CNS Drugs

, Volume 33, Issue 7, pp 677–683 | Cite as

Long-Term Neuropsychological Outcomes from an Open-Label Phase I/IIa Trial of 2-Hydroxypropyl-β-Cyclodextrins (VTS-270) in Niemann-Pick Disease, Type C1

  • Cristan A. Farmer
  • Audrey Thurm
  • Nicole Farhat
  • Simona Bianconi
  • Lee Ann Keener
  • Forbes D. PorterEmail author
Short Communication



Niemann-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).


The 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.


An open-label, dose-escalation phase I/IIa study of VTS-270 was performed in participants with NPC1 aged 4–23 years.


Fourteen 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.


Findings 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.


In conjunction with previous findings, these results provide support for the slowing of disease progress up to 36 months post-initiation of intrathecal VTS-270.

Registration identifier NCT01747135: Hydroxypropyl Beta Cyclodextrin for Niemann-Pick type C1 Disease.



We thank the study participants and their families.

Compliance with Ethical Standards

Conflict of interest

VTS-270 was provided by Janssen Pharmaceuticals, a Johnson & Johnson company. CAF, AT, NF, SB, LAK, and FDP have no other disclosures.


This research was supported by the Intramural Research Programs of the National Institute of Mental Health (1ZICMH002961) and the Division of Translational Research of the Eunice Kennedy Shriver National Institute of Child Health and Development (ZIA HD008824).

Ethical approval

This study was approved by the Institutional Review Board of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed guardian permission or participant consent was obtained. Assent was obtained when possible.

Data availability statement

The datasets analyzed during the current study are available from the corresponding author upon reasonable request.

Supplementary material

40263_2019_642_MOESM1_ESM.docx (1.2 mb)
Supplementary material 1 (DOCX 1275 kb)


  1. 1.
    Thurm A, Farmer C, Farhat NY, Wiggs E, Black D, Porter FD. Cohort study of neurocognitive functioning and adaptive behaviour in children and adolescents with Niemann-Pick Disease type C1. Dev Med Child Neurol. 2016;58(3):262–9. Scholar
  2. 2.
    Klarner B, Klunemann HH, Lurding R, Aslanidis C, Rupprecht R. Neuropsychological profile of adult patients with Niemann-Pick C1 (NPC1) mutations. J Inherit Metab Dis. 2007;30(1):60–7. Scholar
  3. 3.
    Yanjanin NM, Velez JI, Gropman A, King K, Bianconi SE, Conley SK, et al. Linear clinical progression, independent of age of onset, in Niemann-Pick disease, type C. Am J Med Genet B Neuropsychiatr Genet. 2010;153B(1):132–40. Scholar
  4. 4.
    Iturriaga C, Pineda M, Fernandez-Valero E, Vanier M, Coll M. Niemann-Pick C disease in Spain: clinical spectrum and development of a disability scale. J Neurol Sci. 2006;249(1):1–6.CrossRefGoogle Scholar
  5. 5.
    Stampfer M, Theiss S, Amraoui Y, Jiang X, Keller S, Ory DS, et al. Niemann-Pick disease type C clinical database: cognitive and coordination deficits are early disease indicators. Orphanet J Rare Dis. 2013;8(1):35.CrossRefGoogle Scholar
  6. 6.
    Camargo F, Erickson RP, Garver WS, Hossain GS, Carbone PN, Heidenreich RA, et al. Cyclodextrins in the treatment of a mouse model of Niemann-Pick C disease. Life Sci. 2001;70(2):131–42.CrossRefGoogle Scholar
  7. 7.
    Liu B, Li H, Repa JJ, Turley SD, Dietschy JM. Genetic variations and treatments that affect the lifespan of the NPC1 mouse. J Lipid Res. 2008;49(3):663–9. Scholar
  8. 8.
    Liu B, Turley SD, Burns DK, Miller AM, Repa JJ, Dietschy JM. Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1−/− mouse. Proc Natl Acad Sci USA. 2009;106(7):2377–82. Scholar
  9. 9.
    Davidson CD, Ali NF, Micsenyi MC, Stephney G, Renault S, Dobrenis K, et al. Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PLoS One. 2009;4(9):e6951. Scholar
  10. 10.
    Vite CH, Bagel JH, Swain GP, Prociuk M, Sikora TU, Stein VM, et al. Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease. Sci Transl Med. 2015;7(276):276ra26. Scholar
  11. 11.
    Ory DS, Ottinger EA, Farhat NY, King KA, Jiang X, Weissfeld L, et al. Intrathecal 2-hydroxypropyl-beta-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1–2 trial. Lancet. 2017;390(10104):1758–68. Scholar
  12. 12.
    Wechsler D. Wechsler preschool and primary scale of intelligence. 3rd ed. San Antonio: Pearson; 2002.Google Scholar
  13. 13.
    Wechsler D. Wechsler intelligence scale for children. 4th ed. San Antonio: Psychological Corporation; 2003.Google Scholar
  14. 14.
    Wechsler D. Wechsler abbreviated scale of intelligence. San Antonio: Psychological Corporation; 1999.Google Scholar
  15. 15.
    Mullen EM, editor. Mullen scales of early learning. Circle Pines: American Guidance Service; 1995.Google Scholar
  16. 16.
    Sparrow SS, Cicchetti DV, Balla DA. Vineland adaptive behavior scales. 2nd ed. Circle Pines: AGS Publishing; 2005.Google Scholar
  17. 17.
    Sheslow D, Adams W. Wide range assessment of memory and learning second edition administration and technical manual. Lutz: Psychological Assessment Resources; 2003.Google Scholar
  18. 18.
    Hooper EH. Hooper visual organization test (VOT). Los Angeles: Western Psychological Services; 1983.Google Scholar
  19. 19.
    Beery KE, Beery NA. Beery VMI: the Beery-Buktenica developmental test of visual-motor integration with supplemental developmental tests of visual perception and motor coordination: and, stepping stones age norms from birth to age six. Administration, scoring, and teaching manual. San Antonio: PsychCorp; 2010.Google Scholar
  20. 20.
    Instrument L. Purdue pegboard test: user instructions. Lafayette: Lafayette Instrument; 2002.Google Scholar
  21. 21.
    McNeish DM, Stapleton LM. The effect of small sample size on two-level model estimates: a review and illustration. Educ Psychol Rev. 2016;28(2):295–314.CrossRefGoogle Scholar
  22. 22.
    Kenward MG, Roger JH. An improved approximation to the precision of fixed effects from restricted maximum likelihood. Comput Stat Data Anal. 2009;53(7):2583–95.CrossRefGoogle Scholar
  23. 23.
    Wasserstein RL, Schirm AL, Lazar NA. Moving to a world beyond “p < 0.05”. Am Stat. 2019;73(suppl 1):1–19. Scholar
  24. 24.
    Thurm A, Farmer C, Farhat NY, Wiggs E, Black D, Porter FD. Cohort study of neurocognitive functioning and adaptive behaviour in children and adolescents with Niemann-Pick Disease type C1. Dev Med Child Neurol. 2016;58(3):262–9.CrossRefGoogle Scholar

Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  1. 1.Intramural Research Program, National Institute of Mental HealthNational Institutes of HealthBethesdaUSA
  2. 2.Division of Translational Research, Eunice Kennedy Shriver National Institute of Child Health and DevelopmentNational Institutes of HealthBethesdaUSA

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