This document discusses various biologic therapies for treating severe asthma, including anti-IgE, anti-IL5, and anti-IL4 receptor therapies. It provides details on currently approved therapies such as omalizumab, mepolizumab, benralizumab, dupilumab, and reslizumab. For each therapy, it outlines the mechanisms of action, clinical trial results demonstrating efficacy in reducing exacerbations and corticosteroid use, safety profiles, and criteria for use in treating severe eosinophilic asthma. It also compares the potential advantages of different anti-IL5 biologics like benralizumab.

1. Newer Biologics in asthma
management

2. How commonis severeasthma?
Hekking et al, JACI 2015
Hekking et al, JACI 2015

3. * Off-label; data only with budesonide-formoterol (bud-form)
† Off-label; separate or combination ICS and SABA inhalers
STEP 2
Daily low dose inhaled corticosteroid (ICS),
or as-needed low dose ICS-formoterol *
STEP 3
Low dose
ICS-LABA
STEP 4
Medium dose
ICS-LABA
Leukotriene receptor antagonist (LTRA), or
low dose ICS taken whenever SABA taken †
As-needed low dose ICS-formoterol *
As-needed short-acting β2 -agonist (SABA)
Medium dose
ICS, or low dose
ICS+LTRA #
High dose
ICS, add-on
tiotropium, or
add-on LTRA #
Add low dose
OCS, but
consider
side-effects
As-needed low dose ICS-formoterol ‡
STEP 5
High dose
ICS-LABA
Refer for
phenotypic
assessment
± add-on
therapy,
e.g.tiotropium,
anti-IgE,
anti-IL5/5R,
anti-IL4R
Symptoms
Exacerbations
Side-effects
Lung function
Patient satisfaction
Confirmation of diagnosis if necessary Symptom control
& modifiable risk factors (including lung function)
Comorbidities Inhaler technique & adherence Patient
goals
Treatment of modifiable risk
factors & comorbidities
Non-pharmacological strategies
Education & skills training
Asthma medications
1
© Global Initiative for Asthma, www.ginasthma.org
STEP 1
As-needed
low dose
ICS-formoterol *
Low dose ICS
taken whenever
SABA is taken†
‡ Low-dose ICS-form is the reliever for patients prescribed
bud-form or BDP-form maintenance and reliever therapy
# Consider adding HDM SLIT for sensitized patients with
allergic rhinitis and FEV >70% predicted
PREFERRED
CONTROLLER
to prevent exacerbations
and control symptoms
Other
controller options
Other
reliever option
PREFERRED
RELIEVER
Adults & adolescents 12+ years
Personalized asthma management:
Assess, Adjust, Review response
Asthma medication options:
Adjust treatment up and down for
individual patient needs
anti-IgE,
anti-IL5/5R,
anti-IL4R

4. © Global Initiative for Asthma, www.ginasthma.org
GINA GUIDELINE 2019 UPDATE

5. © Global Initiative for Asthma, www.ginasthma.org

6. © Global Initiative for Asthma, www.ginasthma.org

7. © Global Initiative for Asthma, www.ginasthma.org

8. Activationtype2-highandtype2-lowinflammatorypathways

9. Endotypesin asthmaand biologictargets
currently in useor underinvestigation.

10. Analytic Framework:Asthma Managementwith
Biologic Therapies
https://icer-review.org/wp-content/uploads/2018/04/ICER_Asthma_Draft_Report_092418v1.pdf

11. BiologicApprovedforUseorStudiedinSevereAsthma
• L.A.
MankaandM.E.Wechsler/AnnAllergyAsthmaImmunol121(2018)
406 413
L.A. MankaandM.E.Wechsler/AnnAllergyAsthmaImmunol121(2018)406413

13. Anti-IgE therapy
• The anti-IgE monoclonal antibody, omalizumab, has been
shown to reduce the frequency of asthma exacerbations by
approximately 50%.
• Omalizumab is reserved for patients with:
• Difficult to control asthma who have documented allergies
and
• Whose asthma symptoms remain uncontrolled despite ICS
therapy
Kim H et al. Allergy, Asthma & Clinical Immunology 2011, 7(Suppl 1):S2

14. Biologics -- Anti-IgE
• Not controlled on GINA step 4 (or 5 with high dose ICS)
• Used in atopic or non-atopic asthma
• SC, dosing based on weight
• Q2-4 weeks based on dose/weight
• A/E: <1% with anaphylaxis, but 12% with injection site reaction
• May have greater exacerbation prevention effect in those with
eos >300
• Persons with high allergen IgE but low total IgE may benefit
from omalizumab
UpToDate, Tx of Sev Asthma in adol and adults
Omalizumab

