Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment

Background:Niemann-Pick disease Type C (NPC) is a genetic, incurable, neurodegenerative disorder. This orphan disease is most frequently caused by mutations in the NPC1 protein, resulting in intralysossomal cholesterol accumulation. NPC1 is found in neuronal cell bodies, axon terminals and synaptoso...

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Autores: Gascón Bayarri, Jordi, Simon, Petru Cristian, Llop, Roser, Carnaval, Thiago, Ledesma, María Dolores, Rico, Imma, Sánchez Castañeda, Cristina, Campdelacreu Fumadó, Jaume, Calvo Malvar, Nahum, Cos, Mònica, De Lama, Eugenia, Cortés Romera, Montserrat, Rodríguez Bel, Laura, Pérez Sousa, Celia, Cerdán Sánchez, María, Muelas, Nuria, Sevillano, María Dolores, Mir, Pablo, López de Munain Arregui, Adolfo José, Ferrer, Anna, Videla, Sebastián
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/59488
Acceso en línea:http://hdl.handle.net/10810/59488
Access Level:acceso abierto
Palabra clave:cognitive impairment
efavirenz
Niemann-pick disease type C
NPC1
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spelling Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairmentGascón Bayarri, JordiSimon, Petru CristianLlop, RoserCarnaval, ThiagoLedesma, María DoloresRico, ImmaSánchez Castañeda, CristinaCampdelacreu Fumadó, JaumeCalvo Malvar, NahumCos, MònicaDe Lama, EugeniaCortés Romera, MontserratRodríguez Bel, LauraPérez Sousa, CeliaCerdán Sánchez, MaríaMuelas, NuriaSevillano, María DoloresMir, PabloLópez de Munain Arregui, Adolfo JoséFerrer, AnnaVidela, Sebastiáncognitive impairmentefavirenzNiemann-pick disease type CNPC1Background:Niemann-Pick disease Type C (NPC) is a genetic, incurable, neurodegenerative disorder. This orphan disease is most frequently caused by mutations in the NPC1 protein, resulting in intralysossomal cholesterol accumulation. NPC1 is found in neuronal cell bodies, axon terminals and synaptosomes, suggesting it plays a role in lysosomal degradation pathway and in synaptic transmission. Neuronal function is especially vulnerable to NPC1 deficiency and synaptic changes seem a key element in disease development. Currently, Miglustat (Zavesca (R)) is the only approved treatment for NPC. However, preclinical evidence showed that low-dose Efavirenz reverted synaptic defects through pharmacological activation of the enzyme CYP46. Methods:This is a single-center, phase II clinical trial to evaluate the efficacy and safety of Efavirenz in addition to standard of care in patients diagnosed with adult or late juvenile-onset NPC with cognitive impairment. All enrolled patients will be treated orally with 25 mg/d of Efavirenz for 52 weeks (1 year). Secondary objectives include evaluating clinical (neurological and neuropsychological questionnaires) and biological (imaging and biochemical biomarkers) parameters. Discussion:NPC is still an unmet medical need. Although different therapeutic approaches are under study, this is the first clinical trial (to the best of our knowledge) studying the effects of Efavirenz in adult- and late-juvenile-onset NPC. Despite the small sample size and the single-arm design, we expect the results to show Efavirenz's capacity of activating the CYP46 enzyme to compensate for NPC1 deficiency and correct synaptic changes, therefore compensating cognitive and psychiatric changes in these patients. This study may provide direct benefit to enrolled patients in terms of slowing down the disease progression.We thank the Spanish Niemann-Pick Foundation for provid-ing financial support. We also thank the Bellvitge University Hospital, IDIBELL and CERCA Program/Generalitat de Catalunya for institutional support.Wolters Kluwer Health202320232022info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/59488reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoIngléshttps://journals.lww.com/md-journal/Fulltext/2022/12020/Efficacy_and_safety_clinical_trial_with_efavirenz.45.aspxinfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/3.0/es/© 2022 the Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Atribución 3.0 Españaoai:addi.ehu.eus:10810/594882026-06-18T09:23:17Z
dc.title.none.fl_str_mv Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment
title Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment
spellingShingle Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment
Gascón Bayarri, Jordi
cognitive impairment
efavirenz
