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Introduction: Niemann-Pick disease, type C (NPC) is a neurodegenerative lysosomal disease due to dysfunction of either NPC1 or NPC2.Dysfunction of these lysosomal proteins impairs intracellular cholesterol transport and leads to endolysosomal accumulation of unesterified cholesterol and lipids.The NPC neurological phenotype is characterized by progressive cerebellar ataxia and cognitive impairment.Age of neurological onset is variable, but individuals with neurological onset prior to six years of age are the most severely affected with rapid progression leading to premature death.The investigational drug, adrabetadex is a proprietary mixture of 2-hydroxypropyl-beta-cyclodextrin isomers that has been shown to reestablish intracellular cholesterol transport and increase survival of NPC1 mice and cats models.In this abstract we report biomarker, clinical progression and survival data from individuals with NPC treated with intrathecal adrabetadex.Methods: Cerebrospinal fluid (CSF) biomarkers of neuronal damage (Calbindin-D, Fatty Acid Binding Protein 3 and total Tau) as well as the neuronal specific pharmacodynamic biomarker 24(S)-hydroxycholesterol (24(S)-OHC) were measured by quantitative immunoassay and mass spectrometry, respectively, and reported as percent change from baseline.Disease progression was assessed in pre-and post-adrabetadex treated individuals was assessed using the 4-domain (fine motor, gross motor, speech and swallowing) Rescored NPC Clinical Severity Score (R4DNPCCSS, range 0-20) and evaluated with longitudinal mixed-effects models estimating the mean annual progression.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.Weight-adjusted Kaplan-Meier estimates, and log-rank p-values were determined.Hazard ratios (HR) were estimated from a weightadjusted Cox regression model.Survival analysis compared adrabetadex-treated individuals with infantile-onset NPC with data from four major disease databases or publications using a many-to-one matching algorithm which controlled for age, disease subtype, miglustat use and age of neurological onset.Weighted Kaplan-Meier estimates, and log-rank p-values were determined, and hazard ratios (HR) were estimated from a weighted Cox regression model.Results: Consistent with improved intracellular neuronal cholesterol transport, CSF 24(S)-OHC levels increased by 27.7% (n=22, P=0.001) after 52 weeks of intrathecal adrabetadex treatment in individuals with NPC.Additionally, increased levels of 24(S)-OHC are observed following intrathecal adrabetadex administration in older individuals with NPC treated for over four years.CSF calbindin D levels (a biomarker of cerebellar neuronal damage) decreased by 18.3% (n=24, p=0.002).CSF Fatty Acid Binding Protein 3 and total Tau levels (biomarkers of pan-neuronal damage) decreased by 40.5% (n=24, P=0.008) and 19% (n = 101, P=0.008), respectively, in association with treatment.Neurological disease progression was assessed using the R4DNPCCSS and intrathecal adrabetadex treatment significantly decreases mean annual disease progression by 43% or 0.58 points/year (n=79, P=0.006).The mean (median) duration of pre-treatment follow-up from first recorded R4DNPCCSS assessment to last untreated R4DNPCCSS assessment was 1.37 (0.08) years.Mean follow-up for the pre-treatment period (from first recorded to last untreated R4DNPCCSS assessment) was 1.37 (SD = 2.7) years, and for treatment (from first to last treated assessment) was 3.47 (SD = 2.38) years.Comparing infantile-onset individuals treated with intrathecal adrabetadex to external controls, a survival benefit is observed (n=80, HR 0.289, 95% CI 0.049-0.398,p<0.0001).This survival benefit is independent of miglustat use. Conclusion: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.