Kidney Week

Abstract: SA-OR98

Small Molecule Premature Termination Codon Readthrough Therapy: A Phase 2 Pediatric and Adult Trial in Nonsense Mutation Alport Syndrome

Session Information

• Late-Breaking Science Orals - 2
  October 26, 2024 | Location: Room 6C, Convention Center
  Abstract Time: 04:40 PM - 04:50 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Gale, Daniel P., University College London, London, United Kingdom

Daniel P. Gale, MA, MBChB, PhD

• Bockenhauer, Detlef, University College London, London, United Kingdom

Detlef Bockenhauer, MD, PhD

• Chan, Melanie M.Y., University College London, London, United Kingdom

Melanie M.Y. Chan, MBBS, PhD

• Wong, Katie, UK National Registry of Rare Kidney Diseases (RaDaR), Bristol, United Kingdom

Katie Wong, MBBS

• Pospiech, Johannes, Evotec International GmbH, Gottingen, Niedersachsen, Germany

Johannes Pospiech

• Bohnenpoll, Tobias, Evotec International GmbH, Gottingen, Niedersachsen, Germany

Tobias Bohnenpoll, PhD

• Skroblin, Philipp, Evotec International GmbH, Gottingen, Niedersachsen, Germany

Philipp Skroblin, MSc, PhD

• Radresa, Olivier, Evotec International GmbH, Gottingen, Niedersachsen, Germany

Olivier Radresa, PhD

• Andag, Uwe, Evotec International GmbH, Gottingen, Niedersachsen, Germany

Uwe Andag, PhD

• Endlich, Nicole, Nipoka GmbH, Greifswald, Germany

Nicole Endlich, PhD

• Najafian, Behzad, University of Washington, Seattle, Washington, United States

Behzad Najafian, MD

• Aggarwal, Sumit, Eloxx Pharmaceuticals Inc, Watertown, Massachusetts, United States

Sumit Aggarwal, MBA

Background

Alport syndrome is the second commonest Mendelian kidney disease and shows strong correlation between severity and mutation type, with Nonsense Mutation Alport Syndrome usually associated with kidney failure by late adolescence. ELX-02 is a small molecule that induces readthrough of premature (but not native) stop codons and is efficiently taken up by cells expressing megalin, allowing full length protein to be made by podocytes or tubular cells in the presence of a nonsense mutation.

Methods

An open label study was performed in 3 patients with autosomal recessive Alport syndrome, aged 13, 13 and 19, who each had the stop codon COL4A4:p.(Ser969Ter) in trans with another pathogenic COL4A4 variant. Participants required eGFR >60ml/min/1.73m² and >0.5g per day proteinuria. Each received 0.75mg/kg subcutaneous ELX-02 daily for 8 weeks with follow-up for a further 12 weeks. Proteinuria was assessed before, during and after treatment. Filtration Slit Density (FSD), with automated 3D-SIM (structured illumination microscopy), and Foot Process Width (FPW), with stereology in a masked fashion, were assessed in pre- and post-treatment kidney biopsies.

Results

No significant safety signals were observed. Immunostaining for Collagen IV alpha 5 chain was globally (2 patients) or partially (1 patient) absent before treatment and detectable segmentally following treatment in all 3 patients. FSD improved in all patients after 2 months’ treatment: pre-treatment 1.0 (48.5% of the mean (±standard deviation) of 2.06 (±0.12) in healthy individuals), 1.54 (74.8%) and 0.8 (38.8%); post-treatment: 1.5 (72.8%), 1.75 (85.0%) and 1.73 (80.6%), p=0.06, paired t-test. FPW was significantly reduced in 2 patients, changing by -19%, +6% and -45% respectively. Proteinuria was variable but reduced in 2 of the 3 patients during or following treatment.

Conclusion

This first evidence of efficacy of a gene-targeted therapy in a podocyte-based Mendelian disease justifies a follow-on randomised-controlled study to quantify the potential for clinical benefit. Therapeutic readthrough of premature termination codons in Alport Syndrome suggests other genes expressed by megalin-expressing kidney cells may be targetable with this approach.

Funding

• Commercial Support – Eloxx Pharmaceuticals Inc