ACR CONVERGENCE 2021—The mitogen-activated protein kinase (MAPK) activated protein kinase-2 (MK2) pathway increases pro-inflammatory factors including, but not limited to, tumor necrosis factor (TNF-α), interleukin (IL) 6 and IL-17. A phase 1 study of an irreversible inhibitor of MK2, CC-99677, was presented by Kofi Mensah, MD, PhD, professor of medicine and rheumatology at Yale School of Medicine, New Haven, Conn., and a rheumatologist at Yale New Haven Health/Yale New Haven Hospital, during ACR Convergence 2021.1
Methods
This double-blind, placebo-controlled study sought to characterize the safety, pharmacokinetics and pharmacodynamics of CC-99677 in healthy adults (NCT03554993). Thirty-seven healthy adults were enrolled in five dose-level groups, which ranged from 10 mg to 150 mg of CC-99677 or placebo, randomized in a 3:1 ratio of those taking the study drug to those taking placebo. Study participants were given their respective doses daily for 14 days. The primary study outcome was the safety and tolerability of multiple daily doses of CC-99677. The study’s secondary and exploratory outcomes included an assessment of the CC-99677 plasma pharmacokinetic profile and its pharmacodynamic effects, as measured by MK2 target occupancy and ex vivo inhibition of inflammatory cytokines in the whole blood of study participants.
The Results
The CC-99677 multiple-dose pharmacokinetic characteristics showed linear, dose-proportional increases in drug uptake from 10 mg to 150 mg using a once-daily dosing schedule over 14 days. In the study, the daily dosing of CC-99677 up to 150 mg was shown to be safe and well tolerated by participants. The drug showed a proportional and linear increase in drug levels across the 14-day study. During the study, once-daily dosing led to the desired effect of a sustained decrease in TNF-α and other cytokines and chemokines throughout the 14 days. This finding was noted for all five dosing groups. Steady-state levels were reached by day 8.
According to Mensah et al., “Daily treatment resulted in dose-dependent increases in target engagement between 10 and 120 mg and plateauing at the 120- and 150 mg-dose levels.” Sustained reductions of TNF-α and other cytokines occurred during dosing.
Overall, this small preliminary study showed that administration of once-daily CC-99677 was safe and well tolerated, with linear pharmacokinetics and sustained reductions of TNF-α and pro-inflammatory cytokines and chemokine creation, making CC-99677 inhibition of MK2 a promising new therapeutic approach to the management of inflammatory diseases. Phase 2 studies in patients with spondyloarthritis are in the planning stages.
