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Exacerbation reduction study (MENSA)

Mepolizumab effect on exacerbations: Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma (MENSA)

Ortega HG, et al. N Engl J Med 2014;371:1198–207.1

MENSA was a randomised, double-blind, double-dummy trial that compared the effects of mepolizumab 75 mg i.v. and 100 mg s.c. with placebo. The study was designed to specifically examine the effect of mepolizumab versus placebo added to maintenance asthma therapy on clinically significant asthma exacerbations.

The patient population was required to have a history of two or more exacerbations in the prior year, and be using high-dose ICS plus additional controllers. The eosinophil entry criteria were defined by retrospective analysis of the DREAM study: blood eosinophils ≥150 cells/μL at initiation of treatment or ≥300 cells/μL in the past 12 months.

In addition to assessing exacerbation rate with mepolizumab versus placebo, MENSA also compared clinical efficacy and safety with mepolizumab 75 mg i.v., mepolizumab 100 mg s.c. and placebo at 32 weeks. Results were similar between i.v. and s.c. arms.

Further trials investigated only the effects of the 100 mg s.c. dose.2

Only the 100 mg s.c. dose is discussed in this section, as this is the dose that received regulatory approval for adults with severe refractory eosinophilic asthma.3 Please see the ‘Mepolizumab dose’ tab on this page for a discussion on dose selection.

The MENSA study further confirmed the benefit of mepolizumab for reducing exacerbations in patients with severe refractory eosinophilic asthma. It also further detailed the benefits of quality of life and asthma control in these patients.

*This is an unlicensed dose/route of administration.

  • Patient eligibility

    Selected inclusion criteria

    Selected exclusion criteria

    • Clinical diagnosis of asthma
    • At least two exacerbations requiring systemic corticosteroid treatment in the previous year
    • Receiving high-dose ICS and an additional controllers
      • Peripheral blood eosinophil count ≥150 cells/µL at screening or ≥300 cells/µL during the previous year



         
    • Present smoking or >10 pack-year smoking history
    • Concurrent respiratory disease, eosinophilic disease or other substantial uncontrolled morbidity
    • Parasitic infection in the previous 6 months
    • Possibility of pregnancy
    • History of poor treatment adherence
    • Recent treatment with omalizumab or another biologic for inflammatory disease
      • Previous participation in any mepolizumab study

    ICS, inhaled corticosteroids.

  • Endpoints

    Primary endpoint: the annualised frequency of clinically significant asthma exacerbations, defined as:

    • Worsening of asthma, such that the treating physician administered systemic corticosteroids for ≥3 days
      and/or
    • The patient visited an emergency department and/or was hospitalised

    Secondary and other endpoints: frequency of exacerbations requiring hospitalisation or emergency department visit; frequency of exacerbations requiring hospitalisation; spirometry profile; haematologic parameters; ACQ-5 and SGRQ scores; safety; anti-mepolizumab antibodies

  • Efficacy

    The MENSA primary outcome

    The MENSA primary outcome was the rate of clinically significant exacerbations with mepolizumab or placebo.

    Mepolizumab 100 mg s.c. significantly reduced the rate of clinically significant exacerbations by 53% compared with placebo (mean rate: 0.83 events/patient/year with mepolizumab 100 mg s.c. and 1.74 events/patient/year with placebo; p<0.001).

    MENSA study: Rate of clinically significant exacerbations

    Graph showing rate of clinically significant exacerbations with mepolizumab or placebo.

    Data for the mepolizumab 100 mg s.c. dose only are shown, as this is the dose that received regulatory approval.
    CI, confidence interval; s.c., subcutaneous.
    Ortega, et al. 2014.
    1

    From N Engl J Med 2014;371:1198–207. Copyright © (2014) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

    Time to first exacerbation

    The time to first exacerbation was extended in the mepolizumab 100 mg s.c. group compared with placebo. The hazard ratio for mepolizumab 100 mg s.c. versus placebo was 0.44 (95% CI: 0.32–0.60; p<0.001).

    MENSA study: Time to first exacerbation

    Graph showing time to first exacerbation in MENSA study with mepolizumab or placebo.

    Data for the mepolizumab 100 mg s.c. dose only are shown, as this is the dose that received regulatory approval.
    s.c., subcutaneous.
    Adapted from Ortega HG, et al. 2014.
    1

    From N Engl J Med 2014; 371:1198–207. Copyright © (2014) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

    Exacerbations resulting in hospitalisation/emergency department visits

    The rate of exacerbations that resulted in either hospitalisation or emergency department visits was analysed as a secondary outcome measure in MENSA. Consistent with the primary outcome, the rate of these events was 61% lower in the mepolizumab 100 mg s.c. group compared with placebo (mean rate: 0.08 events/patient/year with mepolizumab 100 mg s.c. and 0.20 events/patient/year with placebo; p=0.02).

