Development

Sanofi's BsAb lunsekimig hits endpoints for asthma, CRSwNP, falls short in dermatitis

Edited by Robert McTiernan··4 min read

Sanofi (EURONEXT: SAN; NASDAQ: SNY) reported that lunsekimig, its bispecific Nanobody targeting both TSLP and IL-13, met primary and key secondary endpoints in two Phase II studies in moderate-to-severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), while a separate exploratory study in atopic dermatitis did not meet its primary endpoint — a mixed but directionally meaningful readout for a molecule now entering Phase III in asthma.

The trial specifics

The AIRCULES trial is a randomized, double-blind, placebo-controlled, dose-ranging Phase IIb study that enrolled adults with moderate-to-severe asthma on standard of care, spanning the full range of fractional exhaled nitric oxide and eosinophil values. The DUET study is a randomized, double-blind, placebo-controlled Phase IIa proof-of-concept trial in adults with CRSwNP, assessed over 24 weeks.

In AIRCULES, lunsekimig produced a statistically significant reduction in the annualized rate of asthma exacerbations over 48 weeks — the primary endpoint — and improved pre-bronchodilator forced expiratory volume in one second at Week 48. No quantitative effect sizes were disclosed; full data are expected at upcoming medical congresses. In DUET, lunsekimig met its primary endpoint of change in nasal polyp score from baseline at Week 24 by bilateral endoscopy, and also met key secondary endpoints measuring patient-reported nasal congestion and Lund-Mackay CT score versus placebo. The exploratory VELVET Phase IIb study in atopic dermatitis did not meet its primary endpoint of percent change in EASI score at Week 24, though the company noted improvements in secondary skin-clearance measures including EASI-75 and vIGA-AD 0/1.

Across the respiratory studies, the most common treatment-emergent adverse events (≥5%) in AIRCULES were nasopharyngitis, upper respiratory tract infection, headache, and dose scheduling errors; in DUET, they included injection site reactions, viral upper respiratory tract infection, nasopharyngitis, epistaxis, ear pain, and elevated creatine phosphokinase. Rates of serious adverse events and discontinuations due to adverse events were similar between the lunsekimig and placebo groups in both respiratory studies.

Luneskimig's competitive context

Lunsekimig is a pentavalent Nanobody VHH — five linked antibody fragments — engineered to simultaneously neutralize TSLP, an upstream epithelial-derived initiator of airway inflammation, and IL-13, a downstream type-2 effector cytokine driving tissue remodeling. An albumin-binding domain extends its half-life. The mechanistic rationale is that blocking only one node leaves the other pathway intact; preclinical data cited by Sanofi suggest additive or synergistic effects from dual blockade, though clinical validation of that premise awaits quantitative Phase II and Phase III data.

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The asthma biologic market is well-populated but largely segmented by biomarker phenotype. Approved agents — mepolizumab, reslizumab, and benralizumab targeting IL-5 or its receptor, dupilumab blocking the shared IL-4/IL-13 receptor, and tezepelumab (Tezspire) targeting TSLP — each address defined patient subgroups or pathways. The closest mechanistic comparator is tezepelumab, which blocks TSLP alone and carries a biomarker-agnostic label in severe asthma following Phase III NAVIGATOR data. Lunsekimig's design extends that logic by adding simultaneous IL-13 neutralization — a strategy that, if borne out in Phase III, could position it as a dual-layer intervention where tezepelumab acts on only one. Cross-trial comparisons are limited by differences in patient populations, endpoints, and study designs, and no head-to-head data exist.

The AIRCULES enrollment criterion — patients across the full FeNO and eosinophil spectrum — mirrors tezepelumab's biomarker-agnostic positioning and stands in contrast to the eosinophil-restricted labels of the IL-5 class. Whether dual TSLP and IL-13 blockade translates into a measurably larger exacerbation reduction than TSLP blockade alone is the central question Phase III will need to answer. The atopic dermatitis miss in VELVET adds a complicating note: dupilumab, which also suppresses IL-13 signaling via IL-4Rα, is approved across multiple type-2 inflammatory conditions including atopic dermatitis and CRSwNP. Lunsekimig's failure on the primary EASI endpoint — despite signals in secondary skin endpoints — suggests that IL-13 blockade alone, or in combination with TSLP suppression, may not be sufficient in that indication at the doses and regimens tested, or that the patient population or trial design did not favor detection of an effect. Sanofi did not elaborate on the reasons for the discordance.

The CRSwNP result in DUET is notable given the high comorbidity between that condition and asthma; a single agent effective across both could offer practical advantages in a patient population that frequently requires treatment for both. Dupilumab already holds approvals in both indications, setting a commercial and clinical benchmark that lunsekimig would need to meet or exceed in larger trials.

Lunsekimig is currently in the PERSEPHONE and THESEUS Phase III studies in asthma, as well as the ongoing AIRLYMPUS Phase II study in high-risk asthma; detailed Phase II data presentations at medical congresses will be the next substantive milestone for assessing the magnitude of the efficacy signal before Phase III results become available.

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