Lucerastat is an investigational treatment for Fabry disease that is being developed by the biopharmaceutical company Idorsia. It functions as a substrate reduction therapy.

How Lucerastat works

Fabry disease patients are unable to make the enzyme alpha-galactosidase A because of a mutation in the gene that contains the information to make this enzyme. Alpha-galactosidase A is necessary to break down fat molecules called globotriaosylceramide (Gb3 or GL-3). Without the enzyme, Gb3 builds up inside cells and causes damage that leads to the symptoms of Fabry.

Lucerastat is a small molecule called an “iminosugar,” which is almost identical to a sugar, except for the substitution of a nitrogen atom in place of an oxygen atom. It inhibits the production of another enzyme, glucosylceramide synthase, which plays a role in the production of Gb3. With less glucosylceramide synthase, less Gb3 is produced, reducing build-up even in the absence of alpha-galactosidase A.

Lucerastat in clinical trials

Lucerastat has been tested in three Phase 1 clinical trials in healthy volunteers to assess its safety, tolerability, and how the body absorbs and processes the medication. These trials showed that the medication was well-tolerated and did not cause any serious adverse events.

Lucerastat also has been tested in a Phase 1 trial (NCT02930655) in Fabry disease patients who were  being treated with enzyme replacement therapy (ERT). This small, open-label exploratory trial included 10 participants who received Lucerastat in addition to ERT and four participants who received ERT only. The results showed that plasma levels of Gb3 and related fats decreased significantly in the Lucerastat group. In addition, the medication was well-tolerated, suggesting that Lucerastat has a potential for clinical use in Fabry disease patients.

A Phase 3 clinical trial called MODIFY (NCT03425539) will assess the safety and effectiveness of Lucerastat on its own in adults with Fabry disease. During the double-blind, placebo-controlled trial, participants will be treated with Lucerastat or a placebo for six months. Effectiveness will be measured by patient-reported neuropathic pain, gastrointestinal symptoms, and plasma Gb3 levels. The trial is not yet recruiting participants.


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