 (-91, 203) 114 (-42, 271) NA The effect of mepolizumab on lung function was also studied in a 12-week placebo-controlled trial enrolling patients with asthma on a moderate dose of ICS with evidence of symptoms and lung function impairment. Enrollment was not dependent on a history of exacerbations or a pre-specified eosinophil count. Change from baseline in FEV 1 Figure 1 A total of 407 adult patients with CRSwNP were evaluated in a randomized, double‑blind, placebo-controlled, multicenter, 52-week trial (NCT03085797). Patients received NUCALA 100 mg or placebo administered subcutaneously once every 4 weeks while continuing nasal corticosteroid therapy. Patients must have received background nasal corticosteroid for >=8 weeks pre‑screening. Patients had recurrent and symptomatic CRSwNP, and had at least 1 surgery for the removal of nasal polyps within the previous 10 years. Patients were required to have nasal obstruction symptoms with a visual analog scale (VAS) score of >5 out of a maximum score of 10. Patients were also required to have an endoscopic bilateral nasal polyp score (NPS) of >=5 out of 8 with NPS >=2 in each nasal cavity. Patients reported nasal obstruction VAS scores daily by placing a single mark on a continuous line labeled from 0 (none) to 100 (as bad as you can imagine). The distance along the line was converted to a 0 to 10 point scale for scoring. For NPS, polyps on each side of the nose were graded on a categorical scale (0 = no polyps, 1 = small polyps in the middle meatus not reaching below the inferior border of the middle concha, 2 = polyps reaching below the lower border of the middle turbinate, 3 = large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle concha, 4 = large polyps causing almost complete congestion/obstruction of the inferior meatus) for a total score of 0 to 8. Sinus CT scans were not performed at baseline nor during treatment to evaluate for sinus opacification. The co-primary endpoints were change from baseline to Week 52 in total endoscopic NPS (0 to 8 scale) as graded by independent blinded assessors and change from baseline in nasal obstruction VAS score (0 to 10 scale) during Weeks 49 to 52. The key secondary endpoint was the time to first nasal surgery (nasal polypectomy) up to Week 52 in this trial. Other secondary endpoints were change from baseline in loss of smell VAS score during Weeks 49 to 52, and proportion of patients requiring systemic steroids for nasal polyps up to Week 52. All VAS scores were collected daily by the patients and reported on a 0 to 10 scale (0 = none, 10 = as bad as you can imagine). The demographics and baseline characteristics of patients in this trial are provided in Table 8 Table 8. Demographics and Baseline Characteristics in Chronic Rhinosinusitis with Nasal Polyps CRSwNP = chronic rhinosinusitis with nasal polyps, SD = standard deviation, OCS = oral corticosteroid, NPS = nasal polyp score, VAS = visual analog scale, CI = confidence interval, AERD = aspirin-exacerbated respiratory disease. a N = 407 Mean age, years 49 Female, n (%) 143 (35) White, n (%) 379 (93) Mean CRSwNP duration in years (SD) 11. 4) Patients with >=1 surgery in past 10 years (%) 407 (100) Patients with >=3 surgeries in past 10 years (%) 124 (30) OCS use (>=1 course) in past 12 months, n (%) 197 (48) Mean bilateral endoscopic NPS a 5. 29) Mean nasal obstruction VAS score, (SD), range 0-10 9. 83) Geometric mean blood eosinophil cells/mcL (95% CI) 390 (360, 420) Asthma, n (%) 289 (71) AERD, n (%) 108 (27) Endoscopic Nasal Polyp Score and Nasal Obstruction Visual Analog Scale Scores Patients who received NUCALA 100 mg had a statistically significant improvement (decrease) in bilateral NPS at Week 52 and nasal obstruction VAS score from Weeks 49 to 52 at the end of the 52 week treatment period ( Table 9 Table 9. Analyses of Endpoints in Chronic Rhinosinusitis with Nasal Polyps SD = standard deviation, SE = standard error, CI = confidence interval, NPS = nasal polyp score at Week 52. a b Scores a (range) Placebo n = 201 NUCALA 100 mg n = 206 Mean Difference vs. Placebo (95% CI) Baseline Mean (SD) Mean Change b (SE) Baseline Mean (SD) Mean Change b (SE) NPS (0-8) 5. 