Nomlabofusp Treatment Produces Frataxin Levels That Correlate Across Peripheral Tissues: Preclinical and Clinical Support for Surrogate Tissue Sampling

Abstract

Nomlabofusp is a recombinant, cell-penetrating human frataxin (hFXN) fusion protein in development for the treatment of Friedreich's ataxia (FRDA). This study evaluated whether nomlabofusp-derived hFXN concentrations covary across accessible peripheral matrices and FRDA-relevant tissues, supporting the feasibility of surrogate tissue sampling to monitor drug-derived hFXN exposure. Following subcutaneous administration in mice, rats, non-human primates, and patients with FRDA, we quantified nomlabofusp-derived hFXN and assessed cross-tissue correlations across target tissues (brain, heart, skeletal muscle, dorsal root ganglia) and accessible peripheral matrices (skin, buccal cells, platelets). We observed significant and consistent cross-tissue correlations, with concordant relationships among heart, skeletal muscle, dorsal root ganglia, skin, buccal cells, liver, and mitochondrial fractions, indicating coordinated distribution and/or retention of nomlabofusp-derived hFXN across these matrices. Correlation patterns were maintained across species, supporting the robustness and translational relevance of the observed relationships. Collectively, these data support the use of peripheral tissues—particularly skin and buccal cells—for cross-sectional and longitudinal monitoring of hFXN supplementation in FRDA.