# Severe Asthma and Biologic Therapies — GINA 2024

## Definition of Severe Asthma

Severe asthma is asthma that is uncontrolled despite optimized treatment with high-dose ICS-LABA, or that requires high-dose ICS-LABA to prevent it from becoming uncontrolled. Before confirming severe asthma, the following must be verified:
- Correct diagnosis of asthma (exclude mimics such as inducible laryngeal obstruction, COPD, cardiac disease, bronchiectasis)
- Good inhaler technique (verified by physical demonstration)
- Good medication adherence (objective assessment, e.g., prescription records, electronic monitoring)
- Comorbidities addressed (chronic rhinosinusitis, nasal polyposis, GERD, obesity, obstructive sleep apnea, anxiety/depression)
- Trigger avoidance (allergens, occupational exposures, tobacco smoke, medications such as beta-blockers and NSAIDs if aspirin-exacerbated respiratory disease)

Severe asthma represents approximately 3-10% of all people with asthma.

## Difficult-to-Treat vs. Severe Asthma

- **Difficult-to-treat asthma:** Uncontrolled despite Step 4 or Step 5 treatment, OR requiring high-dose treatment to maintain good symptom control. Investigate and address modifiable factors before labeling as severe.
- **Severe asthma:** A subset of difficult-to-treat asthma that remains uncontrolled despite addressing all modifiable factors and using optimized high-dose ICS-LABA treatment.

## Phenotyping for Biologic Therapy Selection

### Type 2 (T2)-High Asthma

Identified by one or more of:
- Blood eosinophils >=150 cells/mcL
- FeNO >=20 ppb
- Sputum eosinophils >=2%
- Asthma is clinically driven by allergen exposure
- Need for maintenance OCS

Approximately 50% of severe asthma patients have T2-high inflammation.

### T2-Low Asthma

- Blood eosinophils <150 cells/mcL AND FeNO <20 ppb
- Currently no approved biologic therapies specifically targeting T2-low asthma (except tezepelumab which may have benefit regardless of inflammatory phenotype)
- Optimize non-biologic add-ons: LAMA, low-dose macrolide (azithromycin), manage comorbidities

## Biologic Therapies for Severe Asthma (Step 5 Add-On)

### Anti-IgE: Omalizumab

- **Mechanism:** Binds free IgE, reducing IgE-mediated airway inflammation
- **Eligibility:** Severe allergic asthma; sensitization to a perennial aeroallergen on skin prick test or specific IgE; total serum IgE 30-1500 IU/mL (dosing dependent on IgE level and body weight)
- **Dose:** 75-600 mg SC every 2 or 4 weeks (determined by baseline IgE and body weight per dosing table)
- **Age:** Approved for >=6 years
- **Key trials:** INNOVATE

### Anti-IL5: Mepolizumab

- **Mechanism:** Binds IL-5, reducing eosinophil maturation and survival
- **Eligibility:** Severe eosinophilic asthma; blood eosinophils >=150 cells/mcL at initiation OR >=300 cells/mcL in the past 12 months
- **Dose:** 100 mg SC every 4 weeks
- **Age:** Approved for >=6 years
- **Key trials:** MENSA, MUSCA

### Anti-IL5 Receptor Alpha: Benralizumab

- **Mechanism:** Binds IL-5 receptor alpha on eosinophils, inducing direct eosinophil apoptosis via antibody-dependent cell-mediated cytotoxicity
- **Eligibility:** Severe eosinophilic asthma; blood eosinophils >=150 cells/mcL at initiation OR >=300 cells/mcL in the past 12 months
- **Dose:** 30 mg SC every 4 weeks for the first 3 doses, then every 8 weeks thereafter
- **Age:** Approved for >=12 years (>=6 years in some jurisdictions)
- **Key trials:** SIROCCO, CALIMA

### Anti-IL5: Reslizumab

- **Mechanism:** Binds IL-5 (similar to mepolizumab)
- **Eligibility:** Severe eosinophilic asthma; blood eosinophils >=400 cells/mcL
- **Dose:** 3 mg/kg IV infusion every 4 weeks
- **Age:** Approved for >=18 years
- **Note:** IV administration only; requires clinic-based infusion

