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  string(146) "Intrathecal Adrabetadex for Niemann-Pick Type C (NPC): Case Control Study in Early Onset NPC and Comparison of Natural History and Treated Cohorts"
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  string(695) "NPC is a heterogenous fatal neurogenerative disease due to impaired cholesterol trafficking. A phase 1/2a trial of adrabetadex showed cholesterol efflux from brain, normalization of biomarkers, and slowing of disease progression. A phase 2/3 1-year sham-controlled trial showed no benefit, as the sham group had little progression. In the proposed study, data from this dataset and other natural history cohorts will be used to 1) match patients with early onset disease treated with adrabetadex in expanded access to historical controls and evaluate long-term outcomes of survival and loss of ambulation; 2) compare progression of disease combined cohorts of all treated and untreated patients."
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      string(2) "MT"
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      string(13) "Mandos Health"
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      string(148) "NPC Registry (AC-056C501) Registry is an international, multi-center, prospective, observational, long-term project for patients diagnosed with NP-C"
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  string(91) "Individual Participant-Level Data, which includes Full CSR and all supporting documentation"
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  string(2499) "Background: Niemann Pick type C is a heterogeneous fatal neurodegenerative disease resulting from mutations in NPC1 or NPC2, with resultant impaired cholesterol trafficking and cholesterol accumulation in the lysosomes and late endosomes. Adrabetadex showed benefit in NPC cats and mice, with substantial prolongation of life , slower motor decline, and rescue of cerebellar Purkinje cells. A phase 1/2a trial of adrabetedex showed cholesterol efflux from the brain, normalization of biomarkers of neurodegeneration in CSF, and slowing of disease progression. A phase 2b/3 one year sham controlled trial failed to show benefit as the sham group had little progression. Patients with early onset disease under age 5 not eligible for the trial have been treated through an Expanded Access Program (EAP) and many seem to be showing strong responses with no progression over years and ongoing developmental gains. When patient groups treated long-term through both EAP or open-label extensions of trials are combined and compared to a natural history cohort, the treated patients show a slower rate of progression. Objectives: To determine 1) if early onset patients with NPC treated with adrabetadex show improved survival and delay in loss of ambulation relative to matched untreated patients and 2) if patient cohorts treated long-term with adrabetadex progress more slowly than natural history controls. Study Design: Each patient with disease onset under age 5 years who has been treated with adrabetadex will be matched to as many historical controls as possible from this database and other sources, based on developmental milestones and clinical features and will be compared with respect to age of loss of ambulation and death, as well as other secondary outcomes to be determined based on data available.  Data from all adrabetadex-treated patients from both EAP and trials as well as natural history controls from multiple cohorts including this dataset will be compared with respect to time to progression and overall survival. Participants: All patients treated with adrabetabex through EAP or trials and natural history controls from this and other existing databases. Main Outcome measures: age of death and age of loss of independent ambulation for matched case-control study of treated/untreated patients with early onset disease; time to progression and overall survival for treated and control cohorts of all patients. Statistical Analysis: Kaplan-Meier methodology and other methods."
  ["project_brief_bg"]=>
  string(3199) "Niemann Pick type C is an ultra-rare heterogeneous fatal neurodegenerative disease resulting from mutations in NPC1 or NPC2, with resultant impaired cholesterol trafficking and cholesterol accumulation in the lysosomes/late endosomes (1,2). Adrabetadex showed benefit in NPC models, with substantial prolongation of life in mice (3,4) and cats (5), slowing motor of decline and rescue of cerebellar Purkinje cells in cats (5). A phase 1/2a trial of intrathecal adrabetadex showed cholesterol efflux from the brain after infusions, normalization of biomarkers of neurodegeneration in CSF, and slowing of disease progression over 18 months relative to matched natural history controls (6). A phase 2b/3 one year sham controlled trial failed to show benefit as the sham group had little progression (7). Some patients treated through an Expanded Access Program (EAP) seem to show an excellent response (8), particularly those with early onset under age 5, who were not eligible for trials, and have had no progression in years and ongoing developmental gains (9). When patient groups treated long-term through EAP or open-label extensions or trials are combined the treated patients show a slower rate of progression compared to a natural history cohort (10) and reduction of progression slope in individual patients compared pre- and post-treatment (11,12). In NPC, placebo/sham-controlled trials are highly challenging due to variability of the disease (1,13), slow progression over years, and limited numbers of