Five biologic therapies are now approved for severe asthma — a remarkable change from 2015, when mepolizumab was first approved and the entire concept of biologic treatment for asthma was new. The research question in 2026 is no longer whether targeting specific inflammatory cytokines works in severe asthma — it demonstrably does — but rather which biologic for which patient, whether two biologics are better than one, whether treatment can induce lasting remission, and whether these approaches can be extended to the larger moderate asthma population. The biologic discontinuation trials are particularly interesting from a patient perspective: can people who have achieved well-controlled severe asthma on mepolizumab or benralizumab safely stop? PONENTE's Phase 3 data is close, and that answer matters to a lot of people already on these drugs.
This article is for informational purposes only and does not constitute medical advice. Clinical trial eligibility and availability vary. Always consult a qualified healthcare professional before making any medical decisions or considering participation in a clinical trial.
Summary
Severe asthma — defined as disease requiring high-dose ICS/LABA and/or continuous or frequent oral corticosteroids, or uncontrolled despite maximum inhaler therapy — affects approximately 5–10% of the 260 million people with asthma globally. Five biologics are now approved for severe asthma: mepolizumab (anti-IL-5), benralizumab (anti-IL-5Rα), reslizumab (anti-IL-5), dupilumab (anti-IL-4Rα), and tezepelumab (anti-TSLP). In 2026, active trials are addressing four questions the approved drugs don't answer: whether biologics are safe to stop after inducing remission, whether the T2-low non-eosinophilic phenotype can be targeted, whether combination biologic therapy outperforms monotherapy, and whether oral or inhaled alternatives can deliver comparable efficacy without injection burden.
The Approved Biologics: What the Phase 3 Trial Data Actually Showed
Understanding the trial data behind approved biologics is essential context for interpreting what the 2026 trials are trying to improve upon:
- Mepolizumab (Nucala, anti-IL-5): MENSA Phase 3 trial (n=576) showed mepolizumab 100mg SC Q4W reduced exacerbation rate by 47% vs placebo (rate ratio 0.53, 95% CI 0.44–0.64, p<0.001) in eosinophilic severe asthma (blood eos ≥150 cells/µL). DREAM trial extension showed sustained benefit at 3+ years. Best evidence-based choice for high blood eosinophil count (≥300 cells/µL) with severe exacerbation history.
- Benralizumab (Fasenra, anti-IL-5Rα): SIROCCO and CALIMA Phase 3 trials (combined n=2,505) showed benralizumab 30mg Q4W (loading) then Q8W reduced exacerbations by 51% vs placebo (p<0.001). Anti-IL-5Rα depletes eosinophils to near-zero (rather than reducing their production, as mepolizumab does) — producing more complete eosinophil ablation. This mechanistic difference may be clinically meaningful in patients with very high eosinophil counts.
- Dupilumab (Dupixent, anti-IL-4Rα): LIBERTY ASTHMA QUEST Phase 3 (n=1,902) showed dupilumab 200mg Q2W reduced severe exacerbations by 46% vs placebo (p<0.001) in Type 2 asthma (eos ≥150 or FeNO ≥25 ppb). Dupilumab also approved for atopic dermatitis, eosinophilic esophagitis, CRSwNP, and COPD — the broadest approved indication range of any biologic in allergic/eosinophilic disease.
- Tezepelumab (Tezspire, anti-TSLP): NAVIGATOR Phase 3 (n=1,061) showed tezepelumab 210mg SC Q4W reduced exacerbations by 70% vs placebo (p<0.001) — the highest single-trial exacerbation reduction rate of any approved severe asthma biologic. Critically, benefit was observed regardless of eosinophil count, FeNO, or atopic status. TSLP (thymic stromal lymphopoietin) acts upstream of IL-4, IL-5, and IL-13 — its inhibition blocks the entire Type 2 inflammatory cascade rather than a single downstream cytokine.
Biologic Discontinuation: Can Severe Asthma Go Into Remission?
This is the clinical question most relevant to the growing number of patients who have achieved well-controlled severe asthma on biologic therapy. PONENTE (NCT03142607, AstraZeneca) is a Phase 3 trial evaluating whether patients with severe eosinophilic asthma who have achieved clinical remission (well-controlled asthma for 12+ months) on benralizumab can safely stop treatment. Participants were randomized to continue benralizumab Q8W or switch to placebo, with the primary endpoint being time to first asthma worsening event.
The trial rationale is biologically grounded. Biologic therapy doesn't just suppress inflammation — it may modify the underlying allergic sensitization and airway remodeling that perpetuate severe asthma. Sustained eosinophil depletion over years may reduce the pool of sensitized Type 2 immune cells that drive exacerbations, potentially producing durable remission even after drug withdrawal. Small case series and registry analyses have shown that a subset of patients who discontinue biologics maintain disease control — but the proportion and the clinical predictors of success are poorly characterized. PONENTE Phase 3 data is expected in 2026 and will likely influence guidelines for biologic duration decisions.
