Core Insights - Idorsia Ltd has announced the design of its FDA-agreed Phase 3 registration program for lucerastat in treating Fabry disease, focusing on its impact on renal pathology to secure market authorization [1][4] - The Fabry disease market is projected to reach around USD 4 billion by 2034, indicating a growing demand for innovative therapies [2] - Lucerastat is positioned as a differentiated oral therapy that addresses the underlying biology of Fabry disease, with a mutation-independent mechanism and long-term evidence supporting its efficacy [3][21] Company Developments - The registration program includes two clinical trials aimed at characterizing lucerastat's renal effects, aligning with feedback from health authorities [4] - A pivotal kidney biopsy study and a renal function comparative study are part of the program, with a potential regulatory filing expected as early as 2029 [5][6] - Long-term data from the MODIFY study indicates that lucerastat treatment is associated with a slower decline in kidney function compared to historical data [11] Clinical Findings - The MODIFY study did not meet its primary endpoint of reducing neuropathic pain, but showed significant reductions in plasma and urinary Gb3 levels, indicating robust pharmacodynamic effects [10][21] - An interim analysis revealed a notable reduction in the rate of eGFR decline in patients treated with lucerastat, particularly in those with severe disease [11] - Kidney biopsy results from long-term treated patients demonstrated low-to-no levels of kidney Gb3 inclusions, supporting the drug's efficacy [12] Market Context - Fabry disease is a rare disorder with approximately 16,000 diagnosed patients in major markets, expected to increase to around 21,000 by 2034 [2] - Current treatment options have limitations, creating a significant unmet need for a well-tolerated, oral, disease-modifying therapy [17] - Lucerastat's mechanism of action allows it to be effective regardless of α-Gal A activity or prior treatment history, broadening therapeutic options for patients [18][21]

Core Insights - Idorsia Ltd announces the presentation of long-term results from the lucerastat treatment at the 22nd Annual WORLDSymposium™, highlighting its potential as a first-in-class oral substrate reduction therapy for Fabry disease [1][7] Study Overview - The MODIFY study was a multicenter, double-blind, randomized, placebo-controlled trial involving 118 patients to assess the efficacy and safety of lucerastat as an oral monotherapy for Fabry disease [3] - The study did not meet its primary endpoint of reducing neuropathic pain but showed significant reductions in plasma and urinary Gb3 levels compared to placebo, sustained over time in the open-label extension [4][14] Long-term Efficacy - An interim analysis of the open-label extension revealed a notable reduction in the rate of eGFR decline among patients treated with lucerastat, suggesting a potential disease-modifying effect [5] - Patients with impaired renal function at baseline experienced a marked attenuation of kidney function loss, indicating lucerastat's promise in long-term organ protection [5][14] Kidney Biopsy Sub-study - A kidney biopsy sub-study evaluated Gb3 accumulation in key kidney cell types in male patients with classic Fabry disease who received lucerastat for at least two years, providing insights into its impact on renal disease biology [2] Patient Population and Disease Background - Fabry disease is a rare, X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to the accumulation of Gb3 and progressive damage across multiple organ systems [6][8] - Recent studies suggest a higher prevalence of Fabry disease than previously estimated, with over 21,000 diagnosed patients expected across the US, EU5, and Japan by 2034 [9] Current Treatment Landscape - Current treatment options for Fabry disease include enzyme replacement therapies and oral chaperone therapy, which have limitations, highlighting the unmet need for a well-tolerated, oral, disease-modifying therapy [10][11]

Core Insights - Idorsia Ltd has published results from the pivotal Phase 3 MODIFY study and its open-label extension, highlighting the potential of lucerastat as an oral substrate reduction therapy for Fabry disease, particularly in patients with renal impairment [1][3]. Study Overview - The MODIFY study was a multicenter, double-blind, randomized, placebo-controlled trial involving 118 patients, aimed at assessing the efficacy and safety of lucerastat as an oral monotherapy for adult patients with Fabry disease [2]. - The study's primary endpoint of reducing neuropathic pain over six months was not met; however, lucerastat showed significant reductions in plasma and urinary Gb3 levels compared to placebo, with sustained effects observed in the open-label extension [3][17]. Renal Function Insights - An interim analysis of the open-label extension indicated a notable improvement in renal function trajectory, with a reduced rate of eGFR decline in patients treated with lucerastat compared to their eGFR slope prior to enrollment [4][9]. - In patients with impaired renal function or fast-deteriorating eGFR at baseline, lucerastat was associated with a significant reduction in kidney function loss, suggesting a potential disease-modifying effect [4][17]. Long-term Treatment and Tolerability - The open-label extension has collected data from patients treated with lucerastat for over 42 months, with some receiving treatment for more than 6 years, demonstrating good tolerability and no serious treatment-related adverse events [5][8]. - A kidney biopsy sub-study was conducted to evaluate Gb3 inclusions in kidney cells of male participants with classic Fabry disease treated for over 3 years with lucerastat [5]. Future Directions - The company is collaborating with the US FDA to design a new Phase 3 program to ensure a regulatory pathway for lucerastat's approval [6][10]. - A post-trial access program is being established to ensure continuity of care for participants still receiving lucerastat at the study's closure [7].