Cost-effectiveness of miglustat versus symptomatic therapy of Niemann-Pick disease type C.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a progressive neurodegenerative disorder with early infantile (< 2 years), late infantile (2-6 years), juvenile (7-15 years) and adolescent (> 15 years) onset. The mainstay of therapy for NP-C patients with neurological symptoms is miglustat, a drug that may modify the course of the disease. AIM: Our aim was to evaluate the cost-effectiveness of miglustat in comparison to symptomatic therapy in patients with NP-C in the socio-economic settings of the Republic of Serbia, an upper-middle-income European economy. METHOD: The perspective of the Serbian Republic Health Insurance Fund was chosen for this study, and the time horizon was eighty years. The main outcomes of the study were quality-adjusted life years gained with miglustat and comparator, and direct costs of treatment. The study was conducted through the generation and simulation of the Discrete-Event Simulation model. The model results were obtained after Monte Carlo microsimulation of a sample with 1000 virtual patients. RESULTS: Treatment with miglustat was not cost-effective when compared with symptomatic therapy and was associated with negative values of net monetary benefit regardless of the onset of neurological manifestations (- 110,447,627.00 ± 701,614.00 RSD, - 343,871,695.00 ± 2,577,441.00 RSD, - 1,397,908,502.00 ± 23,084,235.00 RSD and - 2,953,680,879.00 ± 33,297,412.00 RSD) for early infantile, late infantile, juvenile and adolescent cohorts, respectively). CONCLUSION: When traditional pharmacoeconomic evaluation is employed, miglustat is not a cost-effective option in comparison to symptomatic therapy for the treatment of NP-C. However, given the proven efficacy of miglustat, there is a need to find ways to make this drug available to all patients with NP-C.

Phenotype assessment for neurodegenerative murine models with ataxia and application to Niemann-Pick disease, type C1.

Identifying meaningful predictors of therapeutic efficacy from preclinical studies is challenging. However, clinical manifestations occurring in both patients and mammalian models offer significant translational value. Many neurological disorders, including inherited, metabolic Niemann-Pick disease, type C (NPC), exhibit ataxia. Both individuals with NPC and murine models manifest ataxia, and investigational therapies impacting this phenotype in mice have been reported to slow disease progression in patients (e.g. miglustat, intrathecal 2-hydroxypropyl-beta-cyclodextrin, and acetyl-L-leucine). Reproducible phenotypic scoring of animal models can facilitate comparisons between genotypes, sexes, disease course, and therapies. Previously, other groups have developed a composite phenotypic scoring system (CPSS), which was subsequently used to distinguish strain-dependent phenotypes and, with modifications, to evaluate potential therapies. However, high inter-rater reliability is paramount to widespread use. We have created a comprehensive, easy-to-follow phenotypic assessment based on the CPSS and have verified its reproducibility using murine models of NPC disease. Application of this scoring system is not limited to NPC disease and may be applicable to other models of neurodegeneration exhibiting motor incoordination, thereby increasing its utility in translational studies.

Assessment of FDA-Approved Drugs as a Therapeutic Approach for Niemann-Pick Disease Type C1 Using Patient-Specific iPSC-Based Model Systems.

Niemann-Pick type C1 (NP-C1) is a fatal, progressive neurodegenerative disease caused by mutations in the NPC1 gene. Mutations of NPC1 can result in a misfolded protein that is subsequently marked for proteasomal degradation. Such loss-of-function mutations lead to cholesterol accumulation in late endosomes and lysosomes. Pharmacological chaperones (PCs) are described to protect misfolded proteins from proteasomal degradation and are being discussed as a treatment strategy for NP-C1. Here, we used a combinatorial approach of high-throughput in silico screening of FDA-approved drugs and in vitro biochemical assays to identify potential PCs. The effects of the hit compounds identified by molecular docking were compared in vitro with 25-hydroxycholesterol (25-HC), which is known to act as a PC for NP-C1. We analyzed cholesterol accumulation, NPC1 protein content, and lysosomal localization in patient-specific fibroblasts, as well as in neural differentiated and hepatocyte-like cells derived from patient-specific induced pluripotent stem cells (iPSCs). One compound, namely abiraterone acetate, showed comparable results to 25-HC and restored NPC1 protein level, corrected the intracellular localization of NPC1, and consequently decreased cholesterol accumulation in NPC1-mutated fibroblasts and iPSC-derived neural differentiated and hepatocyte-like cells. The discovered PC altered not only the pathophysiological phenotype of cells carrying the I1061T mutation- known to be responsive to treatment with PCs-but an effect was also observed in cells carrying other NPC1 missense mutations. Therefore, we hypothesize that the PCs studied here may serve as an effective treatment strategy for a large group of NP-C1 patients.

