Preclinical characterization of itacitinib (INCB039110), a novel selective inhibitor of JAK1, for the treatment of inflammatory diseases

Eur J Pharmacol. 2020 Oct 15;885:173505. doi: 10.1016/j.ejphar.2020.173505. Epub 2020 Aug 28.


Pharmacological modulation of the Janus kinase (JAK) family has achieved clinically meaningful therapeutic outcomes for the treatment of inflammatory and hematopoietic diseases. Several JAK1 selective compounds are being investigated clinically to determine their anti-inflammatory potential. We used recombinant enzymes and primary human lymphocytes to assess the JAK1 specificity of itacitinib (INCB039110) and study inhibition of signal transducers and activators of transcription (STAT) signaling. Rodent models of arthritis and inflammatory bowel disease were subsequently explored to elucidate the efficacy of orally administered itacitinib on inflammatory pathogenesis. Itacitinib is a potent and selective JAK1 inhibitor when profiled against the other JAK family members. Upon oral administration in rodents, itacitinib achieved dose-dependent pharmacokinetic exposures that highly correlated with STAT3 pharmacodynamic pathway inhibition. Itacitinib ameliorated symptoms and pathology of established experimentally-induced arthritis in a dose-dependent manner. Furthermore, itacitinib effectively delayed disease onset, reduced symptom severity, and accelerated recovery in three distinct mouse models of inflammatory bowel disease. Low dose itacitinib administered via cannula directly into the colon was highly efficacious in TNBS-induced colitis but with minimal systemic drug exposure, suggesting localized JAK1 inhibition is sufficient for disease amelioration. Itacitinib treatment in an acute graft-versus-host disease (GvHD) model rapidly reduced inflammatory markers within lymphocytes and target tissue, resulting in a marked improvement in disease symptoms. This is the first manuscript describing itacitinib as a potent and selective JAK1 inhibitor with anti-inflammatory activity across multiple preclinical disease models. These data support the scientific rationale for ongoing clinical trials studying itacitinib in select GvHD patient populations.

Keywords: Arthritis; Colitis; Cytokines; GvHD; Janus kinase.

MeSH terms

  • Animals
  • Arthritis, Experimental / drug therapy
  • Azetidines / pharmacokinetics
  • Azetidines / pharmacology*
  • Azetidines / therapeutic use
  • Chemokine CCL2 / drug effects
  • Colitis / chemically induced
  • Colitis / drug therapy
  • Dose-Response Relationship, Drug
  • Graft vs Host Disease / drug therapy
  • Humans
  • Inflammation / drug therapy*
  • Inflammatory Bowel Diseases / drug therapy
  • Isonicotinic Acids / pharmacokinetics
  • Isonicotinic Acids / pharmacology*
  • Isonicotinic Acids / therapeutic use
  • Janus Kinase 1 / antagonists & inhibitors*
  • Lymphocytes / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Primary Cell Culture
  • Rats
  • Rats, Inbred Lew
  • STAT Transcription Factors / drug effects
  • STAT3 Transcription Factor / drug effects
  • Signal Transduction / drug effects
  • T-Lymphocytes / drug effects


  • Azetidines
  • CCL2 protein, human
  • Chemokine CCL2
  • INCB039110
  • Isonicotinic Acids
  • STAT Transcription Factors
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • JAK1 protein, human
  • Janus Kinase 1