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Original article

Safety, pharmacokinetics and pharmacodynamics of selgantolimod, an oral Toll-like receptor 8 agonist: a Phase Ia study in healthy subjects

Maribel Reyes, Justin D Lutz, Audrey H Lau, Anuj Gaggar, Ethan P Grant, Adarsh Joshi, Richard L Mackman, John Ling, Susanna K Tan, Natarajan Ayithan, Stephane Daffis, Jacky Woo, Peiwen Wu, Tina Lam, Simon P Fletcher, Shyamasundaran Kottilil, Bhawna Poonia, Edward J Gane, Anita Mathias, Polina German

Corresponding author name: Polina German
Corresponding author e-mail: Polina.German@gilead.com

doi: 10.3851/IMP3363

Abstract

Background: Selgantolimod is a novel oral, selective Toll-like receptor 8 (TLR8) agonist in development for the treatment of chronic hepatitis B (CHB). TLR8 is an endosomal innate immune receptor and a target for treatment of viral infections. This first-in-human study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of selgantolimod in healthy volunteers.

Methods: Of 71 subjects enrolled, 59 received a single dose of selgantolimod (0.5, 1.5, 3, or 5 mg) or placebo, and 12 were evaluated for food effect. Safety, pharmacokinetics and pharmacodynamic activity by induction of cytokines, chemokines and acute phase proteins were assessed. PK/PD analyses were conducted.

Results: Single doses of 0.5-5 mg were generally safe. No serious adverse events (AEs) or AEs leading to discontinuation were reported, and most were Grade 1 in severity. Selgantolimod displayed rapid absorption and dose-proportional PK and PD activity. Food had minimal effect on PK but resulted in diminished PD activity. In PK/PD analyses, near-saturation of induction for most evaluated biomarkers occurred at the 5-mg dose.

Conclusions: Single doses of up to 5 mg selgantolimod were safe and induced dose-dependent PD responses. These data support evaluation of selgantolimod in combination with other agents in future clinical studies of CHB.

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