Neuropsychological assessment in Niemann-Pick disease type C: a systematic review.

BACKGROUND: The neuropsychological profile of Niemann-Pick type C (NP-C) patients is characterized by an early deterioration in executive functions and attention. There are few studies on cognitive impairment and on neuropsychological assessment of NP-C disease. The purpose of this review is to analyze the studies on a psychological assessment for NP-C patients. METHOD: This review aims to identify a neuropsychological assessment to evaluate cognitive domains and neuropsychological changes in these patients. There were a total of 73 articles. The search terms were identified as titles and abstracts. All articles were evaluated by title, abstract, and text. RESULTS: Only four of the 73 articles were included because they met the criteria of our review. Furthermore, in these studies, possible diagnostic protocols are proposed on NP-C subjects. DISCUSSION AND CONCLUSION: The cognitive impairment in NP-C has a negative impact on daily functioning and quality of life. Early diagnosis could identify cognitive deficits and promote cognitive interventions to improve the neuropsychological profile. The management of NP-C disease should be based on a multidisciplinary approach, to treating symptoms, preserving neurological functions, and guaranteeing the best possible quality of life. Early identification of neurological and psychological symptoms of the disease is necessary in order to decrease the progression of neurological disease and improve patient care and treatment outcomes. Furthermore, research should focus more on cognitive aspects, not only in the diagnostic process but also in the rehabilitation process.

Assessment and rehabilitation of cognitive deficit in a Niemann-Pick type C disease patient.

Niemann-Pick type C (NP-C) disease is a lipid storage disorder characterized by visceral (hepatosplenomegaly) and neurological symptoms: ataxia, dystonia, cognitive disorder, psychiatric disorder, and vertical supranuclear gaze palsy. Cognitive impairment is one of the core symptoms of NP-C disease, but there are few data about the cognitive rehabilitation treatment in NP-C patients. This case report aims to evaluate the effects of the cognitive rehabilitation treatment of a young woman affected by NP-C. Cognitive rehabilitation was performed with pc-based and paper and pencil exercises. We used a clinical approach that includes psychotherapy-based diagnostic and rehabilitation procedures and neuropsychological methods, using strategies to improve cognitive residual abilities. Our data showed an improvement of cognitive functions and quality of life after an intensive rehabilitation program.

Application of a glycinated bile acid biomarker for diagnosis and assessment of response to treatment in Niemann-pick disease type C1.

Niemann-Pick disease type C (NPC) is a neurodegenerative disease in which mutation of NPC1 or NPC2 gene leads to lysosomal accumulation of unesterified cholesterol and sphingolipids. Diagnosis of NPC disease is challenging due to non-specific early symptoms. Biomarker and genetic tests are used as first-line diagnostic tests for NPC. In this study, we developed a plasma test based on N-(3ß,5α,6ß-trihydroxy-cholan-24-oyl)glycine (TCG) that was markedly increased in the plasma of human NPC1 subjects. The test showed sensitivity of 0.9945 and specificity of 0.9982 to differentiate individuals with NPC1 from NPC1 carriers and controls. Compared to other commonly used biomarkers, cholestane-3ß,5α,6ß-triol (C-triol) and N-palmitoyl-O-phosphocholine (PPCS, also referred to as lysoSM-509), TCG was equally sensitive for identifying NPC1 but more specific. Unlike C-triol and PPCS, TCG showed excellent stability and no spurious generation of marker in the sample preparation or aging of samples. TCG was also elevated in lysosomal acid lipase deficiency (LALD) and acid sphingomyelinase deficiency (ASMD). Plasma TCG was significantly reduced after intravenous (IV) 2-hydroxypropyl-ß-cyclodextrin (HPßCD) treatment. These results demonstrate that plasma TCG was superior to C-triol and PPCS as NPC1 diagnostic biomarker and was able to evaluate the peripheral treatment efficacy of IV HPßCD treatment.

