Lucerastat Extension Trial Will Continue, Focus on Long-term Possibilities

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by Margarida Maia PhD |

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Idorsia will continue its open-label extension of the Phase 3 MODIFY trial to better determine if lucerastat, the company’s investigational oral therapy for Fabry disease, may be of benefit to patients’ kidneys and the heart.

The decision comes despite the therapy having failed to outperform a placebo at reducing neuropathic pain over a period of about six months, which was the primary goal (endpoint) of the MODIFY study.

An interim analysis of 107 patients continuing in the open-label extension showed a potential for kidney and cardiac benefits that needs to be confirmed with longer-term data, Idorsia reported.

“We are in the very fortunate position to have a large cohort of patients on treatment. By now, many have been treated for 1 year and some for up to 2 years,” Jean-Paul Clozel, MD, CEO of Idorsia, said in a press release. “By continuing to collect data we will further characterize the signal we have observed and determine whether lucerastat can offer benefit for the kidneys and the heart.”

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Data will be shared with health authorities by mid-year. “We will discuss our results with health authorities globally to define the regulatory pathway forward for lucerastat in patients with Fabry disease,” Clozel added.

Fabry disease is caused by mutations in a gene containing the instructions for the alpha-galactosidase A enzyme, important for breaking down fatty molecules known as globotriaosylceramide (Gb3) and globotriaosylsphingosine (LysoGb3).

Lucerastat is an oral substrate reduction therapy that works by reducing the damage-causing, toxic buildup of these fatty molecules in several organs. Two of the most affected are the kidneys and the heart.

The Phase 3 MODIFY study (NCT03425539) evaluated how well 1,000 mg of lucerastat, given as two 250-mg capsules twice daily, worked in reducing neuropathic pain compared with a placebo over six months. Secondary measures included levels of abdominal pain, stool consistency, and Gb3 levels.

The study included 118 adults with Fabry disease, 107 of whom are continuing in the ongoing extension study (NCT03737214). This open-label (no placebo group) extension is looking at lucerastat’s safety and tolerability over a period of up to four years, and whether treatment can improve kidney and heart function.

Six months of treatment with lucerastat in MODIFY brought plasma Gb3 levels down to about half, with reductions seen in virtually every treated patient. In contrast, an increase of 12% was observed in the placebo group.

Significant differences in the levels of plasma lysoGb3 from the study’s beginning to month six were also observed between those treated with lucerastat and those given a placebo.

Levels of these biomarkers remained low or fell further with continued treatment in the open-label extension study, the company reported.

“I have been impressed to consistently see such a substantial decrease in plasma Gb3, in almost every patient treated with lucerastat, even after switching from enzyme replacement therapy,” Clozel said.

“Accumulation of Gb3 is the main cause of organ damage in Fabry disease, therefore it stands to reason to me that decreasing plasma Gb3 should translate into a beneficial effect on the organs effected by Fabry disease,” he added. “Following the analysis of the 6-month data from MODIFY and now the first interim analysis of the open label extension study, we have an indication that this is indeed the case.”

Based on patient records, kidney function was measured using the estimated glomerular filtration rate (eGFR), which calculates how much blood passes through the kidneys each minute. Specifically, that rate is calculated in milliliters per minute per square meter, or mL/min/1.73 m2.

While mean eGFR was decreasing prior to the study, during the MODIFY trial and its open-label extension, there was a slight increase in eGFR in the lucerastat group versus placebo patients.

In the extension study data, average eGFR decline was of -2.75 mL/min/1.73m2 per year on treatment overall, while in the two years preceding the study the decline was -3.55 mL/min/1.73m2 per year.

In a subgroup of patients with impaired kidney function, a slower eGFR decline of -3.41 mL/min/1.732 per year was observed with lucerastat treatment versus an historical decrease of -6.29 mL/min/1.732 per year.

A decrease was also seen in the left ventricular mass index (LVMI), a predictor of cardiovascular disease, in several lucerastat-treated patients. This decrease was especially evident among those with a high LVMI value at the study’s start.

Lucerastat continues to be safe and well-tolerated. The extension study’s interim analysis, which included 114 patients treated for an average duration of 15 months (a bit longer than one year), provided a safety and tolerability profile that was consistent with that observed during the MODIFY study, Idorsia reported.

Results of a separate open-label efficacy study of lucerastat in 22 Japanese patients with Fabry disease are expected to be announced soon.