Phase 3 trial launches to evaluate new treatment for Fabry disease
Study will assess whether oral therapy can reduce fatty buildup in kidneys
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A global Phase 3 clinical trial will test whether lucerastat, an experimental oral treatment, can reduce the buildup of fatty substances in the kidneys of people with Fabry disease. These substances can contribute to kidney damage.
The study, called FAB-KLEAR (NCT07778667), aims to enroll 16 men with Fabry disease, ages 18 to 60. Participants must either have never received treatment specifically for Fabry disease or have stopped such treatment at least six months before entering the trial. Enrollment is planned at sites worldwide, although specific locations have not yet been announced.
FAB-KLEAR is part of a broader Phase 3 development program led by Idorsia, the company developing lucerastat. Idorsia said it has aligned its development strategy with the U.S. Food and Drug Administration (FDA). The program’s design is also consistent with earlier feedback from European regulators. If the studies are successful, the company said it could seek approval for lucerastat as a treatment targeting kidney problems in Fabry disease, with regulatory applications possible as early as 2029.
Idorsia partners with Nxera to advance Fabry disease treatment
Idorsia also announced a partnership with Nxera Pharma to advance lucerastat’s Phase 3 development. Under the agreement, Nxera will have exclusive rights to develop and market lucerastat in Japan and selected Asia-Pacific markets, excluding China.
“With a clearly defined regulatory pathway, compelling long-term clinical experience, and now the support of Nxera as a development and commercialization partner, we are entering an important new phase for lucerastat,” Roland Wandeler, CEO of Idorsia, said in a company press release. “The decision by Nxera to exercise its option and invest alongside us represents a significant endorsement of both the program and the opportunity to change the treatment paradigm for people living with Fabry disease.”
Fabry disease is caused by mutations in the GLA gene, which provides instructions for making an enzyme called alpha-galactosidase A (alpha-Gal A). When the enzyme is missing or does not work properly, a fatty substance called globotriaosylceramide (Gb3) builds up inside cells throughout the body. Over time, this buildup can damage organs, including the kidneys, heart and nervous system.
Current Fabry treatments include enzyme replacement therapy, which provides a working version of the missing or faulty enzyme. Another option is chaperone therapy, which helps certain faulty forms of the enzyme work better.
Lucerastat is an experimental substrate-reduction therapy taken by mouth. Instead of replacing or helping the faulty alpha-Gal A enzyme, lucerastat is designed to reduce the body’s production of Gb3 without relying on that enzyme. It works by blocking another enzyme, called glucosylceramide synthase, which helps produce a substance needed to make Gb3.
In FAB-KLEAR, all participants will take lucerastat for 18 months. Researchers will collect small tissue samples from the kidneys, called biopsies, before treatment and again after 18 months. They will compare the samples to see whether the average number of Gb3 deposits per tiny blood vessel in the kidneys has decreased. The study will also measure changes in Gb3 levels in the blood, monitor lucerastat’s safety, and assess how the body processes the treatment.
Second Phase 3 trial will assess effects on kidney function
The development program also includes a second Phase 3 trial, called FAB-SWITCH, which is expected to enroll up to 74 patients. Researchers will compare lucerastat with standard enzyme replacement therapies to assess its effects on kidney function.
Both new trials build on findings from the earlier MODIFY Phase 3 trial (NCT03425539) and its long-term extension study (NCT03737214). MODIFY included 118 adults with Fabry disease who had moderate to severe nerve pain. Participants were randomly assigned to receive lucerastat or a placebo for six months. Lucerastat was given at a starting dose of 1,000 mg twice daily, with adjustments based on kidney function. Everyone who entered the extension study then received lucerastat.
Lucerastat did not meet the trial’s main goal of reducing nerve pain more than a placebo. However, patients taking lucerastat showed greater reductions in Gb3 levels in their blood and urine than those taking a placebo.
Longer-term analyses also suggested that kidney function declined more slowly during lucerastat treatment than in the years before treatment began. However, researchers compared kidney function during treatment with earlier measurements, not with an untreated control group. As a result, the findings cannot establish that lucerastat slowed kidney damage.
Kidney biopsies from six men who had received lucerastat for a median of nearly five years also showed little to no Gb3 buildup. However, the small number of patients and the lack of biopsies from before treatment made it difficult to determine how much the buildup had changed.
“The recently published Phase 3 MODIFY study and its long-term extension have provided strong evidence of lucerastat’s disease-modifying potential,” said Amer Joseph, MD, chief medical officer and head of global clinical development at Idorsia. “While the primary endpoint of neuropathic pain reduction was not met, a subjective outcome that is proving difficult to reach in Fabry disease, lucerastat demonstrated robust and sustained biomarker reductions and a promising signal for slowing renal function decline in patients.
“The next step is to generate the baseline-controlled data required by authorities for registration,” Joseph added.
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