TSLP vs IL-33 blockade in severe asthma

Why epithelial alarmins sit at the top of the atopic cascade

Epithelial-derived alarmins — TSLP, IL-33, and IL-25 — are the first responders when barrier tissues encounter environmental insults, and they are the cytokines that set the entire type 2 inflammatory programme in motion. Blocking them upstream, before the downstream cascade of IL-4, IL-5, and IL-13 amplifies, is the defining logic of the newest generation of severe asthma biologics.

The concept of the atopic march — the clinical progression from early food allergy and atopic dermatitis through to asthma and allergic rhinitis — maps closely onto the biology of these alarmins. TSLP and IL-33 are released by airway epithelial cells and keratinocytes in response to allergens, pollutants, and pathogens, and they activate overlapping but mechanistically distinct immune cascades. Understanding precisely where those cascades diverge is essential for matching the right biologic to the right patient phenotype.

Both TSLP and IL-33 are produced by airway epithelial cells and keratinocytes, but their receptor distributions and downstream cellular targets differ in ways that have significant clinical consequences. TSLP signals through a heterodimeric receptor (TSLPR + IL-7Rα) expressed on dendritic cells, ILC2s, T cells, and mast cells. IL-33 signals through ST2 (IL-1RL1) plus IL-1RAcP, a receptor complex expressed on ILC2s, Th2 cells, mast cells, eosinophils, and basophils. This receptor distribution difference is the mechanistic root of their divergent phenotype coverage.

TSLP vs. IL-33: how the signalling diverges

Tezepelumab (anti-TSLP) and the IL-33 blockers itepekimab (anti-IL-33) and astegolimab (anti-ST2) each intercept the alarmin cascade at a different node, and that positional difference determines which downstream pathways are suppressed — and which are not.

Tezepelumab: breadth through dendritic cell polarisation

Tezepelumab blocks TSLP from binding its receptor, preventing the polarisation of OX40L-expressing dendritic cells that drive Th2 differentiation. Critically, TSLP also activates Th17 pathways and neutrophil recruitment — non-type 2 mechanisms that are entirely outside the reach of IL-33 blockade. By suppressing multiple downstream cytokines simultaneously — IL-4, IL-5, IL-13, IL-17, IL-8, and TNF-α — tezepelumab reduces both eosinophils and neutrophils in airway biopsies. This broad cytokine suppression is the mechanistic basis for its efficacy in non-eosinophilic and mixed granulocytic asthma phenotypes.

IL-33 blockers: precision in eosinophilic type 2 disease

IL-33 is released from epithelial and endothelial cells upon necrosis or protease activation and drives immediate ILC2 responses — allergen challenge models show ILC2 activation within less than one hour of IL-33 exposure. This rapid kinetics underpins the acute exacerbation biology of eosinophilic asthma. Itepekimab neutralises the IL-33 cytokine directly; astegolimab blocks its ST2 receptor. Both achieve strong suppression of IL-5 and IL-13 and directly prevent eosinophil survival via ST2 binding on eosinophils themselves. However, neither has meaningful impact on Th17 activation, neutrophilic inflammation, or the DC–T cell axis that sustains chronic non-type 2 disease. IL-33 also has a dual function as a nuclear regulator involved in epithelial barrier repair — a factor that may explain why its blockade in atopic dermatitis produced unexpected compensatory effects (discussed below).

“Tezepelumab reduces both eosinophils and neutrophils in airway biopsies — a phenotype breadth that IL-33 blockers, confined to type 2 immunity, cannot match.”

Head-to-head clinical evidence in severe asthma

The most clinically significant distinction between these biologics emerges in the eosinophil-low and biomarker-negative patient subgroups — populations that represent a substantial proportion of severe asthma patients and for whom prior IL-5/IL-4Rα-targeting biologics offer limited benefit.

The NAVIGATOR Phase 3 trial (NEJM 2021) enrolled 1,061 severe asthma patients, deliberately including patients with low blood eosinophils (below 150 cells/μL) and non-atopic disease. Tezepelumab achieved a 56% overall reduction in annualized asthma exacerbation rate (AAER) versus placebo, with efficacy sustained across all biomarker subgroups: 70% AAER reduction in eosinophil-high patients (≥300 cells/μL), 41% in eosinophil-low patients (below 150 cells/μL), and 37% in FeNO-low patients. Lung function improved by +0.14L FEV1 regardless of baseline biomarkers — a finding with direct implications for patient selection.

Itepekimab’s Phase 2 trial (NEJM 2021, n=296) showed a 65% AAER reduction in eosinophilic asthma (blood eosinophils ≥300 cells/μL) — comparable to tezepelumab in this subgroup — but minimal efficacy in eosinophil-low subgroups. A rapid FeNO reduction observed by day 2 is consistent with direct ILC2 suppression. Astegolimab’s Phase 2b trial (Lancet Respiratory Medicine 2021, n=502) showed 60% AAER reduction in the high-ST2 subgroup (ST2 ≥35.5 ng/mL), with no significant benefit in low-ST2 patients, confirming the receptor-level biomarker dependence of this approach.

