Study Design | NUCALA (mepolizumab) for HCPs

NUCALA has a strong foundation of evidence: 5 clinical trials, 1 real-world study, 1900+ patients enrolled collectively

The efficacy and safety of NUCALA in SEA was examined in numerous studies. See below for detailed information for select studies.^1-8

On this page:

Trial 2 (MENSA)

Trial 3 (SIRIUS)

Real-world study (REALITI-A)

4.5-year open-label study (COLUMBA)

Open-label extension study (COSMOS)

MUSCA (phase 3b quality of life trial)

Trial 2 (MENSA)¹

Pivotal exacerbation reduction trial.

Description
32-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled study comparing treatment with NUCALA or mepolizumab 75 mg IV to placebo, each added to SOC in 576 patients aged ≥12 years with severe eosinophilic asthma.

Select inclusion criteria⁸

Blood eosinophil counts of ≥150 cells/µL at baseline or ≥300 cells/µL within the last 12 months
≥2 exacerbations* in previous year
High-dose ICS^† plus an additional controller(s) with or without OCS.

Primary endpoint/results
Exacerbations^*/year: 0.83 for NUCALA vs 1.74 for placebo (53% reduction; P<0.001).

^*Defined as worsening of asthma requiring: systemic corticosteroids or hospitalization or ED visit; or at least double the existing maintenance systemic corticosteroid dose for ≥3 days.

^†High dose ICS defined as ≥880 μg of fluticasone propionate [FP], or the equivalent, per day in patients ≥18 years of age, and ≥440 μg of FP, or the equivalent, per day in patients 12 to 17 years of age.²

**Trial 2 Baseline characteristics^1,2**
	NUCALA (N=194)	Placebo (N=191)
Mean age	51 years	49 years
Female	60%	56%
Body mass index^‡	27.6	28.0
Duration of athma	20.5 years	19.5 years
Use of Oral Glucocorticoids
Maintenance use	27%	23%
Mean daily dose^§	12.6 mg	15.1 mg
Allergic rhinitis	49%	50%
Nasal polyposis	14%	17%
FEV₁
Before bronchodilation^\|\|	1.73 L	1.86L
Predicted value before bronchodilation^¶	59.3%	62.4%
Reversibility	27.9%	27.4%
FEV₁/FVC ratio	63%	64%
ACQ-5 score^#	2.26	2.28
SGRQ score^**	47.9	46.9
Geometric mean IgE on log_e scale	150 U/mL	150 U/mL
Geometric mean blood eosinophil count on log_e scale	290 cells/μL	320 cells/μL
Asthma exacerbations
Severe episodes in previous year	3.8	3.6
Necessitating hospitalization in the previous year	17%	18%

^‡Body mass index is the weight in kilograms divided by the square of the height in meters.

^§The listed value is the prednisone equivalent.

^||Reversibility was measured at baseline.

^¶The percent of predicted value before bronchodilation was assessed at the screening visit.

^#Scores on the ACQ range from 0 to 6 with higher scores indicating worse control; a change of 0.5 points is the minimal clinically important difference.⁹

^**Scores on the SGRQ range from 0 to 100 with higher scores indicating worse function; a change of 4 points is considered to be clinically relevant.^10,11

ACQ=Asthma Control Questionnaire; CI=confidence interval; ED=emergency department; FEV₁=forced expiratory volume in 1 second; FVC=forced vital capacity; ICS=inhaled corticosteroid; IgE=immunoglobulin E; IV=intravenous; OCS=oral corticosteroid; QOL=quality of life; SC=subcutaneous; SGRQ=St George’s Respiratory Questionnaire; SOC=standard of care.

See exacerbation data

Trial 3 (SIRIUS)³

Pivotal OCS reduction trial

Description
24-week, multicenter, randomized, double-blind, placebo-controlled study comparing treatment with NUCALA to placebo in 135 patients ≥12 years of age with SEA requiring daily OCS in addition to regular use of high-dose ICS^* plus and additional controller. Patients were not required to have a history of exacerbations in the previous 12 months.

Select inclusion criteria

Blood eosinophil counts of ≥150 cells/µL at baseline or ≥300 cells/µL within the last 12 months
Treatment with 5 mg to 35 mg of prednisone or its equivalent per day in addition to regular use of high-dose ICS* plus an additional controller

Primary endpoint/results
Percent reduction in daily OCS dose (Weeks 20 to 24) while maintaining asthma control. NUCALA reduced daily OCS dose while maintaining asthma control vs placebo (P=0.008).

