Clinical disease progression and biomarkers in Niemann-Pick disease type C: a prospective cohort study

Eugen Mengel, Bruno Bembi, Mireia Del Toro, Federica Deodato, Matthias Gautschi, Stephanie Grunewald, Sabine Grønborg, Bénédicte Héron, Esther M Maier, Agathe Roubertie, Saikat Santra, Anna Tylki-Szymanska, Simon Day, Tara Symonds, Stacie Hudgens, Marc C Patterson, Christina Guldberg, Linda Ingemann, Nikolaj H T Petersen, Thomas Kirkegaard, Christine Í Dali, Eugen Mengel, Bruno Bembi, Mireia Del Toro, Federica Deodato, Matthias Gautschi, Stephanie Grunewald, Sabine Grønborg, Bénédicte Héron, Esther M Maier, Agathe Roubertie, Saikat Santra, Anna Tylki-Szymanska, Simon Day, Tara Symonds, Stacie Hudgens, Marc C Patterson, Christina Guldberg, Linda Ingemann, Nikolaj H T Petersen, Thomas Kirkegaard, Christine Í Dali

Abstract

Background: Niemann-Pick disease type C (NPC) is a rare, progressive, neurodegenerative disease associated with neurovisceral manifestations resulting from lysosomal dysfunction and aberrant lipid accumulation. A multicentre, prospective observational study (Clinical Trials.gov ID: NCT02435030) of individuals with genetically confirmed NPC1 or NPC2 receiving routine clinical care was conducted, to prospectively characterize and measure NPC disease progression and to investigate potential NPC-related biomarkers versus healthy individuals. Progression was measured using the abbreviated 5-domain NPC Clinical Severity Scale (NPCCSS), 17-domain NPCCSS and NPC clinical database (NPC-cdb) score. Cholesterol esterification and heat shock protein 70 (HSP70) levels were assessed from peripheral blood mononuclear cells (PBMCs), cholestane-3β,5α-,6β-triol (cholestane-triol) from serum, and unesterified cholesterol from both PBMCs and skin biopsy samples. The inter- and intra-rater reliability of the 5-domain NPCCSS was assessed by 13 expert clinicians' rating of four participants via video recordings, repeated after ≥ 3 weeks. Intraclass correlation coefficients (ICCs) were calculated.

Results: Of the 36 individuals with NPC (2-18 years) enrolled, 31 (86.1%) completed the 6-14-month observation period; 30/36 (83.3%) were receiving miglustat as part of routine clinical care. A mean (± SD) increase in 5-domain NPCCSS scores of 1.4 (± 2.9) was observed, corresponding to an annualized progression rate of 1.5. On the 17-domain NPCCSS, a mean (± SD) progression of 2.7 (± 4.0) was reported. Compared with healthy individuals, the NPC population had significantly lower levels of cholesterol esterification (p < 0.0001), HSP70 (p < 0.0001) and skin unesterified cholesterol (p = 0.0006). Cholestane-triol levels were significantly higher in individuals with NPC versus healthy individuals (p = 0.008) and correlated with the 5-domain NPCCSS (Spearman's correlation coefficient = 0.265, p = 0.0411). The 5-domain NPCCSS showed high ICC agreement in inter-rater reliability (ICC = 0.995) and intra-rater reliability (ICC = 0.937).

Conclusions: Progression rates observed were consistent with other reports on disease progression in NPC. The 5-domain NPCCSS reliability study supports its use as an abbreviated alternative to the 17-domain NPCCSS that focuses on the most relevant domains of the disease. The data support the use of cholestane-triol as a disease monitoring biomarker and the novel methods of measuring unesterified cholesterol could be applicable to support NPC diagnosis. Levels of HSP70 in individuals with NPC were significantly decreased compared with healthy individuals.

Trial registration: CT-ORZY-NPC-001: ClincalTrials.gov NCT02435030, Registered 6 May 2015, https://ichgcp.net/clinical-trials-registry/NCT02435030 ; EudraCT 2014-005,194-37, Registered 28 April 2015, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-005194-37/DE . OR-REL-NPC-01: Unregistered.

Keywords: Biomarkers; Cholestane-triol; Heat shock protein; Lysosomal storage disease; NPC Clinical Severity Scale (NPCCSS); Natural history of disease; Niemann–Pick type C (NPC) disease; Observational study; Reliability.

