NEurotrophin MImetic compound for the modulation of ischemia-reperfusion injury in liver transplantation with Extended criteria Donors (the NEMILED study) and for the treatment of diabetic foot Ulcers (the NEMUS study)

Udonitrectag (MT8) is a non-peptidic neurotrophin mimetic compound with activity on TrkA and TrkB receptors, developed to modulate cellular survival, apoptosis, inflammation, and tissue repair. Owing to these biological properties and to a favorable preclinical safety profile, MT8 represents a promising candidate for clinical application in conditions characterized by ischemia-reperfusion injury and impaired tissue healing. This PhD project explored the translational potential of MT8 in two distinct but mechanistically related settings: liver transplantation using extended criteria donors, addressed in the NEMILED study, and chronic diabetic foot ulcers, addressed in the NEMUS study. The thesis first reviews the pathophysiological rationale for the use of MT8 in liver transplantation and diabetic wound healing. In the transplant setting, MT8 was proposed as a pharmacological strategy to attenuate ischemia-reperfusion injury, a major determinant of graft dysfunction and poorer outcomes when organs from extended criteria donors are used. In diabetic foot ulcers, the rationale derived from the known role of neurotrophin-related signalling in keratinocyte and fibroblast survival, angiogenesis, modulation of apoptosis, and wound repair. These applications were supported by a broad package of non-clinical studies showing biological activity of MT8 together with an overall favorable toxicological, pharmacokinetic, and genotoxicity profile. The NEMILED study is still ongoing. The NEMUS study was designed as a phase I/II, multicentre, randomized, single-blind exploratory clinical trial evaluating two topical doses of MT8 added to standard of care in 24 patients with difficult-to-heal diabetic foot ulcers. Patients were selected after a 2-week run-in phase under standard care, in order to enrich the study population for lesions showing limited spontaneous improvement. The primary objective of the study was safety and tolerability, while efficacy was explored through reduction in ulcer area during the 6-week treatment period and subsequent follow-up. The results of the NEMUS study suggest an excellent safety profile and a favorable therapeutic signal, particularly at the higher MT8 dose. In both the per-protocol and modified intention-to-treat analyses, the high-dose arm showed the highest proportion of patients achieving the predefined efficacy endpoint of at least 50% reduction in ulcer area from baseline, whereas the low-dose arm showed an intermediate pattern and standard care alone the least pronounced response. Longitudinal analyses of healing kinetics were consistent with this finding, showing greater and more sustained wound reduction over time in the high-dose group. Time-to-efficacy analyses also supported a more rapid achievement of clinically meaningful healing with high-dose MT8. Additional exploratory analyses suggested that treatment effects may have been more evident in deeper ulcers, while early percentage reduction in ulcer area appeared to be associated with subsequent healing. Overall, MT8 was well tolerated, in keeping with the safety-oriented design of the study and the favorable non-clinical profile. In conclusion, this thesis supports the translational relevance of MT8 as an innovative neurotrophin mimetic with potential applications in conditions characterized by defective tissue resilience and repair. While the NEMILED study is currently in progress, the NEMUS study offers preliminary clinical evidence that topical MT8 may improve healing outcomes in refractory diabetic foot ulcers, especially at higher doses. These findings justify further investigation in larger and adequately powered studies to better define efficacy, dose-response relationships, and the role of MT8 in regenerative and transplant medicine.