55) Nasal obstruction (0-10) 9. 19) Nasal Polypectomy The key secondary endpoint was the time to first nasal surgery (nasal polypectomy) up to Week 52. The proportion of patients who had surgery was significantly reduced by 57% (hazard ratio [HR]: 0. 43, 95% CI: 0. 76) in the group treated with NUCALA 100 mg compared with the placebo group ( Figure 2 Figure 2. Kaplan-Meier Plot of Time to First Nasal Surgery in Chronic Rhinosinusitis with Nasal Polyps SC = subcutaneous. Additional Chronic Rhinosinusitis with Nasal Polyps Symptoms Scores For patients who received NUCALA 100 mg, statistically significant improvement was observed in loss of smell compared to placebo and improvements were also observed in the individual VAS symptom scores compared with patients in the placebo group in the 4-weeks prior to the end of the 52-week treatment period ( Table 10 Table 10: Additional Visual Analog Scale Symptom Scores Assessed at Weeks 49-52 VAS = visual analog scale, SD = standard deviation, SE = standard error, CI = confidence interval. a b c VAS Scores a (range) Placebo n = 201 NUCALA 100 mg n = 206 Mean Difference vs. Placebo (95% CI) Baseline Mean (SD) Mean Change b (SE) Baseline Mean (SD) Mean Change b (SE) Loss of smell (0-10) 9. 81) Nasal discharge c (0-10) 8. 20) Mucus in the throat c (0-10) 8. 99) Facial pain c (0-10) 7. 95) Corticosteroid Reduction Treatment with NUCALA 100 mg significantly reduced the need for systemic steroids for nasal polyps vs. placebo up to Week 52 (OR: 0. 58, 95% CI: 0. In patients who received NUCALA 100 mg, 52 (25%) required >=1 course of systemic steroids compared with 74 (37%) in the placebo group throughout the 52-week treatment period. Results in Patients with Co-Morbid Asthma In 289 (71%) patients with co-morbid asthma, pre-specified analyses showed improvements in the co-primary endpoints consistent with those seen in the overall population in the patients who received NUCALA 100 mg compared with placebo. Additionally, based on a post-hoc analysis in these patients, there was a greater response from baseline at Week 52 in asthma control as measured by the ACQ‑5 for NUCALA 100 mg compared with placebo (57% of the NUCALA patients met the responder threshold reduction of >=0. 5, compared to 35% in the placebo group, with an OR of 2. 42 [95% CI 1. Figure 2 The efficacy of NUCALA as add-on maintenance treatment for adult patients with inadequately controlled chronic obstructive pulmonary disease (COPD) and an eosinophilic phenotype was evaluated in two randomized, double-blind, placebo-controlled, multicenter trials (MATINEE [NCT04133909] and METREX [NCT02105948]). The two trials enrolled a total of 1640 adults who were randomized to receive NUCALA 100 mg or placebo administered subcutaneously every 4 weeks for a treatment duration of 52 to 104 weeks in MATINEE or 52 weeks in METREX. While 1640 adults were enrolled in the two clinical trials (MATINEE and METREX), the efficacy population consisted of 1266 adults. Both trials enrolled patients with a diagnosis of COPD with moderate to very severe airflow limitation (post-bronchodilator FEV 1 1 In MATINEE, patients were required to have a minimum blood eosinophil count of 300 cell/mcL at screening. In METREX, there was no minimum blood eosinophil count requirement, but randomization was stratified by baseline blood eosinophil count: >=150 cell/mcL at screening or >=300 cell/mcL in the previous 12 months, or blood eosinophil count <150 cells/mcL at screening with no evidence of blood eosinophil count >=300 cell/mcL in the previous 12 months. There was