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Severe refractory eosinophilic asthma study (DREAM)

Mepolizumab in severe refractory eosinophilic asthma: Dose Ranging Efficacy and Safety with Mepolizumab in Severe Asthma (DREAM)

Pavord ID, et al. Lancet 2012;380:651–59.1

DREAM was a 12-month Phase IIb/III dose-ranging study. It examined the effects of mepolizumab 75 mg, 250 mg and 750 mg administered i.v. on the frequency of clinically significant asthma exacerbations. The licensed mepolizumab dose and administration route is 100 mg s.c.2

Patients were required to have a history of at least two exacerbations requiring systemic corticosteroid treatment in the previous year, and to be using a high-dose ICS and a second controller with or without maintenance OCS. Furthermore, eligible patients were to have evidence of eosinophilic inflammation according to one or more of a range of criteria, including sputum eosinophil count and peripheral blood eosinophil count.

The study concluded that mepolizumab, as add-on therapy in patients with uncontrolled severe refractory eosinophilic asthma, produced a clinically and statistically significant reduction in exacerbation rate over 1 year compared with placebo. The patients who responded best to mepolizumab had a baseline blood eosinophil count of ≥150 cells/µL. Mepolizumab were generally well tolerated and the rate of adverse events was similar across treatment arms.

  • Patient eligibility

    Selected inclusion criteria

    Selected exclusion criteria

    • Clinical diagnosis of asthma
    • At least two exacerbations requiring systemic corticosteroid treatment in the previous year
    • Evidence of eosinophilic inflammation at study entry or in the previous year, demonstrated by:
      • Sputum eosinophil count ≥3%, OR:
      • FENO ≥50 ppb, OR:
      • Asthma-related peripheral blood eosinophil count ≥300 cells/µL, OR:
      • Prompt deterioration of asthma control after ≤25% reduction in regular maintenance ICS or OCS
    • Present smoking or >10 pack-year smoking history
    • Parasitic infection in the previous 6 months
    • Substantial uncontrolled morbidity
    • Possibility of pregnancy
    • History of poor treatment adherence
    • Treatment in the previous 130 days with omalizumab or another biologic for inflammatory disease
    • Previous participation in any mepolizumab study


       

    FENO, fraction of exhaled nitric oxide; ICS, inhaled corticosteroids; ppb, parts per billion; OCS, oral corticosteroids.

  • Endpoints

    • Primary endpoint: rate of clinically significant asthma exacerbations. Exacerbations were defined as worsening of asthma requiring use of oral/systemic corticosteroids for 3 or more days, hospital admission or a visit to the emergency department
    • Additional measurements: FEV1; ACQ and AQLQ scores; blood and sputum eosinophil counts; safety
  • Efficacy

    Effect of mepolizumab on prespecified efficacy outcomes

    Efficacy endpoints at Week 52

     

    Placebo group (n=155)

    Mepolizumab 75 mg i.v.* (n=153)

    Mepolizumab 250 mg i.v.* (n=152)

    Mepolizumab 750 mg i.v.* (n=156)

    Rate of clinically significant exacerbations/patient/year†

          Ratio to placebo

    2.40 (0.11)

    1.24 (0.12)

    0.52 (0.39 to 0.69)

    1.46 (0.11)

    0.61 (0.46 to 0.81)

    1.15 (0.12)

    0.48 (0.36 to 0.64)

    Rate of exacerbation requiring admission or visit to emergency department/patient/year†

          Ratio to placebo

    0.43 (0.24)

     

    0.17 (0.30)

     

    0.40 (0.19 to 0.81)

    0.25 (0.26)

     

    0.58 (0.30 to 1.12)

    0.22 (0.26)

     

    0.52 (0.27 to 1.02)

    Rate of exacerbations requiring admission†

          Ratio to placebo

    0.18 (0.29)

    0.11 (0.35)

     

    0.61 (0.28 to 1.33)

    0.12 (0.32)

     

    0.65 (0.31 to 1.39)

    0.07 (0.39)

     

    0.37 (0.16 to 0.88)

    Change of prebronchodilator FEV1 from baseline (mL)‡

          Difference from placebo

    60 (38)

    121 (38)


