First-in-Human Safety and Tolerability Study of TOP-N53, a NO-Releasing PDE5 Inhibitor, in Healthy Volunteers

Chronic wounds, such as diabetic and ischemic ulcers, involve impaired perfusion and delayed healing. TOP-N53 is a novel bifunctional molecule combining nitric oxide (NO) release with phosphodiesterase-5 (PDE5) inhibition to enhance local NO-cGMP signalling, resulting in vasodilation and angiogenesis. This first-in-human, randomized, double-blind, vehicle-controlled Phase I trial assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single subcutaneous TOP-N53 doses in 29 healthy male volunteers. Each participant received injections of TOP-N53 and vehicle in the same forearm, but either at the proximal or at the distal site in an intra-individually blinded manner. Safety assessments included local and systemic parameters. PK and PD responses were evaluated by analysis of TOP-N53 and its bioactivation metabolite TOP-52 in plasma, and by Laser Speckle Contrast Imaging (LSCI), a non-invasive method to measure skin perfusion, respectively. TOP-N53 was safe and well tolerated, with no serious adverse events or local or systemic adverse reactions. Plasma concentrations remained below the quantification limit and LSCI showed sustained dose-dependent increases in local skin perfusion at doses of 4.84 {micro}g and 9.075 {micro}g TOP-N53 SC for up to 24 h post injection when compared to vehicle. These findings support the favourable safety and tolerability profile of TOP-N53 associated with locally improved skin perfusion, encouraging its further clinical development as a topical treatment for chronic wounds with microvascular dysfunction.