A proof-of-mechanism trial in asthma with lunsekimig, a bispecific NANOBODY molecule

Abstract

Background: Monovalent biologics blocking thymic stromal lymphopoietin (TSLP) or interleukin (IL)-13 have been shown to elicit pharmacodynamic responses in asthma following a single dose. Therefore, dual blockade of these cytokines may result in an enhanced response compared to single targeting and has the potential to break efficacy ceilings in asthma. This study assessed the safety and tolerability of lunsekimig, a bispecific NANOBODY molecule that blocks TSLP and IL-13, and its effect on type 2 (T2) inflammatory biomarkers and lung function in asthma.

Methods: This was a phase 1b, single-dose (subcutaneous lunsekimig 400 mg or placebo), randomised (2:1), double-blind, proof-of-mechanism study in 36 participants with mild-to-moderate asthma and elevated exhaled nitric oxide fraction (F _ENO; ≥25 ppb), a marker of airway inflammation. The primary end-point was safety and tolerability through day 71. The main pharmacodynamic secondary end-point was change from baseline in F _ENO at day 29.

Results: Lunsekimig was well tolerated, with no serious treatment-emergent adverse events. F _ENO was significantly reduced from day 8 through day 29 after a single dose, with change from baseline of -40.9 (90% CI -55.43- -26.39) ppb (p<0.0001) versus placebo at day 29. Blood-based T2 biomarkers at day 29 were significantly reduced from baseline. Lung function, particularly small airway dysfunction, was numerically improved at day 29, most notably in participants with impaired lung function at baseline.

Conclusions: A single dose of lunsekimig was well tolerated, significantly suppressed T2 inflammation and improved lung function in mild-to-moderate asthma.

Lunsekimig mechanism of action, summary of study population, design and study results. TSLP: thymic stromal lymphopoietin; IL: interleukin; GINA: Global Initiative for Asthma; F_ENO: exhaled nitric oxide fraction; FEV₁: forced expiratory volume in 1 s; ICS: inhaled corticosteroids; D: day; EOS: end-of-study; TEAE: treatment-emergent adverse event; BL: baseline; TARC: thymus- and activation-regulated chemokine.

FIGURE 1

Participant disposition. F_ENO: exhaled nitric oxide fraction; FEV₁: forced expiratory volume in 1 s.

FIGURE 2

Change from baseline in exhaled nitric oxide fraction (F_ENO) levels after a single subcutaneous administration of 400 mg lunsekimig and placebo. a) Change (mean±se) from baseline to day 57 in F_ENO levels over time. b) Percentage change (mean±se) from baseline to day 57 in F_ENO levels over time. ^#: point estimates (90% CI) from a mixed effects model up to day 29 (aligned with the secondary end-point of the study) with repeated measures over time taking into account baseline F_ENO and sex as covariates. As such, no model outcome is reported for day 57 (NA: not analysed). BL: baseline; D: day.

FIGURE 3

Percentage change (median with interquartile range) from baseline in blood eosinophil levels after a single subcutaneous administration of 400 mg lunsekimig and placebo. Note: percentage change from baseline through end-of-study visit in blood eosinophil counts over time. BL: baseline; D: day.

FIGURE 4

Lung function after a single subcutaneous administration of 400 mg lunsekimig compared to placebo. Change (mean±se) from baseline in pre-bronchodilator a) forced expiratory volume in 1 s (FEV₁), b) forced expiratory flow at 25–75% of forced vital capacity (FEF_25–75%), c) area of reactance (AX) and d) frequency dependence of respiratory resistance (difference between respiratory resistance at 5 and 20 Hz (R_5–20)). ^#: point estimates (90% CI) from a mixed effects model up to day 29 (aligned with the secondary end-point of change in F_ENO) with repeated measures over time taking into account baseline FEV₁ and sex as covariates. As such, no model outcome is reported for day 57 (NA: not analysed). BL: baseline; D: day.

FIGURE 5

Lung function based on baseline forced expiratory volume in 1 s (FEV₁) percentage predicted after a single subcutaneous administration of 400 mg lunsekimig compared to placebo. Change (mean±se) from baseline to day 57 in pre-bronchodilator a) FEV₁, b) forced expiratory flow at 25–75% of forced vital capacity (FEF_25–75%), c) area of reactance (AX) and d) frequency dependence of respiratory resistance (difference between respiratory resistance at 5 and 20 Hz (R_5–20)), by baseline FEV₁ percentage predicted. BL: baseline; D: day.