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106 l American Health & Drug Benefits l www.AHDBonline.com Vol 9 l Special Feature l March 2016

Asthma, a condition characterized by the narrow­ing and inflammation of airways and excess mucus, affects 1 in 12 individuals in the United States—approximately 25 million people, or 8% of the US population.1 Overall, 53% of patients with asthma experience an asthma attack (ie, exacerbation) annually.1

Although asthma therapy, when used according to the current management guidelines, controls the disease in the majority of patients, an estimated 10% of patients have severe asthma, characterized by reduced respon­ siveness to standard therapy, as well as increased morbid­ ity and reduced quality of life.2,3 Severe asthma exacer­ bations often lead to hospitalization and can be life­threatening.4 Overall, asthma exacerbations can re­ sult in substantial morbidity, mortality, and healthcare utilization and associated costs.5 According to the Cen­ ters for Disease Control and Prevention, asthma ac­ counts for an estimated 3630 deaths annually in the United States, and 1.8 million emergency department visits with asthma as the primary diagnosis.6 In addition, there are 439,000 asthma­related hospitalizations annu­ ally, with an average length of stay of 3.6 days.6

In the United States, asthma costs accounted for $56 billion annually in 2007, representing a 6% increase from $53 billion in 2002.1 Between 2002 and 2007, the annual per­person cost for patients with asthma was $3300 in medical expenses, missed school or work days, and early mortality.1

The diagnostic tests for asthma may include spirome­ try or a peak flow meter to measure lung function.7 Other diagnostic tools may include imaging; allergy tests; a ni­ tric oxide test; methacholine response; provocative tests (postphysical activity); or a sputum eosinophils test, which measures the presence of eosinophils in the saliva and sputum.7

Eosinophils play a role in asthma­related airway in­ flammation.8 Some patients with eosinophilic airway inflammation experience recurrent asthma exacerba­ tions, despite receiving inhaled glucocorticoid treatment (with or without oral glucocorticoids); long­term use of

oral glucocorticoids is associated with potentially serious adverse reactions.2,9,10

The management of asthma includes the recognition and avoidance of disease triggers, ongoing control of symptoms, and, in the event of a flare­up, the use of a quick­relief (rescue) inhaler, such as albuterol.11 Long­ term control medications include inhaled corticoste­ roids, leukotriene modifiers, long­acting beta agonists, combination inhalers, and theophylline.11 Rescue medi­ cations include the short­acting beta agonists, the anti­ cholinergic bronchodilator ipratropium, and oral and intravenous (IV) corticosteroids.

For asthma that is worsened by allergies, pharmaco­ therapy options include immunotherapy (ie, allergy shots) or omalizumab.11 There is a need for additional treatment options for patients with severe asthma and the eosinophilic phenotype.4,11

Mepolizumab Approved for Maintenance Treatment in Severe Asthma

On November 4, 2015, mepolizumab (Nucala; GlaxoSmithKline), a humanized, interleukin­5 (IL­5) antagonist monoclonal antibody, was approved by the US Food and Drug Administration (FDA) as an add­on subcutaneous maintenance treatment for patients aged ≥12 years with an eosinophilic phenotype who have se­ vere asthma.4,8 Mepolizumab is not indicated for the treatment of other eosinophilic conditions, or for the re­ lief of acute bronchospasm or status asthmaticus.8 Mepo­ lizumab is the first FDA­approved biologic agent that targets IL­5, which regulates the function of eosinophils.12

Badrul Chowdhury, MD, PhD, Director of the FDA’s Division of Pulmonary, Allergy, and Rheumatology Prod­ ucts, commented, “This approval offers patients with se­ vere asthma an additional therapy when current treat­ ments cannot maintain adequate control of their asthma.”4

According to Professor Ian Pavord, University of Ox­ ford, an investigator for a phase 3 clinical trial with me­ polizumab, “Severe asthma is a debilitating condition in which patients are at high risk of frequent and serious

