Idorsia outlines new Phase 3 program for lucerastat in Fabry disease
Company plans two late-stage studies to support potential approval
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Following discussions with regulatory authorities in the U.S. and Europe, Idorsia has outlined a new Phase 3 registration program to evaluate its experimental oral therapy, lucerastat, for its effects on kidney outcomes in people with Fabry disease.
If the studies are successful, Idorsia said the data could serve as the basis for a potential regulatory submission for lucerastat. The company said a filing could occur as early as 2029.
“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 [applications seeking approval in the U.S. and Europe],” Alberto Gimona, MD, head of global clinical development at Idorsia, said in a company press release.
Understanding Fabry disease and current treatment options
Fabry disease is caused by mutations that lead to a deficiency of alpha-galactosidase A (alpha Gal-A), an enzyme needed to break down certain fatty molecules such as globotriaosylceramide (Gb3). Without enough functional alpha Gal-A, Gb3 build ups in cells, which can damage the kidneys and other organs.
Currently approved Fabry treatments include enzyme replacement therapy (ERT), in which a functional version of the alpha Gal-A enzyme is administered by infusion. An oral therapy called Galafold (migalastat) is also approved in the U.S., but it is only suitable for patients with specific mutation types.
Lucerastat is an experimental substrate-reduction therapy. This type of treatment aims to reduce the buildup of Gb3 by blocking its production. Because its mechanism does not depend on alpha Gal-A activity, lucerastat is designed to be suitable for patients regardless of their underlying mutation type. Idorsia is developing it as a potential first oral treatment option for all Fabry patients.
Idorsia previously sponsored a Phase 3 study, MODIFY (NCT03425539), which tested twice-daily oral lucerastat versus placebo in more than 100 adults with Fabry disease. The study did not meet its main goal of showing that lucerastat reduced neuropathic pain (pain caused by nerve damage) compared with placebo.
Although lucerastat did not demonstrate a benefit for pain relief, data from MODIFY and its open-label extension (NCT03737214) showed reductions in Gb3 levels. Long-term analyses also suggested a slower decline in kidney function compared with patients’ prior historical trajectories.
“The body of evidence we have generated to date shows that long-term treatment with lucerastat consistently reduces the glycosphingolipid substrates that accumulate in Fabry disease. We also observe a slower decline in kidney function compared with patients’ prior historical trajectories. Importantly, kidney biopsy data from long-term treated patients demonstrate low-to-no levels of characteristic [fatty molecule buildups],” Gimona said.
New Phase 3 program focuses on kidney outcomes
Idorsia plans to run two new Phase 3 trials to evaluate lucerastat’s effects on kidney function. One study will enroll 16 male Fabry patients who are not currently on treatment. Patients will undergo kidney biopsies before starting lucerastat and after 18 months of oral therapy, with the goal of determining whether lucerastat reduces kidney Gb3 levels. This study is intended to serve as the primary basis for future regulatory submissions, according to the company.
The second study will enroll about 74 adults with Fabry disease, regardless of sex. This study will directly compare lucerastat with approved ERTs on measures of kidney function.
“The agreed program includes a pivotal baseline-controlled biopsy study and a second study which will then show that an oral treatment can potentially achieve a similar effect to today’s cumbersome standard-of-care,” Gimona said.
Idorsia did not provide a timeline for when the two studies are expected to begin enrolling patients.
“Drug development in Fabry disease is challenging, and meaningful innovation requires both scientific rigor and persistence,” said Srishti Gupta, MD, CEO of Idorsia. “With its mutation-independent mechanism and growing body of long-term evidence, we believe lucerastat has the potential to make a real difference for patients.”