*High-dose ICS defined as ≥880 μg of fluticasone propionate [FP], or the equivalent, per day in patients ≥18 years of age, and ≥440 μg of FP, or the equivalent, per day in patients 12 to 17 years of age.²

ICS=inhaled corticosteroid; OCS=oral corticosteroid; SEA=severe eosinophilic asthma; SOC=standard of care.

See OCS reduction data

Real-world study (REALITI-A)⁴

Real-world studies are designed to evaluate associations among variables and not to definitively establish causality. Limitations important when interpreting results: no comparator arm; differences in patient populations and data collection vs randomized controlled trials.

Interim Analysis
These data are a prespecified interim analysis of 368 patients who completed 12 months of follow-up. This analysis may not reflect the results from the final dataset.

Description
Ongoing, 2-year, global, single-arm, prospective, cohort study assessing the real-world effectiveness and safety of NUCALA 100 mg every 4 weeks in adult patients with SEA who met the eligibility requirements to initiate NUCALA. Data were collected prospectively at usual asthma healthcare visits. A 12-month period of relevant medical data was required prior to enrollment and was collected retrospectively at enrollment from medical records and patient recall for the previous year. Baseline visit was first administration of NUCALA.

Enrollment requirements

Patients had to meet eligibility requirements for NUCALA initiation
12-month period of relevant medical data that could be collected retrospectively

Study objectives

Assessed 12-month post-treatment period vs 12-month pre-treatment period (baseline)
Primary: Exacerbation* rate
Secondary: Exacerbation* rates requiring hospitalization and/or ED visit, and maintenance OCS use among users at baseline

Primary Objective Results:
Exacerbations: 12 months post-exposure
NUCALA: 1.43/year vs 12 months pre-exposure: 4.63/year (69% reduction; rate ratio 0.31 [95% CI: 0.27, 0.35]). Results are descriptive.

Study discontinuation
During 12-month follow-up of the study population (N=368), 19% discontinued treatment with NUCALA (2% due to an AE; 4% lack of efficacy; 13% other).

Safety population, N=368
Any drug-related AEs 14%, serious AE, <1%; Most common AE reported was nervous system disorders (predominantly headache), 7%. No new safety signals were reported.

**Real-world study summary of baseline characteristics⁴**
	Total Population (N=368)
Mean age (SD)	53 (13.7) years
Geography (n)
Europe	320
Canada	40
United States	8
Mean duration of severe asthma (SD)	20 (15.1) years
Geometric mean blood eosinophils (n=357)	370 cells/μL
Current maintenance OCS use (n=365)	48%
Median maintenance OCS dose* among current users (n=159)	10.0 mg/day
Mean pre-bronchodilator % predicted FEV1 (SD) (n=200)	64.4% (20.3)
Mean rate of exacerbations/year (SD) (n=366)	4.63 (4.09)
Mean rate of exacerbation requiring hospitalization or ED visits/year (SD) (n=366)	1.14 (2.26)
Mean ACQ-5 score (SD) (n=350)	3.0 (1.4)
Comorbidities (>35%)
Hay fever	52%
Chronic sinusitis	39%
Nasal polyps	38%
Gastroesophageal reflux disease	37%

*Defined as worsening of asthma requiring: systemic corticosteroids or hospitalization or ED visit; or at least double the existing maintenance systemic corticosteroid dose for ≥3 days.

ACQ=Asthma Control Questionnaire; AE=adverse event; CI=confidence interval; ED=emergency department; FEV₁=forced expiratory volume in 1 second; OCS=oral corticosteroid; SD=standard deviation; SEA=severe eosinophilic asthma.

See exacerbation data

See OCS reduction data

4.5-year open-label study (COLUMBA)^2,5

^*Patients continued in the open-label long-term safety study until a protocol-defined stopping criterion was met.

Description
4.5-year, multicenter, open-label, long-term study assessing the safety, immunogenicity, and efficacy of NUCALA in 347 patients ≥12 years of age with SEA previously treated in Trial 1^† at least 12 months prior and met eligibility criteria. All patients received NUCALA added to asthma controller therapy.

Primary endpoints/results
Long-term safety, including AEs, SAEs, and immunogenicity. Most frequent AEs (≥20%): viral upper respiratory tract infection, 49%; headache, 29%; asthma^‡, 27%; upper respiratory tract infection, 23%; bronchitis, 21%. Two SAEs occurred in ≥1% of patients: asthma, 10%; and pneumonia, 2%. A total of 8% of patients had a positive anti-drug antibody result, but all were negative for neutralizing antibodies.