patients. Any trial must be small and cannot be stratified by many variables due to cohort size. Thus, there is high risk of randomizing a group to the control arm which is progressing at a different rate than the treated arm, especially when the control arm is smaller based on a 2:1 randomization scheme often employed to try to limit the number of patients subjected to loss of skills while in the control arm. This is further complicated, in NPC, by the use of miglustat, which slows the natural disease course (14-18),  by a substantial proportion of patients. The phase 2b/3 trial of adrabetadex in NPC was subject to all these issues and the control group failed to progress at a rate that would allow a definitive determination of drug effect for adrabetadex (7). The only way to truly understand the drug effect in this situation is to look at long-term data and compare treated cohorts with available natural history cohorts, look at within patient pre- and post-treatment rates of decline, and use case-control designs to study very young children who were not a part of the phase 2b/3 trial and who have the fastest rate of progression, thus allowing for the shortest treatment time to pass before outcomes like survival can be assessed. In this study, we will use information from the YODA NPC registry to add to the pool of control patients that can be used for case-control and natural history comparator studies to show a long-term effect of adrabetadex that will, if a sufficiently strong result, contribute to a registration application by Mandos for accelerated approval at FDA. If this project is successful it will help make available an important treatment for NPC."
  ["project_specific_aims"]=>
  string(134) "Specific Aim 1: To show decreased longer survival and longer time to loss of ambulation in children with NPC and neurological onset at"
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      string(114) "New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations"
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      string(114) "New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations"
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  string(1202) "Aim 1 data sources for this study will include 1) data from adrabetadex-treated patients in RedCap and excel files housed at Rush University Medical Center (RUMC), data from untreated controls from 2) this YODA NPC registry, 3)  the International Niemann-Pick Disease Registry (19), 4) databases for NPC cohorts in France from Marie Vanier (1) and Germany by Heiko Rutz (20) the NIH natural history study in the NIH CTDB database, and 6) the Allstripes NPC database.  For Aim 2 data sources will include the above and the Mallinckrodt trial/EAP databases (21) : VTS301 (phase 2b/3), VTS302, VTS001 and OLEX .
Aim 1 inclusion criteria will be children with NPC treated with adrabetadex prior to age 5 years due to neurological symptom onset under age 5 years and untreated matched controls from all sources. Matching criteria will be developmental milestones and neurological symptoms at the age of treatment initiation for each treated patient. Aim 2 inclusion criteria will be all adrabetadex treated patients from all sources and controls from all sources. Patients will be excluded from both Aims if they have medical complications or additional diagnoses that would impact the course of NPC." ["project_main_outcome_measure"]=> string(1047) "For Aim 1 the main outcomes will be 1) age of death defined as death from any cause; 2) age of loss of ambulation defined as inability to ambulate independently without a support device or assistance, after having previously ambulated independently. Depending on specific data available in the databases, time to progression may be utilized for this Aim, defined as time to worsening of an existing neurological symptom or appearance of a new neurological symptom (potential symptoms (1,2) would include ataxia , dystonia, dysarthria, dysphagia, dysmetria and cognitive decline (22,23)).
For Aim 2 the main outcomes would be 1) age of death defined as death from any cause; 2) time to progression defined as worsening of at least 2 points on the NPC Severity Scale (NPC-SS) 5 Domain Scale (24,25) and/or (depending on data available) time to worsening of an existing neurological symptom or appearance of a new neurological symptom (potential symptoms would include ataxia, dystonia, dysarthria, dysphagia, dysmetria and cognitive decline)." ["project_main_predictor_indep"]=> string(147) "For both Aim 1 and Aim 2 the main predictor/independent variable will be treatment with intrathecal adrabetadex continuously for at least one year." ["project_other_variables_interest"]=> string(1018) "Other variables of interest that will need to be accounted or controlled for in both Aim 1 and Aim 2 are:
1) use of miglustat defined as continuous use for the majority of the follow up period to be analyzed for the patient
2) severity of disease at initiation of adrabetadex treatment defined as severity of gross motor/ambulation and speech delay (23) for Aim 1 (this will be accounted for in the matching in Aim 1) and defined as NPC-SS 5 Domain score (25) for Aim 2
3) rate of progression at initiation of adrabetadex treatment Annual Severity Increment Score (ASIS) (11) based on the NPC-SS 5 Domain score
4) age at initiation of treatment
Other variables that may be of interest include:
1) NPC1 mutation (20)
2) biomarker measures to be determined, but potentially including 24-OH-cholesterol release post-infusion, calbindin D, fatty acid binding protein 3 (6), bile acid B or other lipid metabolites (26,27) and potential new biomarker of treatment effect, GPNMB (28)" ["project_stat_analysis_plan"]=> string(4040) "General Data Analyses Conventions:
Each patient with disease onset under age 5 years who has been treated with Adrabetadex will be matched to as many historical controls as possible from these databases, based on developmental milestones and clinical features and will be compared with respect to age of loss of ambulation and death, as well as other secondary outcomes to be determined based on data available.
All planned statistical analyses are exploratory. No sample size will be calculated, and no minimum sample size was determined a priori. Unless otherwise stated, descriptive statistics will be used to summarize continuous variables; categorical variables will be summarized using the total number of available values and the number of available values in each category.
The data from various databases will be pooled to form an overall pooled data set. Duplicate records for patients who were included in both the NPC Registry and one of the studies will be identified programmatically and the information censored as needed. The overall survival OS is defined as the time from the study entry or randomization to death from any cause. For patients who are alive at the time of the analysis data cutoff, OS time will be censored at the last date the patient was known to be alive or analysis data cutoff date, whichever occurs first. Patients with no post baseline survival information will be censored on the date of study entry or randomization.
Statistical Analyses for Aim1:
The Primary survival analyses will be performed using an extended Cox model, which will include treatment (adrabetadex-treated vs untreated), category of age at onset of neurological manifestations and country (each country in the NPC Registry and the national cohorts) as covariates. For treatment comparisons, adjusted Kaplan Meier (KM) curves, adjusted hazard ratios (HR), the 95% confidence intervals (CI) and P-values will be calculated as needed.
For Aim 1 the date of loss of ambulation defined as the date when the patient is unable to walk independently without a support device or assistance, after having previously ambulate independently. Depending on specific data available in the databases, time to progression may be utilized for this aim, defined as time to worsening of an existing neurological symptom or appearance of a new neurological symptom (potential symptoms (1,2) would include ataxia, dystonia, dysarthria, dysphagia, dysmetria and cognitive decline (22,23)).
Time to loss of ambulation and /or time to progression will be analyzed using an extended Cox model, which included treatment (adrabetadex-treated vs untreated), category of age at onset of neurological manifestations, and country (each country in the NPC Registry and the national cohorts) as covariates. For treatment comparison, adjusted Kaplan Meier (KM) curves, adjusted hazard ratios (HR), the 95% confidence intervals (CI) and P-values will be calculated as needed.
Statistical Analyses for Aim2:
For Aim 2, the Overall survival analyses will follow the same definition and analyses except the extended cox model will adjust for treatment and country (each country in the NPC Registry and the national cohorts) as covariates only.
The time to progression defined as worsening of at least 2 points on the NPC Severity Scale (NPC-SS) 5 Domain Scale (24,25) and/or (depending on data available) time to worsening of an existing neurological symptom or appearance of a new neurological symptom (potential symptoms would include ataxia, dystonia, dysarthria, dysphagia, dysmetria and cognitive decline). The time to progression will follow the same analyses as in aim1 except the extended cox model will adjust for the treatment (adrabetadex-treated vs untreated) and country (each country in the NPC Registry and the national cohorts) as covariates only.
Miglustat use status (yes/no) will be used as an additional covariate in the extended cox model for the sensitivity analysis purpose" ["project_timeline"]=> string(811) "In this project data must be obtained from multiple sources and so this has resulted in delays. The Mallinckrodt databases were locked in December 2021 but other data sources are not yet available. It is hoped that these can become available by December 2022, matching for the case-control study completed by March 2023, and complete data analyses completed by December 2023. The timeline for Aim 1 could be delayed if data from other sources continues to take longer than expected to obtain. Once data is analyzed this would, depending on results, be used by Mandos to submit an NDA to FDA by December 2023 and then publish data while working with FDA on the response, such that publication would be expected in the second quarter of 2024. Results could be reported back to the YODA project shortly thereafter." ["project_dissemination_plan"]=> string(612) "Results of these studies will be published in peer-reviewed journals. Appropriate journals would be those read by neurologists and geneticists including Neurology, Annals of Neurology, Pediatric Neurology, Science Translational Medicine and multiple others. Results would be presented at relevant national conferences including the Child Neurology Society, WORLD, American Society of Medical Genetics meetings, as well as meetings of disease stakeholders, including but not limited to the Ara Parseghian Medical Research Foundation, the National Niemann-Pick Disease Foundation, and the Niemann-Pick UK meetings." ["project_bibliography"]=> string(7026) "

1. Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis 2010;5:16.
2. Berry-Kravis E. Niemann-Pick Disease, Type C: Diagnosis, Management and Disease-Targeted Therapies in Development. Semin Pediatr Neurol. 2021 Apr;37:100879.
3. 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:e6951.
4. Liu B, Turley SD, Burns DK, Miller AM, Repa JJ, Dietschy JM, et al. Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1?/?mouse. Proc Natl Acad Sci USA 2009;106:2377?2382.
5. 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;7:276ra26.
6. Ory DS, Ottinger EA, Farhat NY, King KA, Jiang X, Weissfeld L, et al. Intrathecal 2- hydroxypropyl?-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. Lancet. 2017; 390:1758?1768.
7. VanMeter S, Berry-Kravis E, Porter FD, Mak C, on behalf of the adrabetadex investigators and the TRND team. Intrathecal adrabetadex for the treatment of Niemann-Pick disease, type C1. WORLD Symposium, Orlando, February 2020.
8. Berry-Kravis E, Chin J, Hoffmann A, Winston A, Stoner R, LaGorio L, et al. Long-term treatment of Niemann-Pick Type C1 disease with intrathecal 2-hydroxypropyl-?-cyclodextrin, Pediatric Neurology 2018;80:24-34.
9. Jaeger R, Friedmann K, Leonczyk C, Hoffmann A, Wainer A, Soorya L, Thurm A, Farmer C, Farhat N, Porter FD. Effects of 2-hydroxypropyl-beta-cyclodexrin (HP-B-CD, VTS-270) in children with NPC1 age 5 and under and comparison to natural history. Michael, Marcia & Christa Parseghian Scientific Conference, Tucson, AZ, June 2019.
10. Berry-Kravis E, Johnson R, Chin J, Friedmann K, Jaeger R, Farhat N, Bianconi S, Porter FD. Evidence for long-term efficacy of intrathecal adrabetadex for the treatment of neurological decline in patients with Niemann-Pick disease, type C1, Platform presentation, WORLD Conference, February 2021.
11. Cortina-Borja M, Vruchte D, Mengel E, Amraoui Y, Imrie J, Jones S, et al. Annual severity increment score as a tool for stratifying patients with Niemann-Pick disease type C and for recruitment to clinical trials. Orphanet J Rare Dis. 2018;13.
12. Berry-Kravis E, Johnson R, Chin J, Friedmann K, Jaeger R, Farhat N, Bianconi S, Porter FD. Evidence for long-term efficacy of intrathecal adrabetadex for the treatment of neurological decline in very young and older patients with Niemann-Pick disease, type C1. National Niemann-Pick Disease Foundation virtual conference, July 2021.
13. Mengel E, Pineda M, Hendriksz CJ, Walterfang M, Torres JV, Kolb SA. Differences in Niemann- Pick disease Type C symptomatology observed in patients of different ages. Mol Genet Metab 2017;120:180?189.
14. Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol. 2007;6:765?772
15. Patterson MC, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luzy C, et al. Long-term miglustat therapy in children with Niemann-Pick disease type C. J Child Neurol. 2010;25:300?305.
16. Patterson MC, Mengel E, Vanier MT, Moneuse P, Rosenberg D, Pineda M. Treatment outcomes following continuous miglustat therapy in patients with Niemann-Pick disease Type C: a final report of the NPC Registry. Orphanet Journal of Rare Diseases 2020;15:104.
17. Patterson MC, Garver WS, Giugliani R, Imrie J, Jahnova H, Meaney FJ, et al. Long-term survival outcomes of patients with Niemann-Pick disease type C receiving miglustat treatment: A large retrospective observational study. J Inherit Metab Dis. 2020 Apr 23. doi: 10.1002/jimd.12245
18. Solomon BI, Smith AC, Sinaii N, Farhat N, King MC, Machielse L, Porter FD. Association of Miglustat With Swallowing Outcomes in Niemann-Pick Disease, Type C1. JAMA Neurol. 2020 Dec 1;77(12):1564-1568.
19. Geberhiwot T, Moro A, Dardis A, Ramaswami U, Sirrs S, Marfa MP, et al. International Niemann-Pick Disease Registry (INPDR). Consensus clinical management guidelines for Niemann-Pick disease type C. Orphanet J Rare Dis 2018;13:50.
20. Runz H, Dolle D, Schlitter AM, Zschocke J. NPC-db, a Niemann-Pick type C disease gene variation database. Hum Mutat 2008;29:345?350.
21. VTS301: https://clinicaltrials.gov/ct2/show/NCT02534844?cond=niemann-Pick+type+C…, https://clinicaltrials.gov/ct2/show/NCT04958642?cond=niemann-Pick+type+C… ; VTS302: https://clinicaltrials.gov/ct2/show/NCT03879655?cond=niemann-Pick+type+C… VTS001: https://clinicaltrials.gov/ct2/show/NCT03643562?cond=niemann-Pick+type+C…
22. Thurm A, Chlebowski C, Joseph L, Farmer C, Adedipe D, Weiss M, Wiggs E, Farhat N, Bianconi S, Berry-Kravis E, Porter FD. Neurodevelopmental characterization of young children diagnosed with Niemann-Pick Disease, Type C1. J Dev Behav Pediatr. 2020;41:388-396.
23. 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;58:262-269.
24. 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;153:132?140.
25. Patterson MC, Lloyd-Price L, Guldberg C, Doll H, Burbridge C, Chladek M, Dali C, Mengel E, Symonds T. Validation of the 5-domain Niemann-Pick type C Clinical Severity Scale. Orphanet J Rare Dis. 2021 Feb 12;16(1):79.
26. Jiang X, Sidhu R, Mydock-McGrane L, Hsu FF, Covey DF, Scherrer DE, et al. Development of a bile acid based newborn screen for Niemann-Pick disease type C. Sci Transl Med. 2016;8:337ra63.
27. Sidhu R, Kell P, Dietzen DJ, Farhat NY, Do AND, Porter FD, Berry-Kravis E, Reunert J, Marquardt T, Giugliani R, Loureno CM, Wang RY, Movsesyan N, Plummer E, Schaffer JE, Ory DS, Jiang X. Application of a glycinated bile acid biomarker for diagnosis and assessment of response to treatment in Niemann-pick disease type C1. Mol Genet Metab. 2020 Dec;131(4):405-417.
28. Rodriguez-Gil JL, Baxter LL, Watkins-Chow DE, Johnson NL, Davidson CD, Carlson SR, Incao AA; NISC Comparative Sequencing Program, Wallom KL, Farhat NY, Platt FM, Dale RK, Porter FD, Pavan WJ. Transcriptome of HP?CD-treated Niemann-pick disease type C1 cells highlights GPNMB as a biomarker for therapeutics. Hum Mol Genet. 2021 Jul 22:ddab194. doi: 10.1093/hmg/ddab194. Epub ahead of print. PMID: 34296265.

