Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHYOX1) in primary hyperoxaluria

Höppe, Bernd; Koch, Annelize; Cochat, Pierre; Garrelfs, Sander F.; Baum, Michelle A.; Groothoff, Jaap W.; Lipkin, Graham; Coenen, Martin; Schalk, Gesa; Amrite, Aniruddha; McDougall, David; Barrios, Kelly; Langman, Craig B.

doi:10.1016/j.kint.2021.08.015

Cited by 62 publications

(99 citation statements)

References 32 publications

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“…First new treatment available are the RNA interference (RNAi) medications, which became available early 2021. RNAi selectively blocks the endogenous oxalate production in the liver by silencing either glycolate oxidase (GO, upstream pathway, Oxlumo TM , for PH 1), or liver specific lactate dehydrogenase A (LDHA, downstream pathway, Nedosiran, theoretically for PH1-3), ( 37 , 38 ). The oxalate-degrading bacteria (Oxalobacter) included in the first-in-class product Oxabact using oxalate as its sole source of energy were extensively studied in patients with PH.…”

Section: Immunological Mechanisms In Kidney Fibrosismentioning

confidence: 99%

New Aspects of Kidney Fibrosis–From Mechanisms of Injury to Modulation of Disease

et al. 2022

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Organ fibrogenesis is characterized by a common pathophysiological final pathway independent of the underlying progressive disease of the respective organ. This makes it particularly suitable as a therapeutic target. The Transregional Collaborative Research Center “Organ Fibrosis: From Mechanisms of Injury to Modulation of Disease” (referred to as SFB/TRR57) was hosted from 2009 to 2021 by the Medical Faculties of RWTH Aachen University and the University of Bonn. This consortium had the ultimate goal of discovering new common but also different fibrosis pathways in the liver and kidneys. It finally successfully identified new mechanisms and established novel therapeutic approaches to interfere with hepatic and renal fibrosis. This review covers the consortium's key kidney-related findings, where three overarching questions were addressed: (i) What are new relevant mechanisms and signaling pathways triggering renal fibrosis? (ii) What are new immunological mechanisms, cells and molecules that contribute to renal fibrosis?, and finally (iii) How can renal fibrosis be modulated?

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Section: Immunological Mechanisms In Kidney Fibrosismentioning

confidence: 99%

New Aspects of Kidney Fibrosis–From Mechanisms of Injury to Modulation of Disease

et al. 2022

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“…However, our therapeutic strategy to inhibit LHD would help to overcome some of the limitations observed with siRNA approaches. In particular, our approach would avoid the requirement of multiple administrations for long-term effect, 14 , 18 , 19 because of the transient effect of siRNAs, which would represent a clear benefit in the quality of life of patients and their families.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the recently completed clinical trial PHYOX1 (ClinicalTrials.gov: NCT03392896) evaluating Nedosiran, an investigational RNAi therapy targeting LDHA, demonstrated some evidence of pharmacodynamic effect, in both PH1 and PH2 subpopulations, with acceptable safety. 19 However, siRNAs or small molecules have several limitations, such as the requirement of multiple administrations for long-term effect or the incomplete inhibition of the target enzyme.…”

Section: Introductionmentioning

confidence: 99%

In vivo CRISPR-Cas9 inhibition of hepatic LDH as treatment of primary hyperoxaluria

Martínez-Turrillas

Martin-Mallo

Rodríguez-Diaz

et al. 2022

Molecular Therapy - Methods & Clinical Development

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“…fda. gov/ news-events/ press-annou nceme nts/ fda-appro ves-first-drug-treat-rare-metab olic-disor der), while a second one (Nedosiran that inhibits production of the hepatic lactate dehydrogenase (LDH) enzyme, involved in the conversion of glyoxylate to oxalate) is currently being evaluated in clinical trials for all three types of PH (NCT04580420; NCT03847909; NCT04042402; NCT04555486, NCT05001269) [30]. Therefore, it is crucial for PH patients to be properly diagnosed and treated with the most appropriate therapy based on their individual mutations and clinical status [31].…”

Section: Discussionmentioning

confidence: 99%

Primary hyperoxaluria in Italy: the past 30 years and the near future of a (not so) rare disease

et al. 2022

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Background Primary hyperoxalurias (PHs) are rare autosomal recessive diseases of the glyoxylate metabolism; PH1 is caused by mutations in the AGXT gene, PH2 in GRHPR and PH3 in HOGA1. Methods Here we report the first large multi-center cohort of Italian PH patients collected over 30 years (1992–2020 median follow-up time 8.5 years). Complete genotype was available for 94/95 PH1 patients and for all PH2 (n = 3) and PH3 (n = 5) patients. Symptoms at onset were mainly nephrolithiasis (46.3%) and nephrocalcinosis (33.7%). Median age at onset of symptoms and diagnosis were 4.0 years and 9.9 years, respectively. Results Fifty-four patients (56.8%) were diagnosed after chronic kidney disease. Sixty-three patients (66.3%) developed end stage kidney disease (median age 14.0 years). Twenty-one patients had a kidney-only transplant and, among them, seven had a second kidney transplant combined with liver transplant. A combined kidney–liver transplant was carried out in 29 patients and a sequential kidney–liver transplant was performed in two. In five cases a preemptive liver transplant was performed. Those receiving a liver-only transplant tended to have lower kidney function at last follow-up. Conclusion Our study of PHs in Italy underlines a considerable diagnostic delay, which has only slightly decreased in recent years. Therefore, we suggest a more extensive use of both metabolic screening among patients with recurrent kidney stones and genotyping, including unambiguous assignment of minor/major allele status in order to promptly begin appropriate treatment. This will be fundamental in order to have access to the new therapies, which are mainly focused on substrate reduction for the oxalate-producing enzymes using RNA-interference. Graphical abstract

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Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHYOX1) in primary hyperoxaluria

Cited by 62 publications

References 32 publications

New Aspects of Kidney Fibrosis–From Mechanisms of Injury to Modulation of Disease

New Aspects of Kidney Fibrosis–From Mechanisms of Injury to Modulation of Disease

In vivo CRISPR-Cas9 inhibition of hepatic LDH as treatment of primary hyperoxaluria

Primary hyperoxaluria in Italy: the past 30 years and the near future of a (not so) rare disease

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