Phase 2a study of readthrough therapy in nonsense mutation Alport syndrome

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Abstract

BACKGROUND. Alport syndrome (AS), a Mendelian kidney disease, is caused by pathogenic mutations in the X- linked gene COL4A5 and autosomal genes COL4A3, COL4A4 encoding the alpha-chains secreted by podocytes to form the glomerular basement membrane collagen α3α4α5(IV) trimer. Nonsense mutations in autosomal recessive and hemizygous X-linked Alport syndrome (NMAS) introduce premature termination codons and have a particularly poor prognosis, with kidney failure typically occurring by early adulthood. There is substantial unmet need for effective therapy for AS, which has no approved treatments. Exaluren (formerly ELX-02) is a novel eukaryotic ribosome-targeted glycoside that is preferentially taken up by kidney cells and promotes readthrough of premature but not native termination codons, allowing full-length protein production. METHODS. In this proof-of-mechanism study, three patients (ages 12–18) with autosomal recessive Alport syndrome and a COL4A4 premature termination codon received daily subcutaneous exaluren (0.75 mg/kg) for 8 weeks. RESULTS. Safety and tolerability assessments (primary endpoint) revealed no new signals. Secondary endpoints assessed by kidney biopsy before and after treatment revealed increased collagen α3(IV), α4(IV) and α5(IV) abundance, physiologically localised collagen α5(IV), and partially improved podocyte morphology in all participants, with changes directionally concordant with increased collagen α3α4(IV) abundance. Proteinuria changes were inconsistent with interpretation limited by intra-patient variability and the short treatment duration; hematuria persisted in all participants. CONCLUSION. These findings provide first-in-human evidence of exaluren-mediated collagen IV readthrough and justify further trials in Alport syndrome and other nonsense mutation-driven kidney diseases, which often cause early-onset kidney failure. TRIAL REGISTRATION. ClinicalTrials.gov Identifier: NCT05448755.

Authors

Daniel P. Gale, Detlef Böckenhauer, Maryline Fresquet, Emily Williams, Conor J. Sugden, Melanie M.Y. Chan, Katie Wong, Meei-Hua Lin, Kohei Omachi, Konstantinos Tzoumkas, Lior Horonchik, Roger B. Clark, Jochen Reiser, Peter Mundel, Uwe Andag, Jeffrey H. Miner, Rachel Lennon, Nicole Endlich, Behzad Najafian, Sumit Aggarwal