    61 (–39 to 161)

    140 (37)


    81 (–19 to 180)

    115 (37)

     

    56 (–43 to 155)

    Change in score on asthma control questionnaire from baseline‡

          Difference from placebo

    –0.59 (0.09)

     

    –0.75 (0.09)

     

     

    –0.16 (–0.39 to 0.07)

    –0.87 (0.09)

     

     

    –0.27 (–0.51 to 0.04)

    –0.80 (0.09)

     

     

    –0.20 (–0.43 to 0.03)

    Change in score on asthma quality of life questionnaire from baseline‡

          Difference from placebo

    0.71 (0.09)

    0.80 (0.09)

     

     

    0.08 (–0.16 to 0.32)

    0.77 (0.09)

     

     

    0.05 (–0.19 to 0.29)

    0.93 (0.09)

     

     

    0.22 (–0.02 to 0.46)

    Ratio of geometric mean FENO to baseline†

          Ratio to placebo

    1.01 (0.06)

    0.99 (0.06)

    0.97 (0.82 to 1.15)

    0.91 (0.06)

    0.90 (0.76 to 1.06)

    0.97 (0.06)

    0.96 (0.81 to 1.13)

    Data in parentheses are 95% CI unless otherwise stated.

    *This is an unlicensed dose/route of administration.

    †Data are mean (SE logs).
    ‡Data are mean (SE).

    CI, confidence interval; FENO, exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; i.v., intravenous.

    Pavord, et al. 2012.1

    Adapted from Pavord IV, et al. 2012.1

    Effect of mepolizumab on exacerbations

    Cumulative exacerbations in each treatment group over time

    Exacerbations over 13 months with mepolizumab or placebo.

    *This is an unlicensed dose/route of administration.

    i.v., intravenous.
    Pavord, et al. 2012.
    1

    Reprinted from Lancet, Vol 38, Pavord ID et al, Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial, Page No. 654, Copyright (2012), with permission from Elsevier.

    Effect of mepolizumab on blood and sputum eosinophil counts

    Change in blood and sputum eosinophil counts

    Graph showing change in blood and sputum count with mepolizumab or placebo.

    *This is an unlicensed dose/route of administration.

    Blood eosinophil counts were performed for all patients at all study visits. Sputum eosinophil counts were performed in a subset of 94 patients (15%) from sites with previous experience in sputum collection and processing, and only at baseline or screening, and Weeks 4, 16 and 52.
    Error bars indicate SEs.

    i.v., intravenous; SE, standard error.
    Pavord, et al. 2012
    .1

    Reprinted from Lancet, Vol 38, Pavord ID et al, Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial, Page No. 654, Copyright (2012), with permission from Elsevier.

    Effect of mepolizumab on lung function

    Change in pre-bronchodilator FEV1 compared with baseline

    Graph showing change in pre-bronchodilator FEV1 with mepolizumab or placebo compared with baseline.

    *This is an unlicensed dose/route of administration.

    Error bars indicate SEs.
    FEV1, forced expiratory volume in 1 second; i.v., intravenous; SE, standard error.
    Pavord, et al. 2012.1

    Reprinted from Lancet, Vol 38, Pavord ID et al, Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial, Page No. 654, Copyright (2012), with permission from Elsevier.

    Effect of mepolizumab on health-related quality of life

    Change in ACQ and AQLQ compared with baseline

    Graph showing change in ACQ and AQLQ from baseline with mepolizumab

    *This is an unlicensed dose/route of administration.

    Error bars indicate SEs.
    ACQ, Asthma Control Questionnaire; AQLQ, Asthma Quality of Life Questionnaire; i.v., intravenous; SE, standard error.
    Pavord, et al. 2012.1

    Reprinted from Lancet, Vol 38, Pavord ID et al, Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial, Page No. 654, Copyright (2012), with permission from Elsevier.

    Patients most responsive to mepolizumab

    A subanalysis of the DREAM patient population identified clear clinical benefits in patients with a blood eosinophil count of ≥150 cells/µL at screening or ≥300 cells/µL in the previous 12 months.3

    Sputum eosinophils did not predict treatment response with mepolizumab.3

    Effect of mepolizumab on exacerbation rate

    Graph showing the effect of mepolizumab on exacerbation rate correlated with blood eosinophil counts at screening.

