A first-in-human, single and multiple dose study of lunsekimig, a novel anti-TSLP/anti-IL-13 NANOBODY® compound, in healthy volunteers

Abstract

Lunsekimig is a novel, bispecific NANOBODY® molecule that inhibits both thymic stromal lymphopoietin (TSLP) and interleukin (IL)-13, two key mediators of asthma pathophysiology. In this first-in-human study, we evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of lunsekimig in healthy adult participants. Participants received single ascending doses (SAD) of lunsekimig (10-400 mg intravenous [IV] or 400 mg subcutaneous [SC]) (SAD part) or multiple ascending doses (MAD part) of lunsekimig (100 or 200 mg, every 2 weeks [Q2W] for three SC doses), or placebo. Overall, 48 participants were randomized 3:1 in the SAD part and 4:1 in the MAD part for lunsekimig or placebo. The primary endpoint was safety and tolerability. The secondary endpoints included PK, antidrug antibodies (ADAs) and total target measurement. Lunsekimig was well tolerated and common treatment-emergent adverse events were COVID-19, nasopharyngitis, injection site reactions, and headache. Lunsekimig showed dose-proportional increases in exposure and linear elimination. Mean t_1/2z of lunsekimig was around 10 days across all IV and SC doses of the SAD and MAD parts of the study. Increases in the serum concentration of total TSLP and IL-13 for lunsekimig versus placebo indicated target engagement. ADA of low titers were detected in four (11.1%) participants who received lunsekimig in the SAD, and seven (43.8%) in the MAD. In conclusion, lunsekimig was well tolerated in healthy participants with a linear PK profile up to single 400 mg IV and SC dose and multiple doses of 100 and 200 mg SC Q2W, with low immunogenicity.

Trial registration: ClinicalTrials.gov NCT05366764.

FIGURE 1

A schematic representation of lunsekimig molecular structure. Lunsekimig (SAR443765) is a bispecific anti‐TSLP/anti‐IL‐13 NANOBODY® construct, antagonizing the function of these two soluble human cytokines. It is a pentavalent molecule, consisting of two NANOBODY building blocks, each binding to different epitopes of TSLP, two NANOBODY® building blocks targeting different epitopes of IL‐13, and one NANOBODY® building block that binds to human albumin to extend the half‐life (t _1/2). IL, interleukin; TSLP, thymic stromal lymphopoietin.

FIGURE 2

Mean (±SD) lunsekimig serum concentration by time profiles after (a) single IV infusion (10–400 mg) and (b) single SC administration (400 mg) of lunsekimig from SAD part or after (c) the first SC administration (Day 1) and (d) the third administration (Day 29) of 100 to 200 mg of lunsekimig Q2W from MAD part. IV, intravenous; MAD, multiple ascending dose; Q2W, every 2 weeks; SAD, single ascending dose; SC, subcutaneous.

FIGURE 3

Total target concentration–time profile semi‐log plots of (a) TSLP of SAD part, (b) IL‐13 of SAD part (individual), (c) TSLP of MAD part, and (d) IL‐13 of MAD part (individual). 100 mg/200 mg Q2W corresponds to 100/200 mg administration (on Day 1, 15 and 29). D, day; IL, interleukin; IV, intravenous; MAD, multiple ascending doses; Q2W, twice in a week; SAD, single ascending dose; SC, subcutaneous; TSLP, thymic stromal lymphopoietin.