Translational development of crisugabalin for neuropathic pain

Abstract Crisugabalin (HSK16149) is a next‐generation α2δ ligand developed to preserve the mechanistic rationale of gabapentinoids while refining target engagement and exposure‐related tolerability constraints. We performed a translational review of molecular/structural studies, in vivo pharmacology and behavioural safety assessments, phase I clinical pharmacology and randomized clinical trials in diabetic peripheral neuropathic pain (DPNP) and postherpetic neuralgia (PHN), with searches across major bibliographic databases and trial registries updated through June 2026. Evidence was synthesized qualitatively along a molecular‐to‐clinical sequence. Structural and kinetic studies indicate stable engagement of the α2δ1 binding site, with slower dissociation from α2δ1 than from α2δ2. In rodent models, crisugabalin demonstrated antinociceptive efficacy with a wider separation between antinociceptive and motor‐impairing doses relative to pregabalin and no clear abuse liability signals across standard paradigms. Human phase I data show rapid absorption (T max ~ 1.5–1.7 h), dose‐proportional exposure, slight accumulation and predominant renal elimination. A high‐fat meal delayed absorption without materially changing overall exposure, whereas renal impairment produced graded exposure increases supporting consideration of dose adjustment as renal function declines. Clinically, a seamless adaptive phase II/III trial in DPNP and a confirmatory phase III trial in PHN demonstrated significant reductions in pain intensity at 40–80 mg/day; dizziness was the most frequent dose‐related adverse event. Current evidence supports crisugabalin as a class‐refinement strategy with consistent short‐term efficacy in DPNP and PHN and predictable clinical pharmacology. Generalizability beyond Chinese populations, longer‐term outcomes and comparative effectiveness relative to established therapies remain key gaps.