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Eosinophils, IL-5 and their role in severe asthma

Eosinophilic inflammation

Normal protective immune response

Eosinophils are a leukocyte subclass involved in host defence against parasitic infections. They also form part of the inflammatory response, and are important mediators of the allergic response and asthma pathogenesis.1

Eosinophils normally represent a low proportion of the total white blood count.1They are not normally present in healthy lungs, but are thought to play a major role in maintaining airway inflammation in chronic asthma.2-3

The cytokine IL-5 is the main promoter of eosinophil production, maturation and release from bone marrow and is responsible for elevating blood eosinophil levels.1IL-5 also activates eosinophils and prolongs their survival in the circulation, as well as providing an essential signal for their migration into tissue.1 4-5

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Pathologic effects of eosinophils

  • Eosinophilic inflammation in severe asthma

    Eosinophilic inflammation is a predictor of asthma exacerbations.6 Patients with severe asthma may have few symptoms, but have been shown to be at increased risk of an exacerbation.7

    In a UK cluster analysis of 187 patients with refractory asthma managed in secondary care, 36% were identified as having eosinophilic inflammation.8In a Brazilian cross-sectional study of 74 patients with severe asthma, 79% had eosinophilic disease, marked by sputum eosinophil levels ≥3%.9

    Clinical studies have shown a central role for the eosinophil in asthma pathogenesis, including airway hyperresponsiveness induction, elevated mucus production, airway narrowing and airway remodelling.110-11These are all characteristic features of asthma that result from tissue damage and organ dysfunction, with disease severity correlating with peripheral blood eosinophil levels.1 10-11

  • Th2 expression changes in severe asthma

    T cells respond to specific antigens and, in asthma, play an important role in the inflammatory response process through the release of type 2 cytokines. This can trigger airway remodelling through reticular basement membrane thickening, goblet cell metaplasia/hyperplasia, mucus hyperproduction, airway smooth muscle hyperplasia/hypertrophy and angiogenesis.12It is becoming evident that Th2 inflammation is a characteristic of certain asthma phenotypes.13-14 Th2 cells play a role in both severe asthma and severe allergic asthma. However, emerging evidence suggests that these two asthma phenotypes differ at the level of the effector cell. In severe asthma associated with eosinophilic inflammation the effector cell is the eosinophil, whilst in severe allergic asthma the main effector cells are believed to be mast cells and basophils, both of which express IgE receptors.15

IL-5 as a treatment target

IL-5 is a key player in eosinophilic inflammation

IL-5 is a logical therapeutic target for eosinophilic disorders such as severe refractory eosinophilic asthma, due to its key role in mediating eosinophil maturation and release from bone marrow prior to migration into affected tissues. Its specific effect on eosinophil development and recruitment is an attractive feature as it reduces the likelihood of off-topic or adverse immune effects.16

There are also other additional points in the asthma inflammatory pathway with the potential for specific biologic intervention.

Investigate the pathways towards eosinophilic inflammation

What effect does IL-5 blockade have on blood eosinophil levels?

IL-5 is a logical therapeutic target for eosinophilic disorders such as severe refractory eosinophilic asthma due to its specific role in modulating eosinophil development and recruitment.16

Mepolizumab is a humanised mAb (IgG1, kappa) that targets human IL-5 with high affinity and specificity.22It blocks IL-5 bioactivity by binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface. This inhibits IL-5 signalling and reduces eosinophil production and recruitment.1623

Initial in vivo studies with mepolizumab

Mepolizumab’s in vivo activity was first demonstrated in mouse models of allergic airway disease.

Administration of mouse anti-IL-5 antibody to ovalbumin-sensitised mice demonstrated reduced eosinophilic airway inflammation and a reduced response to methacholine challenge.24In addition, IL-5 knockout mice did not show increased blood and airway eosinophils, airway hyperreactivity or pulmonary injury compared with control animals in a mouse asthma model.25

Together, these observations demonstrated a significant role for IL-5 and eosinophils in asthma pathogenesis. Preclinical studies demonstrated that the features of asthma were significantly improved when IL-5 signalling is defective or eosinophils are absent.22

  • Mepolizumab pharmacokinetics

    Mepolizumab’s pharmacokinetic properties have been studied in both primates and humans.

    Pharmacokinetic properties of mepolizumab

    AUC, area under the curve; Cmax, maximal serum concentration; i.v., intravenous; s.c., subcutaneous.

