Background/Purpose: Mitogen-activated protein kinase-activated protein kinase-2 (MK2), a direct downstream target of p38, has been identified as a promising candidate for treatment of inflammatory diseases. Activation of the p38 pathway leads to increased production of pro-inflammatory cytokines via MK2-mediated increases in the stability and translation of their mRNA (eg, TNF, IL-17, IL-6). Previously, p38 inhibitors were investigated for the treatment of autoimmune diseases, but tachyphylaxis was observed with the lack of sustained inhibition of inflammation despite continuous treatment.^1,2 MK2 inhibition is hypothesized to avoid the negative feedback network that may have limited p38 inhibitors. CC-99677 is a novel covalent MK2 inhibitor being developed for the treatment of inflammatory diseases.

Methods: In the in vitro model of tachyphylaxis, CC-99677 and p38 inhibitors similarly decreased TNF production at early time points. However, on day 9, loss of TNF inhibition was noted for all p38 inhibitors tested. In contrast, the MK2 inhibitor, CC-99677, sustainably suppressed TNF production throughout the treatment period. MK2 inhibition with CC-99677 resulted in reduced TNF and IL-17A/F production in in vitro-stimulated PBMCs from patients with PsA. In the animal model of psoriasis and PsA, a new cumulative score based on paw swelling, ear thickness, skin flaking, and joint severity score was devised: Psoriatic Arthritis Severity Index (PsASI). CC-99677 reduced the PsASI score in a dose-dependent manner.

Results: In the in vitro model of tachyphylaxis, CC-99677 and p38 inhibitors similarly decreased TNF production at early time points. However, on day 9, loss of TNF inhibition was noted for all p38 inhibitors tested. In contrast, the MK2 inhibitor, CC-99677, sustainably suppressed TNF production throughout the treatment period. MK2 inhibition with CC-99677 resulted in reduced TNF and IL-17A/F production in in vitro-stimulated PBMCs from patients with PsA. In the animal model of psoriasis and PsA, a new cumulative score based on paw swelling, ear thickness, skin flaking, and joint severity score was devised: Psoriatic Arthritis Severity Index (PsASI). CC-99677 reduced the PsASI score in a dose-dependent manner.

Conclusion: CC-99677 is an MK2 inhibitor that exhibits sustained inhibition of TNF in vitro and effectively reduces TNF production in stimulated immune cells from patients with PsA. In the in vivo MIP model of psoriasis and PsA, MK2 inhibition was efficacious in reducing skin and joint inflammation, reflected in a dose-dependent reduction in PsASI score. These data extend previous results demonstrating reduction in cytokine production in stimulated PBMCs from patients with AS and efficacy in the rat HLA-B27 transgenic model of AS.⁵ Thus, our in vitro and in vivo data support investigating CC-99677 in clinical studies planned in patients with spondyloarthritis.

References: 1. Genovese MC. Arthritis Rheum. 2009; 60:317-320. 2. Damjanov N, et al. Arthritis Rheum. 2009;60:1232-1241. 3. Khmaladze I, et al. Proc Natl Acad Sci USA. 2014;111:E3669-E3678. 4. Ramirez-Valle F, et al. Proc Natl Acad Sci USA. 2015;112:8046-8051. 5. Ramirez-Valle F, et al. 2019 ACR/ARP Annual Meeting [abstract 1536].

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cc-99677-a-novel-selective-oral-mk2-inhibitor-sustainably-reduces-pro-inflammatory-cytokine-production-and-ameliorates-inflammation-in-the-mannan-induced-murine-model-of-psoriasis-and-psoriatic-ar/