Background Janus activated kinase (Jak) inhibition has shown clinical benefits in treatment of rheumatoid arthritis (RA). However, targeting all isoforms of Jak (Jak1, Jak2, Jak3, and Tyk2) may be associated with increased incidences of anemia and viral infections. ABT-494 is a novel, potent Jak1 inhibitor with reduced activity against Jak2 and Jak3 and has the potential to provide an improved safety profile compared to pan-Jak inhibitors.
Objectives The objective of this work was to evaluate the pharmacokinetics, safety and tolerability of ABT-494 following single and multiple dose in healthy volunteers and subjects with RA who were on stable doses of methotrexate.
Methods Single escalating doses (1, 3, 6, 12, 24, 36, 48 mg or placebo in 3:1 ratio, total n=56) and multiple escalating doses (3, 6, 12, 24 mg or placebo twice-daily for 14 days in 8:3 ratio, total n=44) of ABT-494 were evaluated in healthy volunteers. Multiple doses of ABT-494 (6, 12, 24 mg; n=10) or placebo (n=4) twice-daily for 27 days were evaluated in subjects with RA on stable methotrexate doses. All three evaluations followed randomized, double-blind, placebo-controlled designs. Serial blood samples for characterization of ABT-494 and methotrexate (for subjects with RA) pharmacokinetics were collected, and safety and tolerability were monitored.
Results ABT-494 followed multi-exponential disposition with peak concentrations within 2 hours of dosing. ABT-494 exposure was dose-proportional over the evaluated dose ranges and displayed no significant accumulation with twice-daily dosing. ABT-494 terminal elimination half-life ranged from 6 to 16 hours across dose levels and its functional half-life, estimated from the Cmax to Ctrough ratio at steady-state, was approximately 4 hours. ABT-494 exposures were comparable when administered with and without methotrexate. Similarly, methotrexate exposures were comparable when administered with and without ABT-494. The fraction of ABT-494 dose eliminated unchanged in urine ranged from 14% to 25%. No serious adverse events or early terminations due to treatment-emergent adverse events (TEAEs) occurred. The frequency and types of TEAEs were typical of Phase 1 findings given a small sample size and were all considered mild or moderate in severity. The TEAEs that occurred in more than one healthy volunteer in ABT-494-treated groups were headache (2/42) and presyncope (2/42) following single dosing and the most frequently reported TEAEs following multiple dosing of ABT-494 were headache (5/32), abdominal pain (2/32), diarrhea (2/32), and nasopharyngitis (2/32), with no evidence of dose-dependent increase in the observed TEAEs. Five subjects with RA experienced at least 1 TEAE (total of 7 TEAEs: nausea, vomiting, viral gastroenteritis, upper respiratory tract infection, post-traumatic neck syndrome, back pain, and insomnia) after receiving ABT-494 on background stable doses of methotrexate. Compared to placebo, no safety signals in ABT-494-treated groups were observed. No clinically significant changes in laboratory values, vital signs or ECG findings were observed.
Conclusions Based on the favorable pharmacokinetics, safety and tolerability profiles observed for ABT-494 in these evaluations, ABT-494 was advanced to three dose ranging Phase 2 trials in RA and Crohn's disease.
Disclosure of Interest M.-E. Mohamed Shareholder of: AbbVie, Employee of: AbbVie, H. Camp Shareholder of: AbbVie, Employee of: AbbVie, P. Jiang Shareholder of: AbbVie, Employee of: AbbVie, R. Padley Shareholder of: AbbVie, Employee of: AbbVie, A. Asatryan Shareholder of: AbbVie, Employee of: AbbVie, A. Othman Shareholder of: AbbVie, Employee of: AbbVie