adrabetadex (VTS-270) / Mandos Health - LARVOL DELTA

Survival, Clinical, and Biomarker Data Support the Efficacy of Intrathecal Adrabetadex in Niemann-Pick Disease Type C (ACMG 2026) - "Survival analysis compared adrabetadex-treated individuals with infantile neurological onset NPC with data from four independent control datasets using a many-to-one matching which controlled age, miglustat use and age of neurological onset. The efficacy of intrathecal adrabetadex in individuals with NPC is supported by biomarker data showing improved intracellular neuronal cholesterol trafficking, reduced CSF proteins indicative of cerebellar and pan-neuronal damage, and slowed progression of neurological symptoms. Clinical benefit is further evidenced by substantially improved survival in individuals with severe, infantile-onset neurological disease when compared to matched external controls. Together, these data suggest adrabetadex addresses the core pathology of NPC and supports its potential as a disease-modifying therapy for individuals with NPC."

Biomarker • Clinical • Alzheimer's Disease • Ataxia • CNS Disorders • Cognitive Disorders • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Movement Disorders • Rare Diseases • CALB1 • FABP3 • NPC2

Beren, Through its Subsidiary Mandos, Submits New Drug Application to U.S. FDA for Adrabetadex in Infantile-Onset NPC (Businesswire) - "The application was based on data supporting a finding of improved survival in an externally controlled survival analysis, biomarker and nonclinical confirmatory evidence, and patient experience narratives....Priority Review was requested on the basis that the application meets the qualifying criteria."

FDA filing • Genetic Disorders

FDA Grants Breakthrough Therapy Designation to Investigational Drug Adrabetadex for Individuals with Infantile-Onset Niemann-Pick Disease Type C (Businesswire) - "The FDA decision was informed by an externally controlled survival analysis that showed adrabetadex improves survival in individuals with infantile-onset NPC and was reviewed alongside supportive biomarker and nonclinical data."

Breakthrough therapy • Genetic Disorders • Lysosomal Storage Diseases • Rare Diseases

Utility of 24(S)-hydroxycholesterol as a proximal biomarker to monitor long-term intrathecal adrabetadex therapy in individuals with Niemann-Pick disease, type C1. (PubMed, Mol Genet Metab) - "Increased levels of 24(S)-hydroxycholesterol (24(S)OHC) after intrathecal administration of adrabetadex reflect correction of the biochemical defect in neurons. In this study, we show that 24(S)OHC remains a robust proximal biomarker in individuals treated with IT adrabetadex for over four years."

Biomarker • Journal • CNS Disorders • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

Study of IV VTS-270 for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C (clinicaltrials.gov) - P1/2 | N=4 | Completed | Sponsor: Washington University School of Medicine | Active, not recruiting ➔ Completed | N=12 ➔ 4 | Trial completion date: Oct 2025 ➔ Oct 2024 | Trial primary completion date: Oct 2025 ➔ Oct 2024

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Frontotemporal Lobar Degeneration • Genetic Disorders • Hepatology • Lysosomal Storage Diseases • Metabolic Disorders

Study of IV VTS-270 for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C (clinicaltrials.gov) - P1/2 | N=12 | Active, not recruiting | Sponsor: Washington University School of Medicine | Recruiting ➔ Active, not recruiting

Enrollment closed • Frontotemporal Lobar Degeneration • Genetic Disorders • Hepatology • Lysosomal Storage Diseases • Metabolic Disorders

Study of IV VTS-270 for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C (clinicaltrials.gov) - P1/2 | N=12 | Recruiting | Sponsor: Washington University School of Medicine | Trial completion date: Jun 2024 ➔ Oct 2025 | Trial primary completion date: Jun 2024 ➔ Oct 2025

Trial completion date • Trial primary completion date • Frontotemporal Lobar Degeneration • Genetic Disorders • Hepatology • Lysosomal Storage Diseases • Metabolic Disorders

Elevated Cerebrospinal Fluid Total Tau in Niemann-Pick Disease Type C1: Correlation With Clinical Severity and Response to Therapeutic Interventions. (PubMed, J Inherit Metab Dis) - "Baseline CSF total Tau levels were decreased 40% (p = 0.0066) in individuals being treated with miglustat, and longitudinal analysis substantiated this observation with a 40% decrease (p < 0.0001, 95% CI 32%-47.4%). Longitudinal analysis also showed a significant (p = 0.004) decrease of 19% (95% CI 7%-30%) in total Tau levels associated with intrathecal 2-hydroxypropyl-β-cyclodextrin therapy. These data show that CSF total Tau levels are significantly increased in individuals with NPC1, positively correlated with increased disease severity, and respond to therapeutic interventions."

Biomarker • Journal • CNS Disorders • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Pediatrics • Rare Diseases • CSF T-tau

Niemann-Pick Type C Treatment With Adrabetadex for Symptoms of Brain and Nervous System (clinicaltrials.gov) - P3 | N=27 | Terminated | Sponsor: Mandos LLC | Completed ➔ Terminated; Sponsor had determined that the benefit-risk profile of adrabetadex was not favorable and the clinical development program for adrabetadex was discontinued.