Application of N-palmitoyl-O-phosphocholineserine for diagnosis and assessment of response to treatment in Niemann-Pick type C disease.

Niemann-Pick type C (NPC) disease is a rare lysosomal storage disorder caused by mutations in either the NPC1 or the NPC2 gene. A new class of lipids, N-acyl-O-phosphocholineserines were recently identified as NPC biomarkers. The most abundant species in this class of lipid, N-palmitoyl-O-phosphocholineserine (PPCS), was evaluated for diagnosis of NPC disease and treatment efficacy assessment with 2-hydroxypropyl-ß-cyclodextrin (HPßCD) in NPC. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were developed and validated to measure PPCS in human plasma and cerebrospinal fluid (CSF). A cutoff of 248 ng/mL in plasma provided a sensitivity of 100.0% and specificity of 96.6% in identifying NPC1 patients from control and NPC1 carrier subjects. PPCS was significantly elevated in CSF from NPC1 patients, and CSF PPCS levels were significantly correlated with NPC neurological disease severity scores. Plasma and CSF PPCS did not change significantly in response to intrathetical (IT) HPßCD treatment. In an intravenous (IV) HPßCD trial, plasma PPCS in all patients was significantly reduced. These results demonstrate that plasma PPCS was able to diagnose NPC1 patients with high sensitivity and specificity, and to evaluate the peripheral treatment efficacy of IV HPßCD treatment.

Miglustate para manifestações neurológicas da doença de niemann-pick tipo c (NPC) / Miglustate para manifestações neurológicas da doença de niemann-pick tipo c (NPC)

