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Validated TTR and RBP4 assays as critical PD markers to guide clinical development

13 Jun 2025

China Bioanalysis Forum 2025 -- In general, oligonucleotide therapeutics (ONTs) are rapidly cleared from systemic circulation. These drugs tend to distribute extensively and accumulate within tissues, exhibiting a prolonged pharmacodynamic (PD) half-life that leads to sustained pharmacological responses. Clinical pharmacology considerations include the fact that systemic pharmacokinetics may not accurately reflect drug distribution in target tissues, PD effects, safety profiles or efficacy outcomes. Therefore, it is important to incorporate assessments of appropriate PD markers or other relevant response measurements. Small interfering RNA (siRNA) conjugated to triantennary N-acetyl galactosamine (GalNAc3) inhibits hepatic transthyretin (TTR) protein synthesis via RNA interference. The retinol-binding protein 4 (RBP4)-retinol complex interacts with TTR, and the formation of this complex increases serum half-life. Target TTRs siRNA indirectly reduce RBP4. This poster introduces a validated RBP4 assay, which has been used to provide critical PD data to guide clinical development.