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2021-4741

General Information

How did you learn about the YODA Project?: Data Holder (Company)

Conflict of Interest

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Associated Trial(s):
  1. NPC Registry (AC-056C501) Registry is an international, multi-center, prospective, observational, long-term project for patients diagnosed with NP-C
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Data Request Status

Status: Ongoing

Research Proposal

Project Title: Intrathecal Adrabetadex for Niemann-Pick Type C (NPC): Case Control Study in Early Onset NPC and Comparison of Natural History and Treated Cohorts

Scientific Abstract: Background: Niemann Pick type C is a heterogeneous fatal neurodegenerative disease resulting from mutations in NPC1 or NPC2, with resultant impaired cholesterol trafficking and cholesterol accumulation in the lysosomes and late endosomes. Adrabetadex showed benefit in NPC cats and mice, with substantial prolongation of life , slower motor decline, and rescue of cerebellar Purkinje cells. A phase 1/2a trial of adrabetedex showed cholesterol efflux from the brain, normalization of biomarkers of neurodegeneration in CSF, and slowing of disease progression. A phase 2b/3 one year sham controlled trial failed to show benefit as the sham group had little progression. Patients with early onset disease under age 5 not eligible for the trial have been treated through an Expanded Access Program (EAP) and many seem to be showing strong responses with no progression over years and ongoing developmental gains. When patient groups treated long-term through both EAP or open-label extensions of trials are combined and compared to a natural history cohort, the treated patients show a slower rate of progression. Objectives: To determine 1) if early onset patients with NPC treated with adrabetadex show improved survival and delay in loss of ambulation relative to matched untreated patients and 2) if patient cohorts treated long-term with adrabetadex progress more slowly than natural history controls. Study Design: Each patient with disease onset under age 5 years who has been treated with adrabetadex will be matched to as many historical controls as possible from this database and other sources, based on developmental milestones and clinical features and will be compared with respect to age of loss of ambulation and death, as well as other secondary outcomes to be determined based on data available. Data from all adrabetadex-treated patients from both EAP and trials as well as natural history controls from multiple cohorts including this dataset will be compared with respect to time to progression and overall survival. Participants: All patients treated with adrabetabex through EAP or trials and natural history controls from this and other existing databases. Main Outcome measures: age of death and age of loss of independent ambulation for matched case-control study of treated/untreated patients with early onset disease; time to progression and overall survival for treated and control cohorts of all patients. Statistical Analysis: Kaplan-Meier methodology and other methods.

Brief Project Background and Statement of Project Significance: Niemann Pick type C is an ultra-rare heterogeneous fatal neurodegenerative disease resulting from mutations in NPC1 or NPC2, with resultant impaired cholesterol trafficking and cholesterol accumulation in the lysosomes/late endosomes (1,2). Adrabetadex showed benefit in NPC models, with substantial prolongation of life in mice (3,4) and cats (5), slowing motor of decline and rescue of cerebellar Purkinje cells in cats (5). A phase 1/2a trial of intrathecal adrabetadex showed cholesterol efflux from the brain after infusions, normalization of biomarkers of neurodegeneration in CSF, and slowing of disease progression over 18 months relative to matched natural history controls (6). A phase 2b/3 one year sham controlled trial failed to show benefit as the sham group had little progression (7). Some patients treated through an Expanded Access Program (EAP) seem to show an excellent response (8), particularly those with early onset under age 5, who were not eligible for trials, and have had no progression in years and ongoing developmental gains (9). When patient groups treated long-term through EAP or open-label extensions or trials are combined the treated patients show a slower rate of progression compared to a natural history cohort (10) and reduction of progression slope in individual patients compared pre- and post-treatment (11,12). In NPC, placebo/sham-controlled trials are highly challenging due to variability of the disease (1,13), slow progression over years, and limited numbers of patients. Any trial must be small and cannot be stratified by many variables due to cohort size. Thus, there is high risk of randomizing a group to the control arm which is progressing at a different rate than the treated arm, especially when the control arm is smaller based on a 2:1 randomization scheme often employed to try to limit the number of patients subjected to loss of skills while in the control arm. This is further complicated, in NPC, by the use of miglustat, which slows the natural disease course (14-18), by a substantial proportion of patients. The phase 2b/3 trial of adrabetadex in NPC was subject to all these issues and the control group failed to progress at a rate that would allow a definitive determination of drug effect for adrabetadex (7). The only way to truly understand the drug effect in this situation is to look at long-term data and compare treated cohorts with available natural history cohorts, look at within patient pre- and post-treatment rates of decline, and use case-control designs to study very young children who were not a part of the phase 2b/3 trial and who have the fastest rate of progression, thus allowing for the shortest treatment time to pass before outcomes like survival can be assessed. In this study, we will use information from the YODA NPC registry to add to the pool of control patients that can be used for case-control and natural history comparator studies to show a long-term effect of adrabetadex that will, if a sufficiently strong result, contribute to a registration application by Mandos for accelerated approval at FDA. If this project is successful it will help make available an important treatment for NPC.

