Idorsia launches redesigned Fabry disease trial with Nxera backing

Fabry disease and lucerastat: Fabry disease is a rare inherited disorder caused by mutations in the GLA gene. Patients lack enough functioning alpha-galactosidase A, an enzyme that normally breaks down a fatty substance called globotriaosylceramide (Gb3). As Gb3 accumulates in cells, it progressively damages organs, particularly the kidneys, heart and nervous system. Patients can experience nerve pain and, over time, develop kidney failure, heart problems or stroke.

Enzyme replacement therapies, including Fabrazyme, Replagal and Elfabrio in Europe, supply a working version of the deficient enzyme through regular intravenous infusions. This helps cells break down the accumulated Gb3. Galafold (migalastat), an oral treatment, is also approved but only works for a subgroup of patients with specific mutations.

Lucerastat has a different approach and aims to reduce how much Gb3 the body produces. The oral drug inhibits glucosylceramide synthase, an enzyme involved in making the fatty molecules that accumulate in Fabry disease. Because this approach does not depend on restoring the defective enzyme, Idorsia hopes it could offer an oral option regardless of patients’ underlying mutation. The new trials will test whether that mechanism reduces kidney deposits and helps preserve kidney function.

Backstory: Lucerastat completed a Phase 1b study in 2016 and entered the Phase 3 MODIFY trial in 2018. MODIFY randomized 118 adults to lucerastat or placebo, testing whether six months of treatment reduced neuropathic pain.

In October 2021, Idorsia reported that the study missed its primary endpoint. Lower Gb3 levels showed biological activity, but that did not translate into a statistically significant improvement in pain.

Development continued through an open-label extension involving 107 participants. Longer-term analyses suggested slower kidney function decline compared with patients’ historical trajectories. Kidney biopsies from six men treated for almost five years also showed low levels of Gb3 deposits, providing a rationale for a redesigned program.

Strategy pivot: Idorsia is now pursuing a different route to approval for the same experimental drug. Its new pivotal study will measure changes in disease-related fatty deposits in kidney biopsies, replacing the patient-reported pain endpoint that failed in 2021.

The new FAB-KLEAR trial will enroll 16 adult men who have never received Fabry-specific treatment or have been off it for at least six months. The open-label study’s primary endpoint is the change after 18 months in a biopsy score measuring Gb3 inclusions in small kidney blood vessels. Each patient’s pretreatment biopsy will provide the comparison; there is no placebo group.

A second planned Phase 3 study, FAB-SWITCH, will compare lucerastat with standard enzyme replacement therapies in 74 adults, assessing kidney function.

“We have now followed some patients receiving lucerastat for more than six years, generating over 400 patient-years of safety and efficacy experience, something rarely achieved for an investigational therapy in a rare disease program. The findings from our previous work with lucerastat suggest that it may offer long-term kidney protection and broaden therapeutic options for Fabry patients, especially those underserved by current treatments,” explained Prof. Dominique P Germain, an investigator in Idorsia’s Fabry disease development program.

The deal on top: In addition to the new trial, Nxera exercised an option originating from its 2023 acquisition of Idorsia’s Asia-Pacific operations. It will pay 7 million Swiss francs (about €7.6 million), contribute to global Phase 3 development and receive exclusive rights in Japan, South Korea, Taiwan and selected other Asia-Pacific markets, excluding China.

Nxera will participate in FAB-SWITCH and manage clinical development in Japan. Idorsia is also eligible for sales royalties. The royalty rate and development contribution were not disclosed.

“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. 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,” said Roland Wandeler, CEO of Idorsia.

What’s next: Idorsia says the program is aligned with the U.S. Food and Drug Administration and consistent with earlier European Medicines Agency feedback. It targets a potential regulatory filing as early as 2029.