PharmacologyTier 1Medical Sciences concept

Anti-IgE and anti-cytokine biologics in asthma (omalizumab, mepolizumab, benralizumab, dupilumab)

Core concept

Severe asthma splits into type 2-high (eosinophilic and/or allergic, corticosteroid-responsive) and type 2-low
- Type 2 inflammation is driven by IL-4, IL-5, IL-13 from Th2 cells and ILC2s, above them the epithelial alarmins TSLP, IL-33, IL-25
Each biologic interrupts one node, and the height of the block determines the breadth of effect

Target	Agent	Node
IgE	Omalizumab - binds free IgE at the FcERI-binding site	Downstream, allergic only
IL-5	Mepolizumab, reslizumab; depemokimab (6-monthly)	Eosinophil maturation and survival
IL-5 receptor alpha	Benralizumab	Afucosylated -> ADCC -> near-complete eosinophil depletion
IL-4Ralpha (blocks IL-4 and IL-13)	Dupilumab	Two cytokines at once
TSLP	Tezepelumab	Upstream alarmin - works in type 2-low disease too

Biologic	Biomarker required	Other indications
Omalizumab	Total IgE 30-1500 + perennial aeroallergen sensitisation; dose by IgE and weight	Chronic spontaneous urticaria, nasal polyps
Mepolizumab	Blood eosinophils (>=150-300)	EGPA, hypereosinophilic syndrome, nasal polyps, COPD with eosinophilia
Benralizumab	Blood eosinophils	EGPA
Dupilumab	Eosinophils or FeNO >=25, or OCS-dependent	Atopic dermatitis, nasal polyps, eosinophilic oesophagitis, COPD, prurigo nodularis
Tezepelumab	None - no biomarker restriction, including type 2-low	Nasal polyps

Dupilumab can cause a transient blood eosinophilia (blocks eosinophil tissue trafficking, not production) - usually benign but rarely unmasks EGPA; check before and during
Benralizumab depletes eosinophils to zero; mepolizumab reduces but does not abolish them
Omalizumab is dosed from serum IgE and weight - and total IgE cannot be used to monitor response once started (it rises as complexed IgE)
Anaphylaxis is rare but real with omalizumab (observe after early doses)
Before starting any biologic, exhaust the fundamentals: adherence, inhaler technique, comorbidities (rhinosinusitis, reflux, obesity, OSA, ABPA, dysfunctional breathing), smoking, and confirm the diagnosis
Chronic spontaneous urticaria ladder: non-sedating H1 antihistamine, up-titrated to 4x the standard dose (~50% still refractory) -> omalizumab 300 mg SC monthly (60-70% effective) -> ciclosporin; oral steroids for flares only

Choose by phenotype and comorbidity, because most severe asthma patients qualify for more than one
- Allergic, early onset, high IgE -> omalizumab
- Late-onset eosinophilic, nasal polyps, EGPA -> anti-IL-5/5R
- Atopic dermatitis, eosinophilic oesophagitis, or oral steroid dependence -> dupilumab
- Type 2-low, or no clear biomarker, or all-comers -> tezepelumab
The goal is oral corticosteroid elimination - and the OCS-sparing effect is the outcome that matters most
Australian PBS access requires documented severe asthma, optimised inhaled therapy, exacerbation frequency and biomarker thresholds, with response review at 6-12 months for continuation
Do not stop inhaled corticosteroid when a biologic starts - the biologic is added, not substituted
Eosinophil counts fall on oral steroids - measure the biomarker off systemic steroid where possible

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