15. Omalizumab
• Omalizumab approved by US FDA for use in chronic spontaneous urticaria.
• Dosage in urticaria is independent of body weight, serum IgE levels, and
type of urticaria.
• Precautions for Omalizumab-associated anaphylaxis.
• Putative mechanisms of omalizumab in urticaria
Biologics: Targets and Therapy 2018:12 135–142

16. Anti IL-5 Therapy
•
•
•
•
Mepolizumab and Reslizumab
Reduce exacerbations in refractory eosinophilic
inflammation
For Step 5 treatment, add-on treatment options for
patients with severe asthma uncontrolled on Step 4
treatment now also include Mepolizumab for patients
aged ≥12 years with severe eosinophilic asthma*
An antibody against the IL-5 receptor (IL-5Rα)
Benralizumab is also being studied in clinical trials.**
*GINA 2019 Guidelines
*Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a
multicentre, doubleblind, placebo-controlled trial. Lancet 2012;380:651-9.
**Wang B, Yan L, Yao Z, Roskos LK. Population Pharmacokinetics and Pharmacodynamics of Benralizumab in
Healthy Volunteers and Patients With Asthma. CPT Pharmacometrics Syst Pharmacol. 2017 Jan 21.

17. Mepolizumab cs -- Eosinophilic Subtype
• Mepolizumab (Anti-IL-5) is ascendant among drugs in this class
• >12 years old
• Blood eos >150
• May not be as effective until >300 and improved response
as eos increase
• Q 4 weeks injection
• HA (19%), Injection site rxn (8-15%), zoster (<1%)
• Long term safety data is ongoing, but it is thought that this is
a reasonably safe medication to keep patients on long term if
needed
UpToDate, Tx of Sev Asthma in adol and adults

18. Mepolizumabfor severe asthmaassociatedwith
peripheralblood eosinophilia
• The anti-interleukin-5 monoclonal antibody mepolizumab has
previously been shown to reduce exacerbations in patients
with severe asthma and eosinophilic airway inflammation.
• Two additional trials validate using peripheral blood eosinophil
counts to select patients with severe asthma who are likely to
respond to mepolizumab.
• They demonstrated comparable effects of intravenous and
subcutaneous preparations, and show a glucocorticoid-sparing
effect.
What's new in pulmonary and critical care medicine. Available from http://www.uptodate.com/contents/whats-new-in-pulmonary-and-critical-care-medicine
accessed on 8.02.15

19. Mepolizumabfor severe asthmaassociatedwith
peripheralblood eosinophilia
• The larger multicenter trial evaluated mepolizumab in patients
with severe asthma and eosinophilic airway inflammation
despite high-dose inhaled glucocorticoids.
• At 32 weeks, exacerbations were reduced by approximately 50
percent for the groups using mepolizumab given by either
route, compared with placebo.
What's new in pulmonary and critical care medicine. Available from http://www.uptodate.com/contents/whats-new-in-pulmonary-and-critical-care-medicine
accessed on 8.02.15

20. Mepolizumabfor severe asthmaassociatedwith
peripheralblood eosinophilia
• In a group of patients with severe asthma requiring systemic
glucocorticoids, a study compared subcutaneous mepolizumab,
given every four weeks, with placebo.
• At 20 weeks:
• Mepolizumab allowed a median reduction in the systemic
glucocorticoid dose of 50 percent
• Decreased the number of asthma exacerbations and
• Improved control of asthma symptoms.
What's new in pulmonary and critical care medicine. Available from http://www.uptodate.com/contents/whats-new-in-pulmonary-and-critical-care-medicine
accessed on 8.02.15

21. Studiesonbiologictherapiesforsevereeosinophilicasthma.

22. Studies on biologic therapies for severe
eosinophilic asthma.

25. Benralizumab
• Benralizumab, is a humanized mAb (IgG1 k) that binds with high
affinity to an epitope within domain 1 of the α-chain of human IL-5R,
blocking its activation and signal transduction
• The activation of ADCC is a unique benralizumab mechanism.
• In fact, the other anti-IL-5 biologics (mepolizumab and reslizumab)
directly bind to IL-5 and act by neutralizing the effects of the cytokine
• Overall, the safety profile was acceptable, and the most common AEs
reported were reduced white blood cell counts, nasopharyngitis, and
increased blood creatine phosphokinase

