Idorsia initiates MODIFY, a Phase 3 registration study to assess lucerastat as a potential new treatment option for patients with Fabry disease - Seite 3

The median prevalence of diagnosed Fabry disease is 1.0 per 100,000 in males and 1.9 per 100,000 in females. As the gene responsible for Fabry disease is found on the X chromosome (of which males have one, and females two), males with deleterious mutations have little or no residual alpha-GalA activity. Therefore, these male patients with Fabry disease experience a wider spectrum of symptoms, and in some cases, a greater severity. It is now widely accepted that women with Fabry disease are heterogeneous with respect to disease severity and may sometimes also develop life threatening complications of the disorder. Up to 70% of female carriers develop Fabry related symptoms at some point in their life.

Current treatment approaches for Fabry disease include enzyme replacement therapy (ERT). ERT requires intravenous infusions every two weeks to replace the deficient enzyme in the cells with a genetically engineered form. Migalastat is the other therapy that has been granted marketing authorization in the EU and Japan as an oral monotherapy for the long-term treatment of a subset of patients with Fabry disease 16 years and older who have an amenable mutation. Other treatments are aimed at alleviating individual symptoms, such as opioids for severe pain. In advanced Fabry disease, hemodialysis and kidney transplantation may be necessary.

Data supporting lucerastat in Fabry disease
Idorsia preclinical research with a mouse model of Fabry disease has shown that glucosylceramide synthase inhibition with lucerastat reduces the accumulation of Gb3 in kidney and certain nerve endings. Furthermore, Idorsia has shown that lucerastat lowers Gb3 in cultured cells from patients with Fabry disease of both sexes harboring different GLA genetic mutation types.

The safety, tolerability, pharmacodynamics, and pharmacokinetics of oral lucerastat were evaluated in an exploratory study in adult patients with Fabry disease. In this single-center, open-label, randomized study, 10 patients received lucerastat 1000 mg b.i.d. for 12 weeks on top of enzyme replacement therapy and four patients with Fabry disease received ERT only. A rapid decrease in plasma Gb3, a marker of Fabry disease, and its precursors was observed, demonstrating that lucerastat 1000 mg b.i.d. inhibits GCS and provides alpha-GalA substrate reduction with a fast onset in adult patients with Fabry disease on ERT.