A First-In-Human Phase 1 Study to Evaluate the Safety and Tolerability of LEM-S401, a Novel siRNA-DegradaBALL Drug Targeting CTGF in Healthy Adults.

This study evaluated the safety, tolerability, and pharmacokinetics of LEM-S401, a novel siRNA therapeutic with DegradaBALL, a mesoporous silica nanoparticle-based delivery system. LEM-S401 is designed to deliver siRNA targeting connective tissue growth factor (CTGF) to fibroblasts for treating hypertrophic scars and keloids, both of which result from abnormal collagen proliferation. LEM-S401, containing unmodified siRNA LEM-17234 encapsulated in DegradaBALL nanoparticles, was administered subcutaneously to healthy adults in a randomized, double-blind, placebo-controlled, single-ascending dose study. Safety and tolerability assessments included vital signs, adverse events (AEs), laboratory tests, and cytokine levels. Pharmacokinetic analysis of LEM-17234 and silicon (Si), the primary component of DegradaBALL, was performed using blood samples collected at specified time points. LEM-S401 demonstrated a favorable safety and tolerability profile with only mild, self-resolving injection site reactions including pain and erythema. No systemic AEs were observed, and cytokine levels showed no significant changes between the treatment and placebo groups. Pharmacokinetic analysis revealed that LEM-17234 was below the plasma detection limit, indicating no notable systemic exposure of siRNA, while Si showed no dose-dependent systemic exposure, suggesting minimal systemic circulation of the mesoporous silica nanoparticles. These findings suggest DegradaBALL effectively encapsulates and delivers siRNA locally without significant systemic exposure. The novel DegradaBALL delivery system enables the stable and targeted delivery of siRNA, which presumably overcomes challenges related to siRNA instability and off-target effects. LEM-S401 has the potential to advance the treatment of fibrotic skin diseases such as keloids and hypertrophic scars by delivering siRNA directly to fibroblasts, thereby inhibiting excessive collagen production. Trial Registration: ClinicalTrials.gov identifier: NCT04707131. https://clinicaltrials.gov/study/NCT04707131?cond=NCT04707131&rank=1.