Key Takeaways SNY said its phase III LEAP2MONO study met all primary endpoints in GD3 patients versus ERT.Sanofi reported significant, clinically meaningful neurological gains at 52 weeks on SARA and RBANS.SNY said venglustat improved spleen and liver size, was well tolerated, and will advance to filings.Sanofi (SNY) announced that a late-stage study, evaluating venglustat, an investigational oral glucosylceramide synthase inhibitor (GCSi), in patients aged 12 years and older with type 3 Gaucher disease (GD ...

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, demonstrating the potential of lucerastat as an oral substrate reduction therapy for Fabry disease, particularly in patients with renal impairment [1][17]. 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][9]. 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, showing 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 monotherapy [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]. Industry Context - Fabry disease is a rare lysosomal storage disorder caused by mutations in the GLA gene, leading to the accumulation of Gb3 and resulting in progressive damage to multiple organ systems [10][11]. - Current treatment options are limited, highlighting the unmet need for a well-tolerated, oral, disease-modifying therapy that can be used regardless of genotype or prior treatment history [13][14].

Core Opinion - The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has issued a negative opinion regarding the revised dosing schedule for Elfabrio, a treatment for Fabry disease, proposed by Protalix BioTherapeutics and Chiesi Group [1][2]. Company Overview - Protalix BioTherapeutics and Chiesi Group are facing selling pressure following the CHMP's decision [2][5]. - The companies had requested approval for a new dosing regimen of 2 mg/kg body weight infused every 4 weeks, in addition to the currently approved regimen of 1 mg/kg body weight infused every 2 weeks [2]. Clinical Data - The CHMP review was based on data from the BRIGHT trial and an ongoing open-label extension study, which collectively provided a median exposure of almost six years [3][4]. - The data from these studies, along with modeling and exposure-response analyses from prior trials, were deemed insufficient to demonstrate similar efficacy for the new dosing schedule [4]. Market Impact - Following the negative opinion, Protalix BioTherapeutics' stock price decreased by 29.83%, closing at $1.68 [5].