Background/Purpose: Inhibitors of p38 are associated with tachyphylaxis in patients with RA and other inflammatory diseases, where early reduction in ex vivo production of cytokines, such as TNF-α, or endogenous inflammatory markers, such as CRP, did not persist despite continued treatment. Thus, p38 inhibitors have not advanced in clinical development. Targets downstream of p38 have been identified to avoid these limitations. The mitogen-activated protein kinase-activated protein kinase-2 (MK2) pathway is activated downstream of p38, and activation of MK2 increases the stability and translation of mRNA of proinflammatory factors (e.g., TNF-α, IL-17, IL-6). CC-99677 is a novel, irreversible, covalent MK2 inhibitor. Here, we report data from the first-in-human multiple ascending-dose study to characterize the safety, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy volunteers dosed with CC-99677.

Methods: A phase 1, randomized, double-blind, placebo-controlled study (NCT03554993) was performed involving 37 healthy adult volunteers who were enrolled into 5 dose-level cohorts ranging from 10 to 150 mg of CC-99677 or placebo with 3:1 randomization. Participants were dosed daily for 14 days. The primary outcome of this study was safety and tolerability of multiple daily doses of CC-99677. Secondary and exploratory outcomes included assessment of the plasma CC-99677 PK profile and evaluation of the PD effects of CC-99677 as measured by MK2 target occupancy and ex vivo inhibition of inflammatory cytokines in participant whole blood.

Results: Multiple doses of CC-99677 up to 150 mg for 14 days were safe and well tolerated by the healthy adult subjects in this study. The multiple-dose PK characteristics of CC-99677 showed a linear, dose-proportional increase in exposure from 10 to 150 mg with a once-daily dosing schedule over 14 days. CC-99677 peak concentration (C_max), time to reach C_max (T_max), and area under the curve from time 0 to the time of last measurement (AUC_0-t) were similar on day 1 and day 14 (last day of dosing) across the dose range of 10 to 150 mg, suggesting limited or no accumulation of CC-99677 with repeat once-daily dosing. There was a cumulative increase in target engagement with once-daily administration of CC-99677 for 14 days, reaching steady-state levels by day 8. 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 reduction during the dosing period in TNF-α and other cytokine and chemokine production was observed in ex vivo stimulated blood from subjects who received once-daily doses >10 mg CC-99677 for 14 days.

Conclusion: Administration of CC-99677 was safe and well tolerated, resulted in linear PK, and demonstrated sustained reduction of ex vivo whole blood TNF-α, IL-6, and chemokine synthesis. The lack of tachyphylaxis in human cells exposed to CC-99677, compared with previous disappointing results targeting the p38 axis, is encouraging. Thus, CC-99677 inhibition of MK2 is a promising approach for the treatment of inflammatory diseases. Phase 2 studies of CC-99677 in patients with spondyloarthritis are planned.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cc-99677-a-novel-oral-selective-mk2-inhibitor-with-sustainable-multi-cytokine-inhibition-for-the-treatment-of-ankylosing-spondylitis-and-other-inflammatory-diseases/