Fabry disease is a rare genetic, lysosomal storage disorder. It is caused by mutations in the GLA gene, leading to a deficiency or dysfunction of alpha-galactosidase A (alpha Gal A), an enzyme that normally breaks down a fatty substance known as globotriaosylceramide (Gb3) in the cells of the body. Over time, this results in an accumulation of Gb3 deposits throughout the body, leading to progressive pathophysiology in the cardiovascular system, the nervous system, and organs including the kidneys, heart, skin, ears, and eyes.
Fabry disease affects a patient’s life expectancy and quality of life. Since most symptoms are non-specific, Fabry disease is often undetected or misdiagnosed. As the disease is progressive, early diagnosis is essential to manage the symptoms as soon as possible and reduce the risk of developing serious complications.
New therapeutic options are needed to treat the underlying mechanism of the disease and provide symptomatic relief.
The prevalence of diagnosed Fabry disease in 2018 was approximately 7,500 patients in the US and the EU-5 (i.e. France, Germany, Italy, Spain, and the UK).
Clinical manifestations of Fabry disease
- Usually more severe in men
- Gradually progressing in severity from childhood to adulthood
- Major impact on quality of life
- Slow progressive damage to vital organs over decades
- Premature death
The normal biosynthesis and degradation of Gb3 is shown schematically in the Figure below. In patients with Fabry disease, deficiency or dysfunction of the enzyme alpha Gal A leads to abnormal accumulation of Gb3, which in turn causes the symptoms of Fabry disease. Current treatments focus on replacing or supporting alpha Gal A – either through infusion of recombinant enzyme, which temporarily increases plasma concentrations of alpha Gal A, or by chaperone therapy, which improves the function of mutated enzymes – but only in patients with amenable mutations.
In contrast, lucerastat, an oral inhibitor of glucosylceramide synthase (GCS), reduces the substrate which forms Gb3. Substrate reduction therapy (SRT) decreases the build-up and is thought to subsequently reduce the Gb3 load in patients with Fabry disease. Since this mechanism is independent of alpha Gal A deficiency or dysfunction, it should not be limited to specific mutations of the GLA gene.
The Gb3 cycle
Abbreviations: α-GalA, α-galactosidase A; Cer, ceramide; Gb3, globotriaosylceramide; GCS, glucosylceramide synthase; GlcCer, glucosylceramide; Sph, sphingosine
Lucerastat is an oral inhibitor of glucosylceramide synthase, offering a potential new treatment approach for all patients living with Fabry disease, irrespective of the mutation type of the GLA gene.
Preclinical studies have shown that lucerastat is an orally available, highly soluble small molecule with rapid and complete absorption. As a small molecule, it is widely distributed to most tissues, including the central nervous system, kidney, and heart.
In an animal model of Fabry disease, treatment with lucerastat reduced Gb3 levels and related biomarkers in dorsal root ganglia, the kidneys, and the heart. This demonstrates that lucerastat has the potential to reduce Gb3 levels in key target organs and, therefore, to show clinical efficacy in Fabry disease.
In an exploratory study in patients with Fabry disease, treatment with lucerastat in addition to enzyme replacement therapy induced a marked decrease in plasma levels of metabolic substrates associated with the development of the disease. The study also indicated that lucerastat is well tolerated in patients with Fabry disease.
MODIFY was a Phase 3 study to determine the efficacy and safety of lucerastat oral monotherapy in adult patients with Fabry disease. 118 patients were randomized in a 2:1 ratio to receive either lucerastat (80 patients) or placebo (38 patients). At the end of the 6-month double-blind period, 107 patients entered an ongoing open label extension (OLE) study, which aims to determine the long-term safety and tolerability of lucerastat oral therapy and to further evaluate its clinical effects on renal and cardiac function in adult patients with Fabry disease over an additional period of up to 48 months.
In October 2021, the company reported that lucerastat 1000 mg b.i.d. did not meet the primary endpoint of reducing neuropathic pain during 6 months of treatment versus placebo. However, observations were made on renal function and cardiac echocardiography which, if confirmed with longer-term data, would indicate a treatment effect on the main organs affected by the disease.
Lucerastat was well tolerated. No clinically meaningful changes in vital signs or ECGs or marked laboratory abnormalities were observed. Two patients in each group (lucerastat 2.5%; placebo 5.4%) discontinued treatment due to adverse events. Serious adverse events were reported in 5 patients (6.3%) in the lucerastat group and in 1 patient (2.7%) in the placebo group.
In October 2022, Idorsia conducted an interim analysis of the OLE study, where all patients who are continuing in this study have now been treated with lucerastat for at least 12 months. The analysis corroborated the long-term effect on the reduction of plasma Gb3 and showed that the signal seen on kidney function after 6 months of treatment is still observed after the longer treatment duration, supporting a potential positive long-term effect on kidney function. The analysis also showed a safety and tolerability profile consistent with that observed during the 6-month randomized treatment period. The OLE study continues, and the company is consulting with health authorities about the regulatory pathway for lucerastat.
Lucerastat for Fabry disease has received orphan drug designation in the US and the EU and is under review in Japan.
2021 Phase 3 open label extension study continues
2021 Phase 3 study completed – primary endpoint not met
2018 Phase 3 study initiated
2016 Phase 1b study completed
Key scientific literature
- Guérard N., et al. Clin Pharmacol Ther. 2018; 103(4):703-11.
- Welford RWD., et al. Hum Mol Genet 2018; 27(19): 3392-3403.