Journal Article

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

Hamdani, Mohamed, Patadia, Chintan, Shankar, Gopi, De Toni, Flavia

2026

Overview

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. Study Highlights What is the current knowledge on the topic? Friedreich's ataxia (FRDA) is caused by frataxin (FXN) deficiency with prominent involvement of dorsal root ganglia, heart, and skeletal muscle, but repeated FXN measurement in these target tissues is invasive and impractical for longitudinal trials. Nomlabofusp is a subcutaneously administered recombinant human FXN (hFXN) fusion protein intended for mitochondrial delivery, and early clinical studies show dose‐dependent hFXN increases in accessible matrices (skin, buccal cells, platelets). However, key translational uncertainties persisted: whether peripheral tissues consistently mirror hFXN in FRDA target organs across species and clinical dosing schedules, and whether whole‐tissue measures capture mitochondrial delivery—both prerequisites for using surrogate tissues in longitudinal trials. What question did this study address? Do nomlabofusp‐derived hFXN concentrations in minimally invasive peripheral tissues (skin biopsy, buccal swab, platelets) correlate with hFXN in FRDA‐relevant tissues (brain, heart, skeletal muscle, dorsal root ganglia) across species and dosing regimens? What does this study add to our knowledge? Across mice, rats, non‐human primates, and FRDA patients, nomlabofusp produced increases in hFXN and showed significant, directionally consistent cross‐tissue associations linking peripheral matrices—especially skin and buccal epithelium—with FRDA‐relevant organs. Mouse whole‐liver and liver‐mitochondrial hFXN were strongly concordant (r = 0.88–1.00 early), supporting mitochondrial uptake and interpretability of whole‐tissue measurements. In patients, skin–buccal correlations were strongest with consistent daily dosing (Spearman r = 0.73 in Phase 2). How might this change clinical pharmacology or translational science? Skin and buccal epithelium are supported as practical surrogate tissues for monitoring hFXN and tissue exposure when target‐organ sampling is infeasible. This enables serial assessment to inform dose/regimen optimization and sampling windows while reducing participant burden and strengthening translational bridging for FXN supplementation strategies.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Animals / Antibodies / Ataxia / Biopsy / Cardiac muscle / cell‐penetrating peptide / Dorsal root ganglia / Female / Frataxin / Friedreich Ataxia - drug therapy / Friedreich's ataxia / Fusion protein / Heart / Hepatocytes / Humans / Iron-Binding Proteins - administration & dosage / Iron-Binding Proteins - pharmacokinetics / Liver / Male / Mice / Musculoskeletal system / nomlabofusp / Peptides / Plasma / preclinical / Protease inhibitors / Proteins / Rats / Recombinant Fusion Proteins - administration & dosage / Recombinant Fusion Proteins - pharmacokinetics / Sampling / Skeletal muscle / Skin / surrogate tissue / Tissue Distribution