Long-term use of lucerastat may protect kidneys in Fabry: Trial data
Treatment over 6 years shown to slow loss of kidney function
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Long-term dosing with lucerastat, an experimental substrate reduction treatment from Idorsia, may slow the loss of kidney function in adults with Fabry disease, perhaps by reducing the buildup of toxic fatty molecules in the body’s cells, a global clinical trial has found.
The oral therapy — given to some study participants for more than six years — was generally safe and well tolerated, Idorsia noted in a company press release announcing the results of the Phase 3 study, dubbed MODIFY (NCT03425539), and its open-label extension (NCT03737214).
A report detailing those findings, titled “Lucerastat, an oral therapy for Fabry disease: results from a pivotal randomized phase 3 study and its open-label extension,” was published in the journal Nature Communications. The study was funded by Idorsia.
The company noted what it called a “promising effect” seen with lucerastat. Idorsia said it is now working with the U.S. Food and Drug Administration to develop an optimal regulatory program for a possible approval.
Alberto Gimona, MD, head of global clinical development at Idorsia, expressed his appreciation to all participants involved in the therapy’s clinical testing.
“The patients who have taken part in MODIFY and the extension study — some of whom have now been treated with lucerastat for over [six] years — have been true heroes for the Fabry community,” Gimona said. “Thanks to their participation, we have gained great insight into the benefits of long-term treatment with lucerastat.”
MODIFY trial tested lucerastat in over 100 adults with Fabry
A genetic disease, Fabry is caused by mutations that result in a lack of alpha-galactosidase A (Gal A). That enzyme breaks down globotriaosylceramide (Gb3) and other fatty molecules inside cells. Without Gal A, these fatty molecules accumulate to toxic levels, damaging tissues and organs, such as nerves and kidneys.
A molecule on which an enzyme exerts its effects is called a substrate; Gb3 is the substrate for Gal A. Lucerastat is a substrate-reduction treatment, meaning it reduces Gb3 levels without the need for a functional enzyme. Such treatment is expected to ease the symptoms of Fabry disease, which are caused by the toxic buildup of fatty molecules.
The MODIFY clinical study enrolled 118 adults with Fabry and moderate to severe neuropathic pain who were randomly assigned to receive either lucerastat or a placebo twice daily for six months. Neuropathic pain is common in Fabry disease, occurring due to damage to the nerves. Most patients continued on in the extension study, where all were given lucerastat for as long as six years.
The main goal of the randomized part was to reduce neuropathic pain compared with the placebo. Lucerastat did not meet this goal over six months, the data showed. However, it significantly reduced Gb3 levels in blood and urine, showing it effectively engaged its target. It also tended to slow the loss of kidney function, supporting its extension into long-term treatment.
Kidney function was measured using the estimated glomerular filtration rate (eGFR), which estimates how well the kidneys filter waste. In Fabry disease, eGFR usually declines over time. An interim analysis of 93 participants in the open-label extension, at 18 months, showed that the decline in eGFR slowed after patients started lucerastat, compared with the decline observed before entering the study.
Before randomization, the annual eGFR declined by 3.50 milliliters per minute per 1.73 square meters per year (mL/min/1.73 m²/year). After randomization, this slowed to a decline of 1.48 mL/min/1.73 m²/year. Similar improvements were observed across subgroups, including those delineated by sex, and whether or not patients had received enzyme replacement treatment.
Patients with kidney function impairments benefited most
Patients with impairment of kidney function benefited the most. They showed a decline of 6.18 before randomization versus 1.88 after randomization. Those whose kidney function worsened rapidly improved from a decline of 9.77 to 1.16.
Additionally, the proportion of patients with stable kidney function increased from 54% to 75%, while the proportion of patients with rapid loss of kidney function decreased from 23% to 11%.
“Stability or the reduction of loss of kidney function is a therapeutic goal for patients with Fabry disease. This can only be seen with long-term treatment,” said Derralynn Hughes, MD, PhD, a professor at University College London in the U.K. and chief investigator in MODIFY, adding the result “is encouraging and warrants further investigation.”
Researchers also used echocardiography to measure the left ventricular mass index, which reflects thickening of the heart muscle. This measure remained stable, which is considered favorable because heart function often worsens over time in Fabry disease, yet it was “mainly collected for safety analysis, as the study was considered too short to evaluate changes conclusively over time,” the researchers wrote.
Stability or the reduction of loss of kidney function is a therapeutic goal for patients with Fabry disease. This can only be seen with long-term treatment. … [These results are] encouraging and [warrant] further investigation.
Patients were treated with lucerastat for at least 3.5 years in the extension study, and some had more than six years of total exposure. Lucerastat was generally tolerated well, with no new safety concerns emerging during long-term treatment, the team noted.
“Lucerastat was safe and well tolerated,” the researchers wrote.
Although the open-label extension will end, a post-study access program is planned, so patients who benefit from the treatment can continue receiving it. This could also continue to drive the company to “generate the regulatory data required to bring lucerastat to patients,” Gimona said, adding, “We remain committed to advancing this innovative treatment for patients living with Fabry disease.”
