Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy
Por:
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
Publicada:
1 sep 2020
Resumen:
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.
Filiaciones:
Previtali, SC:
IRCCS, Dept Neurol, San Raffaele Sci Inst, Milan, Italy
IRCCS, INSPE, San Raffaele Sci Inst, Milan, Italy
Gidaro, T:
Hop Trousseau, I Motion, Inst Myol, Paris, France
Diaz-Manera, J:
Hosp Santa Creu i St Pau Barcelona Serv Neurol, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain
Zambon, A:
IRCCS, Dept Neurol, San Raffaele Sci Inst, Milan, Italy
IRCCS, INSPE, San Raffaele Sci Inst, Milan, Italy
Carnesecchi, S:
Geneva Univ UNIGE, Geneva, Switzerland
Roux-Lombard, P:
Geneva Univ Hosp HUG, Immunol & Allergol Dept, Geneva, Switzerland
Spitali, P:
Leiden Univ, Med Ctr, Leiden, Netherlands
Signorelli, M:
Leiden Univ, Med Ctr, Leiden, Netherlands
Szigyarto, CAK:
Royal Inst Technol, Sch Chem, KTH, Biotechnol & Hlth, Stockholm, Sweden
Johansson, C:
Dept Prot Sci, Div Syst Biol, Sci Life Lab, Solna, Sweden
Gray, J:
EspeRare, Campus Biotech,Innovat Pk,15 Ave Secheron, CH-1202 Geneva, Switzerland
Labolle, D:
EspeRare, Campus Biotech,Innovat Pk,15 Ave Secheron, CH-1202 Geneva, Switzerland
Thome, FP:
EspeRare, Campus Biotech,Innovat Pk,15 Ave Secheron, CH-1202 Geneva, Switzerland
Pitchforth, J:
UCL Great Ormond St Inst Child Hlth, London, England
Great Ormond St Hosp Sick Children, Dubowitz Neuromuscular Ctr, London, England
Domingos, J:
UCL Great Ormond St Inst Child Hlth, London, England
Great Ormond St Hosp Sick Children, Dubowitz Neuromuscular Ctr, London, England
Muntoni, F:
UCL Great Ormond St Inst Child Hlth, London, England
Great Ormond St Hosp Sick Children, Dubowitz Neuromuscular Ctr, London, England
UCL, NIHR Great Ormond St Hosp, Biomed Res Ctr, Ormond St Inst Child Hlth,Great Ormond St Hosp Tr, London, England
Green Published, Hybrid Gold
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