insufficient data from METREX to support the efficacy of NUCALA in patients with COPD with blood eosinophil count <150 cells/mcL at screening with no evidence of blood eosinophil count >=300 cell/mcL in the previous 12 months. Thus, the efficacy population (N = 1266) included patients from MATINEE (n = 804) and patients from METREX who had a blood eosinophil count >=150 cell/mcL at screening or >=300 cell/mcL in the previous 12 months (n = 462). The data from this efficacy population is described below. The demographic and baseline characteristics of MATINEE and METREX efficacy population are provided in Table 11 Table 11: Demographics and Baseline Characteristics of Patients with Chronic Obstructive Pulmonary Disease in MATINEE and METREX a SD = standard deviation, FEV 1 a b c MATINEE METREX a N = 804 N = 462 Mean age (y) (SD) 66 (8. 4) Female, n (%) 253 (31) 163 (35) White, n (%) 673 (84) 391 (85) Asian, n (%) 112 (14) 5 (1) Black or African American, n (%) 10 (1) 6 (1) Other/Multiple, n (%) 9 (1) 60 (13) Hispanic/Latino, n (%) 189 (24) 75 (16) Current smokers, n (%) 222 (28) 134 (29) Average smoking history (pack-years) (SD) 43 (24. 8) Post-bronchodilator % predicted FEV 1 48 (15. 8) Post-bronchodilator FEV 1 0. 12) Mean number of moderate b c 2. 29) Background COPD medications at randomization: ICS/LAMA/LABA, n (%) 794 (99) 454 (98) SGRQ score, mean (SD) 55 (17. 7) Geometric mean eosinophil count at screening, cells/mcL (95% CI) 480 (470, 490) 260 (250, 280) Annualized Rate of Moderate or Severe Exacerbations in Adult Patients with Chronic Obstructive Pulmonary Disease The primary endpoint for the MATINEE and METREX trials was the annualized rate of moderate or severe exacerbations during the 52 to 104-week and 52-week treatment periods, respectively. Moderate exacerbations are defined per protocol as clinically significant exacerbations that require treatment with oral/systemic corticosteroids and/or antibiotics. Severe exacerbations are defined per protocol as clinically significant exacerbations that require in‑patient hospitalization (i. , >=24 hours) or result in death. In both trials, NUCALA demonstrated a statistically significant reduction in the annualized rate of moderate or severe exacerbations compared with placebo when added to triple inhaled therapy (see Table 12 Table 12. Annualized Rate of Moderate a b CI = confidence interval. a b c > MATINEE METREX c NUCALA N = 403 Placebo N = 401 NUCALA N = 233 Placebo N = 229 Exacerbation rate per year 0. 71 Rate ratio vs. placebo (95% CI) 0. 98) The time to first event analysis showed a statistically significant reduction in the risk of moderate or severe exacerbation for patients receiving NUCALA compared to placebo (HR: 0. 77; 95% CI: 0. 93) through 104 weeks in MATINEE. NUCALA reduced the annualized rate of COPD exacerbations requiring emergency department visits and/or hospitalization when compared with placebo (rate ratio [RR] of 0. 65; 95% CI: 0. 96 [not statistically significant due to failure of an endpoint higher in the pre-defined testing hierarchy]) in MATINEE. Health Related Quality of Life In MATINEE and METREX, the St. George’s Respiratory Questionnaire (SGRQ) total score responder rate (defined as the proportion of subjects with SGRQ improvement from baseline of at least 4 points) at Week 52 was evaluated. In MATINEE, the responder rate was 50% in the NUCALA group compared with 46% in the placebo group (N = 783, odds ratio [OR]: 1. 17; 95% CI: 0. In the METREX efficacy population, the responder rate was 42% in the NUCALA group compared to 40% in the placebo group (N = 451, odds ratio [OR]: 1. 