In-Depth Information on the FDA's Favorable Opinion of Nucala for Severe Eosinophilic Asthma

Medication will be used as an add-on maintenance therapy in patients aged 12 years and older.

In a May 7, 2015 meeting of an FDA advisory committee, experts voted 14-0 in favor of GlaxoSmithKline's mepolizumab (Nucala) for treatment of airway inflammation in patients with severe eosinophilic asthma.

Based on the proposed indication statement of mepolizumab, the medication will be used as an add-on maintenance therapy in patients aged 12 years and older with severe eosinophilic asthma. In this context, eosinophilia is defined as a blood eosinophil count ≥150 cells/µL upon treatment initiation, or blood eosinophil levels ≥300 cells/µL at some point in the previous year.

This indication would limit use of mepolizumab to patients with asthma. Patients with other conditions of eosinophilia and patients with acute bronchospasm or status asthmaticus would not qualify for treatment.

Mechanism of action

Inflammation resulting from eosinophil activity in the airways has an important pathogenic role in severe asthma. By binding to human interleukin 5 (IL-5) with high affinity, mepolizumab inhibits the activity of T-helper 2 (Th2) cytokines, which are key promoters of eosinophilic inflammation. By inhibiting IL-5, and Th-2 activity, mepolizumab may reduce eosinophilia-driven lung damage.

Dosage and administration

Proposed dosing of mepolizumab is 100 micrograms administered as a subcutaneous injection into the upper arm, thigh, or abdomen every 4 weeks.

Pharmacology and pharmacokinetics

Mepolizumab has a half-life of approximately 20 days. The medication accumulates at a steady state to approximately twice its initial levels. When administered subcutaneously, the bioavailability of mepolizumab ranges from 74% to 80%, and maximum mepolizumab concentrations are reached within 4 to 8 days of the initial dose. With a volume of distribution at 55 to 85 mL/kg of bodyweight, mepolizumab is largely confined to the plasma and interstitial space. Proteolytic enzymes catabolize the drug.

Due to the large molecular size of mepolizumab antibodies, the medication is not eliminated renally and elimination is not affected by hepatic function. In addition, IL-5 antagonism is not expected to affect CYP450 enzymes. Due to these properties, no drug interaction studies or studies in patients with impaired hepatic or renal function were conducted.

Clinical studies

A total of 5 key studies support the efficacy and safety of mepolizumab, including 3 double-blind, parallel-group, placebo-controlled multicenter trials and 2 open-label extension studies of the initial trials. Studies confirmed the efficacy of mepolizumab in reducing exacerbation rates, and improving quality-of-life, asthma control, and lung function. Studies also confirmed the safety of reducing daily oral corticosteroid dosages when initiating mepolizumab.

Over 32 to 52 weeks of treatment, mepolizumab reduces:

• Exacerbation rates by approximately 50%
• Rates of exacerbations requiring hospitalization by 35% to 63%
• Rates of exacerbations requiring hospitalization and/or emergency department visits by 32% to 61%

Warnings and precautions

Local injection site reactions occurred in 8% of patients taking mepolizumab versus 3% of patients receiving standard-of-care therapies. Importantly, none of the injection site reactions were severe, and no cases of anaphylaxis attributable to mepolizumab have been recorded. Anti-drug antibodies formed in 6% of patients using mepolizumab, but were also present in 1% of patients receiving placebo. Neutralizing antibodies formed in 1 patient.

Nasopharyngitis occurred in 23% of patients and upper respiratory tract infections occurred in 10% of patients. Serious infections, including pneumonia and opportunistic infections, occurred in 2% of patients. These types of infections are common in trials of medications for asthma, and investigators did not attribute the infections to study medication. In addition, researchers did not find any association between mepolizumab use and neoplasms or malignancies.

A total of 11 pregnancies occurred in clinical trials, including 9 pregnancies with known outcomes. Of these 9 pregnancies, 5 resulted in full-term, healthy infants.

Conclusions

GlaxoSmithKline is optimistic about the outlook for approval.

“Our clinical development program has demonstrated the potential of mepolizumab as a targeted treatment for difficult to treat adults with severe asthma, many of whom have been struggling to live with their condition for many years,” said Patrick Vallance, GlaxoSmithKline president of pharmaceuticals research and development.

A decision from the FDA is expected on November 4, 2015.

References

• Vermes K. FDA Advisors Recommend Asthma Drug Approval in Adults. http://www.pharmacytimes.com/product-news/FDA-Advisors-Recommend-Asthma-Drug-Approval-in-Adults. Accessed June 2015.
• FDA. NUCALA® (mepolizumab) for Treatment of Patients with Severe Asthma with Eosinophilic Inflammation. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM450248.pdf. Accessed June 2015.