The document reviews biologic therapies for severe asthma. It provides a case summary of a patient with severe eosinophilic asthma. It then outlines the educational aims, definitions, pathophysiology, and classes of biologic therapies. For each biologic class, it summarizes key trials showing reductions in exacerbation rates. It identifies predictors of response and side effects. The take home messages are that all biologics effectively reduce exacerbations, anti-IL5 therapies are superior for patients on oral corticosteroids, and drug availability and other indications should be considered when choosing therapy.

1. Prepared by: Mahmoud Al-hoor,
pulmonary fellow
21/12/2022
JUH
Biologics in severe asthma
Literature review

2. Outline:
 Case summary.
 Educational aims.
 Definitions.
 Pathophysiology.
 Biologic classes.
 Conclusions.
 References.

3. Case summary:
 Young female lady with severe
eosinophilic asthma with frequent
relapses, on high dose ICS, LABA and
LAMA.
 No obvious exacerbating factors.
 Recurrent use of systemic steroids
complicated by HTN, Pre-diabetes
and osteopenia.

4. Educational aims:
 To review the major outcome data
from phase 3 and real-world studies of
biologic therapies for severe asthma.
 To understand the key baseline
characteristics associated with
response to each biologic therapy.
 To gain awareness of the practical
issues that can impact the choice of
biologic therapies in asthma

5. Definitions:

6. GINA 2022 guidelines:

7. Pathophysiology:
 Abbreviations: T (Tezepelumab), O (Omalizumab ), D (Dupilumab ), M
(Mepolizumab ), R (Reslizumab ), B (Benralizumab )

9. Biologics classes
Class Name Age* Asthma indication* Other indications*
Anti-IgE Omalizumab (SC) ≥6 years Severe allergic asthma Nasal polyposis, chronic
spontaneous urticaria
Anti-IL5
Anti-IL5R
Mepolizumab (SC)
Reslizumab (IV)
Benralizumab (SC)
≥6 years
≥18 years
≥12 years
Severe eosinophilic/Type 2
asthma
Mepolizumab: EGPA,
CRSwNP,
hypereosinophilic
syndrome
Anti-IL4R Dupilumab (SC) ≥6 years Severe eosinophilic/Type 2
asthma, or maintenance
OCS
Moderate-severe atopic
dermatitis, CRSwNP
Anti-TSLP Tezepelumab (SC) ≥12 years Severe asthma

10. Severe asthma phenotypes (5-
10%):
 Type 2/eosinophilic asthma: 70%
 Fraction of exhaled nitric oxide
 Neutrophilic asthma

11.  Methods: Bronchial biopsies from 3 groups
(N 20 each group):
 Subjects with mild steroid-naïve asthma, with either low
or high submucosal eosinophil counts .
 Healthy controls.
 Assessed for in vivo epithelial damage (using EGFR
staining), mucin expression, airway smooth muscle (ASM)
hypertrophy and inflammatory cells within ASM.

12. Results:

17.  Population-based cohort.
 N 1037

18.  At ages 21, 26, 32 and 38 years,
blood was drawn at the end of the
assessment day.
 Spirometry was performed at ages 18,
21, 26, 32 and 38 years.

19. Results:

20. Omalizumab
 Systematic review of 25 trials were
included.
 Inclusion criteria on patients who had
evidence of sensitisation to
aeroallergens, airway
hyperresponsiveness and ongoing
asthma symptoms.

21.  Selection criteria: Randomised
controlled trials.
 Two review authors independently
assessed study quality and extracted
and entered data.

22. Results:
 25% reduction in exacerbation rate
over 16 to 60 weeks
 Reduction in ICS.
 No effect on mOCS reduction.

23. Predictors of response
 Participants who had required emergency
asthma treatment.
 On high dose ICS.
 Lower FEV1 at baseline.
 Neither allergen-specific IgE nor total IgE
predicts response to treatment.
 Elevated T2 biomarkers at the time of
omalizumab cessation was shown to be a
predictor of future exacerbation

24. Mode of administration:
 SC injection every 2-4 weeks.
 frequency determined by weight and
serum IgE.
 S.E:
 Injection site reaction.
 Arthralgia.
 Dizziness.