    • Mepolizumab 100 mg s.c. reduced the rate of exacerbations requiring hospitalisation by 69% versus placebo (mean rate: 0.03 events/patient/year with mepolizumab 100 mg s.c. and 0.10 events/patient/year with placebo; p=0.03)

    Statistical significance cannot be inferred due to the hierarchical ’gatekeeping’ approach used. The p values provided are unadjusted for multiple comparisons.

    MENSA study: Rate of clinically significant exacerbations resulting in hospitalisation or emergency department visits

    Graph showing rate of clinically significant exacerbations resulting in hospitalisation or emergency visit with mepolizumab versus placebo in the MENSA study.

    Data for the mepolizumab 100 mg s.c. dose only are shown, as this is the dose that received regulatory approval.
    CI, confidence interval; s.c., subcutaneous.
    Ortega, et al. 2014.
    1

    From N Engl J Med 2014; 371:1198–207. Copyright © (2014) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

    Quality of life changes with mepolizumab

    The outcome measure of asthma-related quality of life refers to the perceived impact of asthma on a patient’s life and activities.4 Quality of life measures have historically included several constructs, such as:5

    • Health status, usually including symptom levels
    • Functional status, e.g. activity levels, capabilities and impairments
    • The patient’s perception of how their disease or treatment impacts their life

    The SGRQ was designed to measure health impairment and perceived well-being (in terms of quality of life) associated with airway diseases, like asthma.4

    The MENSA study used the SGRQ to assess patients’ quality of life. Mepolizumab treatment led to significant improvements in quality of life as measured by SGRQ total scores, compared with placebo treatment. The mean improvement in SGRQ total score exceeded the minimal clinically important difference for the SGRQ.

    Statistical significance cannot be inferred due to the hierarchical ’gatekeeping’ approach used. The p values provided are unadjusted for multiple comparisons.

    MENSA study: Change from baseline in SGRQ with mepolizumab at Week 32

    Graph showing change from baseline in SGRQ with mepolizumab or placebo at Week 32 in the MENSA study.

    Data for the mepolizumab 100 mg s.c. dose only are shown, as this is the dose that received regulatory approval.
    Statistical significance cannot be inferred due to the hierarchical ‘gatekeeping’ approach used. The p values provided are unadjusted for multiple comparisons.
    s.c., subcutaneous; SGRQ, St George’s Respiratory Questionnaire.
    Ortega, et al. 2014.
    1

    From N Engl J Med 2014; 371:1198–207. Copyright © (2014) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

    Lung function

    Mepolizumab 100 mg s.c. was associated with improvements in FEV1 versus placebo at Week 32:

    • Pre-bronchodilation FEV1 change from baseline was 98 mL greater than placebo (p=0.03)
    • Post-bronchodilation FEV1 change from baseline was 138 mL greater than placebo (p=0.004)

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

     

  • Safety summary

    The most common treatment-related adverse events with mepolizumab in the MENSA study were injection-site reactions, headache and fatigue. These events occurred at a similar incidence across mepolizumab treatment arm except for injection-site reactions, which were more common in the s.c. arm.

    Serious adverse events were experienced by more patients in the placebo group than in either mepolizumab group. The incidence of serious adverse event including asthma-related events in both mepolizumab groups (i.v. mepolizumab 7% and s.c. mepolizumab 8%) was nearly half the number experienced in the placebo group (14%).

    MENSA study: Summary of adverse events and serious adverse events with mepolizumab

    Variable

    Placebo
    (n=191)

    Mepolizumab 100 mg s.c.
    (n=194)

    n (%)

    All adverse events

    158 (83)

    152 (78)

    Non-asthma event

    157 (82)

    152 (78)

    Worsening of asthma

    29 (15)

    13 (7)

    Drug-related event, per investigator assessment*

    30 (16)

    39 (20)

    Leading to study withdrawal

    4 (2)

    1 (1)

    Serious adverse events

    During treatment

    27 (14)

    16 (8)

    Drug-related event, per investigator assessment*

    1 (1)

    1 (1)

    Fatal

    1 (1)

    0

    Most common adverse events

    Nasopharyngitis

    46 (24)

    33 (17)

    Headache

    33 (17)

    39 (20)

    Upper respiratory tract infection

    27 (14)

    24 (12)

    Sinusitis

    18 (9)

    18 (9)

    Bronchitis

    18 (9)

    9 (5)

    Oropharyngeal pain

    15 (8)

    7 (4)

    Injection-site reaction

    6 (3)

    17 (9)

    *The status was assigned by investigators while still blinded.
    The most common adverse events were those that were reported in ≥5% of patients in any study group.
    Data for the mepolizumab 100 mg s.c. dose only are shown, as this is the dose that received regulatory approval.
    s.c., subcutaneous
    Adapted from Ortega HG, et al. 2014.
    1

    Immunogenicity

    Nineteen patients (3.3%) across the three treatment groups had confirmed positive anti-mepolizumab antibody results for at least one visit after baseline.