    The annualised rate of exacerbations for subjects treated with mepolizumab is compared with the rate of exacerbations on placebo. To determine the percent reduction in exacerbations due to treatment with mepolizumab, the rate ratio is subtracted from 1. For a rate ratio that is equal to 1, there is no reduction compared with placebo response. The mean rate of reduction in exacerbations is higher (72%) in those that have a screening eosinophil count of ≥150 cells/µL compared with those who are <150 cells/µL at screening (30%).

    Katz et al. 2014.3

  • Safety summary

    The general safety profile of mepolizumab was similar to placebo. The most frequently reported adverse event in the DREAM study was headache, which was reported by 17% (n=27) of patients in the placebo group and 21% of patients (n=32) in each mepolizumab group.

    The proportion of patients with any adverse event ranged from 78–82% across all all four study groups. Serious adverse events occurred in 12–16% of patients across treatment groups.

    Three patients died during the study; two were in the mepolizumab 250 mg i.v. group and one in the mepolizumab 750 mg i.v. group. None of the deaths were deemed to be related to mepolizumab.

    DREAM study: Summary of adverse events and serious adverse events with mepolizumab.

     

    Placebo group (n=155)

    Mepolizumab 75 mg i.v.* (n=153)

    Mepolizumab 250 mg i.v.* (n=152)*

    Mepolizumab 750 mg i.v.* (n=156)*

    Adverse events leading to withdrawal

    6 (4%)

    5 (3%)

    8 (5%)

    9 (6%)

    Fatal adverse events

    0

    0

    2 (1%)

    1 (<1%)

    Any on-treatment serious adverse events†
          Respiratory, thoracic and mediastinal disorders
          Infections
          Cardiac disorders
          Injury, poisoning and procedural complications
          Gastrointestinal disorders
          Nervous system disorders
          Renal and urinary disorders
          Vascular disorders
     

    25 (16%)

    17 (11%)

    5 (3%)
    1 (<1%)
    2 (1%)

    1 (<1%)
    3 (2%)
    2 (1%)
    0

    20 (13%)

    11 (7%)

    7 (5%)
    2 (1%)
    1 (<1%)

    0
    0
    0
    2 (1%)

    24 (16%)

    16 (11%)

    3 (2%)
    1 (<1%)
    2 (1%)
     

    2 (1%)
    0
    2 (1%)
    1 (<1%)

    19 (12%)

    10 (6%)

    5 (3%)
    4 (3%)
    1 (<1%)

    1 (<1%)
    1 (<1%)
    0
    1 (<1%)

    *This is an unlicensed dose/route of administration.
    †Patients can have more than one event; events shown are those reported in four or more patients across all groups.

    i.v., intravenous.
    Adapted from Pavord ID, et al. 2012.1

    Immunogenicity

    Six patients (1%) tested positive for mepolizumab anti-drug antibodies. There were two false–positive patients (1%) in the placebo group.

    Neutralising antibodies were not detected in any patients.

  • Discussion

    The DREAM study defined a specific population of severe asthma patients who responded to mepolizumab. This population experienced a significant reduction in asthma exacerbations versus placebo, together with reduced blood and sputum eosinophil counts and good tolerability, over 12 months.1Numerical changes in lung function and quality of life measures were observed, but were not significantly different from placebo.1

    These results indicate a likely independence between severe asthma symptom control and exacerbation risk, which could indicate a necessity for different management strategies in this population and improvements in clinical study design.1

    A subanalysis of the DREAM study also identified the patients who would receive clinical benefit from mepolizumab as having a blood eosinophil count of ≥150 cells/μL at screening or ≥300 cells/μL in the prior 12 months.3There was no correlation with sputum eosinophil count and clinical benefit.3

    These data were used to inform the design of future clinical studies.

  • Study design and patient baseline characteristics

    DREAM was a multicentre, double-blind, placebo-controlled trial lasting 52 weeks.

    DREAM study design

    Diagram of DREAM study design.

