Therapeutic safety of RIPK1 inhibitors in human inflammatory diseases: a systematic review and meta-analysis

Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of inflammatory signalling and cell death, making it an attractive therapeutic target for immune-mediated inflammatory diseases. This systematic review evaluated the safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitors in humans, including both healthy participants and patients with immune-mediated inflammatory diseases. CENTRAL, Embase, and Medline were systematically searched for randomised placebo-controlled Phase I-II trials reporting adverse events, pharmacokinetics, and pharmacodynamic outcomes. Random-effects meta-analysis was performed to estimate pooled risk ratios (RRs) of adverse events, with subgroup analyses of single-ascending dose (SAD) and multiple-ascending dose (MAD) regimens. Sixteen trials involving 1072 participants and 10 RIPK1 inhibitors were included; 81.2% were Phase I and 18.8% were Phase II studies. RIPK1 inhibitors were not associated with an increased risk of adverse events compared with placebo (RR = 0.99, 95% CI 0.90–1.09; P = 0.90). Neutral safety findings were consistent across both SAD and MAD subgroups. Although elimination half-life varied substantially between compounds, it remained dose-independent within each drug. All inhibitors demonstrated robust target engagement, achieving up to 97% inhibition of RIPK1 phosphorylation. Overall, RIPK1 inhibitors exhibited favourable short-term safety, predictable pharmacokinetics, and consistent pharmacodynamic activity, supporting their continued clinical development for inflammatory conditions.