Nucala (Mepolizumab): First IL-5 Antagonist Monoclonal Antibody FDA Approved for Maintenance Treatment of Patients with Severe Asthma By Loretta Fala, Medical Writer

107 www.AHDBonline.com l American Health & Drug Benefits lVol 9 l Special Feature l March 2016

asthma attacks. Half of all severe asthma patients have at least one urgent care visit per year. As a clinician, the prospect of a treatment that can specifically target the underlying cause of the disease for patients whose condi­ tion is driven by eosinophilic inflammation is exciting.” 11

Mechanism of Action Mepolizumab is a humanized, IL­5 antagonist mono­

clonal antibody (immunoglobulin G1 kappa).8 The IL­5 cytokine regulates the growth, recruitment, activation, and life cycle of eosinophils—one of several cell types involved in asthma­related airway inflammation.8

Mepolizumab controls severe asthma exacerbations by reducing the levels of blood eosinophils that contrib­ ute to the pathogenesis of asthma.4 Mepolizumab binds to IL­5 and inhibits IL­5 signaling, thereby reducing the production and survival of eosinophils; however, the exact mechanism of action of mepolizumab in asthma has not been firmly established.8

Dosing and Administration Mepolizumab injection is available as 100 mg of lyo­

philized powder in a single­dose glass vial for reconstitu­ tion. Mepolizumab 100 mg is administered via subcuta­ neous injection once every 4 weeks by a healthcare professional into the upper arm, thigh, or abdomen.8

Before administration, mepolizumab is reconstituted in a vial with sterile water, as instructed in the prescrib­ ing information. Patients should be monitored after the administration of mepolizumab, as is the standard clini­ cal practice after the administration of a biologic agent.8

Clinical Trials The clinical development program that evaluated

mepolizumab in patients with asthma included 3 double­ blind, randomized, placebo­controlled studies, including Study 1 (DREAM), a dose­ranging and exacerbation clinical trial, and Study 2 (MENSA) and Study 3 (SIR­ IUS)—2 confirmatory trials.2,5,8,9

In all 3 studies, mepolizumab was administered every 4 weeks as an add­on treatment to background treat­ ment, with patients continuing their background asthma therapy throughout the duration of the study.8 To be included in the 2 confirmatory clinical trials, patients had to have blood eosinophils levels ≥150 cells/mcL at screening (within 6 weeks of dosing) or blood eosino­ phils levels ≥300 cells/mcL within 12 months of enroll­ ment (Table 1).

Study 1 (DREAM): Dose-Ranging and Exacerbation Trial

The findings from Study 1 (DREAM)––a 52­week, dose­ranging and exacerbation­reduction clinical trial—

and the findings from a pharmacodynamic study support­ ed the evaluation of mepolizumab 100 mg administered subcutaneously and mepolizumab 75 mg administered intravenously in subsequent clinical trials; however, me­ polizumab was ultimately approved by the FDA for sub­ cutaneous administration only.5,8

Study 2 (MENSA): Confirmatory Trial The MENSA study, a 32­week clinical trial, included

patients with asthma who had a history of ≥2 exacerba­ tions in the previous year, despite regular treatment with high­dose inhaled corticosteroids plus an additional controller, with or without oral corticosteroids.8,9

Results from Study 1 and 2 The primary end point for Study 1 and 2 was the fre­

quency of exacerbation, defined as the worsening of asthma necessitating the use of an oral or systemic corti­ costeroid and/or hospitalization and/or emergency de­ partment visits.8

Study 2 results showed that the time to the first exac­ erbation was longer in patients who received subcutane­ ous mepolizumab 100 mg and IV mepolizumab 75 mg compared with placebo.8,9 In both studies, patients who received subcutaneous mepolizumab 100 mg and IV me­

Table 1 Mepolizumab Studies 1, 2, and 3: Patient Baseline Characteristics

Patient characteristics Study 1

(N = 616) Study 2

(N = 576) Study 3

(N = 135)

