Kidney Week

Abstract: SA-PO654

Lucerastat Effect on Kidney Function in Patients with Fabry Disease: Results from the Phase 3 Clinical Program

Session Information

• Genetic Kidney Diseases: Models, Mechanisms, and Therapies
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Wallace, Eric L., University of Alabama at Birmingham, Birmingham, Alabama, United States

Eric L. Wallace, MD, FASN

• Germain, Dominique P., University of Versailles, Versailles, France

Dominique P. Germain, MD

• Hughes, Derralynn, University College London, London, United Kingdom

Derralynn Hughes

• Nordbeck, Peter, University Hospital of Würzburg, Würzburg, Germany

Peter Nordbeck, MD

• Clozel, Martine, Idorsia Pharmaceuticals Ltd, Allschwil, Basel-Landschaft, Switzerland

Martine Clozel, MD, PhD

• Frey, Aline, Idorsia Pharmaceuticals Ltd, Allschwil, Basel-Landschaft, Switzerland

Aline Frey, PharmD

• Wanner, Christoph, Fabry Center for Interdisciplinary Therapy, Würzburg, Germany

Christoph Wanner, MD

Background

Substrate reduction therapy with lucerastat, an oral glucosylceramide synthase (GCS) inhibitor, aims to reduce Gb3 synthesis and prevent further Gb3 accumulation in patients with Fabry disease. Here, we describe a surprising effect of lucerastat on kidney function from the ongoing global Phase 3 clinical trial, MODIFY, and its open label-extension (OLE).

Methods

MODIFY (NCT03425539)(Wanner et al. 2022) randomized adult patients with Fabry disease 2:1 to lucerastat 1000 mg b.i.d. orally (dose adjusted based on eGFR) or placebo for 6 months. Participants who completed MODIFY were eligible to enter the OLE (NCT03737214) for up to 72 months. Prespecified efficacy endpoints included the change from baseline to Month-6 in eGFR in MODIFY and the annualized eGFR slope in the OLE.

Results

Of 118 participants randomized, 117 received study treatment (80 lucerastat, 37 placebo), 107 (91%) enrolled in the OLE, and 78 (67%) were ongoing at the Month-18 OLE interim analysis. Participants’ demographic and baseline characteristics were similar across treatment groups. Kidney function remained stable in lucerastat-treated participants in MODIFY, and in the 39 participants with baseline renal impairment (eGFR <90 mL/min/1.73m²), eGFR increased at Month-6 with lucerastat (mean [SE] 3.8 [2.2] mL/min/1.73m²) and decreased with placebo (-1.6 [4.0] mL/min/1.73m²). This unexpected renal effect was confirmed at Month-18, where lucerastat markedly slowed eGFR decline in the 93 participants with pre-randomization eGFR data, including in subgroups with severe disease course (baseline eGFR <90 mL/min/1.73m², classic males) and independent of gene variant amenability to migalastat. Lucerastat was well tolerated.

Conclusion

GCS inhibition with lucerastat might be a novel approach to stabilize or slow the progression of kidney dysfunction, a major therapeutic goal in patients with Fabry disease.

Funding

• Commercial Support – Idorsia Pharmaceuticals Ltd