25. Mepolizumab MENSA trial
 Methods: In this randomized, double-blind, we assigned 576
patients with recurrent asthma exacerbations and evidence
of eosinophilic inflammation despite high doses of inhaled
glucocorticoids to one of three study groups.
 Inclusion criteria included an eosinophilic phenotype (with
blood eosinophils of ≥150 cells・μL−1 at screening, or ≥300
cells・μL−1 in the past 12 months) and frequent
exacerbations

26.  Patients were assigned to receive
mepolizumab, which was
administered as either a 75-mg
intravenous dose or a 100-mg
subcutaneous dose, or placebo every
4 weeks for 32 weeks

27. Results:
 Rate of exacerbations was reduced by
47% in patients receiving IV
mepolizumab and by 53% in those
receiving SC mepolizumab, as
compared with those receiving
placebo.
 ER visits reduced by 32% in IV
mepolizumab and by 61% in SC one.

28. SIRIUS trial
 Randomized, double-blind trial
involving 135 patients with severe
eosinophilic asthma.

29. Results:
 At 24 weeks,14% of subjects treated
with mepolizumab were able to
completely stop prednisolone and
overall, a median reduction of 50%
was achieved.

30. Predictors of response:
 In those with high blood eosinophils of
≥500 cells・μL−1 there was a 79%
reduction in exacerbation rate versus
placebo.

31. Length of treatment:
 Open label extension study
(“COLUMBIA”) has confirmed a
sustained response to mepolizumab
up to 4.5 years of treatment

32. Dosing:
 Fixed 100 mg SC dose every 4 weeks.
 A.E:
 Headache.
 Backache .
 Injection site reactions
 Approved for:
 EGPA
 CRwNP.

33. Reslizumab
 Two phase 3 trials.
 Enrolled patients with asthma aged
12-75 years (from 128 clinical
research centres in study 1 and 104
centres in study 2).

34. Results:
 50–59% reduction in annual
exacerbation rate.
 Improvement in FEV1.
 Despite very good efficacy in severe
eosinophilic asthma, the need to give
reslizumab intravenously is a major
practical consideration

35. Benralizumab
 Primary outcomes: Two large phase
3 trials in severe eosinophilic asthma
(SIROCCO and CALIMA).
 In those with blood eosinophils <300
cells・μL−1, there was a 17–40%
reduction in exacerbation rate
compared with placebo, compared to
a 28–51% reduction in those with
eosinophils ≥300 cells・μL

36.  The ZONDA study enrolled OCS-
dependent patients and demonstrated
a 50% reduction in OCS dose
compared with placebo.

37. Predictors of response
 High baseline exacerbation rate
 Higher blood eosinophils.
 Nasal polyposis.
 Low baseline forced vital capacity
(FVC) (< 65%).
 Dependence on OCS.

38. Duration of therapy:
 MELTEMI study has provided
evidence of continued efficacy along
with reassuring safety data out to 5
years.

39.  Given at fixed dose SC injection,
every 4 weeks for 1st three doses,
then every 8 weeks.
 A.E:
◦ Injection site reactions (2–3%).
◦ Nasopharyngitis

40. Tezepelumab:
 Primary outcomes: “NAVIGATOR”
study.
 Overall, treatment with tezepelumab
led to a reduction in exacerbation rate
of 56% versus placebo

41. Summary:

42. Comparative effectiveness of Anti-IL5 and
Anti-IgE biologic classes in severe asthma
patients eligible for both:
 Prospective cohort study.
 22 countries.
 long-term-oral corticosteroid (LTOCS) use.
 Asthma-related emergency room (ER) attendance.
 Hospital admissions.

47. Take home messages:
 All biologics are effective in terms of
number exacerbations reduction.
 In patient on mOCS, anti-IL5 are
superior.
 Presence of other indications.
 Availability of drugs.
 Based on currently available data, for
most patients with severe eosinophilic
asthma the majority of these therapies
are likely to be effective.

48. Refferences:
 Normansell R, Walker S, Milan SJ, et al. Omalizumab for
asthma in adults and children. Cochrane Database Syst Rev
2014; 1: CD003559.
 Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment
in patients with severe eosinophilic asthma. N Engl J Med.
 Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and
safety of benralizumab for patients with severe asthma
uncontrolled with high-dosage inhaled corticosteroids and
long-acting β2-agonists (SIROCCO): a randomised,
multicentre, placebo-controlled phase 3 trial. Lancet 2016;
 FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an
anti-interleukin-5 receptor α monoclonal antibody, as add-on
treatment for patients with severe, uncontrolled, eosinophilic
asthma (CALIMA): a randomised, double-blind, placebo
controlled phase 3 trial. Lancet 2016;
 Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment
in patients with severe eosinophilic asthma. N Engl J Med.

49. 
Thank you