Mean age, yrs 49 50 50

Female, N (%) 387 (63) 328 (57) 74 (55)

White, N (%) 554 (90) 450 (78) 128 (95)

Duration of asthma, mean, yrs

19 20 19

Never smoked, N (%) 483 (78) 417 (72) 82 (61)

Baseline FEV1, L 1.88 1.82 1.95

Baseline predicted FEV1, %

60 61 59

Baseline reversibility, % 25 27 26

Baseline post­SABA FEV1/FVC

0.67 0.66 0.66

Geometric mean eosinophil count at baseline, cells/mcL

250 290 240

Mean exacerbations in previous year, N

3.6 3.6 3.1

FEV1 indicates forced expiratory volume in 1 second; FVC, forced vital capacity; SABA, short­acting beta2­agonist. Source: Nucala (mepolizumab) for injection prescribing information; November 2015.

108 l American Health & Drug Benefits l www.AHDBonline.com Vol 9 l Special Feature l March 2016

polizumab 75 mg had significantly fewer exacerbations compared with patients who received placebo (Table 2). Furthermore, patients in the mepolizumab group had fewer exacerbations that required hospitalization and/or emergency department visits and exacerbations requir­ ing only in­patient hospitalization compared with the placebo group.8

Study 3 (SIRIUS): Confirmatory Trial SIRIUS, a 24­week clinical trial, evaluated the effect

of mepolizumab on reducing the use of maintenance oral corticosteroids; the primary efficacy outcome was the percent reduction of the oral corticosteroid dose in weeks 20 to 24 compared with the baseline dose, while maintaining asthma control.8

Treatment with mepolizumab demonstrated a signifi­ cant glucocorticoid­sparing effect compared with place­ bo (Table 3).8 Mepolizumab was 2.39 times more likely to reduce glucocorticoid doses versus placebo (95% confidence interval, 1.25­4.56; P = .008).2

Lung Function: Study 1, 2, and 3 In Study 1, 2, and 3, treatment with mepolizumab did

not show consistent improvements in the mean change from baseline in the forced expiratory volume in 1 sec­ ond (Table 4).8

Adverse Reactions The most common adverse reactions (≥5% inci­

dence) associated with mepolizumab were headache (19%), injection­site reaction (8%), back pain (5%), and fatigue (5%).8

Based on the data from the 3 randomized, placebo­ controlled studies lasting 24 to 52 weeks, 2% of patients receiving mepolizumab withdrew from the studies be­ cause of adverse events compared with 3% of patients receiving placebo.8 One serious adverse event (herpes zoster) occurred in 2 patients who received mepolizumab versus none in patients receiving placebo. Additional cases of herpes zoster have been reported in ongoing open­label, extension clinical trials in the 998 patients receiving mepolizumab.8

Overall, 6% (15/260) of patients who received mepo­ lizumab developed antimepolizumab antibodies, which increased by approximately 20% the clearance of mepo­ lizumab.8 The clinical relevance of these antimepolizu­

Table 2 Mepolizumab versus Placebo: Rate of Exacerbations in Study 1 and 2 (Intent-to-Treat Population)

Study Treatment

Exacerbations, annually

Rate Difference Rate ratio

All exacerbations

Study 1 Placeboa 2.40

Mepolizumab 75 mg IVb 1.24 1.16 0.52 (95% CI, 0.39­0.69)

Study 2 Placeboc 1.74

Mepolizumab 75 mg IVc 0.93 0.81 0.53 (95% CI, 0.40­0.72)

Mepolizumab 100 mg SCd 0.83 0.91 0.47 (95% CI, 0.35­0.64) Exacerbations requiring hospitalization and/or emergency department visit

Study 1 Placeboa 0.43

Mepolizumab 75 mg IVb 0.17 0.26 0.40 (95% CI, 0.19­0.81)

Study 2 Placeboc 0.20

Mepolizumab 75 mg IVc 0.14 0.06 0.68 (95% CI, 0.33­1.41)