### Anti-IL4 Receptor Alpha: Dupilumab

- **Mechanism:** Blocks IL-4 and IL-13 signaling via IL-4 receptor alpha subunit
- **Eligibility:** Severe eosinophilic/T2 asthma; blood eosinophils >=150 cells/mcL OR FeNO >=25 ppb; OR OCS-dependent severe asthma; OR comorbid moderate-to-severe atopic dermatitis or chronic rhinosinusitis with nasal polyps
- **Dose:**
  - Loading dose: 400 mg SC (or 600 mg if OCS-dependent or comorbid atopic dermatitis), then
  - Maintenance: 200 mg SC every 2 weeks (or 300 mg every 2 weeks if OCS-dependent, comorbid moderate-severe atopic dermatitis, or baseline eosinophils >=1500 cells/mcL)
- **Age:** Approved for >=6 years
- **Key trials:** LIBERTY ASTHMA QUEST, LIBERTY ASTHMA VENTURE
- **Caution:** Transient eosinophilia may occur after initiation; avoid in patients with pre-treatment eosinophils >1500 cells/mcL unless closely monitored

### Anti-TSLP: Tezepelumab

- **Mechanism:** Blocks thymic stromal lymphopoietin (TSLP), an upstream epithelial cytokine involved in multiple inflammatory pathways
- **Eligibility:** Severe asthma, irrespective of phenotype (both T2-high and T2-low); no specific biomarker requirement for eligibility
- **Dose:** 210 mg SC every 4 weeks
- **Age:** Approved for >=12 years
- **Key trials:** NAVIGATOR, SOURCE
- **Note:** The only biologic that does not require a specific eosinophil or IgE threshold, making it an option for T2-low severe asthma

## Assessing Response to Biologic Therapy

- Assess after 4 months of treatment (minimum)
- **Good response indicators:** Reduced exacerbations, improved symptom control, reduced OCS requirement, improved lung function
- **If poor response after 4 months:** Re-check phenotype and adherence; consider switching to a different biologic targeting a different pathway
- **If good response:** Continue biologic; attempt OCS dose reduction first, then consider ICS step-down

## Add-On Therapies for Severe Asthma (Non-Biologic)

- **Tiotropium (LAMA):** 5 mcg soft-mist inhaler once daily; add-on for patients with exacerbations despite medium-high dose ICS-LABA
- **Low-dose azithromycin:** 250 mg PO 3 days/week or 500 mg PO 3 days/week for >=6 months; reduces exacerbations in persistent symptomatic asthma; requires baseline ECG (exclude QTc prolongation) and sputum culture (exclude atypical mycobacteria); primarily studied in adults
- **Low-dose OCS:** Prednisolone <=7.5 mg/day or equivalent as last resort; consider adrenal axis monitoring, bone density screening, and gastroprotection; use the lowest effective dose for the shortest duration

## Special Populations

### Pregnancy

- Active management of asthma during pregnancy is strongly recommended
- GINA advises against stepping down treatment during pregnancy (except if ICS dose is very high), because of the high priority placed on avoiding exacerbations that could harm the fetus
- ICS and LABA are considered safe during pregnancy; budesonide has the most safety data
- Biologic therapy should be continued during pregnancy if indicated (stopping may trigger loss of control)
- Exacerbation during labor is rare; continue controller medications during labor and delivery

### Obesity

- Obesity is associated with more severe asthma symptoms, reduced response to ICS, and increased exacerbation risk
- Weight reduction of 5-10% of body weight can improve asthma control, lung function, and quality of life
- Consider alternative diagnoses (deconditioning, obstructive sleep apnea, dysfunctional breathing) in obese patients with asthma-like symptoms

### Elderly Patients

- Comorbidities are more common (cardiac disease, COPD, GERD, osteoporosis)
- Inhaler technique may be impaired; choose devices appropriate for inspiratory flow and dexterity
- Monitor for drug interactions (e.g., beta-blockers)
- Side effects of OCS are more pronounced; minimize OCS exposure

### Exercise-Induced Bronchoconstriction (EIB)

- EIB can occur in patients with or without a diagnosis of asthma
- Pre-exercise dose of as-needed ICS-formoterol (Track 1) or SABA (Track 2) is effective
- Regular ICS use reduces the frequency and severity of EIB
- Warm-up before exercise may reduce EIB occurrence

### Aspirin-Exacerbated Respiratory Disease (AERD)

- Avoid NSAIDs/aspirin; use COX-2 selective inhibitors (e.g., celecoxib) or acetaminophen (paracetamol) as alternatives
- Typically requires high-dose ICS-LABA and often biologic therapy
- Aspirin desensitization may be considered under specialist supervision

## Limitations

- Biologic eligibility criteria and access vary by country and payer.
- Blood eosinophil counts can be suppressed by recent OCS use; interpret with caution.
- FeNO can be elevated by atopy or allergic rhinitis independent of asthma severity.
- Long-term safety data for newer biologics (tezepelumab) continue to accumulate.
- T2-low severe asthma has limited targeted therapeutic options beyond tezepelumab.
- Head-to-head biologic trials are lacking; choice of biologic is guided by phenotype, comorbidities, dosing convenience, and local availability.
