Idorsia to further characterize lucerastat for the treatment of Fabry disease by continuing the open-label extension of the Phase 3 MODIFY study

Idorsia to further characterize lucerastat for the treatment of Fabry disease by continuing the open-label extension of the Phase 3 MODIFY study

• Idorsia will consult with health authorities and share the data collected so far to define the regulatory pathway for lucerastat in Fabry disease

Allschwil, Switzerland – December 13, 2021
Idorsia Ltd (SIX: IDIA) today announced that after the planned interim analysis of the open-label extension (OLE) of the Phase 3 MODIFY study with lucerastat for the treatment of adult patients with Fabry disease, the study will continue. The company will consult with health authorities in the first half of 2022, and discuss the data collected up until the first interim analysis of the OLE study. The data includes the placebo-controlled 6-month treatment period with 118 patients in MODIFY, as well as the analysis of 107 patients who continued into the OLE, many of whom are treated with lucerastat for one year and some who have received treatment for up to 2 years.

While lucerastat (1000 mg b.i.d) did not meet the primary endpoint of reducing neuropathic pain during 6 months of treatment versus placebo, the company has made observations on renal function and cardiac echocardiography which, if confirmed with longer-term data, would indicate a treatment effect on the main organs affected by the disease.

Lucerastat demonstrated a substantial reduction in levels of the Fabry-disease biomarker plasma Gb3 after 6 months of treatment. A nominally significant (p<0.0001) difference in the change from baseline to month 6 in plasma Gb3 between lucerastat and placebo was observed, with a decrease of approximately 50% observed in plasma Gb3 in the lucerastat treatment group compared to an increase of 12% in the placebo group. Interestingly, a decrease in plasma Gb3 was observed in virtually every patient on treatment with lucerastat. Likewise, a nominally significant (p=0.02) difference in the percent change from baseline to month 6 in plasma lysoGb3 between lucerastat and placebo was also observed. The change in these Fabry-disease biomarkers was maintained or further improved with continued lucerastat treatment in the OLE.

Based on patient historical data, mean estimated glomerular filtration rate (eGFR), a measure of kidney function, was decreasing prior to the study. During the 6 months of the MODIFY study, a slightly higher increase in eGFR was observed in the lucerastat group versus placebo, as measured by the eGFR slope. This potential effect of lucerastat on kidney function over 6 months of treatment was further evaluated at the interim analysis of the extension study. The average eGFR decline was
-2.75 mL/min/1.73m² per year on treatment overall, while in the two years preceding the study (historical values), the decline was -3.55 mL/min/1.73m² per year. In a subgroup of patients with an eGFR value of less than or equal to 90 mL/min/1.73m² at baseline, denoting kidney function impairment, a slower decline of eGFR of -3.41 mL/min/1.73² per year was observed on treatment versus an historical decrease of -6.29 mL/min/1.73² per year.
Also, in several patients treated with lucerastat, especially those with a high left ventricular mass index (LVMI) at baseline, a decrease of LVMI with lucerastat was seen. These data need to be further characterized.

In MODIFY, of the 118 patients enrolled, 80 patients were randomized to lucerastat. Lucerastat was well tolerated. No clinically meaningful change in vital signs, ECGs, or marked laboratory abnormalities was observed. Two patients in each group (lucerastat 2.5%; placebo 5.4%) discontinued due to adverse events. Serious adverse events (SAE) were reported in 5 patients (6.3%) and 1 patient (2.7%) in the lucerastat and placebo groups, respectively. No SAE was fatal, and all were considered as not related to study treatment. The interim analysis of the OLE study, which included 114 patients treated for an average duration of 15 months, provided a safety and tolerability profile consistent with that observed during 6-month randomized treatment period.

Jean-Paul Clozel, MD and Chief Executive Officer of Idorsia, commented:
“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. 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. 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.”

Jean-Paul Clozel, concluded:
“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. 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. In the meantime, we will discuss our results with health authorities globally to define the regulatory pathway forward for lucerastat in patients with Fabry disease.”

About the MODIFY study (NCT03425539) and its open label extension (NCT03737214)
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. 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 in an ongoing open label extension study, which aims to determine 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.

About lucerastat in Japan
The efficacy of lucerastat has been evaluated in an open-label Phase 3 study in 22 Japanese patients with Fabry disease. The results of the study are currently in preparation for scientific disclosure in a peer-reviewed publication.