Pulmonary Pharmacology  ·  Module 4 of 7

Biologic Agents in Severe Asthma

T2-high phenotypes and biomarkers · Anti-IgE · Anti-IL-5 and anti-IL-5Rα · Anti-IL-4Rα dupilumab · Biologic selection framework

• Approximately 50–60% of severe asthma is T2-high — driven by IL-4, IL-5, and IL-13 from Th2 cells and ILC2s. IL-4 promotes IgE class switching and eosinophil recruitment; IL-5 is the principal eosinophil maturation, recruitment, and survival signal; IL-13 drives goblet cell metaplasia, airway smooth muscle hyperresponsiveness, and subepithelial fibrosis. All approved biologic targets (IgE, IL-5/IL-5Rα, IL-4Rα) operate within this T2-high pathway. T2-low disease (neutrophilic, non-eosinophilic) has no approved biologic — managed with optimized inhaled therapy and low-dose oral corticosteroids.
• Three biomarkers guide biologic eligibility: blood eosinophil count (≥300 cells/µL strongest predictor of anti-IL-5 response; ≥150 cells/µL lower-boundary eligibility); fractional exhaled nitric oxide (≥25 ppb suggests T2-high; ≥50 ppb strong IL-4/IL-13 signal, predicts dupilumab response); serum total IgE (required for omalizumab dosing by weight-based table — very high or very low IgE falls outside eligible range). All biologic candidates must have confirmed severe asthma on step 4 therapy, verified adherence, and correct inhaler technique before biologic evaluation.
• Omalizumab (anti-IgE): humanized mAb binds free IgE at the FcεRI binding site → prevents IgE attaching to mast cells/basophils → no allergen crosslinking → no degranulation. Secondary: downregulates FcεRI expression on mast cells over weeks. Does not displace IgE already bound to cell surfaces. Dose determined by baseline IgE × body weight table (150–375 mg SC q2–4w). Indications: moderate-to-severe allergic asthma + confirmed perennial allergen sensitization + age ≥6. Also approved for chronic urticaria. Anaphylaxis risk ~0.1–0.2% (most common within 2 h of first 3 injections): must administer in healthcare setting with 30-minute observation; patient must carry epinephrine autoinjector.
• Anti-IL-5 class: mepolizumab and reslizumab bind IL-5 directly → block IL-5 receptor binding → reduce eosinophil bone marrow production, airway recruitment, and survival. Mepolizumab: SC q4w; eosinophils ≥150 cells/µL; age ≥6; also approved for EGPA and HES. Reslizumab: IV q4w; eosinophils ≥400 cells/µL; adults only. Benralizumab targets IL-5Rα on eosinophils/basophils — not IL-5 itself; afucosylated Fc region enhances FcγRIII binding on NK cells and macrophages → antibody-dependent cellular cytotoxicity → near-complete eosinophil depletion (more profound than IL-5 neutralization alone); SC q4w ×3 then q8w (most convenient dosing); age ≥12; also approved for EGPA.
• Dupilumab (anti-IL-4Rα): blocks the shared IL-4Rα subunit of both the type I receptor (IL-4Rα/γc — mediates IL-4 on hematopoietic cells) and type II receptor (IL-4Rα/IL-13Rα1 — mediates IL-4 and IL-13 on airway epithelium and smooth muscle) → simultaneous IL-4 + IL-13 blockade → suppresses IgE production, reduces FeNO, reduces goblet cell metaplasia, improves smooth muscle hyperresponsiveness. No specific eosinophil threshold required — effective across T2-high including FeNO-dominant phenotype. SC q2w. Approved indications: severe asthma (age ≥6), atopic dermatitis, CRSwNP, eosinophilic esophagitis, prurigo nodularis — treats all T2 comorbidities with one biologic. AEs: injection site reactions; conjunctivitis (more prominent at atopic dermatitis dosing). Biologic switching: if initial agent fails after 4–6 months trial, switch to different pathway (e.g., anti-IL-5 failure → dupilumab). OCS tapering is a key biologic benefit — taper gradually after initiation. Combination biologic therapy not standard practice.