Lucerastat Fails to Lessen Neuropathic Pain in Phase 3 Trial

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by Patricia Inacio PhD |

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Lucerastat, an investigational substrate reduction therapy for Fabry disease, has failed to outperform placebo at reducing neuropathic pain in patients, updated results from the MODIFY Phase 3 trial show.

The findings mean that Idorsia‘s MODIFY study (NCT03425539) did not meet its primary goal, despite lucerastat being well tolerated and reducing the levels of globotriaosylceramide (Gb3) — the fat molecule that builds up and causes damage in Fabry patients.

As most patients chose to enter MODIFY’s extension study (NCT03737214), the company is waiting for results from that open-label portion to decide the best route forward for lucerastat’s development, which might happen in the next couple of months.

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“Taking into account the quality of the study, the volume of data we have collected, and some observations made in [MODIFY], we need to wait for the results of the interim analysis of the open-label phase before making a decision. I expect to be in a position to share our future direction before the end of year,” Jean-Paul Clozel, MD, CEO of Idorsia, said in a press release.

Fabry disease is caused by mutations in a gene containing the instructions for the alpha-galactosidase A enzyme, important for breaking down the fat molecule Gb3.

In the absence of a functioning galactosidase A enzyme, Gb3 builds up to toxic levels in cells, leading to damage and symptoms such as neuropathic pain — often described as a shooting or burning pain — caused by chronic, progressive nerve fiber damage.

Lucerastat is an oral substrate reduction therapy designed to lower the amount of Gb3 in cells by inhibiting an enzyme responsible for generating glucosylceramide, a precursor of Gb3. A reduction in glucosylceramide is expected to prevent Gb3 accumulation and to ease disease symptoms.

The treatment was investigated in a Phase 1b clinical trial (NCT02930655) as an add-on to enzyme replacement therapy (ERT) — which replaces the missing alpha-galactosidase A — in 10 Fabry patients who were on ERT for the past two years. Results showed that adding lucerastat to the standard ERT was well tolerated and significantly reduced Gb3 levels.

MODIFY was designed to investigate lucerastat in a larger group of Fabry patients. A total of 118 adults were included and randomly assigned to receive two 250 mg capsules of lucerastat twice daily (1,000 mg in total) or a placebo for six months.

The trial’s main goal was to determine if lucerastat could reduce neuropathic pain, compared with a placebo. This was 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 measures included changes in abdominal pain, stool consistency, and Gb3 levels.

According to Idorsia, lucerastat was well tolerated and worked as expected, leading to a “substantial and consistent reduction of plasma Gb3, confirming the pharmacological activity of lucerastat,” said Guy Braunstein, MD, head of global clinical development at Idorsia.

However, “no reduction in neuropathic pain was observed after six months of treatment, using the patient reported outcome tool,” he added.

A total of 107 patients have enrolled in the trial’s open-label extension, in which all will receive lucerastat for up to two years. The trial is expected to conclude in November 2025, but interim data should be announced soon.

“I’m very proud of everyone involved with MODIFY for delivering a very high-quality study, one of the largest in Fabry disease,” Braunstein said.

“Many parameters have been collected and data are still being analyzed. In addition, most patients chose to continue in the open-label extension study and in a few weeks, we will see more results that will inform our decision on the future of lucerastat,” he added.