OP-0044 – Initial Efficacy of INCB018424, a Selective Janus Kinase 1&2 (JAK 1&2) Inhibitor in Rheumatoid Arthritis (RA)
Williams, Scherle, Newton, McKeever, Fridman, Vaddi, Levy, Moreland. InCyte Corporation (Wilmington) and Univ of Pittsburgh.
Objective
The aim of this study was to evaluate the initial efficacy of INCB018424 in patients with RA, and the PK and PD of this drug in healthy volunteers. Janus kinases (JAKs) mediate activation signals from a variety of cytokines that are relevant to RA, including IL-6, -12, -15, -23, GM-CSF and IFNg. INCB018424 is a small molecule inhibitor of JAKs, especially JAK1 and JAK2.
Methods
Patients with active RA (> 6 tender, > 4 swollen joints, ESR > 28 or CRP > 15 mg/L) who were on no DMARDs or on stable doses of methotrexate, hydroxychloroquine and/or sulfasalazine were recruited. Subjects were dosed with 15 mg BID for 28 days with clinical, laboratory and PD assessments of disease activity on Days 1, 8, 14 and 28 of dosing with a randomization ratio of 3:1 (active drug to placebo). Two phase 1 studies were carried out in healthy control subjects to characterize the safety, tolerability, PK and PD of INCB018424 with dosing up to 10 days.
Results
28 day data were available on 12 RA patients. Of those on active drug, ACR 20, 50, 70 and 90 responses were 75%, 50%, 25% and 17%, respectively. Of those on placebo, these responses were 50%, 0, 0 and 0, respectively. There was a 50% improvement in ESR, CRP, DAS28 and HAQ at 28 days. Improvements in DAS28 were observed as early as one week. The CRP was observed to rise quickly again after the drug was discontinued. Adverse events were reported in 4 of 12 patients (including self-limited mild diarrhea in one active and one placebo patient), but no serious adverse events were reported. INCB018424 was absorbed rapidly, attaining peak plasma concentrations 1-2 hours following dosing with a half-life of approximately 3 hours, and exhibited dose proportional PK with no accumulation on BID dosing. At 15 mg BID, unbound drug levels exceeded the IC50 for JAK1 and JAK2, but not TYK2 or JAK3.
Conclusion
INCB018424 appears to be safe and well-tolerated at a dose of 15 mg BID and demonstrates preliminary efficacy in the treatment of RA. This is the first demonstration of clinical activity of a selective JAK1 and JAK2inhibitor in RA.
Editorial Comment
These preliminary results are very exciting and mimic those of the Pfizer compound that inhibits a different signal transduction molecule (STAT) but that also plays a role in mediating activation signals from RA-relevant cytokines. There has been considerable excitement but also concern about inhibiting signal transduction molecules that are so proximal in cellular inflammation pathways. On the one hand, moving proximal will allow for the inhibition of multiple inflammatory cytokines, not just TNF. On the other hand, these pathways mediate cellular functions other than just inflammation and their inhibition may theoretically cause impairment of normal physiological functions. What is most surprising about both the JAK and the STAT inhibitor studies in RA to date is the rapidity of their actions and the apparent relative safety, at least in these short term studies. We will anxiously await the results of larger Phase II and III studies.
