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.