Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment
Gascon Bayarri, Jordi (Hospital Universitari de Bellvitge)
Simon, Petru Cristian (Hospital Universitari de Bellvitge)
Llop, Roser (Hospital Universitari de Bellvitge)
Carnaval, Thiago (Hospital Universitari de Bellvitge)
Ledesma, María Dolores (Centro de Biología Molecular Severo Ochoa)
Rico, Imma (Hospital Universitari de Bellvitge)
Sánchez-Castañeda, Cristina (Hospital Universitari de Bellvitge)
Campdelacreu, Jaume (Hospital Universitari de Bellvitge)
Calvo-Malvar, Nahum (Hospital Universitari de Bellvitge)
Cos, Mònica (Hospital Universitari de Bellvitge)
de Lama, Eugenia (Hospital Universitari de Bellvitge)
Cortés-Romera, Montserrat (Hospital Universitari de Bellvitge)
Rodríguez-Bel, Laura (Hospital Universitari de Bellvitge)
Pérez-Sousa, Celia (Complejo Hospitalario Universitario de A Coruña)
Cerdán Sánchez, María (Hospital General Universitario Santa María del Rosell)
Muelas, Nuria (Hospital Universitari i Politècnic La Fe (València))
Sevillano, María Dolores (Hospital Universitario de Salamanca)
Mir, Pablo (Universidad de Sevilla)
Lopez de Munain, Adolfo (Hospital de Donostia (Sant Sebastià, País Basc))
Ferrer, Anna (Hospital Universitari de Bellvitge)
Videla, Sebastián (Hospital Universitari de Bellvitge)
Universitat Autònoma de Barcelona

Data:	2022
Resum:	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®) 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. 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. 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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cognitive impairment ; Efavirenz ; Niemann-pick disease type C ; NPC1
Publicat a:	Medicine, Vol. 101 (december 2022) , ISSN 1536-5964

DOI: 10.1097/MD.0000000000031471
PMID: 36482560

10 p, 841.1 KB

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