NUCALA

Adapted from Pavord et al. 2012.

Nucala is indicated as an add-on treatment for adults and children ≥ 6 years with severe refractory eosinophilic asthma. 2

The recommended dose of Nucala is 100mg SC once every 4 weeks in adults and adolescents 12 years and older available in pre-filled pen, pre-filled syringe or lyophilised powder. The licensed dose of Nucala in children aged 6-11 years is 40mg SC regardless of weight and available in lyophilised powder. 2

Key safety findings

• Incidence of serious adverse events (AEs) was similar across treatment groups 1
• The most frequently reported AEs were headache and nasopharyngitis 1
• The most frequent drug-related AE was injection site reaction 1
  

Summary

• All doses of mepolizumab significantly reduced clinically significant exacerbations vs. placebo (p<0.05) and were well tolerated, when both were added to high dose ICS and an additional maintenance treatment(s)
  

MENSA3 - Investigating the safety and efficacy of Nucala add-on therapy in patients with severe refractory eosinophilic asthma

The MENSA (Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma) study was a randomised, multicentre, double-blind, double-dummy, placebo-controlled, phase IIIa clinical trial that investigated the safety and efficacy of mepolizumab in patients with severe refractory eosinophilic asthma. 3

Study design

The study included 576 patients,aged 12–82 years* entry criteria, which were informed from the DREAM study outcomes, included: 3

• Dependency on high dose ICS and an additional maintenance treatment(s) for at least 3 months, with or without OCS
• ≥2 asthma exacerbations in the prior 12 months
• Blood eosinophil levels of ≥150 cells/μL (≥0.15 x 109 cells/L) at initiation of treatment or ≥300 cells/μL (≥0.3 x 109 cells/L) in the prior 12 months
  

Patients were randomised to receive Nucala 100mg subcutaneous (SC), mepolizumab 75mg IV† or placebo in a 1:1:1 ratio added on to high dose ICS and an additional maintenance treatment(s). 3Only the data from the Nucala 100mg SC vs. placebo comparison are reported here.

*Nucala is indicated for SC use in adults and children ≥ 6 years with severe refractory eosinophilic asthma.
†Unlicensed dose/route of administration

Adapted from Ortega et al. N Engl J Med 2014. 3

*Patients who received mepolizumab 75mg IV also received placebo SC, patients who received Nucala 100mg SC also received placebo IV and patients in the placebo arm received placebo both IV and SC.

Key efficacy findings

Reduction in exacerbation frequency vs. placebo at Week 32 (primary endpoint)

Nucala added to high dose ICS and an additional maintenance treatment(s) provided the following benefits compared with placebo added on to high dose ICS and an additional maintenance treatment(s):

• Significant reduction in clinically significant exacerbations* by 53% (primary endpoint, 95% CI 36-65%; p<0.001) 3
• Significant reduction in exacerbations resulting in hospitalisations and/or ED visits by 61% (secondary endpoint, Nucala: 0.08/year, placebo: 0.2/year; 95% CI 17-82%; p=0.02)† 2
• Significant reduction in exacerbations resulting in hospitalisations by 69% (secondary endpoint: Nucala: 0.03/year, placebo: 0.10/year; 95% CI 9-89%; p=0.03) † 2
• Clinically meaningful improvement in health-related quality of life (SGRQ total score) by 7.0 units (secondary endpoint, 95% CI -10.2 to -3.8; p<0.001). 3
  • SGRQ is a validated disease-specific health status assessment for use in asthma and COPD and a difference of ≥4.0 units is considered clinically meaningful 45
• Improvement in lung function (as measured by pre-bronchodilator FEV1) by 98mL (secondary endpoint, 95% CI 11-184mL; p=0.03). 2

*Defined as worsening of asthma that required use of systemic corticosteroids or hospitalisation and/or emergency department visit 3

†Statistical significance for these secondary endpoints cannot be inferred due to the hierarchical ‘gatekeeping’ approach used. The p-values provided are unadjusted for multiple comparisons.