CONTEXTO: A doença de Niemann-Pick C é uma doença genética rara causada por mutações nos genes NPC 1 e NPC 2. A apresentação clínica é heterogênea e envolve sintomas neurológicos (alteração de movimentos oculares, cognição, prejuízos no desenvolvimento neurológico, alterações de manipulação, linguagem, deambulação e deglutição, crises convulsivas), sistêmicos/ viscerais (hepatomegalia, esplenomegalia, icterícia) e psiquiátricos. Não existe cura para a doença até o momento. O tratamento é baseado em cuidados paliativos, com o objetivo de melhorar a qualidade de vida, reduzir incapacidade e diminuir a progressão da doença. Atualmente, o miglustate é a única terapia modificadora da doença aprovada para uso no tratamento de manifestações neurológicas da NPC. TECNOLOGIa: Miglustate (Zavesca®). PERGUNTA: Qual a eficácia e a segurança do miglustate via oral para o tratamento da doença de Niemann-Pick C? EVIDÊNCIAS CIENTÍFICAS: Foram realizadas buscas nas bases de dados Medline (via Pubmed) e Embase. Foram localizados 525 estudos, sendo doze incluídos neste PTC. Os estudos que avaliaram a eficácia e a segurança do miglustate para o tratamento de manifestações neurológicas da Doença de Niemann-Pick Tipo C mostraram que a intervenção não resultou em ganhos significativos na sobrevida, bem como diferenças em deambulação, deglutição e cognição em relação aos controles (12 meses). Movimentos oculares apresentaram diferença significante apenas quando se excluiu o grupo de pacientes em uso de benzodiazepínicos, classe de medicamentos que poderia interferir nos parâmetros oculares avaliados. Estudos de extensão que incluíram apenas pacientes adultos e pediátricos mostraram que houve tendência à estabilização da maioria dos parâmetros. Em um estudo em que se avaliou a eficácia do miglustate em 24 meses, observou-se que, daqueles que completaram os 24 meses de tratamento, houve melhora da função cognitiva nos primeiros 12 meses, com posterior declínio, retornando a escores próximos dos basais. Os resultados foram controversos quanto ao status de episódios convulsivos: em dois estudos, que incluíram pacientes com as mesmas formas de doença, encontrou-se, em um deles, que houve estabilização em dois terços da amostra, enquanto em outro, cerca de 21% apresentou piora dos episódios convulsivos, com novas crises e cataplexia. Quanto à segurança do medicamento, os eventos adversos mais comuns foram os gastrointestinais (diarreia, flatulência e desconforto abdominal), perda de peso (sem prejuízo no crescimento na amostra pediátrica) e tremores. Outros eventos menos frequentemente relatados, foram trombocitopenia, fadiga, cefaleia, alterações comportamentais, surtos psiquiátricos e novas convulsões. A qualidade metodológica do conjunto da evidência científica advinda desses estudos é baixa, visto que o único ensaio clínico incluído neste PTC teve qualidade metodológica incerta, já que deixou de mencionar aspectos importantes para avaliação de sua robustez metodológica. Os demais estudos tiveram alto risco de viés. ANÁLISE DE CUSTO EFETIVIDADE (ACE): A ACE foi conduzida sob a perspectiva do SUS e o horizonte temporal considerado foi de 12 meses. Os parâmetros de efetividade foram baseados no aumento de 2 pontos em escala de função cognitiva (MEEM) obtidos em ensaio clínico randomizado. Os custos de procedimentos fornecidos pelo SUS para os cuidados paliativos foram obtidos da tabela SIGTAP e incluíram a passagem de gastrostomia e acompanhamento fonoaudiológico e fisioterápico. Os custos dos medicamentos foram obtidos do painel de preços de saúde e incluíram anticonvulsivantes e miglustate. A inclusão do miglustate ao tratamento atualmente oferecido (cuidados paliativos) resultou em razão de custo-efetividade incremental de R$459.120,00. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO (AIO): A AIO foi conduzida sob a perspectiva do Sistema Único de Saúde em horizonte temporal de 5 anos (2020-2024). Foi considerado tratamento contínuo, com consumo de 180 cápsulas/paciente/mês (total de 2160 cápsulas/ ano). Considerando que o diagnóstico da doença é tardio e, muitas vezes, realizado somente quando as alterações neurológicas já estão instaladas, considerou-se que 100% dos pacientes portadores da doença de Niemann-Pick C deveriam receber o tratamento. Foram realizadas três simulações: (1) O acesso ao tratamento abrangeria todos os pacientes portadores da condição (100%); (2) O acesso ao medicamento ao longo dos cinco anos ocorreria de modo gradual (50%- 60%-70%-80%-90%); e (3) População elegível baseada em estimativas da Interfarma (100 pacientes elegíveis no país). Na simulação 1, o custo em 5 anos seria de R$ 1.781.458.228,70. Já na simulação 2, o impacto orçamentário de 2020 a 2024 seria de R$ 1.393.210.574,12 e na simulação 3, de R$172.681.200. CONSIDERAÇÕES FINAIS: As evidências disponíveis não são conclusivas quanto aos ganhos clinicamente relevantes para o paciente com alterações neurológicas decorrentes da Doença de Niemann-Pick Tipo C. De acordo com a melhor evidência disponível, para um desfecho clinicamente pouco importante (movimento sacádico ocular), o subgrupo que mais se beneficia do tratamento é aquele que não faz uso de benzodiazepínicos. Os desfechos de estabilidade e melhora são descritivos, sem grupo comparador atrelado e não refletem significância estatística. A definição de melhora e estabilidade é subjetiva do ponto de vista da significância clínica dos desfechos avaliados. A qualidade global da evidência para todos os desfechos apresentados foi muito baixa. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Considerando a escassez de estudos com boa qualidade metodológica e baixa qualidade da evidência, os membros da CONITEC, em sua 76ª reunião ordinária, no dia 03 de abril de 2019, recomendaram que a matéria fosse disponibilizada em consulta pública com recomendação preliminar pela não incorporação no SUS do miglustate para tratamento de sintomas neurológicos da doença de Niemann-Pick tipo C. CONSULTA PÚBLICA: Foram recebidas 921 contribuições de pessoa física e 3 de pessoa jurídica, sendo que, a maioria (92%) discordou da recomendação preliminar pela não incorporação no SUS do miglustate para tratamento de sintomas neurológicos da doença de Niemann-Pick tipo C. A indústria fabricante do medicamento realizou 4 cenários de impacto orçamentário com base nos dados de prevalência (a); nos dados da Interfarma para doentes com NPC (b); na população ajustada (c); e baseado na população com referência nos dados da Interfarma. No primeiro cenário o acesso a 100% dos pacientes resultaria em um impacto orçamentário (AIO) em 5 anos de R$ 839.176.344,30 e o acesso progressivo de 10% ao ano, iniciando por 50%, acumulado de 50 anos foi de R$590.534.879,08. Para o segundo cenário, não foram apresentados resultados. Para o terceiro, com acesso progressivo (50% - 90%), o AIO em 5 anos foi de R$312.884.146,08. No último cenário com acesso de 100%, o AIO em 5 anos estimado foi de R$ 27.437.597,72. Após análise dos resultados da CP, a CONITEC entendeu que não houve argumentação suficiente para alterar sua recomendação inicial. RECOMENDAÇÃO FINAL: Os membros da CONITEC presentes na 78ª reunião do plenário no dia 06/06/2019 deliberaram por recomendar a não incorporação do miglustate para o tratamento de manifestações neurológicas da doença de Niemann-Pick tipo C. Foi assinado o Registro de Deliberação nº 451/2019. DECISÃO: Não incorporar o miglustate para manifestações neurológicas da doença de NiemannPick tipo C, no âmbito do Sistema Único de Saúde - SUS. Dada pela Portaria nº 35, publicada no Diário Oficial da União nº 141, seção 1, página 89, em 24 de julho de 2019.

