Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy

Rimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophys...

Descripción completa

Detalles Bibliográficos
Autores: Previtali, SC, Gidaro, T, Diaz-Manera, J, Zambon, A, Carnesecchi, S, Roux-Lombard, P, Spitali, P, Signorelli, M, Szigyarto, CAK, Johansson, C, Gray, J, Labolle, D, Thome, FP, Pitchforth, J, Domingos, J, Muntoni, F
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p1473
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=1473
Access Level:acceso abierto
Palabra clave:Duchenne Muscular Dystrophy
NHE-1
Rimeporide
Safety
Pharmacokinetic
Cardiomyopathy
id ES_f37cf38b0ebaaaf06d97eecc1dd43dbe
oai_identifier_str oai:iibsantpau.fundanetsuite.com:p1473
network_acronym_str ES
network_name_str España
repository_id_str
spelling Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular DystrophyPrevitali, SCGidaro, TDiaz-Manera, JZambon, ACarnesecchi, SRoux-Lombard, PSpitali, PSignorelli, MSzigyarto, CAKJohansson, CGray, JLabolle, DThome, FPPitchforth, JDomingos, JMuntoni, FDuchenne Muscular DystrophyNHE-1RimeporideSafetyPharmacokineticCardiomyopathyRimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophysiological mechanisms in Congestive Heart Failure (CHF) and in cardiomyopathy in DMD, therefore NHE-1 inhibition could be a promising pharmacological approach to the cardiac dysfunctions observed in DMD. Extensive preclinical data was collected in various animal models including dystrophin-deficient (mdx) mice to characterise Rimeporide's anti-fibrotic and anti-inflammatory properties and there is evidence that NHE-1 inhibitors could play a significant role in modifying DMD cardiac and also skeletal pathologies, as the NHE-1 isoform is ubiquitous. We report here the first study with Rimeporide in DMD patients. This 4-week treatment, open label phase Ib, multiple oral ascending dose study, enrolled 20 ambulant boys with DMD (6-11 years), with outcomes including safety, pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. Rimeporide was safe and well-tolerated at all doses. PK evaluations showed that Rimeporide was well absorbed orally reaching pharmacological concentrations from the lowest dose, with exposure increasing linearly with dose and with no evidence of accumulation upon repeated dosing. Exploratory PD biomarkers showed positive effect upon a 4-week treatment, supporting its therapeutic potential in patients with DMD, primarily as a cardioprotective treatment, and provide rationale for further efficacy studies.ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=1473PHARMACOLOGICAL RESEARCHISSN: 10436618ISSNe: 10961186reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p14732026-06-14T12:41:47Z
dc.title.none.fl_str_mv Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy
title Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy
spellingShingle Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy
Previtali, SC
Duchenne Muscular Dystrophy
NHE-1
Rimeporide
Safety
Pharmacokinetic
Cardiomyopathy
title_short Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy
title_full Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy
title_fullStr Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy
title_full_unstemmed Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy
title_sort Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy
dc.creator.none.fl_str_mv Previtali, SC
Gidaro, T
Diaz-Manera, J
Zambon, A
Carnesecchi, S
Roux-Lombard, P
Spitali, P
Signorelli, M
Szigyarto, CAK
Johansson, C
Gray, J
Labolle, D
Thome, FP
Pitchforth, J
Domingos, J
Muntoni, F
author Previtali, SC
author_facet Previtali, SC
Gidaro, T
Diaz-Manera, J
Zambon, A
Carnesecchi, S
Roux-Lombard, P
Spitali, P
Signorelli, M
Szigyarto, CAK
Johansson, C
Gray, J
Labolle, D
Thome, FP
Pitchforth, J
Domingos, J
Muntoni, F
author_role author
author2 Gidaro, T
Diaz-Manera, J
Zambon, A
Carnesecchi, S
Roux-Lombard, P
Spitali, P
Signorelli, M
Szigyarto, CAK
Johansson, C
Gray, J
Labolle, D
Thome, FP
Pitchforth, J
Domingos, J
Muntoni, F
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Duchenne Muscular Dystrophy
NHE-1
Rimeporide
Safety
Pharmacokinetic
Cardiomyopathy
topic Duchenne Muscular Dystrophy
NHE-1
Rimeporide
Safety
Pharmacokinetic
Cardiomyopathy
description Rimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophysiological mechanisms in Congestive Heart Failure (CHF) and in cardiomyopathy in DMD, therefore NHE-1 inhibition could be a promising pharmacological approach to the cardiac dysfunctions observed in DMD. Extensive preclinical data was collected in various animal models including dystrophin-deficient (mdx) mice to characterise Rimeporide's anti-fibrotic and anti-inflammatory properties and there is evidence that NHE-1 inhibitors could play a significant role in modifying DMD cardiac and also skeletal pathologies, as the NHE-1 isoform is ubiquitous. We report here the first study with Rimeporide in DMD patients. This 4-week treatment, open label phase Ib, multiple oral ascending dose study, enrolled 20 ambulant boys with DMD (6-11 years), with outcomes including safety, pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. Rimeporide was safe and well-tolerated at all doses. PK evaluations showed that Rimeporide was well absorbed orally reaching pharmacological concentrations from the lowest dose, with exposure increasing linearly with dose and with no evidence of accumulation upon repeated dosing. Exploratory PD biomarkers showed positive effect upon a 4-week treatment, supporting its therapeutic potential in patients with DMD, primarily as a cardioprotective treatment, and provide rationale for further efficacy studies.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=1473
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=1473
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
publisher.none.fl_str_mv ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
dc.source.none.fl_str_mv PHARMACOLOGICAL RESEARCH
ISSN: 10436618
ISSNe: 10961186
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869424381921329152
score 15,81155

Similares en LA Referencia