OP-0124 – ARRY-162, A Novel Inhibitor of MEK Kinase: Phase 1A-1B Pharmacokinetic and Pharmacodynamic Results.
Carter, Brown, Klopfenstein, Simmons, Litwiler, Karan, Gaddis, Venendaal, Kivitz, Fogarty, Yates, Rojas-Caro. USA. [Sponsor, Array BioPharma Inc.]
Objective
To evaluate the safety, pharmacokinetic (PK) and pharmacodynamic (PD) properties of ARRY-162, an oral inhibitor of MEK. MEK is a MAPKK that mediates signals from various growth factors, pro-inflammatory cytokines and toll like receptors. Pre-clinical studies in the collagen induced model of arthritis in mice show significant attenuation of disease in drug-treated, compared to placebo-treated, mice. ARRY-162 is highly specific for MRK in in vitro studies of panels of kinases.
Methods
The studies were conducted in a double-blind, placebo-controlled manner with an escalating dose approach in normal healthy volunteers, and fixed dosing in RA patients. Normal healthy volunteers (n=50) received 5, 10, 20, 40, 60, 80 mg QD or 20 mg BID of ARRY-162 for 14 days. Patients with RA (n=30) on background MTX received 10, 20, 40 mg QD or 10, 20 mg BID for 28 days. Blood was collected pre and post dosing, stimulated ex vivo with TPA. Plasma levels of IL1β, TNF and IL-6 were measured 24 hours later. Plasma concentrations of ARRY-162 and MTX were also measured.
Results
ARRY-162 was generally well-tolerated for 14 and 28 days. There were no laboratory abnormalities noted such as LFT elevations or decreases in blood cell counts. The most common adverse events in the drug treated patients included diarrhea, rash, nausea and edema but all were mild and did not result in discontinuation of drug in any participant. Dose-dependent inhibition of TPA-induced IL-1β, TNF and IL-6 was observed. In the 40 mg QD cohort after 28 days of dosing in RA patients, there was >90% inhibition of IL-1β, >95% inhibition of TNF and >95% inhibition of IL-6. Each of these cytokine levels remained suppressed throughout each 24 hours following 40 mg QD. There was no indication of PK drug-drug interactions between ARRY-162 and MTX. Levels of the ex vivo biomarkers were closely linked to plasma concentrations of ARRY-162.
Conclusion
In these Phase 1a and 1b studies, ARRY-162 was well tolerated and significantly inhibited the production of clinically relevant biomarkers such as IL-1, TNF and IL-6. Based on these encouraging data, a 12-week Phase 2 study of ARRY-162 in patients with RA has been initiated.
Editorial Comment
These results are very tantalizing. Of course, the proof will be in the larger clinical trial in RA that is underway, to see if the reductions in cytokines are paralleled by significant clinical improvement. In the phase I studies above, it was not clear that the patients really had active disease.
MEK acts fairly proximally in the inflammatory pathway. The concern for targeting many of these signal transduction molecules is that their targeting will also result in inhibition of critical homeostatic or physiological pathways. The safety data in this small sampling of healthy volunteers and RA patients did not generate any early safety signals, but of course much larger numbers of patients will need to be tested.