Key safety findings

In placebo-controlled clinical trials with Nucala (added to high dose ICS and additional maintenance treatment[s]), the rate of adverse events was similar across treatment arms, with the exception of injection site reactions (9% (17/194) for Nucala, 3% (6/191) for placebo). 2

• Incidence of AEs was 78% (152/194) in the Nucala group and 83% (158/191) in the placebo group 3
• Incidence of serious AEs was 8% (16/194) in the Nucala group and 14% (27/191) in the placebo group 3

Summary

• The MENSA study demonstrated the benefits of Nucala in terms of exacerbation reduction in patients with severe refractory eosinophilic asthma. Improvements in quality of life and lung function were also observed but statistical significance cannot be inferred due to the hierarchical ‘gatekeeping’ approach used. The p-values provided are unadjusted for multiple comparisons 3
• Furthermore, the the rate of adverse events was similar across treatment arms, with the exception of injection site reactions (9% (17/194) for Nucala, 3% (6/191) for placebo) 3
  

SIRIUS 6- Investigating the corticosteroid-sparing effect of Nucala as an add-on therapy in patients with severe refractory eosinophilic asthma

The SIRIUS (SteroId ReductIon with MepolizUmab Study) trial was a randomised, multicentre, double-blind, placebo-controlled, parallel-group, phase IIIa clinical trial that investigated the effect of Nucala in reducing the use of maintenance OCS while maintaining asthma control in patients with severe refractory eosinophilic asthma. 6

Study design

The study included 135 patients, aged 16-74 years and entry criteria included: 6

• Dependency on high dose ICS and an additional maintenance treatment(s),
• Maintenance treatment with OCS for at least 6 months (5-35mg/day prednisone or equivalent)
• Blood eosinophil level of ≥150 cells/μL(≥0.15 x 109 cells/L) at the start of the study or ≥300 cells/μL(≥0.3 x 109 cells/L) in the prior 12 months
  

Unlike the DREAM and MENSA trials, patients were not required to have a history of exacerbations but all patients were maintained on daily OCS medication for at least 6 months prior to the study. 6

Patients were randomised to receive Nucala 100mg SC or placebo in a 1:1 ratio added on to OCS, high dose ICS and an additional maintenance treatment(s). 6

Adapted from Bel et al. N Engl J Med 2014. 6

*During the optimisation phase (3–8 weeks before study start), OCS dose was reduced weekly until there was an exacerbation in asthma symptoms or an increase of at least 0.5 points from the visit 1 score on the asthma control questionnaire (ACQ)-5. The median OCS dose following optimisation was 10.0mg for patients receiving Nucala and 12.5mg for placebo recipients. 6

†During the reduction phase (Weeks 4–20), OCS dose was reduced according to a pre-specified schedule by 1.25mg to 10mg per day every 4 weeks on the basis of asthma control and symptoms of adrenal insufficiency. 6

Key efficacy findings

The odds of achieving a reduction in OCS dose while maintaining symptom control were 2.39 times higher in patients receiving Nucala compared with placebo recipients, when both were added to high dose ICS and an additional maintenance treatment(s) (primary endpoint, 95% CI 1.25-4.56; p=0.008). Median OCS dose at baseline (during optimisation phase) was 10mg for Nucala (n=69) and 12.5mg for placebo (n=66). 6

• 54% (37/69) of Nucala patients achieved at least a 50% reduction in the daily OCS dose compared with 33% (22/66) of patients receiving placebo, when both were added to high dose ICS and an additional maintenance treatment(s) (secondary endpoint, odds ratio 2.26 (95% CI 1.10-4.65); p=0.03) 6
• 54% (37/69) of Nucala patients achieved a reduction in the daily OCS dose to ≤5mg compared with 32% (21/66) of subjects receiving placebo, when both were added to high dose ICS and an additional maintenance treatment(s) (secondary endpoint, odds ratio 2.45 (95% CI 1.12-5.37); p=0.02) 6
• The median percentage reduction in daily OCS dose was 50% (95% CI 20.0 to 75.0%) in the Nucala group, compared with 0% in the placebo group (secondary endpoint, p=0.007) 6