Rimeporide as a first- in-class NHE-1 inhibitor : Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy
Previtali, Stefano C. (IRCCS San Raffaele Scientific Institute (Milà, Itàlia))
Gidaro, Teresa (Hopital Trousseau)
Diaz-Manera, Jordi (Institut d'Investigació Biomèdica Sant Pau)
Zambon, Alberto (IRCCS San Raffaele Scientific Institute (Milà, Itàlia))
Carnesecchi, Stephanie (Geneva University (UNIGE))
Roux-Lombard, Pascale (Geneva University Hospitals)
Spitali, Pietro (Leiden University Medical Center)
Signorelli, Mirko (Leiden University Medical Center)
Szigyarto, Cristina Al-Khalili (Kungl. Tekniska högskolan (Estocolm (Suècia))
Johansson, Camilla (Science for Life Laboratory)
Gray, Julian (EspeRare)
Labolle, Delphine (EspeRare)
Porte Thomé, Florence (EspeRare)
Pitchforth, Jacqueline (UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital Dubowitz Neuromuscular Centre)
Domingos, Joana (UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital Dubowitz Neuromuscular Centre)
Muntoni, Francesco (University College London)
Universitat Autònoma de Barcelona

Data:	2020
Resum:	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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cardiomyopathy ; Duchenne Muscular Dystrophy ; NHE-1 ; Pharmacokinetic ; Rimeporide ; Safety
Publicat a:	Pharmacological Research, Vol. 159 (september 2020) , p. 104999, ISSN 1096-1186

DOI: 10.1016/j.phrs.2020.104999
PMID: 32535224

10 p, 813.6 KB

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