Safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral allosteric TYK2 inhibitor ESK-001 using a randomized, double-blind, placebo-controlled study design

Clin Transl Sci. 2024 Dec;17(12):e70094. doi: 10.1111/cts.70094.

Abstract

ESK-001 is a highly selective allosteric inhibitor of tyrosine kinase 2 (TYK2), which plays an essential role in mediating cytokine signaling in multiple immune-mediated diseases. In 2 phase I studies, a first-in-human single ascending dose (SAD) and multiple ascending dose (MAD) study and a multiple-dose (MD) study, we evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of orally administered ESK-001 in healthy participants using a randomized, double-blind, placebo-controlled study design. ESK-001 was rapidly absorbed with systemic exposures generally increasing dose-proportionally across all cohorts. The mean terminal half-life ranged from 8 to 13 h with no to minimal accumulation of ESK-001 following q.d. doses and ~2-fold accumulation following Q12 doses. Less than 1% of unchanged ESK-001 was eliminated in urine. ESK-001 inhibited the downstream TYK2 pathway as shown by inhibition of pSTAT1 expression. Transcriptomic analysis of unstimulated whole blood samples confirmed dose-dependent inhibition of Type I IFN-induced genes and SIGLEC1, a novel TYK2-responsive biomarker. By correlating PK exposure data with PD readouts, a strong PK/PD relationship was demonstrated. There were no deaths, serious treatment-emergent adverse events (TEAEs), nor severe TEAEs, and most TEAEs were mild in severity. In conclusion, ESK-001 was generally safe and well-tolerated in healthy participants, showed linear dose-dependent PK characteristics, and maximally inhibited TYK2-dependent pathways with a predictable concentration-dependent PK/PD relationship. These findings were used to select the dose range of ESK-001 for the STRIDE phase II trial in plaque psoriasis and to support further clinical development of ESK-001 in other TYK2-mediated diseases.

Publication types

  • Randomized Controlled Trial
  • Clinical Trial, Phase I

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Allosteric Regulation / drug effects
  • Dose-Response Relationship, Drug*
  • Double-Blind Method
  • Female
  • Half-Life
  • Healthy Volunteers*
  • Humans
  • Male
  • Middle Aged
  • Protein Kinase Inhibitors* / administration & dosage
  • Protein Kinase Inhibitors* / adverse effects
  • Protein Kinase Inhibitors* / pharmacokinetics
  • Protein Kinase Inhibitors* / pharmacology
  • STAT1 Transcription Factor / metabolism
  • TYK2 Kinase* / antagonists & inhibitors
  • TYK2 Kinase* / metabolism
  • Young Adult

Substances

  • TYK2 Kinase
  • TYK2 protein, human
  • Protein Kinase Inhibitors
  • STAT1 Transcription Factor
  • STAT1 protein, human