Mepolizumab 100 mg SCd 0.08 0.12 0.39 (95% CI, 0.18­0.83) Exacerbations requiring hospitalization

Study 1 Placeboa 0.18

Mepolizumab 75 mg IVb 0.11 0.07 0.61 (95% CI, 0.28­1.33)

Study 2 Placeboc 0.10

Mepolizumab 75 mg IVc 0.06 0.04 0.61 (95% CI, 0.23­1.66)

Mepolizumab 100 mg SCd 0.03 0.07 0.31 (95% CI, 0.11­0.91) aN = 155; bN = 153; cN = 191; dN = 194. CI indicates confidence interval; IV, intravenous; SC, subcutaneous. Source: Nucala (mepolizumab) for injection prescribing information; November 2015.

109 www.AHDBonline.com l American Health & Drug Benefits lVol 9 l Special Feature l March 2016

mab antibodies is unknown; there was no evidence that these antibody titers effected changes in the blood eosin­ ophil levels.8

Contraindications Mepolizumab is contraindicated in patients with a

history of hypersensitivity to mepolizumab or its excipi­ ents in the formulation.8

Warnings and Precautions Hypersensitivity reactions. Hypersensitivity reac­

tions (eg, angioedema, bronchospasm, hypotension, rash, urticaria) have been reported after mepolizumab administration; mepolizumab should be discontinued in a patient with hypersensitivity reaction.8

Acute asthma symptoms or deteriorating disease. Mepolizumab should not be used for the treatment of patients with acute asthma symptoms, acute exacerba­ tions, acute bronchospasm, or status asthmaticus. Pa­ tients whose asthma worsens or remains uncontrolled after initial treatment with mepolizumab should seek medical advice.8

Herpes zoster. In clinical studies, 2 serious herpes zoster adverse reactions occurred in patients who re­ ceived mepolizumab. Varicella vaccination should be considered before starting treatment with mepolizumab.8

Reduction of corticosteroid dosage. Systemic or in­ haled corticosteroids should not be discontinued abrupt­ ly when initiating treatment with mepolizumab. Any

reductions of the corticosteroid dose should be gradual and performed under a physician’s direct supervision.8

Helminth infection. Patients with preexisting hel­ minth infections should receive treatment before starting mepolizumab therapy. If a patient is helminth­infected while receiving mepolizumab and does not respond to antihelminth treatment, mepolizumab should be discon­ tinued until the infection resolves.8

Use in Specific Populations Pregnancy. Clinical trial data on mepolizumab expo­

sure during pregnancy are insufficient to determine drug­associated risks. It is recommended that healthcare providers enroll patients in a pregnancy exposure registry to monitor pregnancy outcomes in women exposed to mepolizumab during pregnancy.8

Lactation. No data are available on the presence of mepolizumab in human milk, its effects on breastfed in­ fants, or its effects on the production of milk.8

Pediatric use. The safety and efficacy of mepolizumab in patients aged ≤12 years have not been determined.8

Geriatric use. There were insufficient numbers of patients aged ≥65 years in the mepolizumab clinical trials to determine whether their treatment response was dif­ ferent from that of younger patients. The dose selection for elderly patients should start at the low end of the dosing range. Available data suggest that no dosage ad­ justment is required in geriatric patients, but the poten­ tial for increased sensitivity should be considered.8

Table 3 Mepolizumab versus Placebo: Oral Glucocorticoid-Sparing Effect in Study 3 Outcome Mepolizumab, N (%) Placebo, N (%)

Patients achieving a 90%­100% reduction in oral corticosteroid dose 16 (23) 7 (11)

Patients who achieved at least a 50% reduction in the daily prednisone dose 37 (54) 22 (33)

Patients with no reduction in oral glucocorticoid dose, a lack of asthma control, or treatment withdrawal

25 (36) 37 (56)

Sources: Nucala (mepolizumab) for injection prescribing information; November 2015; Bel EH, et al. N Engl J Med. 2014;371:1189­1197.

