Lucerastat Phase 3 Trial Fully Enrolled, Results Likely Late in Year

A Phase 3 trial evaluating lucerastat, an investigational substrate reduction therapy for Fabry disease, is fully enrolled and underway in 118 adult patients.

Results from the MODIFY trial (NCT03425539) are expected toward the end of this year. Those who complete the trial will be invited to continue or start treatment with oral lucerastat in an open-label extension study scheduled to run for about two years.

“This first quarter of 2021 is loaded with important progress and milestones,” Jean-Paul Clozel, MD, CEO at Idorsia — which is developing lucerastat — said in a press release. Among other milestones, we “completed the recruitment of patients into the pivotal [trial] for lucerastat.”

People with Fabry lack the enzyme alpha-galactosidase A due to mutations in its coding gene, GLA gene. This enzyme breaks down a fat molecule called globotriaosylceramide (Gb3). 

Without the enzyme, Gb3 builds to toxic levels in cells, causing damage and symptoms such as neuropathic pain — often described as a shooting or burning pain — caused by chronic, progressive nerve fiber damage.

Gastrointestinal symptoms, including abdominal pain, frequent bowel movements, diarrhea, reduced appetite, nausea, and vomiting, are also common to people with Fabry.

Lucerastat is a substrate reduction therapy that works by lowering the amount of Gb3 in cells. This is achieved through the inhibition of an enzyme responsible for generating glucosylceramide, a precursor molecule of Gb3. By lowering glucosylceramide production, the formation of Gb3 is reduced, which is expected to ease disease symptoms.

A combination of lucerastat plus enzyme replacement therapy (ERT) — which replaces the missing alpha-galactosidase A — has been evaluated in a Phase 1 clinical trial (NCT02930655) involving 10 Fabry patients. The treatment was well tolerated and led to a significant reduction in levels of Gb3 and related fat molecules, compared with baseline (study initiation, when patients were on ERT alone).

The MODIFY Phase 3 trial, which enrolled 118 adults at sites across the U.S., Australia, Canada, and Europe, is testing lucerastat, taken as two 250 mg capsules twice daily (1,000 mg in total) against placebo over six months.

The study’s primary goal is a change in neuropathic pain from baseline to six months. This will be assessed with the modified Brief Pain Inventory-Short Form 3 (BPI-SF3) score, based on a daily collection of patient-reported outcomes describing neuropathic pain at its worst in the past 24 hours. 

Secondary outcomes include changes in the 11-point Numerical Rating Scale (NRS-11) score for abdominal pain, and the number of days with at least one stool of a Bristol Stool Scale (BSS) consistency type 6 or 7, which indicates diarrhea. Researchers will also assess changes in Gb3 levels in the bloodstream. 

MODIFY’s extension study (NCT03737214) is open label, meaning patients who move into this trial will all receive lucerastat for up to two years. The study will monitor long-term safety and efficacy, and is expected to conclude in November 2025.