Idorsia’s Fabry Therapy Fails in Late-Stage Study

Swiss biotech Idorsia reported that MODIFY, the phase 3 study to investigate the effect of lucerastat as an oral substrate reduction therapy for the treatment of adult patients with Fabry disease, did not meet the primary endpoint.

Photo: Jean-Paul Clozel, CEO of Idorsia

“Lucerastat was well tolerated and biochemically it did exactly what we were expecting; as previously seen, in this study we saw a substantial and consistent reduction of plasma Gb3, confirming the pharmacological activity of lucerastat,” said Guy Braunstein, head of Global Clinical Development at Idorsia. “Despite this biological effect, no reduction in neuropathic pain was observed after six months of treatment, using the patient reported outcome tool.”

Fabry disease is a rare, genetic, lysosomal storage disorder that results in reduced or absent α-galactosidase A (alpha-GalA) an enzyme that normally breaks down a fatty product known as globotriaosylceramide (Gb3) in the cells of the body. Over time, this results in an accumulation of Gb3 deposits throughout the body, leading to progressive pathophysiology in the nervous system, such as neuropathic pain (pain primarily in the hands and feet), the gastrointestinal system, and the cardiovascular system, as well as in organs, including the kidneys, skin, ears, eyes, and lung. Symptoms of Fabry disease affect a patient’s life expectancy and their quality of life.

Lucerastat, a small molecule glucosylceramide synthase inhibitor, is in development as a novel, substrate reduction therapy for Fabry disease. Preclinical studies showed that lucerastat is a soluble, bioavailable inhibitor of glucosylceramide synthase that reduces the accumulation of α-galactosidase A substrates in tissues affected by Fabry disease, including kidneys, liver, and dorsal root ganglia. In clinical pharmacology studies, lucerastat had reproducible pharmacokinetics, characterized by rapid absorption, quick elimination, and no evidence for saturation of absorption or elimination mechanisms. Across phase 1 studies, lucerastat doses up to 4,000 mg were well tolerated and the safety profile was not affected by concomitant treatments.

MODIFY was a multicenter, double-blind, randomized, placebo‑controlled, parallel-group study to determine the efficacy and safety of lucerastat as an oral monotherapy in adult patients with Fabry disease. MODIFY determined the effect of study treatment on neuropathic pain during 6 months of treatment, measured with Idorsia’s validated Fabry disease pain instrument. Some 118 patients were randomized in a 2:1 ratio to either lucerastat or placebo. At the end of the double-blind period, 107 patients entered into an ongoing open label extension study, which is investigating the long-term safety and tolerability of lucerastat oral therapy and to further evaluate its clinical efficacy on renal and cardiac function, in adult patients with Fabry disease over a period of up to a further 48 months.

MODIFY trial data are continuing to be analyzed that will inform Idorsia’s decision on further development of lucerastat.

“Taking into account the quality of the study, the volume of data we have collected, and some observations made in the six-month double-blind placebo-controlled treatment period, we need to wait for the results of the interim analysis of the open-label phase before making a decision,” said Jean-Paul Clozel, CEO of Idorsia. I expect to be in a position to share our future direction before the end of year.”

Author: Rare Daily Staff