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General Information

Nucala (mepolizumab) is an interleukin-5 antagonist monoclonal antibody (IgG1 kappa).

Nucala is specifically indicated for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. Nucala was subsequently approved in September of 2019 for use in children ages 6 to 11 years.

Nucala is specifically indicated for the treatment of adult and pediatric patients aged 12 years and older with Hypereosinophilic Syndrome (HES) for ≥ six months without an identifiable non-hematologic secondary cause.

Nucala is supplied as an injection for subcutaneous administration. The recommended dose is 100 mg administered once every 4 weeks by subcutaneous injection into the upper arm, thigh, or abdomen.

Clinical Results

FDA Approval

The FDA approval of Nucala was based on three double-blind, randomized, placebo-controlled trials: 1 dose-ranging and exacerbation trial (Trial 1) and 2 confirmatory trials (Trials 2 and 3).

Trial 1:

Trial 1 was a 52-week dose-ranging and exacerbation-reduction trial in subjects with asthma with a history of 2 or more exacerbations in the previous year despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) with or without oral corticosteroids. Subjects 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 greater than or equal to 300 cells/mcL, sputum eosinophil count greater than or equal to 3%, exhaled nitric oxide concentration greater than or equal to 50 ppb, or deterioration of asthma control after less than or equal to 25% reduction in regular maintenance inhaled corticosteroids/oral corticosteroids. Three IV doses 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 IV and 100 mg SC in the subsequent trials.

Trials 2 and 3:

A total of 711 subjects with asthma were studied in the 2 confirmatory trials (Trials 2 and 3). In these 2 trials subjects were required to have blood eosinophils of greater than or equal to 150 cells/mcL at screening (within 6 weeks of dosing) or blood eosinophils of greater than or equal to 300 cells/mcL within 12 months of enrollment. The screening blood eosinophils of greater than or equal to 150 cells/mcL criterion was derived from exploratory analyses of data from Trial 1. Trial 2 was a 32-week placebo- and active-controlled trial in subjects with asthma with a history of 2 or more exacerbations in the previous year despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) with or without oral corticosteroids. Subjects received mepolizumab 75 mg IV (n = 191), Nucala (n = 194), or placebo (n = 191) once every 4 weeks for 32 weeks. Trial 3 was a 24-week oral corticosteroid-reduction trial in subjects with asthma who required daily oral corticosteroids in addition to regular use of high-dose inhaled corticosteroids plus an additional controller(s) to maintain asthma control. Subjects in Trial 3 were not required to have a history of exacerbations in the prior year. Subjects received Nucala (n = 69) or placebo (n = 66) once every 4 weeks for 24 weeks. The baseline mean oral corticosteroid use was similar in the 2 treatment groups: 13.2 mg in the placebo group and 12.4 mg in the group receiving Nucala.

Results:

The primary endpoint for Trials 1 and 2 was the frequency of exacerbations defined as worsening of asthma requiring use of oral/systemic corticosteroids and/or hospitalization and/or emergency department visits. For subjects on maintenance oral corticosteroids, an exacerbation requiring oral corticosteroids was defined as the use of oral/systemic corticosteroids at least double the existing dose for at least 3 days. Compared with placebo, subjects receiving Nucala or mepolizumab 75 mg IV 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. Trial 3 evaluated the effect of NUCALA on reducing the use of maintenance oral corticosteroids. The primary endpoint was the percent reduction of oral corticosteroid dose during Weeks 20 to 24 compared with baseline dose, while maintaining asthma control. Compared with placebo, subjects receiving Nucala achieved greater reductions in daily maintenance oral corticosteroid dose, while maintaining asthma control. Sixteen (23%) subjects in the group receiving Nucala versus 7 (11%) in the placebo group had a 90% to 100% reduction in their oral corticosteroid dose. Twenty-five (36%) subjects in the group receiving Nucala versus 37 (56%) in the placebo group were classified as having no improvement for oral corticosteroid dose. Additionally, 54% of subjects treated with Nucala achieved at least a 50% reduction in the daily prednisone dose compared with 33% of subjects treated with placebo.

The FDA approval of Nucala for use in children 6 to 11 years of age was based on an open-label study, conducted in children aged six to 11 years with severe eosinophilic asthma. The study investigated Nucala’s pharmacokinetics, pharmacodynamics and long-term safety. Evidence from adequate and well-controlled trials in adults and adolescents also supported approval in this age group. The 52-week long-term phase of the study showed that the safety profile in paediatric patients aged six to 11 years was similar to the known safety profile in patients aged 12 years and older.

Hypereosinophilic Syndrome (HES): The FDA approval of Nucala for HES was based on a pivotal phase 3, 32-week, randomized, double-blind, placebo-controlled study designed to investigate the efficacy and safety of subcutaneous mepolizumab 300mg (3x100) every four weeks compared with placebo in 108 patients aged 12 years and older with uncontrolled HES. Uncontrolled HES was defined by at least two HES flares (worsening of symptoms or eosinophil threshold requiring an escalation in therapy) within the past 12 months and a blood eosinophil count of 1000 cells/µL or higher at screening. The study showed 50 percent fewer patients experienced a HES flare when treated with Nucala, compared to placebo, when added to standard of care treatment over the 32-week study period (28% vs 56%).

Side Effects

Adverse effects associated with the use of Nucala may include, but are not limited to, the following;

headache
injection site reaction
back pain
fatigue

Mechanism of Action

Nucala (mepolizumab) is an interleukin-5 antagonist monoclonal antibody (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. Multiple cell types and mediators 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 has not been definitively established.