FDA Approves NUCALA® (mepolizumab) for the Treatment of Severe Asthma Aged 12 Years and Older, and with an Eosinophilic Phenotype

On November 4, 2015, the United States Food and Drug Administration (FDA) approved NUCALA (mepolizumab) subcutaneous (SC) injection as an add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. The approved recommended dosage is 100 mg once every 4 weeks. Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with NUCALA. Decrease corticosteroids gradually, if appropriate.

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD) of Mepolizumab

  • MOA: Interleukin-5 (IL-5) antagonist monoclonal antibody (IgG1 kappa). IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils.
  • Dose proportionality: Exhibited approximate dose-proportional increases in systemic exposure over the subcutaneous dose range of 12.5 to 250 mg (i.e., 0.125 to 2.5 times the approved recommended dosage).
  • Accumulation: Approximately 2-fold at steady state.
  • Absorption: Approximately 80% is absorbed following SC administration in the arm.
  • Terminal half-life (mean): 16 to 22 days.
  • Metabolism: Proteolytic enzymatic degradation that is widely distributed in the body.
  • Dose-response: Compared with baseline levels, blood eosinophils decreased in a dose-dependent manner following mepolizumab treatment. Model-predicted mepolizumab SC doses of 11 and 99 mg (i.e., 0.11 to 0.99 times the approved recommended dosage) were estimated to result in a 50% and 90% maximal reduction of blood eosinophils, respectively. This supports the approved recommended dosage.

Use in Specific Populations

The following population characteristics were not associated with a clinically significant effect on the pharmacokinetics of mepolizumab: age (12 to 82 years), sex, and race. The effect of any degree of renal or hepatic impairment on mepolizumab exposure is unknown; however, a clinically significant effect is unlikely.

Safety and Efficacy

The safety and effectiveness of NUCALA were evaluated in patients with severe asthma uncontrolled on standard of care therapy who also had 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.  A 52-week dose-ranging study and a 32-week confirmatory study demonstrated that 100 mg SC or 75 mg IV mepolizumab treatment significantly reduced the asthma exacerbation rate by about half compared with placebo treatment.  Another 24-week confirmatory study demonstrated that 54% of subjects treated with 100 mg SC mepolizumab achieved at least a 50% reduction in the daily prednisone dose compared with 33% of subjects treated with placebo.  The most common adverse reactions include headache, injection site reaction, back pain, and fatigue. Hypersensitivity reactions (e.g., angioedema, bronchospasm, hypotension, urticaria, rash) and Herpes zoster infections have occurred in patients receiving NUCALA.

Full prescribing information is available at http://go.usa.gov/c2Ww3.

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The burst was prepared by the OCP Review Team including Yunzhao Ren., M.D., Ph.D., Jingyu Yu, Ph.D., Robert Schuck, Pharm.D., PhD, Suresh Doddapaneni Ph.D., Yaning Wang, Ph.D. and Christian Grimstein, Ph.D., Division of Clinical Pharmacology II, Division of Pharmacometrics, Genomics and Targeted Therapy Group, OCP, Office of Translational Sciences, CDER, FDA.