Secondary endpoints/results

Annualized exacerbation rate^§: 0.68 (95% CI: 0.60, 0.78).
Asthma control: mean change from baseline in ACQ-5 score was -0.47 points at both Week 12 and end of study.
Lung function: mean change from baseline in pre-bronchodilator FEV₁ at Week 12 was 124 mL, and gradually declined to approximate baseline values at end of study.

Results are descriptive.

^†Trial 1: 52-week study comparing mepolizumab IV to placebo IV added to SOC in 616 patients ≥12 years of age with severe asthma. Primary endpoint/results: Exacerbations/year 1.24 for mepolizumab 75 mg vs 2.40 for placebo (48% reduction, P<0.0001).⁶

^‡Asthma reported as an AE means worsening or exacerbation of asthma.

^§Defined as worsening of asthma requiring: systemic corticosteroids or hospitalization or ED visit; or at least double the existing maintenance systemic corticosteroid dose for ≥3 days.

ACQ=Asthma Control Questionnaire; AE=adverse event; CI=confidence interval; ED=emergency department; FEV₁=forced expiratory volume in 1 second; IV=intravenous; SAE=serious adverse event; SEA=severe eosinophilic asthma; SOC=standard of care.

See long-term data

Open-label extension study (COSMOS)⁷

Description
52-week, multicenter, open-label extension study assessing the safety and efficacy of NUCALA in 651 patients ≥12 years of age with SEA who completed Trial 2 or Trial 3. All patients in the 1-year open-label study received NUCALA added to SOC regardless of their previous treatment allocation (NUCALA, mepolizumab 75 mg IV, or placebo).

SOC therapy
Regular treatment with high-dose ICS* plus an additional controller(s) with or without OCS.²

Primary endpoints/results
Long-term safety, including AEs and SAEs. Most frequent AEs (≥10%): nasopharyngitis, 30%; upper respiratory infection, 16%; asthma,^† 14%; headache, 14%; bronchitis, 12%; sinusitis, 10%. The only SAE that occurred in ≥1% of patients: asthma.^†

Efficacy endpoint/results
Included frequency of exacerbations.^‡ 0.99 exacerbations/year for previous placebo group (95% CI: 0.83, 1.18) vs 0.90 exacerbations/year for previous mepolizumab group (95% CI: 0.78, 1.04).⁶Results are descriptive.

^*High-dose ICS defined as ≥880 μg of fluticasone propionate [FP], or the equivalent, per day in patients ≥18 years of age, and ≥440 μg of FP, or the equivalent, per day in patients 12 to 17 years of age.²

^†Asthma reported as an AE means worsening or exacerbation of asthma.

^‡Exacerbations of asthma were defined as worsening of asthma requiring: systemic corticosteroids or hospitalization or ED visit; or at least double the existing maintenance systemic corticosteroid dose for ≥3 days.

AE=adverse event; CI=confidence interval; ED=emergency department; ICS=inhaled corticosteroid; IV=intravenous; OCS=oral corticosteroid; SAE=serious adverse event; SEA=severe eosinophilic asthma; SOC=standard of care.

See long-term data

MUSCA (Phase 3b quality of life trial)⁸

Description
24-week, multicenter, randomized, double-blind, placebo-controlled study comparing treatment with NUCALA to placebo, each added to SOC, in 551 patients ≥12 years of age with SEA.

Select inclusion criteria

Blood eosinophil counts of ≥150 cells/µL at baseline or ≥300 cells/µL within the last 12 months
Patients aged ≥12 years

SOC therapy

Regular treatment with high-dose ICS* plus an additional controller(s) with or without OCS

Primary endpoint/results
Mean change from baseline in SGRQ total score at Week 24: -15.6 for NUCALA vs -7.9 for placebo; treatment difference of -7.7 (P<0.0001). The improvement in both treatment arms was clinically meaningful.^†

Other endpoint/results
Exacerbations^*/year 0.51 for NUCALA vs 1.21 for placebo, 58% reduction (rate ratio 0.42; 95% CI: 0.31, 0.56).

^*High dose ICS defined as ≥880 μg of fluticasone propionate [FP], or the equivalent, per day in patients ≥18 years of age, and ≥440 μg of FP, or the equivalent, per day in patients 12 to 17 years of age.²

^†Defined as a reduction in score of 4 points or more for minimal clinically important difference.¹¹

ICS=inhaled corticosteroid; OCS=oral corticosteroid; QOL=quality of life; SEA=severe eosinophilic asthma; SOC=standard of care; SGRQ=St George’s Respiratory Questionnaire.