    Adapted from Smith, et al. 2011,16Abonia, et al. 201122and the European Medicines Agency 2010.26

  • Primate studies

    Mepolizumab was tested in preclinical studies in cynomolgus monkeys to inform on its efficacy and safety profiles.27Primate studies were required as they represent the only animal model with cross-reactivity between mepolizumab and IL-5 endogenous to the animal.27The primate studies showed that a single dose of mepolizumab suppressed eosinophils in bronchoalveolar lavage when the animals were challenged with inhalation of the parasitic nematode Ascaris suum. However, mepolizumab had no impact on the acute bronchoconstrictor response typically occurring with these inhalations.27These studies also demonstrated that mepolizumab suppressed peripheral blood eosinophils. The animals received either i.v. or s.c. administered mepolizumab. The drug was well tolerated, with no effect on body temperature or on cardiovascular, respiratory or renal function in male monkeys.27

  • Pharmacodynamics

    Mepolizumab’s pharmacodynamic profile was first studied in humans in a trial performed by Leckie, et al. 2000.28

    This was designed as double-blind, randomised, placebo-controlled, parallel-group trial of a single i.v. infusion of mepolizumab at doses of 2.5mg/kg (n=8) and 10mg/kg (n=8) in men with mild allergic asthma.28

    The patients were assessed for airway hyperresponsiveness and blood and sputum eosinophil counts. The study demonstrated long-lasting reduction in both peripheral blood and sputum eosinophils after treatment. However, mepolizumab did not protect against allergen-induced airway hyperresponsiveness.28

    Effect of mepolizumab on blood eosinophil count

    Graph showing mepolizumab lowers blood eosinophil count at both a 2.5 mg/kg and 10 mg/kg dose or placebo.

    Graph is adapted by GSK based on ref. 28.

    Immunogenic potential of mepolizumab

    Mepolizumab has a low immunogenic potential in humans based on both the low incidence and titre of antidrug antibodies and neutralising antibodies. The data demonstrated a low risk for loss of efficacy and adverse events.29

    Six percent of patients (15/260) in the placebo-controlled trials developed anti-mepolizumab antibodies after receiving at least one dose of mepolizumab.31 Neutralising antibodies were detected in one patient.30Anti-mepolizumab antibodies did not noticeably impact mepolizumab’s pharmacokinetics or pharmacodynamics in the majority of patients, and there was no evidence of a correlation between antibody titres and change in blood eosinophil level.30The development of antibodies to protein and peptide therapies is consistent with the potentially immunogenic properties of these agents.30

References:

  1. Rothenberg M. N Engl J Med 1998;338:1592–600. 
  2. Wadsworth S, et al. J Asthma Allergy 2011;4:77–86.
  3. Walsh GM. Expert Opin Emerg Drugs 2012;17:37–42.
  4. Lopez AF, et al. J Exp Med 1988;167:219–24. 
  5. Rosenberg HF, et al. J Allergy Clin Immunol 2007;119:1303–10.
  6. Malinovschi A, et al. J Allergy Clin Immunol 2013;132:821–7.e1–5.
  7. Bradding P, Green RH. Curr Opin Allergy Clin Immunol 2010;10:54–9.
  8. Haldar P, et al. Am J Respir Crit Care Med 2008;178:218–24.
  9. de Carvalho-Pinto RM, et al. Respir Med 2012;106:47–56. 
  10. Bousquet J, et al. N Engl J Med 1990;323:1033–9.
  11. Flood-Page P, et al. Am J Respir Crit Care Med 2007;176:1062–71.
  12. Barnes PJ. Asthma in Harrison's Principles of Internal Medicine. Chapter 254. Available at http://accessmedicine.mhmedical.com/ (Last accessed August 2015)
  13. Brusselle GG, et al. Nat Med 2013;19:977–9.
  14. Chung KF, et al. Eur Respir J 2014;43:343–73.
  15. Wener RRL, Bel EH. Eur Respir Rev 2013;22:227–35. 
  16. Smith DA, et al. Clin Pharmacokinet 2011;50:215–27.
  17. Kindt TJ, et al. Kuby Immunology. 6th ed. W.H. Freeman and Company, Basingstoke, UK: 2007.
  18. Naik SR, Wala SM. Recent Pat Inflamm Allergy Drug Discov 2013;7:62–95.
  19. Wenzel SE. Nat Med 2012;18:716–25.
  20. Holgate ST, Sly PD. Asthma Pathogenesis. Middleton’s Allergy: Principles and Practice. Saunders Elsevier, Philadelphia, PA, USA: 2014.
  21. Woo Y, et al. Immune Netw 2014;14:171–81. 
  22. Abonia JP, Putnam PE. Expert Rev Clin Immunol 2011;7:411–17.
  23. Zia-Amirhosseini P, et al. J Pharmacol Experimental Therapeut 1999;291:1060–7.
  24. Hamelmann E, et al. Am J Respir Crit Care Med 1999;160:934–41.
  25. Foster PS, et al. J Exp Med 1996;183:195–201.
  26. European Medicines Agency. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2010/01/WC500060631.pdf. Last accessed November 2015.
  27. Hart TK, et al. J Allergy Clin Immunol 2001;108:250–7.
  28. Leckie MJ, et al. Lancet 2000;356:2144–8.
  29. Pavord ID et al. Lancet 2012;380:651–659. 
  30. Mepolizumab SmPC; GlaxoSmithKline 2016

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. 
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