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

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

Authors :
Previtali, Stefano C.
Gidaro, Teresa
Diaz-Manera, Jordi
Zambon, Alberto
Carnesecchi, Stephanie
Roux-Lombard, Pascale
Spitali, Pietro
Signorelli, Mirko
Al-Khalili Szigyarto, Cristina
Johansson, Camilla
Gray, Julian
Labolle, Delphine
Thome, Florence Porte
Pitchforth, Jacqueline
Domingos, Joana
Muntoni, Francesco
Previtali, Stefano C.
Gidaro, Teresa
Diaz-Manera, Jordi
Zambon, Alberto
Carnesecchi, Stephanie
Roux-Lombard, Pascale
Spitali, Pietro
Signorelli, Mirko
Al-Khalili Szigyarto, Cristina
Johansson, Camilla
Gray, Julian
Labolle, Delphine
Thome, Florence Porte
Pitchforth, Jacqueline
Domingos, Joana
Muntoni, Francesco
Publication Year :
2020

Abstract

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.<br />QC 20201007

Details

Database :
OAIster
Notes :
English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1235087157
Document Type :
Electronic Resource
Full Text :
https://doi.org/10.1016.j.phrs.2020.104999