    The positive test results of five of the 21 ADA-positive patients were considered unrelated to mepolizumab treatment because patients were in the placebo group, and two had pre-existing antibodies at baseline.

    No patients tested positive for neutralising activity.

  • Discussion

    In MENSA, a placebo-controlled trial of a specific severe asthma patient population previously defined by the DREAM study, mepolizumab reduced the risk of exacerbations by approximately 50% when given both i.v. (mean rate: 0.93 events/patient/year) and s.c. (mean rate: 0.83 events/patient/year) versus placebo (mean rate: 1.74 events/patient/year). The rate of adverse events was similar across treatment groups.

    Differences in exacerbations versus placebo in both mepolizumab groups were significant after adjustment. The mepolizumab 100 mg s.c. dose was also statistically significant versus placebo on an unadjusted basis for all the endpoints in the hierarchy, together with the rate of exacerbations resulting in hospitalisation and/or emergency department visit after adjustment for multiple testing (p=0.03). This was not the case for the i.v. dose (unadjusted p value: 0.30).

  • Study design and patient baseline characteristics

    MENSA was a multicentre, randomised, double-blind, double-dummy, placebo-controlled trial lasting 32 weeks.

    MENSA study design

    Diagram of MENSA study design.

    Data for the mepolizumab 100 mg s.c. dose only are shown, as this is the dose that received regulatory approval.
    ICS, inhaled corticosteroids; s.c., subcutaneous.
    Adapted from Ortega HG, et al. 2014.
    1

    From N Engl J Med 2014; 371:1198–207. Copyright © (2014) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

    Baseline patient characteristics

    Characteristic

    Placebo
    (n=191)

    Mepolizumab 100 mg s.c.
    (n=194)

    Mean age (range) – years

    49 (12–76)

    51 (12–81)

    Female sex – n (%)

    107 (56)

    116 (60)

    BMI – kg/m2†

    28.0 ± 5.6

    27.6 ± 6.2

    Former smoker – n (%)

    57 (30)

    50 (26)

    Duration of asthma – years

    19.5 ± 14.6

    20.5 ± 12.9

    Use of oral glucocorticoids

    Maintenance use – n (%)

    44 (23)

    52 (27)

    Mean daily dose (range) – mg

    15.1 (5–80)

    12.6 (2–50)

    Allergic rhinitis – n (%)

    95 (50)

    95 (49)

    FEV1

    Before bronchodilation – L§

    1.86 ± 0.63

    1.73 ± 0.66

    Predicted value pre-bronchodilation – %

    62.4 ± 18.1

    59.3 ± 17.5

    Reversibility – %

    27.4 ± 20.8

    27.9 ± 24.0

    FEV1:FVC ratio – %

    64 ± 13

    63 ± 13

    Morning peak expiratory flow – L/min

    277 ± 106

    255 ± 108

    ACQ scoreǁ

    2.28 ± 1.19

    2.2.6 ± 1.27

    SGRQ score#

    46.9 ± 19.8

    47.9 ± 19.4

    Loge geometric mean IgE – cells/µL**

    150 ± 1.5

    150 ± 1.5

    Loge geometric mean blood eosinophil count – cells/µL††

    320 ± 938

    290 ± 1050

    Asthma exacerbations

    Severe episodes in previous year – n/patient

    3.6 ± 2.8

    3.8 ± 2.7

    Necessitating hospitalisation in previous year – n (%)

    35 (18)

    33 (17)

    History of asthma-related intubation – n (%)

    3 (2)

    8 (4)

    *Plus–minus values are means (or geometric means) ± SD. There were no significant between-group differences at baseline. FEV1 denotes forced expiratory volume in 1 second, and FVC forced vital capacity.
    BMI = weight in kg divided by square of height in m.
    The listed value is the prednisone equivalent.
    §
    Reversibility was measured at baseline.
    The percent of the predicted value pre-bronchodilation was assessed at the screening visit.
    ǁThe FEV1: FVC ratio was calculated by dividing FEV1 by FVC and multiplying by 100 to express as a percentage.
    #Scores on the ACQ range from 0–6, with higher scores indicating worse control. A change of 0.5 points in the minimal clinically important difference.
    **Scores on the SGRQ range from 0–100, with higher scores indicating worse function. A change of 4 points is considered to be clinically relevance.
    ††Values below the lower limit of quantification were replaced by a value that was 50% of the lower limit of quantification.
    Data for the mepolizumab 100 mg s.c. dose only are shown, as this is the dose that received regulatory approval.

