Dataset Information

Long-Term Treatment of Niemann-Pick Type C1 Disease With Intrathecal 2-Hydroxypropyl-?-Cyclodextrin.

ABSTRACT: BACKGROUND:Intrathecal 2-hydoxypropyl-?-cyclodextrin has been found to mobilize cholesterol, extend life, reduce cerebellar pathology, and delay onset of ataxia in the mouse and cat models of Niemann-Pick disease, type C1, a clinically variable progressive and ultimately fatal neurodegenerative storage disorder characterized by endolysosomal accumulation of unesterified cholesterol. OBJECTIVE:In this study, the long-term effects of intrathecal 2-hydoxypropyl-?-cyclodextrin treatment for 2.5 to three years in humans with Niemann-Pick disease, type C, were evaluated. METHODS:Three patients with Niemann-Pick disease, type C, in different stages of progression and displaying varying disease manifestations were treated with intrathecal 2-hydoxypropyl-?-cyclodextrin (VTS-270) delivered by lumbar puncture infusion through an intermediate-size patient population investigational new drug application for expanded access. Disease progression was monitored with the Niemann-Pick disease, type C, Neurological Severity Scale and numerous objective measures of function in five neurological domains typically impacted by the disease: cognitive/language, gait/balance, fine motor, swallowing, and eye movement. RESULTS:No worsening in any domain except eye movements (vertical pursuit gain) was seen for any of the three patients, and in the other domains, improved scores on measures were seen over time for one or more patients. The Niemann-Pick disease type C (NPC) Neurological Severity Scale (NSS) showed stable to slightly improved ratings. CONCLUSIONS:These trajectories are not consistent with the typical trajectory of the disease and suggest that intrathecal 2-hydoxypropyl-?-cyclodextrin has stabilized the disease over an extended period of time, supporting the current phase 2/3 controlled registration trial with VTS-270.

SUBMITTER: Berry-Kravis E

PROVIDER: S-EPMC5857219 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Long-Term Treatment of Niemann-Pick Type C1 Disease With Intrathecal 2-Hydroxypropyl-β-Cyclodextrin.

Berry-Kravis Elizabeth E Chin Jamie J Hoffmann Anne A Winston Amy A Stoner Robin R LaGorio Lisa L Friedmann Katherine K Hernandez Mariana M Ory Daniel S DS Porter Forbes D FD O'Keefe Joan A JA

Pediatric neurology 20180108

<h4>Background</h4>Intrathecal 2-hydoxypropyl-β-cyclodextrin has been found to mobilize cholesterol, extend life, reduce cerebellar pathology, and delay onset of ataxia in the mouse and cat models of Niemann-Pick disease, type C1, a clinically variable progressive and ultimately fatal neurodegenerative storage disorder characterized by endolysosomal accumulation of unesterified cholesterol.<h4>Objective</h4>In this study, the long-term effects of intrathecal 2-hydoxypropyl-β-cyclodextrin treatme ...[more]

PMID: 29429782

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Project description:2-Hydroxypropyl-beta-cyclodextrin (HPβCD) has gained recent attention as a potential therapeutic intervention in the treatment of the rare autosomal-recessive, neurodegenerative lysosomal storage disorder Niemann-Pick Disease Type C1 (NPC1). Notably, HPβCD formulations are not comprised of a single molecular species, but instead are complex mixtures of species with differing degrees of hydroxypropylation of the cyclodextrin ring. The degree of substitution is a critical aspect of the complex mixture as it influences binding to other molecules and thus could potentially modulate biological effects. VTS-270 (Kleptose HPB) and Trappsol® Cyclo™ are HPβCD products under investigation as novel treatments for NPC1. The purpose of the present work is to compare these two different products; analyses were based on ion distribution and abundance profiles using mass spectrometry methodology as a means for assessing key molecular distinctions between products. The method incorporated electrospray ionization and analysis with a linear low-field ion mobility quadrupole time-of-flight instrument. We observed that the number of hydroxypropyl groups (the degrees of substitution) are substantially different between the two products and greater in Trappsol Cyclo than in VTS-270. The principal ions of both samples are ammonium adducts. Isotope clusters for each of the major ions show doubly charged homodimers of the ammonium adducts. In addition, both products show doubly charged homodimers from adduction of both a proton and ammonium. Doubly charged heterodimers are also present, but are more intense in Trappsol Cyclo than in VTS-270. Based on the analytical differences observed between VTS-270 and Trappsol Cyclo with respect to the degree of substitution, the composition and fingerprint of the complex mixture, and the impurity profiles, these products cannot be considered to be the same; the potential biological and clinical implications of these differences are not presently known.

Project description:BackgroundNiemann-Pick disease, type C1 (NPC1) is a neurodegenerative condition that arises from mutations of NPC1 and is often diagnosed in children. Recently, several drug trials have been implemented to minimize neurodegeneration, including a trial of 2-hydroxypropyl-β-cyclodextrins (VTS-270).ObjectivesThe current study extends findings from a previous report of 18 months of disease severity data by describing neuropsychological outcomes over the course of 36 months post-baseline.DesignAn open-label, dose-escalation phase I/IIa study of VTS-270 was performed in participants with NPC1 aged 4-23 years.MethodsFourteen participants were sequentially assigned to receive monthly initial intrathecal VTS-270 at doses of 50, 200, 300, or 400 mg per month. After initial dosing, participants were dose-escalated (to 600 or 1200 mg) as tolerated. Participants were evaluated at 6-month intervals using a standardized neuropsychological battery, including tests of cognition and adaptive behavior. A random effects model with restricted maximum likelihood estimation was constructed for each outcome, and the slope was the parameter of interest.ResultsFindings based on IQ scores and both standard scores and age equivalents of adaptive functioning indicate that there were not meaningful declines in these areas during the study period. The average annualized change in Full Scale IQ was negative: B = - 1.28, standard error (SE) = 0.70, t(34.2) = - 1.83, p = 0.076. The Vineland-II Adaptive Behavior Composite standard score decreased by 1.76 points per year [SE = 0.67, t(59.1) = - 2.62, p = 0.011], but annualized slopes for each of the domain age equivalents were positive: Communication [B = 0.71, SE = 3.12, t(60.7) = 0.23, p = 0.82], Socialization [B = 2.99, SE = 2.92, t(60.4) = 1.03, p = 0.30], Daily Living Skills [B = 2.76, SE = 2.76, t(60.3) = 1.18, p = 0.24], and Motor Skills [B = 1.42, SE = 0.94, t(50.5) = 1.51, p = 0.14], indicating not worsening but slower-than-average acquisition of skills.ConclusionIn conjunction with previous findings, these results provide support for the slowing of disease progress up to 36 months post-initiation of intrathecal VTS-270.RegistrationClinicalTrials.gov identifier NCT01747135: Hydroxypropyl Beta Cyclodextrin for Niemann-Pick type C1 Disease.

Dataset Information

Long-Term Treatment of Niemann-Pick Type C1 Disease With Intrathecal 2-Hydroxypropyl-?-Cyclodextrin.

Publications

Long-Term Treatment of Niemann-Pick Type C1 Disease With Intrathecal 2-Hydroxypropyl-β-Cyclodextrin.

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