In Vivo Assessment of Neurodegeneration in Type C Niemann-Pick Disease by IDEAL-IQ.

Objective: To noninvasively assess the neurodegenerative changes in the brain of patients with Niemann-Pick type C (NPC) disease by measuring the lesion tissue with the iterative decomposition of water and fat with echo asymmetry and least square estimation-iron quantification (IDEAL-IQ). Materials and Methods: Routine brain MRI, IDEAL-IQ and 1H-proton magnetic resonance spectroscopy (1H-MRS, served as control) were performed on 12 patients with type C Niemann-Pick disease (4 males and 8 females; age range, 15-61 years; mean age, 36 years) and 20 healthy subjects (10 males and 10 females; age range, 20-65 years; mean age, 38 years). The regions with lesion and the normal appearing regions (NARs) of patients were measured and analyzed based on the fat/water signal intensity on IDEAL-IQ and the lipid peak on 1H-MRS. Results: Niemann-Pick type C patients showed a higher fat/water signal intensity ratio with IDEAL-IQ on T2 hyperintensity lesions and NARs (3.7-4.9%, p < 0.05 and 1.8-3.0%, p < 0.05, respectively), as compared to healthy controls (HCs) (1.2-2.3%). After treatment, the fat/water signal intensity ratio decreased (2.2-3.4%), but remained higher than in the HCs (p < 0.05). The results of the 1H-MRS measurements showed increased lipid peaks in the same lesion regions, and the micro-lipid storage disorder of NARs in NPC patients was detectable by IDEAL-IQ instead of 1H-MRS. Conclusion: The findings of this study suggested that IDEAL-IQ may be useful as a noninvasive and objective method in the evaluation of patients with NPC; additionally, IDEAL-IQ can be used to quantitatively measure the brain parenchymal adipose content and monitor patient follow-up after treatment of NPC.

Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C: a prospective observational study.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. The diagnosis of NP-C remains challenging due to the non-specific, heterogeneous nature of signs/symptoms. This study assessed the utility of plasma chitotriosidase (ChT) and Chemokine (C-C motif) ligand 18 (CCL18)/pulmonary and activation-regulated chemokine (PARC) in conjunction with the NP-C suspicion index (NP-C SI) for guiding confirmatory laboratory testing in patients with suspected NP-C. METHODS: In a prospective observational cohort study, incorporating a retrospective determination of NP-C SI scores, two different diagnostic approaches were applied in two separate groups of unrelated patients from 51 Spanish medical centers (n = 118 in both groups). From Jan 2010 to Apr 2012 (Period 1), patients with ≥2 clinical signs/symptoms of NP-C were considered 'suspected NP-C' cases, and NPC1/NPC2 sequencing, plasma chitotriosidase (ChT), CCL18/PARC and sphingomyelinase levels were assessed. Based on findings in Period 1, plasma ChT and CCL18/PARC, and NP-C SI prediction scores were determined in a second group of patients between May 2012 and Apr 2014 (Period 2), and NPC1 and NPC2 were sequenced only in those with elevated ChT and/or elevated CCL18/PARC and/or NP-C SI ≥70. Filipin staining and 7-ketocholesterol (7-KC) measurements were performed in all patients with NP-C gene mutations, where possible. RESULTS: In total across Periods 1 and 2, 10/236 (4%) patients had a confirmed diagnosis o NP-C based on gene sequencing (5/118 [4.2%] in each Period): all of these patients had two causal NPC1 mutations. Single mutant NPC1 alleles were detected in 8/236 (3%) patients, overall. Positive filipin staining results comprised three classical and five variant biochemical phenotypes. No NPC2 mutations were detected. All patients with NPC1 mutations had high ChT activity, high CCL18/PARC concentrations and/or NP-C SI scores ≥70. Plasma 7-KC was higher than control cut-off values in all patients with two NPC1 mutations, and in the majority of patients with single mutations. Family studies identified three further NP-C patients. CONCLUSION: This approach may be very useful for laboratories that do not have mass spectrometry facilities and therefore, they cannot use other NP-C biomarkers for diagnosis.

A Suspicion Index to aid screening of early-onset Niemann-Pick disease Type C (NP-C).

BACKGROUND: Niemann-Pick disease Type C (NP-C) is difficult to diagnose due to heterogeneous and nonspecific clinical presentation. The NP-C Suspicion Index (SI) was developed to identify patients with a high likelihood of NP-C; however, it was less reliable in patients aged <4 years. METHODS: An early-onset NP-C SI was constructed following retrospective chart review of symptom presentation in 200 patients from nine centres comprised of 106 NP-C cases, 31 non-cases and 63 controls. Statistical analyses defined strength of association between symptoms and a diagnosis of NP-C and assigned risk prediction scores to each symptom. RESULTS: Visceral symptoms were amongst the strongest predictors. Except for gelastic cataplexy and vertical supranuclear gaze palsy, central nervous system symptoms were not discriminatory in this population. Performance of the early-onset NP-C SI was superior versus the original NP-C SI in patients aged ≤4 years. CONCLUSIONS: The early-onset NP-C SI can help physicians, especially those with limited knowledge of NP-C, to identify patients aged ≤4 years who warrant further investigation for NP-C.

Longitudinal assessment of reflexive and volitional saccades in Niemann-Pick Type C disease during treatment with miglustat.

BACKGROUND: Niemann-Pick Type C disease (NPC), is an autosomal recessive neurovisceral disorder of lipid metabolism. One characteristic feature of NPC is a vertical supranuclear gaze palsy particularly affecting saccades. However, horizontal saccades are also impaired and as a consequence a parameter related to horizontal peak saccadic velocity was used as an outcome measure in the clinical trial of miglustat, the first drug approved in several jurisdictions for the treatment of NPC. As NPC-related neuropathology is widespread in the brain we examined a wider range of horizontal saccade parameters and to determine whether these showed treatment-related improvement and, if so, if this was maintained over time. METHODS: Nine adult NPC patients participated in the study; 8 were treated with miglustat for periods between 33 and 61 months. Data were available for 2 patients before their treatment commenced and 1 patient was untreated. Tasks included reflexive saccades, antisaccades and self-paced saccades, with eye movements recorded by an infrared reflectance eye tracker. Parameters analysed were reflexive saccade gain and latency, asymptotic peak saccadic velocity, HSEM-α (the slope of the peak duration-amplitude regression line), antisaccade error percentage, self-paced saccade count and time between refixations on the self-paced task. Data were analysed by plotting the change from baseline as a proportion of the baseline value at each test time and, where multiple data values were available at each session, by linear mixed effects (LME) analysis. RESULTS: Examination of change plots suggested some modest sustained improvement in gain, no consistent changes in asymptotic peak velocity or HSEM-α, deterioration in the already poor antisaccade error rate and sustained improvement in self-paced saccade rate. LME analysis showed statistically significant improvement in gain and the interval between self-paced saccades, with differences over time between treated and untreated patients. CONCLUSIONS: Both qualitative examination of change scores and statistical evaluation with LME analysis support the idea that some saccadic parameters are robust indicators of efficacy, and that the variability observed across measures may indicate locally different effects of neurodegeneration and of drug actions.

