Allschwil, Switzerland – – Idorsia Ltd announced a plan to move forward with a Phase 3 registration program for lucerastat, an investigational oral therapy for Fabry disease. The program, agreed upon with the U.S. Food and Drug Administration (FDA), aims to establish lucerastat as a potential treatment option for all patients with this rare, progressive genetic disorder, regardless of their specific genetic mutation.
Fabry disease is a lysosomal storage disorder caused by mutations in the GLA gene, leading to a deficiency in the enzyme α-galactosidase A (α-GalA). This deficiency causes a buildup of a fatty substance called globotriaosylceramide (Gb3) in cells throughout the body, ultimately damaging organs like the kidneys, heart, and nervous system. Approximately 16,000 patients were diagnosed with Fabry disease across major global markets in 2020, a number projected to rise to around 21,000 by 2034, indicating a continued need for innovative therapies.
“This is an important step forward for Idorsia and for the Fabry community,” said Srishti Gupta, MD, CEO of Idorsia. “Fabry disease is a serious, progressive condition with a clear need for effective, convenient therapies that address the underlying biology across the full patient population. The strength of our long-term data and a clearly defined regulatory pathway position lucerastat as a uniquely differentiated oral approach.”
Focus on Renal Pathology
The Phase 3 program will focus on lucerastat’s impact on renal pathology – kidney damage – a leading cause of illness and death in Fabry disease. This focus builds on positive findings from the MODIFY Phase 3 trial and its ongoing open-label extension (OLE) study. Recent data published in Nature Communications suggest lucerastat may slow the decline of kidney function, particularly in patients with more severe disease.
Two Complementary Clinical Trials
The FDA-agreed registration strategy comprises two clinical trials. The first is a pivotal kidney biopsy study involving 16 adult male patients with Fabry disease, who are either treatment-naïve or have previously received treatment but are now off therapy. This study aims to demonstrate a reduction in Gb3 accumulation in the kidneys after 18 months of lucerastat treatment.
The second study will compare lucerastat to established enzyme replacement therapies (ERTs) – agalsidase beta and pegunigalsidase alfa – in approximately 74 adult patients with Fabry disease. This trial is designed to demonstrate that lucerastat, as an oral therapy, can achieve comparable effects to the current standard of care, which typically requires intravenous infusions.
Promising Renal Outcomes from MODIFY and OLE
The rationale for this program is supported by data from the MODIFY study and its OLE. While the primary endpoint of the MODIFY trial – reduction in neuropathic pain – was not met, the study demonstrated a significant reduction in plasma and urinary Gb3 levels with lucerastat compared to placebo. These reductions were sustained over time in the OLE study.
An interim analysis of the OLE, where patients had been treated with lucerastat for at least 42 months (with some exceeding six years of continuous therapy), revealed a notable shift in the rate of kidney function decline. Patients treated with lucerastat experienced a slower rate of estimated glomerular filtration rate (eGFR) decline compared to their eGFR slope observed in the two years prior to enrolling in the MODIFY study. Specifically, the historical eGFR slope was -3.50, while the lucerastat group showed a slope of -1.64.
The benefit was particularly pronounced in patients with more severe disease, including those with classic Fabry disease, impaired renal function at baseline (eGFR <90 mL/min/1.73m2), or the presence of anti-drug antibodies (ADA+). Lucerastat treatment was associated with a 51% decrease in plasma Gb3 levels and was generally well-tolerated.
Kidney Biopsy Data Supports Findings
A kidney biopsy sub-study of six male adult patients with classic Fabry disease, who had received lucerastat monotherapy for a median of 56 months, showed low-to-no levels of kidney Gb3 inclusions. Using established scoring systems, the results indicated minimal Gb3 accumulation in the kidneys of patients treated with lucerastat.
Lucerastat’s Mechanism of Action
Lucerastat is an investigational oral inhibitor of glucosylceramide synthase. By inhibiting this enzyme, lucerastat reduces the production of glycosphingolipids, including Gb3, addressing the underlying cause of Gb3 accumulation in Fabry disease. Preclinical studies have shown that lucerastat effectively penetrates key tissues affected by the disease, including the kidneys, liver, and dorsal root ganglia.
Regulatory Timeline
Idorsia anticipates that the data from these Phase 3 trials will support a regulatory filing with the FDA and the European Medicines Agency (EMA) as early as 2029. Alberto Gimona, MD, Head of Global Clinical Development at Idorsia, commented, “Following constructive discussions with health authorities, we have agreed on the trials that will form the basis for establishing substantial evidence of effectiveness in support of a future NDA and MAA.”
The Fabry disease market is projected to reach around USD 4 billion by 2034, highlighting the need for new treatment options. Lucerastat, with its potential for oral administration and disease-modifying effects, represents a promising advancement for patients living with this challenging condition.