The all-comers AAER data further underscores tezepelumab’s phenotype-agnostic advantage: 56% overall versus 36% for itepekimab and 20% for astegolimab. In eosinophil-high disease, the three agents converge (70%, 65%, 60% respectively), suggesting that in this subgroup, targeting any upstream alarmin is roughly equivalent. The clinical differentiation emerges in the biomarker-negative populations that account for a meaningful share of the severe asthma burden, according to data reviewed by NEJM and published by The Lancet.

Pipeline evidence across the atopic march

The divergence in phenotype coverage seen in asthma trials is replicated — and in some cases amplified — when these biologics are tested across the broader atopic march indications: atopic dermatitis, chronic rhinosinusitis with nasal polyps (CRSwNP), food allergy, COPD, and eosinophilic esophagitis.

Atopic dermatitis: a striking divergence

Tezepelumab Phase 2a data showed a 45% reduction in EASI scores versus 15% for placebo in moderate-to-severe atopic dermatitis, driven by suppression of IL-13 and IL-31 (the key pruritus pathway). IL-33 blockers have performed poorly in this indication: astegolimab Phase 2 failed its primary endpoint (EASI-50), and itepekimab showed only modest efficacy, inferior to dupilumab. The mechanistic explanation is instructive — IL-33 has a dual function as a nuclear regulator involved in epithelial barrier repair, and its blockade may cause compensatory hyperproliferation of epithelial cells, undermining the therapeutic effect.

CRSwNP: IL-33 blockade shows a local advantage

In chronic rhinosinusitis with nasal polyps, astegolimab Phase 2 data showed significant reductions in polyp size (p=0.01) and sinus opacification, with a mechanistic rationale in the direct role of sinonasal epithelial-derived IL-33 in driving local eosinophilia. Tezepelumab’s Phase 3 WAYPOINT trial (NCT04851964) is ongoing, with preclinical data showing reductions in polyp fibroblast activity and IL-6. This is an indication where IL-33 blockade may hold a specific advantage over TSLP inhibition, pending Phase 3 data.

Food allergy and eosinophilic esophagitis

Tezepelumab’s Phase 2 EAVES trial in peanut allergy showed an increased tolerance threshold of 1,000 mg versus 130 mg for placebo, consistent with its ability to block DC-mediated food sensitisation — a mechanism that IL-33 blockers cannot address. In eosinophilic esophagitis, tezepelumab Phase 2 data showed a 64% reduction in esophageal eosinophils, with Phase 3 registrational trials now initiated. For IL-33 blockade in food allergy, itepekimab reduced cashew reactivity in preclinical mouse models but no human trial data are available.

COPD and emerging indications

In COPD, both strategies are being evaluated. Itepekimab Phase 2 data in eosinophilic COPD showed a 34% exacerbation reduction, consistent with the eosinophilic phenotype dependence seen in asthma. Tezepelumab is in Phase 3 for COPD (SUNRISE trial, NCT05507286), targeting a broader eosinophilic COPD population. Astegolimab is in Phase 2b for ulcerative colitis, exploring IL-33’s role in intestinal inflammation beyond the atopic march.

Positioning these biologics in precision medicine for atopic disease

TSLP inhibition with tezepelumab occupies a unique position in the severe asthma landscape: it is the only approved biologic that demonstrates meaningful efficacy across all phenotypic subgroups, including patients with low eosinophils, low FeNO, and non-atopic disease. This phenotype-agnostic profile reflects its upstream position in the immune cascade and its ability to suppress both type 2 and non-type 2 inflammation simultaneously.

IL-33 blockers are best positioned in eosinophil-dominant diseases where the speed and directness of ILC2 and eosinophil suppression is clinically valuable. Itepekimab’s rapid FeNO reduction (observed by day 2 in Phase 2 trials) and astegolimab’s efficacy in ST2-high CRSwNP patients illustrate the precision these agents can achieve when matched to the correct biomarker-defined population. As WHO and major respiratory guidelines increasingly emphasise biomarker-guided biologic selection, the ST2 and eosinophil thresholds identified in these trials will become central to prescribing decisions.

“Tezepelumab increased peanut tolerance threshold to 1,000 mg versus 130 mg for placebo — evidence that DC-mediated food sensitisation, a mechanism IL-33 blockers cannot address, is a viable therapeutic target.”

The combination therapy horizon is also significant. Preclinical data show that dual TSLP/IL-33 blockade eliminates ILC2 activation in mouse asthma models, suggesting additive or synergistic effects. A clinical trial combining itepekimab with dupilumab (anti-IL-4Rα) has shown additive effects in atopic dermatitis in Phase 2, pointing toward combination alarmin strategies as a future direction for patients with inadequate response to single-agent biologics. The EMA approved tezepelumab for severe asthma in 2022, and regulatory pathways for the broader atopic indications will depend on the Phase 3 data currently accumulating across the SUNRISE, WAYPOINT, and AERIS programmes.

For drug discovery teams and IP professionals tracking this space, the pipeline signals are clear: TSLP inhibition is expanding its addressable population across the atopic march, while IL-33 blockade is consolidating around eosinophilic niches and exploring receptor-level biomarker stratification. Both strategies will benefit from the development of companion diagnostics — ST2 for IL-33 inhibitors and composite biomarker panels for tezepelumab — that can identify the patients most likely to respond, consistent with the precision medicine frameworks being developed by organisations including PatSnap’s life sciences intelligence platform.