    *This is an unlicensed dose/route of administration.

    i.v., intravenous.
    Pavord, et al. 2012.1

    Reprinted from Lancet, Vol 38, Pavord ID et al, Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial, Page No. 654, Copyright (2012), with permission from Elsevier.

    Baseline patient characteristics

     

    Placebo
    (n=155)

    Mepolizumab 75 mg i.v. * (n=153)

    Mepolizumab 250 mg i.v. * (n=152)

    Mepolizumab 750 mg i.v. * (n=156)

    Women

    97 (63%)

    104 (68%)

    93 (61%)

    93 (60%)

    Age (years)

    46.4 (11.3)

    50.2 (10.8)

    49.4 (11.6)

    48.6 (11.1)

    White ethnic origin

    140 (90%)

    139 (91%)

    135 (89%)

    140 (90%)

    BMI (kg/m2)

    28.3 (6.1)

    28.4 (6.)

    28.3 (5.9)

    28.9 (5.8)

    Former smoker

    34 (22%)

    31 (20%)

    31 (20%)

    37 (24%)

    Duration of asthma (years)

    17.9 (13.7)

    19.0 (14.1)

    20.4 (13.9)

    19.1 (15.3)

    Use of long-acting β-agonists

    150 (97%)

    143 (93%)

    145 (95%)

    151 (97%)

    Maintenance use of OCS
          Daily dose (mg)†

    45 (29%)
    10 (10–20)

    46 (30%)
    10 (10–20)

    50 (33%)
    10 (8–20)

    47 (30%)
    13 (10–20)

    Nasal polyps‡

    16 (10%)

    11 (7%)

    22 (14%)

    13 (8%)

    Allergy§

    81 (52%)

    78 (51%)

    76 (50%)

    76 (49%)

    Prebronchodilator FEV1 (mL)

    1900 (653)

    1810 (637)

    1850 (672)

    1950 (670)

    Postbronchodilator FEV1 (mL)

    2290 (773)

    2150 (695)

    2220 (732)

    2260 (784)

    Percentage of predicted prebronchodilator FEV1

    59% (15)

    60% (16)

    59% (17)

    61% (16)

    Postbronchodilator FEV1/FVC

    67% (12)

    68% (12)

    66% (13)

    68% (20)

    Score on asthma control questionnaire

    2.5 (1.1)

    2.2 (1.1)

    2.4 (1.1)

    2.3 (1.2)

    Score on asthma quality of life questionnaire

    4.1 (1.2)

    4.2 (1.2)

    4.2 (1.2)

    4.2 (1.2)

    Blood eosinophil count (x109/L)¶ǁ

    0.28 (1.01)

    0.25 (0.95)

    0.23 (1.20)

    0.25 (0.93)

    Sputum eosinophil count (%)¶ǁ

    6.8% (2.01); n=24

    13.9% (1.47); n=18

    8.1% (1.79); n=23

    5.8% (2.15); n=21

    FENO (ppb)¶ǁ

    33.7 (0.79)

    29.2 (0.76)

    31.4 (0.80)

    31.6 (0.81)

    Severe exacerbations in the previous year

    3.7 (3.8)

    3.7 (3.1)

    3.4 (2.4)

    3.5 (2.8)

    Exacerbations requiring administration in previous year

    40 (26%)

    35 (23%)

    36 (24%)

    39 (25%)

    Data are n (%), mean (SD) or median (IQR), unless otherwise stated.
    *This is an unlicensed dose/route of administration.
    †Prednisolone equivalent.
    ‡Self-reported.
    §Positive allergic status was defined as a positive radioallergosorbent test for any of four specified aeroallergens.
    ¶ Values below lower limit of quantification were replaced by half the lower limit of quantification.
    ǁ Geometric mean on long scale.

    BMI, body mass index; FENO, fraction of exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; IQR, inter-quartile range; i.v., intravenous; OCS, oral corticosteroids; ppb, parts per billion; SD, standard deviation.
    Adapted from Pavord ID, et al. 2012.1

This medical product is subject to additional monitoring.

References:

  1. Pavord ID et al. Lancet 2012; 380:651–9.
  2. Mepolizumab. Summary of product characteristics 2016.
  3. Katz LE et al. Ann Am Thorac Soc 2014; 11:531–6.

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.