Specific Aims of the Project: Specific Aim 1: To show decreased longer survival and longer time to loss of ambulation in children with NPC and neurological onset at

Study Design:

What is the purpose of the analysis being proposed? Please select all that apply.: New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations Research on comparison group

Software Used: R

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: Aim 1 data sources for this study will include 1) data from adrabetadex-treated patients in RedCap and excel files housed at Rush University Medical Center (RUMC), data from untreated controls from 2) this YODA NPC registry, 3) the International Niemann-Pick Disease Registry (19), 4) databases for NPC cohorts in France from Marie Vanier (1) and Germany by Heiko Rutz (20) the NIH natural history study in the NIH CTDB database, and 6) the Allstripes NPC database. For Aim 2 data sources will include the above and the Mallinckrodt trial/EAP databases (21) : VTS301 (phase 2b/3), VTS302, VTS001 and OLEX .
Aim 1 inclusion criteria will be children with NPC treated with adrabetadex prior to age 5 years due to neurological symptom onset under age 5 years and untreated matched controls from all sources. Matching criteria will be developmental milestones and neurological symptoms at the age of treatment initiation for each treated patient. Aim 2 inclusion criteria will be all adrabetadex treated patients from all sources and controls from all sources. Patients will be excluded from both Aims if they have medical complications or additional diagnoses that would impact the course of NPC.

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: For Aim 1 the main outcomes will be 1) age of death defined as death from any cause; 2) age of loss of ambulation defined as inability to ambulate independently without a support device or assistance, after having previously ambulated independently. Depending on specific data available in the databases, time to progression may be utilized for this Aim, defined as time to worsening of an existing neurological symptom or appearance of a new neurological symptom (potential symptoms (1,2) would include ataxia , dystonia, dysarthria, dysphagia, dysmetria and cognitive decline (22,23)).
For Aim 2 the main outcomes would be 1) age of death defined as death from any cause; 2) time to progression defined as worsening of at least 2 points on the NPC Severity Scale (NPC-SS) 5 Domain Scale (24,25) and/or (depending on data available) time to worsening of an existing neurological symptom or appearance of a new neurological symptom (potential symptoms would include ataxia, dystonia, dysarthria, dysphagia, dysmetria and cognitive decline).

Main Predictor/Independent Variable and how it will be categorized/defined for your study: For both Aim 1 and Aim 2 the main predictor/independent variable will be treatment with intrathecal adrabetadex continuously for at least one year.

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: Other variables of interest that will need to be accounted or controlled for in both Aim 1 and Aim 2 are:
1) use of miglustat defined as continuous use for the majority of the follow up period to be analyzed for the patient
2) severity of disease at initiation of adrabetadex treatment defined as severity of gross motor/ambulation and speech delay (23) for Aim 1 (this will be accounted for in the matching in Aim 1) and defined as NPC-SS 5 Domain score (25) for Aim 2
3) rate of progression at initiation of adrabetadex treatment Annual Severity Increment Score (ASIS) (11) based on the NPC-SS 5 Domain score
4) age at initiation of treatment
Other variables that may be of interest include:
1) NPC1 mutation (20)
2) biomarker measures to be determined, but potentially including 24-OH-cholesterol release post-infusion, calbindin D, fatty acid binding protein 3 (6), bile acid B or other lipid metabolites (26,27) and potential new biomarker of treatment effect, GPNMB (28)

Statistical Analysis Plan: General Data Analyses Conventions:
Each patient with disease onset under age 5 years who has been treated with Adrabetadex will be matched to as many historical controls as possible from these databases, based on developmental milestones and clinical features and will be compared with respect to age of loss of ambulation and death, as well as other secondary outcomes to be determined based on data available.
All planned statistical analyses are exploratory. No sample size will be calculated, and no minimum sample size was determined a priori. Unless otherwise stated, descriptive statistics will be used to summarize continuous variables; categorical variables will be summarized using the total number of available values and the number of available values in each category.
The data from various databases will be pooled to form an overall pooled data set. Duplicate records for patients who were included in both the NPC Registry and one of the studies will be identified programmatically and the information censored as needed. The overall survival OS is defined as the time from the study entry or randomization to death from any cause. For patients who are alive at the time of the analysis data cutoff, OS time will be censored at the last date the patient was known to be alive or analysis data cutoff date, whichever occurs first. Patients with no post baseline survival information will be censored on the date of study entry or randomization.
Statistical Analyses for Aim1:
The Primary survival analyses will be performed using an extended Cox model, which will include treatment (adrabetadex-treated vs untreated), category of age at onset of neurological manifestations and country (each country in the NPC Registry and the national cohorts) as covariates. For treatment comparisons, adjusted Kaplan Meier (KM) curves, adjusted hazard ratios (HR), the 95% confidence intervals (CI) and P-values will be calculated as needed.
For Aim 1 the date of loss of ambulation defined as the date when the patient is unable to walk independently without a support device or assistance, after having previously ambulate independently. Depending on specific data available in the databases, time to progression may be utilized for this aim, defined as time to worsening of an existing neurological symptom or appearance of a new neurological symptom (potential symptoms (1,2) would include ataxia, dystonia, dysarthria, dysphagia, dysmetria and cognitive decline (22,23)).
Time to loss of ambulation and /or time to progression will be analyzed using an extended Cox model, which included treatment (adrabetadex-treated vs untreated), category of age at onset of neurological manifestations, and country (each country in the NPC Registry and the national cohorts) as covariates. For treatment comparison, adjusted Kaplan Meier (KM) curves, adjusted hazard ratios (HR), the 95% confidence intervals (CI) and P-values will be calculated as needed.
Statistical Analyses for Aim2:
For Aim 2, the Overall survival analyses will follow the same definition and analyses except the extended cox model will adjust for treatment and country (each country in the NPC Registry and the national cohorts) as covariates only.
The time to progression defined as worsening of at least 2 points on the NPC Severity Scale (NPC-SS) 5 Domain Scale (24,25) and/or (depending on data available) time to worsening of an existing neurological symptom or appearance of a new neurological symptom (potential symptoms would include ataxia, dystonia, dysarthria, dysphagia, dysmetria and cognitive decline). The time to progression will follow the same analyses as in aim1 except the extended cox model will adjust for the treatment (adrabetadex-treated vs untreated) and country (each country in the NPC Registry and the national cohorts) as covariates only.
Miglustat use status (yes/no) will be used as an additional covariate in the extended cox model for the sensitivity analysis purpose