08; 95% CI: 0. A total of 136 adult patients with EGPA were evaluated in a randomized, placebo-controlled, multicenter, 52-week trial (NCT02020889). Patients received 300 mg of NUCALA or placebo administered subcutaneously once every 4 weeks while continuing their stable OCS therapy. Starting at Week 4, OCS was tapered during the treatment period at the discretion of the investigator. Efficacy was assessed in this trial using co-endpoints of the total accrued duration of remission over the 52-week treatment period, defined as Birmingham Vasculitis Activity Score (BVAS) = 0 (no active vasculitis) plus prednisolone or prednisone dose less than or equal to 4 mg/day, and the proportion of patients in remission at both Week 36 and Week 48 of treatment. The BVAS is a clinician-completed tool to assess clinically active vasculitis that would likely require treatment, after exclusion of other causes. The demographics and baseline characteristics of patients in this trial are provided in Table 13 Table 13. Demographics and Baseline Characteristics in Eosinophilic Granulomatosis with Polyangiitis EGPA = eosinophilic granulomatosis with polyangiitis, SD = standard deviation. a b N = 136 Mean age, years 48. 5 Female, n (%) 80 (59) White, n (%) 125 (92) Duration of EGPA, years, mean (SD) 5. 63) History of > 100 (74) Refractory disease, n (%) 74 (54) Recurrence of EGPA symptoms, n (%) 68 (50) Failed induction treatment, n (%) 6 (4) Baseline oral corticosteroid a 12 (7. 5-50) Receiving immunosuppressive therapy, b 72 (53) Remission Patients receiving 300 mg of NUCALA achieved a significantly greater accrued time in remission compared with placebo. A significantly higher proportion of patients receiving 300 mg of NUCALA achieved remission at both Week 36 and Week 48 compared with placebo ( Table 14 Table 14 Table 14. Remission and Components of Remission in Eosinophilic Granulomatosis with Polyangiitis OCS = oral corticosteroid, BVAS = Birmingham Vasculitis Activity Score, CI = confidence interval. a Remission (OCS <=4 mg/day + BVAS = 0) OCS <=4 mg/day BVAS = 0 Placebo n = 68 NUCALA 300 mg n = 68 Placebo n = 68 NUCALA 300 mg n = 68 Placebo n = 68 NUCALA 300 mg n = 68 Accrued duration over 52 weeks, n (%) 0 55 (81) 32 (47) 46 (68) 27 (40) 6 (9) 3 (4) >0 to <12 weeks 8 (12) 8 (12) 12 (18) 5 (7) 15 (22) 13 (19) 12 to <24 weeks 3 (4) 9 (13) 6 (9) 12 (18) 11 (16) 5 (7) 24 to <36 weeks 0 10 (15) 2 (3) 10 (15) 17 (25) 2 (3) >=36 weeks 2 (3) 9 (13) 2 (3) 14 (21) 19 (28) 45 (66) Odds ratio (NUCALA/placebo) a 5. 7 (95% CI) (2. 6) Proportion of patients at both Weeks 36 and 48 Patients, n (%) 2 (3) 22 (32) 7 (10) 28 (41) 23 (34) 34 (50) Odds ratio (NUCALA/placebo) a 16. 9 (95% CI) (3. 2) Additionally, a statistically significant benefit for these endpoints was demonstrated using remission defined as BVAS = 0 plus prednisolone/prednisone <=7. Relapse The 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 significantly longer for patients receiving 300 mg of NUCALA compared with placebo with an HR of 0. 32 (95% CI: 0. 5) ( Figure 3 Figure 3. Kaplan-Meier Plot of Time to First Relapse in Eosinophilic Granulomatosis with Polyangiitis SC = subcutaneous. Corticosteroid Reduction Patients receiving 300 mg of NUCALA had a significantly greater reduction in average daily OCS dose compared with patients receiving placebo during Weeks 48 to 52 ( Table 15 Table 15. Average Daily Oral Corticosteroid Dose during Weeks 48 to 52 in Eosinophilic Granulomatosis with Polyangiitis CI = confidence interval. a b Number (%) of Patients Placebo n = 68 NUCALA 300 mg n = 68 0 2 (3) 12 (18) >0 to <=4. 0 mg 3 (4) 18 (26) >4. 5 mg 18 (26) 10 (15) >7. 5 mg 45 (66) 28 (41) Comparison: NUCALA/placebo a Odds ratio b 0. 20 95% CI 0. 41 Asthma Control Questionnaire-6 (ACQ-6) The ACQ-6, a 6-item questionnaire completed by the patient, was developed to measure the adequacy of asthma control and change in asthma control. The on-treatment ACQ-6 responder rate during Weeks 48 to 52 (defined as a decrease in score of 0. 5 or more compared with baseline) was 22% for 300 mg of NUCALA and 16% for placebo (OR: 1. 56; 95% CI: 0. 