Mengel, Eugen

ABSTRACT In 2018, the International Niemann‐Pick Disease Alliance (INPDA) and the International Niemann‐Pick Disease Registry (INPDR) developed and published comprehensive clinical management guidelines to support inclusive and standardized care pathways in Niemann‐Pick disease type C (NPC)—an ultra‐rare, autosomal recessive, neurovisceral lysosomal disorder. Since then, advances in diagnostics, care, and the approval of two novel disease‐modifying agents have underscored the need to revise these guidelines to ensure safe, consistent, and high‐quality care for those affected by NPC. In response, the INPDA and INPDR convened a multidisciplinary Guidelines Development Group (GDG) comprising individuals with NPC expertise from 14 countries across five continents, representing a broad range of specialties, as well as patients and families involved in NPC care. Informed by a comprehensive literature review and two meetings, the GDG systematically reviewed, revised, and updated the 2018 guideline statements, re‐evaluating the level of evidence, strength of recommendations, and expert agreement for each. The resulting 2025 consensus clinical management guidelines constitute a timely, up‐to‐date, and internationally applicable resource for the diagnosis, treatment, and holistic management of individuals with NPC. These guidelines serve as a critical resource for specialist centers, hospital‐based medical teams, staff involved in NPC patient care, family physicians and other primary caregivers, and, importantly, patients and their families.

AbstractNiemann‐Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12‐month, prospective, randomised, double‐blind, placebo‐controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2‐18 years) were randomised 2:1 to arimoclomol:placebo, stratified by miglustat use. Routine clinical care was maintained. Arimoclomol was administered orally three times daily. The primary endpoint was change in 5‐domain NPC Clinical Severity Scale (NPCCSS) score from baseline to 12 months. Fifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5‐domain NPCCSS was 0.76 with arimoclomol vs 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of −1.40 (95% confidence interval: −2.76, −0.03; P = .046) was observed, corresponding to a 65% reduction in annual disease progression. In the prespecified subgroup of patients receiving miglustat as routine care, arimoclomol resulted in stabilisation of disease severity over 12 months with a treatment difference of −2.06 in favour of arimoclomol (P = .006). Adverse events occurred in 30/34 patients (88.2%) receiving arimoclomol and 12/16 (75.0%) receiving placebo. Fewer patients had serious adverse events with arimoclomol (5/34, 14.7%) vs placebo (5/16, 31.3%). Treatment‐related serious adverse events (n = 2) included urticaria and angioedema. Arimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated.

Abstract Background Niemann-Pick disease type C (NPC) is a debilitating condition that impacts patients’ and caregivers’ quality of life (QOL) and reduces the patient’s life expectancy. Since there is little qualitative research from the perspective of patients and family caregivers, this study explored the impact of NPC on patients’ and caregivers’ daily lives to understand the burden of disease.Results A survey of caregivers for patients with NPC and adult patients with NPC (n = 49; patient age: 13 months – 65 years) assessed NPC severity, importance of NPC symptoms, and how symptoms impacted patients’ and caregivers’ activities of daily living (ADLs) and health-related QOL (HRQOL). Follow-up interviews with a subset of survey participants (n = 28) explored the ranking of NPC symptom importance and impact on ADLs and HRQOL.Findings indicated that the most important manifestations of NPC were ambulation, swallowing, speech, fine motor skills, and cognition, which were those that had the most significant impact on ADLs and HRQOL. A wide range of ADLs were affected by NPC, mainly eating/drinking and ability to perform daily tasks, including self-care, communicating, participating in school or work, and moving indoors as well as outside the home. Along with these impacts, there was an increased risk of experiencing dangerous or life-threatening situations leading to loss of patient independence and additional caregiver burden, often requiring changes in lifestyle such as giving up work. All aspects of patients’ and caregivers’ HRQOL were affected. Participants reported feelings of social isolation, loss of enjoyment in activities (patients), and feelings of sadness or worry (caregivers).ConclusionsAmbulation, swallowing, speech, fine motor skills, and cognition are important manifestations of NPC. ADLs and HRQOL were impaired in the majority of patients as well as their caregivers. The findings were independent of current age, age of onset of symptoms, and level of NPC disease-related disability; however, the impact increased at higher levels of disease disability. Knowing the impact of NPC on patients and caregivers is important for understanding the lived experience of NPC and for identifying potential areas of support.Trial registrationNCT02612129. Registered 23 November 2015, https://clinicaltrials.gov/ct2/show/NCT02612129

Abstract BackgroundNiemann–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 (ClinicalTrials.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.ResultsOf 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). ConclusionsProgression 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.

Abstract BackgroundNiemann–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 (ClinicalTrials.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.ResultsOf 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).ConclusionsProgression 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://clinicaltrials.gov/ct2/show/NCT02435030; EudraCT 2014-005194-37, Registered 28 April 2015, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-005194-37/DE. OR-REL-NPC-01: Unregistered.