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 µg and 9.075 µg 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.

The authors have declared no competing interest.

EudraCT number 2020-000672-38

The trial was sponsored by Topadur Pharma AG

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The clinical study protocol (Version 2.0, dated 06 July 2020) received prior approval from both the Independent Ethics Committee (IEC) of the Landesaerztekammer Baden-Wuerttemberg (Chair: Prof. Dr. med. Gerlinde Egerer) and the German competent authority (Bundesinstitut fuer Arzneimittel und Medizinprodukte, BfArM). The IEC provided a favourable opinion on 16 July 2020, and regulatory approval was granted by the BfArM on 07 August 2020.

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Yes

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Yes

All data produced in the present study are available upon reasonable request to the authors