Table 4 Mepolizumab versus Placebo: Change from FEV1 Baseline in Study 1, 2, and 3

Clinical study

Difference from placebo in mean change from baseline FEV1

Week 12, mL Week 24, mL Weeks 32/52, mL

Study 1 (75­mg IV) 10 (95% CI, –87 to 108) 5 (95% CI, –98 to 108) 61 (95% CI, –39 to 161)a

Study 2 (100­mg SC) 52 (95% CI, –30 to 134) 76 (95% CI, –6 to 159) 98 (95% CI, 11 to 184)b

Study 3 (100­mg SC) 56 (95% CI, –91 to 203) 114 (95% CI, –42 to 271) N/A aFEV1 at week 52. bFEV1 at week 32. CI indicates confidence interval; FEV1, forced expiratory volume in 1 second; IV, intravenous; N/A, not applicable; SC, subcutaneous. Source: Nucala (mepolizumab) for injection prescribing information; November 2015.

110 l American Health & Drug Benefits l www.AHDBonline.com Vol 9 l Special Feature l March 2016

Conclusion The FDA approval of mepolizumab marks the avail­

ability of the first biologic agent to target IL­5, a cytokine that regulates the growth, activity, and survival of eosin­ ophils—the inflammatory cells that play a key role in the pathogenesis of asthma. Mepolizumab, an IL­5 antago­ nist monoclonal antibody administered subcutaneously once monthly, is indicated as an add­on maintenance treatment for patients aged ≥12 years with severe asth­ ma, and with an eosinophilic phenotype.

In clinical trials, patients who received mepolizumab had significantly fewer exacerbations than patients re­ ceiving placebo. Patients who received mepolizumab also had fewer exacerbations requiring hospitalization and/or emergency department visits, and fewer exacerbations requiring in­patient hospitalization compared with place­ bo. Treatment with mepolizumab was more than twice as likely to reduce glucocorticoid doses as placebo. n

References 1. Asthma & Allergy Center. Asthma statistics. www.asthmaandallergycenter. net/education/asthma/asthma­statistics. Accessed February 22, 2016. 2. Bel EH, Wenzel SE, Thompson PJ, et al; for the SIRIUS Investigators. Oral

glucocorticoid­sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189­1197. 3. ENFUMOSA Study Group. The ENFUMOSA cross­sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur Re- spir J. 2003;22:470­477. 4. US Food and Drug Administration. FDA approves Nucala to treat severe asthma. Press release. November 4, 2015. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm471031.htm. Accessed December 3, 2015. 5. Pavord ID, Kom S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double­blind, placebo­controlled trial. Lancet. 2012;380:651­659. 6. Centers for Disease Control and Prevention. FastStats: asthma. Updated May 14, 2015. www.cdc.gov/nchs/fastats/asthma.htm. Accessed December 9, 2015. 7. Mayo Clinic staff. Tests and diagnosis. October 17, 2015. www.mayoclinic. org/diseases­conditions/asthma/basics/tests­diagnosis/con­20026992. Accessed February 22, 2016. 8. Nucala (mepolizumab) for injection [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; November 2015. 9. Ortega HG, Liu MC, Pavord ID, et al; for the MENSA Investigators. Mepo­ lizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198­1207. Erratum in: N Engl J Med. 2015;372:1777. 10. Mayo Clinic staff. Prednisone and other corticosteroids. November 26, 2015. www.mayoclinic.org/steroids/art­20045692?pg=2. Accessed December 9, 2015. 11. Mayo Clinic staff. Disease and conditions: asthma: treatments and drugs. October 17, 2015. www.mayoclinic.org/diseases­conditions/asthma/basics/ treatment/con­20026992. Accessed February 22, 2016. 12. GlaxoSmithKline. GSK’s Nucala (mepolizumab) receives approval from US FDA. Press release. November 4, 2015. www.gsk.com/en­gb/media/press releases/2015/gsk­s­nucala­mepolizumab­receives­approval­from­us­fda/. Accessed December 4, 2015.

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