Trial termination • Genetic Disorders • Lysosomal Storage Diseases

Open-label Study of VTS-270 in Participants With Neurologic Manifestations of Niemann-Pick Type C1 (clinicaltrials.gov) - P2/3 | N=2 | Terminated | Sponsor: Mandos LLC | Phase classification: P2b ➔ P2/3

Phase classification • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders

Study of IV VTS-270 for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C (clinicaltrials.gov) - P1/2 | N=12 | Recruiting | Sponsor: Washington University School of Medicine | Active, not recruiting ➔ Recruiting

Enrollment open • Frontotemporal Lobar Degeneration • Genetic Disorders • Hepatology • Lysosomal Storage Diseases • Metabolic Disorders

Study of IV VTS-270 for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C (clinicaltrials.gov) - P1/2 | N=3 | Active, not recruiting | Sponsor: Washington University School of Medicine | Trial completion date: Jun 2023 ➔ Jun 2024 | Trial primary completion date: Jun 2023 ➔ Jun 2024

Trial completion date • Trial primary completion date • Frontotemporal Lobar Degeneration • Genetic Disorders • Hepatology • Lysosomal Storage Diseases • Metabolic Disorders • NPC1

Low Risk Profile of Long-Term Repeated Lumbar Puncture for Intrathecal Delivery of 2-Hydroxypropyl-Beta-Cyclodextrin in Patients With Niemann-Pick Type C. (PubMed, Pediatr Neurol) - "This study shows that frequent repeated LPs are possible for delivery of intrathecal therapy and can be accomplished with a very low rate of post-LP adverse events."

Journal • Anesthesia • Back Pain • Musculoskeletal Pain • Pain

VTS-270 to Treat Niemann-Pick Type C1 (NPC1) Disease (clinicaltrials.gov) - P2b | N=56 | Completed | Sponsor: Mandos LLC | Active, not recruiting ➔ Completed

Trial completion • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • NPC1

Neurofilament Light Chain in Cerebrospinal Fluid as a Novel Biomarker in Evaluating Both Clinical Severity and Therapeutic Response in Niemann-Pick Disease, Type C1. (PubMed, Genet Med) - "CSF NfL levels are increased in individuals with NPC1, are associated with clinical disease severity and are decreased with miglustat therapy. These data suggest that NfL is a biomarker that may have utility in future therapeutic trials."

Biomarker • Journal • CNS Disorders • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • CSF NfL • NEFL

Combined Intrathecal and Intravenous VTS-270 Therapy for Liver and Neurological Disease Associated With Niemann-Pick Disease, Type C1 (clinicaltrials.gov) - P1/2 | N=2 | Terminated | Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Completed ➔ Terminated; Enrollment was poor due to COVID-19 pandemic

Trial termination • CNS Disorders • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • NPC1

Open-label Study of VTS-270 in Participants With Neurologic Manifestations of Niemann-Pick Type C1 (clinicaltrials.gov) - P2b | N=2 | Terminated | Sponsor: Mandos LLC | Active, not recruiting ➔ Terminated; Terminated by previous Sponsor decision

Trial termination • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders

Adrabetadex to Treat Niemann-Pick Type C1 (NPC1) Disease (clinicaltrials.gov) - P2b | N=66 | Terminated | Sponsor: Mandos LLC | Active, not recruiting ➔ Terminated; Terminated by previous Sponsor decision

Trial termination • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders

Niemann-Pick Type C Treatment With Adrabetadex for Symptoms of Brain and Nervous System (clinicaltrials.gov) - P3 | N=27 | Completed | Sponsor: Mandos LLC | Active, not recruiting ➔ Completed | N=60 ➔ 27

Enrollment change • Trial completion • Genetic Disorders • Lysosomal Storage Diseases

Study of IV VTS-270 for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C (clinicaltrials.gov) - P1/2 | N=3 | Active, not recruiting | Sponsor: Washington University School of Medicine | Trial completion date: Feb 2022 ➔ Jun 2023 | Trial primary completion date: Feb 2022 ➔ Jun 2023

Trial completion date • Trial primary completion date • Frontotemporal Lobar Degeneration • Genetic Disorders • Hepatology • Lysosomal Storage Diseases • Metabolic Disorders

Consistently High Agreement Between Independent Raters of Niemann-Pick Type C1 Clinical Severity Scale in Phase 2/3 Trial. (PubMed, Pediatr Neurol) - "These results support the NPC-SS, including derived four- and five-item composite scores, as reliable measures for use in a clinical trial setting."

Clinical • Journal • P2/3 data • CNS Disorders • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

Combined Intrathecal and Intravenous VTS-270 Therapy for Liver and Neurological Disease Associated With Niemann-Pick Disease, Type C1 (clinicaltrials.gov) - P1/2; N=2; Completed; Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders

Combined Intrathecal and Intravenous VTS-270 Therapy for Liver and Neurological Disease Associated With Niemann-Pick Disease, Type C1 (clinicaltrials.gov) - P1/2; N=2; Active, not recruiting; Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Recruiting ➔ Active, not recruiting; N=30 ➔ 2

Enrollment change • Enrollment closed • CNS Disorders • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders

Adrabetadex to Treat Niemann-Pick Type C1 (NPC1) Disease (clinicaltrials.gov) - P2b; N=66; Active, not recruiting; Sponsor: Vtesse, LLC, a Mallinckrodt Pharmaceuticals Company

Clinical • New P2b trial • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders

Adrabetadex for Patients With Nerve Symptoms of Niemann-Pick Type C Disease (NPC) (clinicaltrials.gov) - P3; N=60; Active, not recruiting; Sponsor: Vtesse, Inc., a Mallinckrodt Pharmaceuticals Company; Trial completion date: Jul 2021 ➔ Nov 2021; Trial primary completion date: May 2021 ➔ Oct 2021

Clinical • Trial completion date • Trial primary completion date