26. Efficacyandsteroid-sparingeffectofbenralizumab:hasit
anadvantageoveritscompetitors?
Menzella F, Biava M, Bagnasco D, Galeone C, Simonazzi A, Ruggiero P, Facciolongo N. Drugs in Context 2019; 8: 212580. DOI: 10.7573/dic.212580 7 of 11
ISSN: 1740-4398

27. Outcomescomparisonbetween
mepolizumabandbenralizumab
Menzella F, Biava M, Bagnasco D, Galeone C, Simonazzi A, Ruggiero P, Facciolongo N. Drugs in Context 2019; 8: 212580. DOI: 10.7573/dic.212580 7 of 11
ISSN: 1740-4398

28. In conclusion
Study summarized how benralizumab may be of
advantage in the treatment of eosinophilic refractory severe
asthma and how it may have a competitive superiority, due to
the particular mechanism of action, clinical efficacy, and greater
steroid-sparing effect.
Menzella F, Biava M, Bagnasco D, Galeone C, Simonazzi A, Ruggiero P, Facciolongo N. Drugs in Context 2019; 8: 212580. DOI: 10.7573/dic.212580 7 of 11
ISSN: 1740-4398

29. Reslizumab
• Reslizumab is a humanized monoclonal antibody against human interleukin-5 (IL-5).
• Reslizumab binds specifically to IL-5, a key cytokine responsible for the
differentiation, maturation, recruitment and activation of human eosinophils.
• Reslizumab is indicated for add-on maintenance treatment of patients with severe
asthma aged 18 years and older, and with an eosinophilic phenotype.
• Unlike the other anti-IL-5 molecules, its efficacy in patients with the most severe
form of asthma, i.e. those who require daily oral corticosteroids such as prednisone,
has not been previously evaluated in large studies
• Indirect comparison suggests that reslizumab may be more efficacious than
benralizumab in patients with eosinophilic asthma in Global Initiative for Asthma
step 4/5 with elevated blood eosinophil levels
Drugs. 2017 May;77(7):777-784. doi: 10.1007/s40265-017-0740-2.

30. Dupilumabs -- Anti IL4
Receptor Subunit
• Inhibits both IL-4 AND IL-13
• Blood eos >150
• But also more effective at higher eos levels
• Only biologic approved in the EU for severe asthma with type 2
inflammation, as characterized by raised blood eosinophils and/or
raised fractional exhaled nitric oxide (FeNO)
• A/E: Transient eosinophilia (4%), injection site rxn (<1%), herpes
reactivation (rare)
UpToDate, Tx of Sev Asthma in adol and adults

31. LIBERTYASTHMA Clinical Program
• 2,888 adults and adolescents
• Phase 3 QUEST and VENTURE trials
• QUEST enrolled 1,902 patients with persistent asthma and evaluated whether
adding Dupilumab to standard-of-care therapy could reduce severe
exacerbations and improve lung function (measured by FEV1).
• VENTURE enrolled 210 patients with severe oral corticosteroid-dependent
asthma and evaluated whether adding Dupilumab to standard-of-care therapy
could reduce the use of maintenance oral corticosteroids.
• The Phase 2b trial enrolled 776 adult patients with moderate-to-severe
asthma and showed that adding Dupilumab to standard-of-care therapy could
improve lung function.
https://newsroom.regeneron.com/news-releases/news-release-details/dupixentr-dupilumab-approved-severe-asthma-european-commission

32. Risk Ratio for Serious Adverse Events
• There were trends towards greater drug
discontinuation rates due to adverse
events for omalizumab and
benralizumab
• Significant increase in drug
discontinuation rates for the 300 mg
dose of dupilumab.
• However, there was a significant
reduction in discontinuation due to
adverse events for dupilumab at the 200
mg dose
https://icer-review.org/wp-content/uploads/2018/04/ICER_Asthma_Draft_Report_092418v1.pdf

33. BiologicApprovedforUseorStudiedinSevereAsthma
L.A. MankaandM.E.Wechsler/AnnAllergyAsthmaImmunol121(2018)406413
Approved

34. BiologicApprovedforUseorStudiedinSevereAsthma
L.A. MankaandM.E.Wechsler/AnnAllergyAsthmaImmunol121(2018)406413

35. ICERRatings for Biologic Therapiesfor the
Treatment of Asthma
• There are no head to head trials and the heterogeneity in the populations
studied in the randomized trials precluded performing a network meta-
analysis.
• When comparing the effect sizes from the meta-analyses of the individual
drugs compared with placebo, the improvements in exacerbation rates and
quality of life appear qualitatively similar, but this may be misleading.
https://icer-review.org/wp-content/uploads/2018/04/ICER_Asthma_Draft_Report_092418v1.pdf

36. Thank You