Narrative Summary: NPC is a heterogenous fatal neurogenerative disease due to impaired cholesterol trafficking. A phase 1/2a trial of adrabetadex showed cholesterol efflux from brain, normalization of biomarkers, and slowing of disease progression. A phase 2/3 1-year sham-controlled trial showed no benefit, as the sham group had little progression. In the proposed study, data from this dataset and other natural history cohorts will be used to 1) match patients with early onset disease treated with adrabetadex in expanded access to historical controls and evaluate long-term outcomes of survival and loss of ambulation; 2) compare progression of disease combined cohorts of all treated and untreated patients.

Project Timeline: In this project data must be obtained from multiple sources and so this has resulted in delays. The Mallinckrodt databases were locked in December 2021 but other data sources are not yet available. It is hoped that these can become available by December 2022, matching for the case-control study completed by March 2023, and complete data analyses completed by December 2023. The timeline for Aim 1 could be delayed if data from other sources continues to take longer than expected to obtain. Once data is analyzed this would, depending on results, be used by Mandos to submit an NDA to FDA by December 2023 and then publish data while working with FDA on the response, such that publication would be expected in the second quarter of 2024. Results could be reported back to the YODA project shortly thereafter.

Dissemination Plan: Results of these studies will be published in peer-reviewed journals. Appropriate journals would be those read by neurologists and geneticists including Neurology, Annals of Neurology, Pediatric Neurology, Science Translational Medicine and multiple others. Results would be presented at relevant national conferences including the Child Neurology Society, WORLD, American Society of Medical Genetics meetings, as well as meetings of disease stakeholders, including but not limited to the Ara Parseghian Medical Research Foundation, the National Niemann-Pick Disease Foundation, and the Niemann-Pick UK meetings.

Bibliography:

1. Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis 2010;5:16.
2. Berry-Kravis E. Niemann-Pick Disease, Type C: Diagnosis, Management and Disease-Targeted Therapies in Development. Semin Pediatr Neurol. 2021 Apr;37:100879.
3. 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:e6951.
4. Liu B, Turley SD, Burns DK, Miller AM, Repa JJ, Dietschy JM, et al. Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1?/?mouse. Proc Natl Acad Sci USA 2009;106:2377?2382.
5. 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;7:276ra26.
6. Ory DS, Ottinger EA, Farhat NY, King KA, Jiang X, Weissfeld L, et al. Intrathecal 2- hydroxypropyl?-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. Lancet. 2017; 390:1758?1768.
7. VanMeter S, Berry-Kravis E, Porter FD, Mak C, on behalf of the adrabetadex investigators and the TRND team. Intrathecal adrabetadex for the treatment of Niemann-Pick disease, type C1. WORLD Symposium, Orlando, February 2020.
8. Berry-Kravis E, Chin J, Hoffmann A, Winston A, Stoner R, LaGorio L, et al. Long-term treatment of Niemann-Pick Type C1 disease with intrathecal 2-hydroxypropyl-?-cyclodextrin, Pediatric Neurology 2018;80:24-34.
9. Jaeger R, Friedmann K, Leonczyk C, Hoffmann A, Wainer A, Soorya L, Thurm A, Farmer C, Farhat N, Porter FD. Effects of 2-hydroxypropyl-beta-cyclodexrin (HP-B-CD, VTS-270) in children with NPC1 age 5 and under and comparison to natural history. Michael, Marcia & Christa Parseghian Scientific Conference, Tucson, AZ, June 2019.
10. Berry-Kravis E, Johnson R, Chin J, Friedmann K, Jaeger R, Farhat N, Bianconi S, Porter FD. Evidence for long-term efficacy of intrathecal adrabetadex for the treatment of neurological decline in patients with Niemann-Pick disease, type C1, Platform presentation, WORLD Conference, February 2021.
11. Cortina-Borja M, Vruchte D, Mengel E, Amraoui Y, Imrie J, Jones S, et al. Annual severity increment score as a tool for stratifying patients with Niemann-Pick disease type C and for recruitment to clinical trials. Orphanet J Rare Dis. 2018;13.
12. Berry-Kravis E, Johnson R, Chin J, Friedmann K, Jaeger R, Farhat N, Bianconi S, Porter FD. Evidence for long-term efficacy of intrathecal adrabetadex for the treatment of neurological decline in very young and older patients with Niemann-Pick disease, type C1. National Niemann-Pick Disease Foundation virtual conference, July 2021.
13. Mengel E, Pineda M, Hendriksz CJ, Walterfang M, Torres JV, Kolb SA. Differences in Niemann- Pick disease Type C symptomatology observed in patients of different ages. Mol Genet Metab 2017;120:180?189.
14. Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol. 2007;6:765?772
15. Patterson MC, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luzy C, et al. Long-term miglustat therapy in children with Niemann-Pick disease type C. J Child Neurol. 2010;25:300?305.
16. Patterson MC, Mengel E, Vanier MT, Moneuse P, Rosenberg D, Pineda M. Treatment outcomes following continuous miglustat therapy in patients with Niemann-Pick disease Type C: a final report of the NPC Registry. Orphanet Journal of Rare Diseases 2020;15:104.
17. Patterson MC, Garver WS, Giugliani R, Imrie J, Jahnova H, Meaney FJ, et al. Long-term survival outcomes of patients with Niemann-Pick disease type C receiving miglustat treatment: A large retrospective observational study. J Inherit Metab Dis. 2020 Apr 23. doi: 10.1002/jimd.12245
18. Solomon BI, Smith AC, Sinaii N, Farhat N, King MC, Machielse L, Porter FD. Association of Miglustat With Swallowing Outcomes in Niemann-Pick Disease, Type C1. JAMA Neurol. 2020 Dec 1;77(12):1564-1568.
19. Geberhiwot T, Moro A, Dardis A, Ramaswami U, Sirrs S, Marfa MP, et al. International Niemann-Pick Disease Registry (INPDR). Consensus clinical management guidelines for Niemann-Pick disease type C. Orphanet J Rare Dis 2018;13:50.
20. Runz H, Dolle D, Schlitter AM, Zschocke J. NPC-db, a Niemann-Pick type C disease gene variation database. Hum Mutat 2008;29:345?350.
21. VTS301: https://clinicaltrials.gov/ct2/show/NCT02534844?cond=niemann-Pick+type+C…, https://clinicaltrials.gov/ct2/show/NCT04958642?cond=niemann-Pick+type+C… ; VTS302: https://clinicaltrials.gov/ct2/show/NCT03879655?cond=niemann-Pick+type+C… VTS001: https://clinicaltrials.gov/ct2/show/NCT03643562?cond=niemann-Pick+type+C…
22. Thurm A, Chlebowski C, Joseph L, Farmer C, Adedipe D, Weiss M, Wiggs E, Farhat N, Bianconi S, Berry-Kravis E, Porter FD. Neurodevelopmental characterization of young children diagnosed with Niemann-Pick Disease, Type C1. J Dev Behav Pediatr. 2020;41:388-396.
23. 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;58:262-269.
24. 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;153:132?140.
25. Patterson MC, Lloyd-Price L, Guldberg C, Doll H, Burbridge C, Chladek M, Dali C, Mengel E, Symonds T. Validation of the 5-domain Niemann-Pick type C Clinical Severity Scale. Orphanet J Rare Dis. 2021 Feb 12;16(1):79.
26. Jiang X, Sidhu R, Mydock-McGrane L, Hsu FF, Covey DF, Scherrer DE, et al. Development of a bile acid based newborn screen for Niemann-Pick disease type C. Sci Transl Med. 2016;8:337ra63.
27. Sidhu R, Kell P, Dietzen DJ, Farhat NY, Do AND, Porter FD, Berry-Kravis E, Reunert J, Marquardt T, Giugliani R, Loureno CM, Wang RY, Movsesyan N, Plummer E, Schaffer JE, Ory DS, Jiang X. Application of a glycinated bile acid biomarker for diagnosis and assessment of response to treatment in Niemann-pick disease type C1. Mol Genet Metab. 2020 Dec;131(4):405-417.
28. Rodriguez-Gil JL, Baxter LL, Watkins-Chow DE, Johnson NL, Davidson CD, Carlson SR, Incao AA; NISC Comparative Sequencing Program, Wallom KL, Farhat NY, Platt FM, Dale RK, Porter FD, Pavan WJ. Transcriptome of HP?CD-treated Niemann-pick disease type C1 cells highlights GPNMB as a biomarker for therapeutics. Hum Mol Genet. 2021 Jul 22:ddab194. doi: 10.1093/hmg/ddab194. Epub ahead of print. PMID: 34296265.