88 for 300 mg of NUCALA compared with placebo). Figure 3 A total of 108 adult and adolescent patients aged 12 years and older with HES for at least 6 months were evaluated in a randomized, double-blind, placebo-controlled, multicenter, 32‑week trial (NCT02836496). Patients with non-hematologic secondary HES (e. , drug hypersensitivity, parasitic helminth infection, HIV infection, non-hematologic malignancy) or FIP1L1-PDGFRalpha kinase-positive HES were excluded from the trial. Patients received 300 mg of NUCALA or placebo subcutaneous once every 4 weeks while continuing their stable HES therapy. Patients entering the trial had experienced at least 2 HES flares within the past 12 months and a blood eosinophil count of 1,000 cells/mcL or higher during screening. Historical HES flares for the trial entry criteria were defined as HES‑related worsening of clinical symptoms or blood eosinophil counts requiring an escalation in therapy. Patients must have been on stable HES therapy for the 4 weeks prior to randomization. HES therapy could include chronic or episodic OCS, immunosuppressive, or cytotoxic therapy. The efficacy of NUCALA in HES was established based upon the proportion of patients who experienced a HES flare during the 32-week treatment period. A HES flare was defined as worsening of clinical signs and symptoms of HES or increasing eosinophils (on at least 2 occasions), resulting in the need to increase OCS or increase/add cytotoxic or immunosuppressive HES therapy. The demographics and baseline characteristics of patients in this trial are provided in Table 16 Table 16. Demographics and Baseline Characteristics in Hypereosinophilic Syndrome SD = standard deviation, HES = Hypereosinophilic Syndrome. N = 108 Mean age, years (SD) 46. 78) Female, n (%) 57 (53) White, n (%) 100 (93) Mean duration of HES, years 5. 55 Flares The trial compared the proportion of patients who experienced a HES flare or withdrew from the trial in the NUCALA and placebo treatment groups ( Table 17 Table 17. Overview of Hypereosinophilic Syndrome Flares HES = Hypereosinophilic Syndrome, CMH = Cochran-Mantel-Haenszel, CI = confidence interval. a b Number (%) of Patients Placebo n = 54 NUCALA 300 mg n = 54 Patients with >=1 HES flare or who withdrew from trial 30 (56) 15 (28) Patients with >=1 HES flare 28 (52) 14 (26) Patients with no HES flare who withdrew from trial 2 (4) 1 (2) Comparison: NUCALA/placebo a CMH P 0. 002 Odds ratio b 0. 28 95% CI (0. 64) Time to First Flare Difference was observed between NUCALA and placebo arms in the time to first HES flare ( Figure 4). Kaplan-Meier Curve for Time to First Hypereosinophilic Syndrome Flare SC = subcutaneous. Proportion of Patients Who Experienced Flares during Week 20 through Week 32 From Week 20 through Week 32, significantly fewer patients experienced a HES flare or withdrew from the trial when treated with 300 mg of NUCALA compared with placebo (17% vs. 35%, respectively, P Rate of Flares Patients who received NUCALA experienced significantly fewer HES flares during the 32-week treatment period compared with the placebo group ( Table 18 Table 18. Frequency of Flares CI = confidence interval. a P b Number (%) of Patients Placebo n = 54 NUCALA 300 mg n = 54 0 26 (48) 40 (74) 1 15 (28) 11 (20) 2 7 (13) 3 (6) 3 5 (9) 0 4 1 (2) 0 >=5 0 0 Comparison: NUCALA/placebo Wilcoxon P a 0. 02 Rate/year 1. 50 Rate ratio b 0. 34 95% CI (0. 63) Brief Fatigue Inventory Brief Fatigue Inventory (BFI) Item 3 asks patients to record their worst level of weariness/tiredness severity during the past 24 hours (scale: 0 = no fatigue to 10 = as bad as you can imagine). At baseline, median BFI Item 3 scores were similar between treatment groups (4. 46 for NUCALA 300 mg and 4. 69 for placebo). At Week 32, BFI Item 3 scores improved with NUCALA compared with placebo ( P Figure 4.

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