Niemann-pick disease type C
NPC1
title_short Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment
title_full Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment
title_fullStr Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment
title_full_unstemmed Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment
title_sort Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment
dc.creator.none.fl_str_mv Gascón Bayarri, Jordi
Simon, Petru Cristian
Llop, Roser
Carnaval, Thiago
Ledesma, María Dolores
Rico, Imma
Sánchez Castañeda, Cristina
Campdelacreu Fumadó, Jaume
Calvo Malvar, Nahum
Cos, Mònica
De Lama, Eugenia
Cortés Romera, Montserrat
Rodríguez Bel, Laura
Pérez Sousa, Celia
Cerdán Sánchez, María
Muelas, Nuria
Sevillano, María Dolores
Mir, Pablo
López de Munain Arregui, Adolfo José
Ferrer, Anna
Videla, Sebastián
author Gascón Bayarri, Jordi
author_facet Gascón Bayarri, Jordi
Simon, Petru Cristian
Llop, Roser
Carnaval, Thiago
Ledesma, María Dolores
Rico, Imma
Sánchez Castañeda, Cristina
Campdelacreu Fumadó, Jaume
Calvo Malvar, Nahum
Cos, Mònica
De Lama, Eugenia
Cortés Romera, Montserrat
Rodríguez Bel, Laura
Pérez Sousa, Celia
Cerdán Sánchez, María
Muelas, Nuria
Sevillano, María Dolores
Mir, Pablo
López de Munain Arregui, Adolfo José
Ferrer, Anna
Videla, Sebastián
author_role author
author2 Simon, Petru Cristian
Llop, Roser
Carnaval, Thiago
Ledesma, María Dolores
Rico, Imma
Sánchez Castañeda, Cristina
Campdelacreu Fumadó, Jaume
Calvo Malvar, Nahum
Cos, Mònica
De Lama, Eugenia
Cortés Romera, Montserrat
Rodríguez Bel, Laura
Pérez Sousa, Celia
Cerdán Sánchez, María
Muelas, Nuria
Sevillano, María Dolores
Mir, Pablo
López de Munain Arregui, Adolfo José
Ferrer, Anna
Videla, Sebastián
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv cognitive impairment
efavirenz
Niemann-pick disease type C
NPC1
topic cognitive impairment
efavirenz
Niemann-pick disease type C
NPC1
description Background:Niemann-Pick disease Type C (NPC) is a genetic, incurable, neurodegenerative disorder. This orphan disease is most frequently caused by mutations in the NPC1 protein, resulting in intralysossomal cholesterol accumulation. NPC1 is found in neuronal cell bodies, axon terminals and synaptosomes, suggesting it plays a role in lysosomal degradation pathway and in synaptic transmission. Neuronal function is especially vulnerable to NPC1 deficiency and synaptic changes seem a key element in disease development. Currently, Miglustat (Zavesca (R)) is the only approved treatment for NPC. However, preclinical evidence showed that low-dose Efavirenz reverted synaptic defects through pharmacological activation of the enzyme CYP46. Methods:This is a single-center, phase II clinical trial to evaluate the efficacy and safety of Efavirenz in addition to standard of care in patients diagnosed with adult or late juvenile-onset NPC with cognitive impairment. All enrolled patients will be treated orally with 25 mg/d of Efavirenz for 52 weeks (1 year). Secondary objectives include evaluating clinical (neurological and neuropsychological questionnaires) and biological (imaging and biochemical biomarkers) parameters. Discussion:NPC is still an unmet medical need. Although different therapeutic approaches are under study, this is the first clinical trial (to the best of our knowledge) studying the effects of Efavirenz in adult- and late-juvenile-onset NPC. Despite the small sample size and the single-arm design, we expect the results to show Efavirenz's capacity of activating the CYP46 enzyme to compensate for NPC1 deficiency and correct synaptic changes, therefore compensating cognitive and psychiatric changes in these patients. This study may provide direct benefit to enrolled patients in terms of slowing down the disease progression.
publishDate 2022
dc.date.none.fl_str_mv 2022
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/59488
url http://hdl.handle.net/10810/59488
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://journals.lww.com/md-journal/Fulltext/2022/12020/Efficacy_and_safety_clinical_trial_with_efavirenz.45.aspx
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/3.0/es/
Atribución 3.0 España
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/3.0/es/
Atribución 3.0 España
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Wolters Kluwer Health
publisher.none.fl_str_mv Wolters Kluwer Health
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.300719

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