Targeting T2-Low Asthma: The Remaining Gap
All five approved severe asthma biologics work primarily through the Type 2 inflammatory axis — IL-4, IL-5, IL-13, and TSLP. The T2-high phenotype (characterized by elevated blood eosinophils ≥300, elevated FeNO ≥25 ppb, atopic history) has multiple effective biologic options. The T2-low phenotype — roughly 30–40% of severe asthma patients who lack these markers — has essentially no approved biologic therapy. This is where the unmet need is greatest and where current trials are focusing:
- Astegolimab (anti-IL-33, Genentech/Roche): SOLSTICE Phase 3 trial (NCT04257669, n=826) showed astegolimab reduced exacerbation rate across all blood eosinophil levels, including patients with eos <150 cells/µL (RR 0.47, 95% CI 0.33–0.66 in the low-eos subgroup). IL-33 acts at a level upstream of IL-5 and IL-13 but modulates both Type 2 and non-Type 2 inflammatory pathways, which may explain activity in eosinophil-low patients where IL-5 or IL-13 targeting is ineffective. A biologics license application is under FDA review.
- Itepekimab (anti-IL-33, Regeneron/Sanofi): LIBERTY ASTHMA QUEST + analyses showed itepekimab had particular benefit in ex-smoker asthmatics — a population with predominantly T2-low disease, higher neutrophilic inflammation, and limited current biologic options. Phase 3 extension and dedicated ex-smoker asthma trials are ongoing.
- Anti-IL-17 approaches: A subset of T2-low asthma has elevated IL-17 and neutrophilic inflammation. Secukinumab (approved for psoriasis) showed modest Phase 2 signal in high-neutrophil asthma; dedicated Phase 3 trials for this phenotype are in planning stages at multiple centers.
Combination Biologics: Is Two Better Than One?
The MABEL Phase 2 trial (2023) evaluated mepolizumab + dupilumab (anti-IL-5 + anti-IL-4Rα) versus either alone in severe eosinophilic asthma. The combination reduced blood eosinophils more completely than mepolizumab alone and reduced FeNO more completely than either drug alone — suggesting complementary mechanism effects. Whether this translates to superior exacerbation reduction is being evaluated in Phase 3. The practical challenge for combination biologic trials is enormous: the efficacy bar must be meaningfully higher than monotherapy to justify the cost and added injection burden, and current Phase 2 biomarker improvements need to be validated against hard clinical endpoints.
Bronchial Thermoplasty: What 10-Year Data Shows
Bronchial thermoplasty (BT) uses radiofrequency energy delivered through a bronchoscope to ablate airway smooth muscle — reducing bronchoconstriction in patients where smooth muscle hypertrophy is a dominant feature of airway obstruction. The original AIR2 sham-controlled Phase 3 trial (2010, n=288) showed BT reduced severe exacerbations by 32% versus sham bronchoscopy at 1 year. Ten-year follow-up data (2021, Thomson et al.) showed that treated patients maintained reduced exacerbation rates and stable lung function (no accelerated FEV1 decline), providing important long-term safety data for a procedure that was initially viewed with significant skepticism. Second-generation BT devices with more precise energy delivery and potentially better patient selection through endobronchial biopsy biomarkers are in Phase 2 in 2026.
Who Qualifies for Asthma Trials
Biologic trials for severe asthma typically require: documented asthma diagnosis ≥12 months, current controller therapy (ICS ≥880µg budesonide equivalent + LABA ± LAMA ± SABA), ≥2 exacerbations requiring systemic corticosteroids or hospitalization in the prior 12 months (or continuous OCS use), and disease-specific biomarker criteria (blood eosinophil count, FeNO, total IgE depending on the biologic's mechanism). Most trials exclude current smokers (≥10 pack-year history sometimes excluded for T2 trials), significant comorbid COPD, active malignancy, and other systemic immunosuppressive conditions. Having your eosinophil count, FeNO, and recent spirometry data available when you contact a research coordinator significantly accelerates pre-screening.
Key Takeaways
- Tezepelumab (anti-TSLP) remains the broadest approved biologic — NAVIGATOR showed 70% exacerbation reduction regardless of eosinophil count, FeNO, or atopy, making it the option most likely to work in patients who don't clearly fit the T2-high phenotype.
- Astegolimab Phase 3 (SOLSTICE) showed exacerbation reduction even in low-eosinophil patients — potentially the first biologic with meaningful activity in T2-low asthma. FDA review is underway.
- PONENTE Phase 3 data will address whether biologic-induced remission in severe eosinophilic asthma can be sustained after drug discontinuation — data expected in 2026.
- Itepekimab (anti-IL-33) shows particular benefit in ex-smokers with asthma — a population with limited options under current approved biologics targeting the T2 pathway.
- Blood eosinophil count, FeNO, and total IgE are the key biomarkers for biologic eligibility — having these values from a recent blood test and lung function assessment significantly speeds up trial pre-screening.
Finding Asthma Trials in 2026
Search ClinicalMetric or ClinicalTrials.gov for "severe asthma" or "eosinophilic asthma" filtered to Phase 3, Recruiting. Academic centers with dedicated Severe Asthma or Airway Disease programs — Cleveland Clinic, UCSF, Mayo Clinic, National Jewish Health, Imperial College London — typically run 3–5 concurrent biologic trials and have research coordinators who can match your biomarker profile to the most relevant study. Having blood eos, FeNO, and spirometry from the past 12 months significantly speeds up the pre-screening call.