Trial 2 (MENSA)/MUSCA Meta-analysis

Post hoc meta-analysis of two clinical studies with NUCALA (Trial 2 and MUSCA) in patients ≥ 12 years of age with SEA.^2, 12 The purpose was to assess NUCALA vs placebo on the annual rate of exacerbations at the end of the treatment period for each study in select subgroups, including the presence of nasal polyps and atopic status.

Trial 2 (MENSA) design and primary endpoint¹

Description

32-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled study comparing treatment with NUCALA or mepolizumab 75 mg IV to placebo, each added to SOC in 576 patients of ≥ 12 years of age with SEA, identified by blood eosinophil counts of ≥ 150 cells/µL at baseline or ≥ 300 cells/µL within the last 12 months.

Primary endpoint/results

Exacerbations^*/year 0.83 for NUCALA vs 1.74 for placebo (53% reduction; P<0.001).

MUSCA design and primary endpoint⁸

Description

24-week, multicenter, randomized, double-blind, placebo-controlled study comparing treatment with NUCALA to placebo, each added to SOC, in 551 patients ≥12 years of age with SEA, identified by blood eosinophil counts of ≥150 cells/µL at baseline or ≥300 cells/µL within the last 12 months.

Endpoint/results

Primary endpoint: Mean change from baseline in SGRQ total score at Week 24: -15.6 for NUCALA vs -7.9 for placebo; treatment difference of -7.7 (P<0.0001). The improvement in both treatment arms was clinically meaningful.^†

Other endpoint: Exacerbations^*/year 0.51 for NUCALA vs 1.21 for placebo, 58% reduction (rate ratio 0.42; 95% CI: 0.31, 0.56).

^*Defined as worsening of asthma requiring: systemic corticosteroids or hospitalization or emergency department visit; or at least double the existing maintenance systemic corticosteroid dose for ≥3 days.

SOC=regular treatment with high-dose inhaled corticosteroids (defined as ≥880 μg of fluticasone propionate [FP], or the equivalent, per day in patients ≥18 years of age, and ≥440 μg of FP, or the equivalent, per day in patients 12 to 17 years of age) and at least 1 other controller with or without oral corticosteroids.²

^†Defined as a reduction in score of 4 points or more for minimal clinically important difference.¹¹

CI=confidence interval; IV=intravenous; SEA=severe eosinophilic asthma; SOC=standard of care; SGRQ=St George’s Respiratory Questionnaire.

See exacerbation data

Safety profile

Learn about the safety profile of NUCALA

Indication & Important Safety Info

Indication

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. NUCALA is not indicated for the relief of acute bronchospasm or status asthmaticus.

Important Safety Information

CONTRAINDICATIONS
Known hypersensitivity to mepolizumab or excipients.

WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions
Hypersensitivity reactions (eg, anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, rash) have occurred with NUCALA. These reactions generally occur within hours of administration but can have a delayed onset (ie, days). Discontinue if a hypersensitivity reaction occurs.

Acute Asthma Symptoms or Deteriorating Disease
NUCALA should not be used to treat acute asthma symptoms, acute exacerbations, or acute bronchospasm.

Opportunistic Infections: Herpes Zoster
In controlled clinical trials, 2 serious adverse reactions of herpes zoster occurred with NUCALA compared to none with placebo. Consider vaccination if medically appropriate.

Reduction of Corticosteroid Dosage
Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with NUCALA. Decreases in corticosteroid doses, if appropriate, should be gradual and under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.

Parasitic (Helminth) Infection
Treat patients with pre-existing helminth infections before initiating therapy with NUCALA. If patients become infected while receiving NUCALA and do not respond to anti-helminth treatment, discontinue NUCALA until infection resolves.

ADVERSE REACTIONS
In patients receiving NUCALA, the most common adverse reactions (≥5%) were headache, injection site reaction, back pain, and fatigue. Systemic reactions (allergic and nonallergic), including hypersensitivity, also occurred. Manifestations included rash, pruritus, headache, myalgia, and flushing; the majority were experienced the day of dosing.

USE IN SPECIFIC POPULATIONS
The data on pregnancy exposures are insufficient to inform on drug-associated risk. Monoclonal antibodies, such as mepolizumab, are transported across the placenta in a linear fashion as the pregnancy progresses; therefore, potential effects on a fetus are likely to be greater during the second and third trimesters.

Please see full Prescribing Information and Patient Information for NUCALA.

MPLWCNT230011 March 2023.

References