Health economic evaluation of plasma oxysterol screening in the diagnosis of Niemann-Pick Type C disease among intellectually disabled using discrete event simulation.

BACKGROUND: Recently a less invasive method of screening and diagnosing Niemann-Pick C (NP-C) disease has emerged. This approach involves the use of a metabolic screening test (oxysterol assay) instead of the current practice of clinical assessment of patients suspected of NP-C (review of medical history, family history and clinical examination for the signs and symptoms). Our objective is to compare costs and outcomes of plasma oxysterol screening versus current practice in diagnosis of NP-C disease among intellectually disabled (ID) patients using decision-analytic methods. METHODS: A discrete event simulation model was conducted to follow ID patients through the diagnosis and treatment of NP-C, forecast the costs and effectiveness for a cohort of ID patients and compare the outcomes and costs in two different arms of the model: plasma oxysterol screening and routine diagnosis procedure (anno 2013) over 5 years of follow up. Data from published sources and clinical trials were used in simulation model. Unit costs and quality-adjusted life-years (QALYs) were discounted at a 3% annual rate in the base case analysis. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: The outcomes of the base case model showed that using plasma oxysterol screening for diagnosis of NP-C disease among ID patients is a dominant strategy. It would result in lower total cost and would slightly improve patients' quality of life. The average amount of cost saving was $3642 CAD and the incremental QALYs per each individual ID patient in oxysterol screening arm versus current practice of diagnosis NP-C was 0.0022 QALYs. Results of sensitivity analysis demonstrated robustness of the outcomes over the wide range of changes in model inputs. CONCLUSION: Whilst acknowledging the limitations of this study, we conclude that screening ID children and adolescents with oxysterol tests compared to current practice for the diagnosis of NP-C is a dominant strategy with clinical and economic benefits. The less costly, more sensitive and specific oxysterol test has potential to save costs to the healthcare system while improving patients' quality of life and may be considered as a routine tool in the NP-C diagnosis armamentarium for ID. Further research is needed to elucidate its effectiveness in patients presenting characteristics other than ID in childhood and adolescence.

Collaborative development of 2-hydroxypropyl-ß-cyclodextrin for the treatment of Niemann-Pick type C1 disease.

In 2010, the National Institutes of Health (NIH) established the Therapeutics for Rare and Neglected Diseases (TRND) program within the National Center for Advancing Translational Sciences (NCATS), which was created to stimulate drug discovery and development for rare and neglected tropical diseases through a collaborative model between the NIH, academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies. This paper describes one of the first TRND programs, the development of 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) for the treatment of Niemann-Pick disease type C1 (NPC1). NPC is a neurodegenerative, autosomal recessive rare disease caused by a mutation in either the NPC1 (about 95% of cases) or the NPC2 gene (about 5% of cases). These mutations affect the intracellular trafficking of cholesterol and other lipids, which leads to a progressive accumulation of unesterified cholesterol and glycosphingolipids in the CNS and visceral organs. Affected individuals typically exhibit ataxia, swallowing problems, seizures, and progressive impairment of motor and intellectual function in early childhood, and usually die in adolescence. There is no disease modifying therapy currently approved for NPC1 in the US. A collaborative drug development program has been established between TRND, public and private partners that has completed the pre-clinical development of HP-ß-CD through IND filing for the current Phase I clinical trial that is underway. Here we discuss how this collaborative effort helped to overcome scientific, clinical and financial challenges facing the development of new drug treatments for rare and neglected diseases, and how it will incentivize the commercialization of HP-ß-CD for the benefit of the NPC patient community.

In vivo assessment of neurodegeneration in Niemann-Pick type C mice by quantitative T2 mapping and diffusion tensor imaging.

