A PHASE II TRIAL investigating an MK2 inhibitor in ankylosing spondylitis found the treatment was generally well tolerated but failed to produce significant clinical improvements compared with placebo, despite promising earlier preclinical evidence targeting inflammatory signalling pathways.
New Targets Continue to Emerge in AS Research
Ankylosing spondylitis remains a challenging inflammatory disease, with some patients experiencing persistent symptoms despite non-steroidal anti-inflammatory drugs and existing biologic therapies. Researchers therefore evaluated CC-99677, a covalent MK2 inhibitor designed to suppress pro-inflammatory cytokine production, to determine whether MK2 inhibition could improve disease activity in ankylosing spondylitis.
Placebo-Controlled Trial Assessed MK2 Inhibitor
This phase II multicentre, randomised, double-blind, placebo-controlled study enrolled 147 patients with ankylosing spondylitis who fulfilled modified New York criteria and had active disease, defined by a Bath Ankylosing Spondylitis Disease Activity Index score of at least 4 and total back pain score of at least 4 despite treatment with at least two non-steroidal anti-inflammatory drugs. Participants were biologic disease-modifying antirheumatic drug naïve and were randomised 1:1:1 to once-daily CC-99677 150 mg, CC-99677 60 mg, or placebo.
Clinical Outcomes Failed to Reach Significance
At Week 12, ASAS20 response rates were 51.2% in the CC-99677 60 mg group, 56.1% in the 150 mg group, and 48.8% in the placebo group. ASAS40 responses were 25.6%, 34.1%, and 22.0%, respectively. Investigators reported no statistically significant differences between treatment groups across primary or secondary endpoints. Although MRI spine and sacroiliac joint inflammation scores showed numerical improvement trends with active treatment, reductions remained substantially lower than those previously observed with TNF inhibitors, IL-17 inhibitors, filgotinib, or upadacitinib. Minimal inhibition of pro-inflammatory cytokines was detected in serum.
Implications for Future Drug Development
Researchers concluded that MK2 inhibition with CC-99677 was insufficient to achieve meaningful clinical benefit in ankylosing spondylitis at the doses tested. While the treatment demonstrated an acceptable safety profile, the findings highlight the importance of phase II trials in validating promising inflammatory targets before larger-scale development proceeds.
Reference
Maksymowych WP et al. Phase II randomised, placebo-controlled study to evaluate the efficacy and safety of an MK2 inhibitor in ankylosing spondylitis. RMD Open. 2026;12:e006527.
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