Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick Disease, type C1: an ad-hoc analysis of a non-randomized, open-label, phase 1/2 trial

Details

• Alternative Title:
  Lancet
• Personal Author:
  Ory, Daniel S. ; Ottinger, Elizabeth A. ; Farhat, Nicole Yanjanin ; King, Kelly A. ; Jiang, Xuntian ; Weissfeld, Lisa ; Berry-Kravis, Elizabeth ; Davidson, Cristin D. ; Bianconi, Simona ; Keener, Lee Ann ; Rao, Ravichandran ; Soldatos, Ariane ; Sidhu, Rohini ; Walters, Kimberly A. ; Xu, Xin ; Thurm, Audrey ; Solomon, Beth ; Pavan, William J. ; Machielse Drs, Bernardus N. ; Kao, Mark ; Silber, Steven A. ; McKew, John C. ; Brewer, Carmen C. ; Vite, Charles H. ; Walkley, Steven U. ; Austin, Christopher P. ; Porter, Forbes D.
• Description:
  Background
  
  Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterized by progressive neurodegeneration. In preclinical testing 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological signs, and increased lifespan in murine and feline models of NPC1.
  
  Methods
  
  Safety and clinical efficacy of intrathecal HPβCD were evaluated in an open-label, dose- escalation phase 1/2a study. Intrathecal doses ranging from 50–1200 mg were evaluated in 14 neurologically affected NPC1 participants treated monthly for 12 to 18 months. Three additional participants were treated every two weeks for 18 months. Serum and CSF 24(S)- hydroxycholesterol, which served as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NSS) were used to compare disease progression in HPβCD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range.
  
  Findings
  
  No drug-related serious adverse events were observed. Mid- to high-frequency hearing loss, an expected adverse event, was documented. When managed with hearing aids, this did not have an appreciable impact on daily communication. Biomarker studies were consistent with improved neuronal cholesterol homeostasis and decreased neuronal pathology. The NSS score for the 14 participants treated monthly increased at a rate of 122 ± 0 34 points/year compared to 2 92 ± 0 27 points/year (p=0 0002) for the comparison group. Decreased progression was observed for NSS domains of ambulation (p=0 0622), cognition (p=0 0040) and speech (p=0 0423).
  
  Interpretation
  
  This phase 1/2a study of intrathecal HPβCD for the treatment of NPC1 demonstrated an acceptable safety profile and slowing of disease progression.
  
  
• Subjects:
  2-Hydroxypropyl-beta-cyclodextrin Adolescent Article Biomarkers Calbindins Child Child, Preschool Disease Progression Dose-Response Relationship, Drug Fatty Acid Binding Protein 3 Female Hearing Loss, High-Frequency Humans Hydroxycholesterols Injections, Spinal Male Niemann-Pick Disease, Type C Rare Diseases Young Adult

  More +
• Source:
  Lancet. 390(10104):1758-1768.
• Pubmed ID:
  28803710
• Pubmed Central ID:
  PMC6176479
• Document Type:
  Journal Article
• Funding:
  ZIA HD000139-20/NULL/Intramural NIH HHS/United States ; R01 NS073661/NS/NINDS NIH HHS/United States ; ZIA HD008824-11/NULL/Intramural NIH HHS/United States ; HHSN261200800001C/RC/CCR NIH HHS/United States ; E11 CH000001/CH/OID CDC HHS/United States ; R01 NS081985/NS/NINDS NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States
• Volume:
  390
• Issue:
  10104
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:d715885101d88181c4351e7894956e4ddebcf8ca9ecfc50df380de6e14230330
• Download URL:
  https://stacks.cdc.gov/view/cdc/59715/cdc_59715_DS1.pdf
• File Type:
  [PDF - 949.59 KB ]