Conflict of interest statement

EM has received investigator fees and consultant honoraria from Actelion, Alexion Pharmaceuticals, Orphazyme A/S, Prevail, Sanofi Genzyme and Takeda. BB has received consultancy fees from Actelion, Sanofi Genzyme and Takeda. MDT has received consulting fees and speaker honoraria, travel expenses and congress fees from BioMarin, Sanofi Genzyme and Takeda, and is an investigator for industrial trials for Mallinckrodt Pharmaceuticals, Orphazyme A/S and Takeda. FD has received speaker honoraria from Sanofi Genzyme and Takeda, and travel reimbursement and congress fees from Actelion, Sanofi Genzyme and Takeda. MG has received investigator fees from Orphazyme A/S, consultancy fees from Sanofi Genzyme, and travel grants from Takeda. StG has participated in commercially funded research and received travel grants from Orphazyme A/S and has received consultancy fees from Moderna and Ultragenyx. SaG has received speaker honoraria from Actelion and Novo Nordisk, and travel grants from Sanofi Genzyme. BH has received consulting fees and speaker honoraria from Actelion and Takeda, travel expenses and congress fees reimbursements from Sanofi Genzyme and Takeda, and is an investigator for industrial studies and trials for Abeona Therapeutics, Lysogene, Idorsia, Mallinckrodt Pharmaceuticals and Orphazyme A/S. SS has participated in commercially funded research and has received education and travel grants from Actelion and Orphazyme A/S and has participated in commercially funded research from Mallinckrodt Pharmaceuticals. ATS has received speaker honoraria and/or travel grants from BioMarin, Chiesi, Sanofi Genzyme and Takeda. MCP has received, or will receive, research support from Actelion, Amicus, Glycomine, National Institutes of Health (NIH), Takeda and Orphazyme A/S; he served as Chair of the Scientific Advisory Committee of a Registry of Niemann–Pick disease type C, sponsored by Actelion Pharmaceuticals US, Inc (now closed), and has received consultancy fees from Amicus Therapeutics, IntraBio, Mallinckrodt Pharmaceuticals, Novartis, Orphazyme A/S, Sanofi Genzyme and Takeda; he holds stock in IntraBio. He receives a stipend as the Editor-in-Chief of the Journal of Child Neurology and Child Neurology Open (Sage), as an editor of the Journal of Inherited Metabolic Disease (JIMD) and JIMD Reports (SSIEM), and royalties from Up-To-Date (Section Editor for Pediatric Neurology). SD, TS and SH are paid consultants to Orphazyme A/S. NHTP, LI, CD and TK are employees and shareholders of Orphazyme A/S. CG is an employee of Orphazyme A/S. AR and EMM have nothing to disclose. EM current address: SphinCS GmbH, Hochheim, Germany.

Figures

Fig. 1
Fig. 1
Sub-domains of the 5-domain and 17-domain Niemann–Pick type C Clinical Severity Scale. These are the five domains selected by individuals with NPC, their caregivers and NPC experts as the most clinically relevant domains. NPC: Niemann–Pick disease type C; NPCCSS: NPC Clinical Severity Scale
Fig. 2
Fig. 2
Participant flow diagram. N = overall number of enrolled participants; n = number of participants per category. One participant who withdrew early had an end-of-trial visit and is included in efficacy assessments
Fig. 3
Fig. 3
5-domain NPCCSS scores at Visit 1 and Visit 2. a Mean (SD) overall scores at Visit 1 and Visit 2 for all participants.* b Change in overall scores from Visit 1 to Visit 2 by length of follow-up time. c Mean (SD) individual scores for the five key sub-domains at Visit 1 and Visit 2, with mean change. NPCCSS: Niemann–Pick disease type C Clinical Severity Scale; SD: standard deviation. *One participant who withdrew early had relocated, but had an end-of-trial visit and is included in efficacy assessments. According to the statistical analysis plan, the NPC-001 study ended at a study site once the interventional NPC-002 study commenced at that specific site. The NPC-002 study had not started at the site of this particular participant when they relocated, therefore the end of study visit was planned (prior to completion of the study). The participant had a planned withdrawal visit after 162 days. Of the study withdrawals, only this participant had an end of study visit. Their screening visit and end of study visit are therefore included as per statistical analysis plan
Fig. 4
Fig. 4
Biomarker results at Visit 1 and Visit 2 in comparison to healthy individuals. a Median and interquartile lengths of average follow-up time. b Skin unesterified cholesterol, p = 0.0006. c PBMC unesterified cholesterol, p = 0.8979. d Serum cholestane-triol, p = 0.008. e PBMC cholesterol esterification, p < 0.0001. f PBMC HSP70, p < 0.0001. HSP70: heat shock protein 70; NPCCSS: Niemann–Pick disease type C Clinical Severity Scale; NS: not significant; PBMC: peripheral blood mononuclear cell
Fig. 5
Fig. 5
Biomarker correlations with disease severity as measured by the 5-domain NPCCSS. a PBMC unesterified cholesterol. b Skin unesterified cholesterol. c Serum cholestane-triol. d PBMC cholesterol esterification. e PBMC HSP70. HSP70: heat shock protein 70; NPCCSS: Niemann–Pick disease type C Clinical Severity Scale; PBMC: peripheral blood mononuclear cell

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