PURPOSE: To quantitatively and noninvasively assess neurological disease progression in a mouse model of Niemann-Pick type C (NPC) disease by measuring white matter status with magnetic resonance imaging (MRI) techniques of T2 mapping and diffusion tensor imaging (DTI). MATERIALS AND METHODS: Quantitative T2 and DTI experiments were performed in vivo in NPC disease model and control mice at three timepoints to quantify differences and changes in white matter with measurements of T2 relaxation and DTI parameters. Histological staining for myelin content was also performed at two timepoints to compare with the MRI findings. RESULTS: The results of the T2 and DTI measurements show significant differences in white matter areas of the brain in the NPC disease model compared to control mice at several timepoints, and were seen to change over time in both groups. CONCLUSION: The findings of this study suggest that quantitative MRI measurements may be suitable in vivo biomarkers of disease status for future studies of NPC disease models. The changes in white matter measurements between timepoints in both control and NPC disease groups suggest that white matter structures continue to change and develop over time in the NPC model and can be tracked with MRI techniques.

Defining natural history: assessment of the ability of college students to aid in characterizing clinical progression of Niemann-Pick disease, type C.

Niemann-Pick Disease, type C (NPC) is a fatal, neurodegenerative, lysosomal storage disorder. It is a rare disease with broad phenotypic spectrum and variable age of onset. These issues make it difficult to develop a universally accepted clinical outcome measure to assess urgently needed therapies. To this end, clinical investigators have defined emerging, disease severity scales. The average time from initial symptom to diagnosis is approximately 4 years. Further, some patients may not travel to specialized clinical centers even after diagnosis. We were therefore interested in investigating whether appropriately trained, community-based assessment of patient records could assist in defining disease progression using clinical severity scores. In this study we evolved a secure, step wise process to show that pre-existing medical records may be correctly assessed by non-clinical practitioners trained to quantify disease progression. Sixty-four undergraduate students at the University of Notre Dame were expertly trained in clinical disease assessment and recognition of major and minor symptoms of NPC. Seven clinical records, randomly selected from a total of thirty seven used to establish a leading clinical severity scale, were correctly assessed to show expected characteristics of linear disease progression. Student assessment of two new records donated by NPC families to our study also revealed linear progression of disease, but both showed accelerated disease progression, relative to the current severity scale, especially at the later stages. Together, these data suggest that college students may be trained in assessment of patient records, and thus provide insight into the natural history of a disease.

Cost of illness associated with Niemann-Pick disease type C in the UK.

OBJECTIVE: Niemann-Pick disease type C (NP-C) is a rare and devastating genetic disorder characterised by a range of progressive neurological symptoms, which imposes a burden on patients, family members, the healthcare system and society overall. The objective of this study was to assess direct and indirect costs associated with NP-C in the UK. METHODS: This was a non-interventional, retrospective, cross-sectional cohort study based on responses from patients and/or their carers/guardians recruited from a UK NP-C database. Resource use and direct medical, direct non-medical and indirect costs were evaluated using data collected via postal survey in October 2007, which included a Medical Resource Use questionnaire. Total annual costs per patient were estimated. RESULTS: In total, 18 Medical Resource Use questionnaires (29% response rate) were received and analysed. The mean total annual cost (SD) of NP-C per patient was 39,168 pounds (50,315 pounds); 46% were direct medical costs, to which home visits and residential care contributed 68% and 15%, respectively. Direct non-medical costs accounted for 24% of the average annual cost per patient, mainly due to specialist education, and indirect costs 30%. If only direct medical costs were considered, the mean annual cost (SD) per patient was reduced to 18,012 pounds (46,536 pounds). CONCLUSIONS: The direct annual per-patient cost of NP-C illness in 2007 appears moderate when compared with other rare and severely disabling diseases. However, cost estimates may be conservative, since findings are limited by a small sample size, low survey response rate and potential recall bias. As demonstrated by this study, a substantial proportion of the cost is shifted from the healthcare system to the patient, family and non-medical providers. These findings highlight the need for treatments that can slow or stop disease progression in NP-C.

Critical assessment of chitotriosidase analysis in the rational laboratory diagnosis of children with Gaucher disease and Niemann-Pick disease type A/B and C.

Laboratory diagnosis of lysosomal storage disorders, especially sphingomyelinase deficiency (Niemann-Pick disease type A/B) and Niemann-Pick disease type C (NPC) can be challenging. We therefore aimed to analyse the feasibility of first-step screening with specific chitotriosidase cut-off values in children