    ACQ, Asthma Control Questionnaire; ADA, adenosine deaminase; BMI, body mass index; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; IgE, immunoglobulin E; s.c., subcutaneous; SD, standard deviation; SGRQ, St George’s Respiratory Questionnaire.
    Adapted from Ortega HG, et al. 2014.
    1

This medical product is subject to additional monitoring.

References:

  1. Ortega HG, et al. N Engl J Med 2014; 371:1198–207.
  2. Bel EH, et al. N Engl J Med 2014; 371:1189–97.
  3. Nucala (Mepolizumab). Summary of product characteristics 2016.
  4. Jones PW, et al. Resp Med 1991; 85(Suppl. B):25–31.
  5. Barley EA, Jones PW. Eur Resp J 1999; 14:591–6.

NUCALA (mepolizumab), 100 mg pulver till injektionsvätska, lösning, 100 mg injektionsvätska, lösning i förfylld spruta, 100 mg injektionsvätska, lösning i förfylld penna. Medel vid obstruktiva luftvägssjukdomar, övriga systemiska medel för obstruktiva lungsjukdomar
Rx (F), ATC kod: R03DX09.
Terapeutiska indikationer: Nucala är indicerat som tilläggsbehandling vid svår refraktär eosinofil astma hos vuxna patienter, ungdomar och barn från 6 års ålder. (För barn 6 till 11 år är endast Nucala 100 mg pulver till injektionsvätska godkänd). Dosering: Rekommenderad dos för mepolizumab hos vuxna och ungdomar från 12 års ålder är 100 mg administrerat subkutant en gång var fjärde vecka. Rekommenderad dos för mepolizumab hos barn från 6 till 11 år är 40 mg administrerat subkutant en gång var fjärde vecka. Nucala är avsett för långtidsbehandling. Behovet av fortsatt behandling ska omprövas minst en gång om året baserat på läkarens bedömning av sjukdomens svårighetsgrad och patientens kontroll över exacerbationer. Ytterligare information: I kliniska studier visades effekt hos följande subpopulation: aktuell standardbehandling som minst inkluderade högdosbehandling med inhalerade kortikosteroider (ICS) plus ytterligare en underhållsbehandling, två eller fler exacerbationer under de senaste 12 månaderna eller beroende av systemiska kortikosteroider samt blodeosinofilvärde minst 150 celler/μl vid behandlingsstart eller minst 300 celler/μl under de senaste 12 månaderna. Kontraindikationer: Överkänslighet mot den aktiva substansen eller mot något hjälpämne. Varningar och försiktighet: För att underlätta spårbarheten av biologiska läkemedel ska den administrerade produktens namn och batchnummer tydligt anges i patientjournalen. Mepolizumab ska inte användas för att behandla akuta astmaexacerbationer. Astmarelaterade biverkningar eller exacerbationer kan förekomma under behandling. Abrupt utsättning av kortikosteroider efter behandlingsstart med mepolizumab rekommenderas ej. Akuta och fördröjda systemiska reaktioner, inklusive överkänslighetsreaktioner (t.ex. anafylaxi, urtikaria, angioödem, hudutslag, bronkospasm, hypotoni), har förekommit efter administrering av mepolizumab. Patienter med befintliga maskinfektioner ska behandlas innan behandling med mepolizumab påbörjas. Om patienten blir infekterad under behandling med Nucala och inte svarar på maskmedel ska temporär utsättning av Nucala övervägas. 
Subventionsbegränsning: Subventioneras endast för patienter med svår eosinofil astma som är otillräckligt kontrollerade trots standardbehandling och antingen behandling med perorala kortikosteroider (OCS) i doser som ger ökad risk för biverkningar eller när OCS är kontraindicerat.

För fullständig förskrivningsinformation och pris, se www.fass.se. Datum för översyn av produktresumén: 2021-06-15. 
GlaxoSmithKline AB, Box 516, 169 29 Solna. Tel 08-638 93 00, www.se.gsk.com.