GRC Conference 2024 – Barriers of the CNS

NX210c peptide: a drug candidate to repair the BBB in neurological disorders Download Poster Sighild Lemarchant 1 , Chris Greene 2 , Nicolas Rebergue 1 , Gwen Fewell 3 , Supriya Mahajan 4 , Damir Janigro 4 , Daniël Dumas 5 , Philip Kremer 5 , Juliette Le Douce 1 , Sébastien Marie 1 , Yann Godfrin 1,6 , Annette Janus 1 , Matthew Campbell 2 1 Axoltis Pharma, Lyon, France 2 Smurfit Institute of Genetics, Lincoln Place Gate, Trinity College Dublin, Dublin 2, Ireland 3 SynVivo, Huntsville, USA 4 Flocel, Cleveland, USA 5 CHDR, Neurology, Leiden, Netherlands 6 Godfrin Life-Sciences, Caluire-et-Cuire, France BBB dysfunction is likely a disease-driving feature of several neurological disorders, including PD, ALS and MS, yet today no treatment exists to repair the BBB. Here, we screened the effect of a subcommissural organ-spondin-derived peptide (NX210c), known to promote functional recovery in several models of neurological disorders, on BBB integrity in vitro and in vivo including in healthy elderly volunteers (HEVs). In vitro, bEnd.3 endothelial cell (EC) monolayers and two different primary human BBBs containing EC, astrocytes and pericytes, in static and microfluidic conditions, were treated with NX210c (1-100 μM), or its vehicle (water). NX210c induced a transient increase in occludin protein expression after 24h treatment (+37% at 100 µM; western-blot) in mouse EC. Claudin5 protein expression was also increased after 24h (+43% at 100 µM) and 72h (immunocytochemistry). Accordingly, NX210c decreased the permeability of EC by half to a 40-kDa-FITC Dextran and increased transendothelial electrical resistance (TEER). In the human static BBB model, NX210c increased the TEER by 30% at 100 µM after 3 and 5 days. NX210c also increased TEER in the human 3D dynamic BBB model at 100 µM after 4h, which was associated with a reduced permeability to a 4-kDa-FITC Dextran. In vivo, young and old mice (3- and 21-month-old, respectively) were treated intraperitoneally with NX210c at 10 mg/kg or its vehicle for 5 days once a day and their brains collected at day 6 to perform immunohistochemistry in the cortex and hippocampus. NX210c restored aging induced reduction of tight junction levels in the brain (+24% and +19% for claudin-5 and occludin respectively, compared to untreated old mice in the hippocampus). In a phase 1b randomized, double-blind, placebo-controlled, multiple ascending dose study, two cohorts of 15 HEVs were planned to receive NX210c treatment at 5 or 10 mg/kg or its vehicle (4:1 ratio; 2 sentinels/cohort) intravenously 3×/week for 4 weeks. Safety and tolerability were evaluated as the primary objectives and blood pharmacokinetics as the secondary objective. Exploratory objectives assessed pharmacodynamic parameters including plasma and CSF biomarkers of BBB permeability alterations. NX210c was safe and well tolerated by HEVs. Furthermore, we observed positive signals of BBB repair, including a significant reduction overtime of the release of claudin-5 in the plasma in HEVs treated with NX210c. By repairing the BBB, NX210c may represent a disease-modifying treatment for several neurological disorders which will in turn reduce neurodegenerative processes and promote functional recovery LinkedIn Axoltis 60 avenue Rockefeller, 69008 Lyon, France © 2026 Axoltis. All rights reserved. Disclaimer : NX210c is a drug candidate currently in a Phase 2 clinical trial for ALS and is not yet approved for commercialization. Legal Notice

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