Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2025 Jun;40(6):1939-1948.
doi: 10.1007/s00467-025-06675-8. Epub 2025 Jan 28.

Nedosiran in pediatric patients with PH1 and relatively preserved kidney function, a phase 2 study (PHYOX8)

David J Sas  1   2   3 , Sevcan A Bakkaloglu  4 , Vladimir Belostotsky  5 , Wesley Hayes  6 , Gema Ariceta  7 , Jing Zhou  8 , Verity Rawson  8
Affiliations
Clinical Trial

Nedosiran in pediatric patients with PH1 and relatively preserved kidney function, a phase 2 study (PHYOX8)

David J Sas et al. Pediatr Nephrol. 2025 Jun.

Abstract

Background: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder with dysregulated glyoxylate metabolism in the liver. Oxalate over-production leads to renal stones, progressive kidney damage and renal failure, with potentially life-threatening systemic oxalosis. Nedosiran is a synthetic RNA interference therapy, designed to reduce hepatic lactate dehydrogenase (LDH) to decrease oxalate burden in PH.

Methods: Currently, in the PHYOX8 study (NCT05001269), pediatric participants (2-11 years) with PH1 (N = 15) and estimated glomerular filtration rate (eGFR) ≥ 30mL/min/1.73m2 received nedosiran once monthly for 6 months.

Results: Urinary oxalate:creatinine (Uox:Ucr) levels reduced by 64% on average. Mean Uox:Ucr reduction was 52% at day 60 and ˃60% at day 180. At one or more study visits, 93.3% (N = 14) of participants reached Uox:Ucr < 1.5 × upper limit of normal (ULN), and 53.3% (N = 8) reached ≤ 1.0 × ULN. Median percent change in plasma oxalate (12.0 µmol/L at baseline) to day 180 was -39.23% (n = 10). Average number of kidney stones per participant remained stable, whilst a 10.1% average decrease in summed surface area was observed. Median percent change from baseline in eGFR was 2.5%, indicating preservation of renal function.

Conclusions: Nedosiran was well tolerated, with only 3 participants experiencing at least one serious adverse event, none considered treatment-related. The incidence of injection site reactions was 6.7% (1/15 participants). In conclusion, nedosiran treatment led to a significant and sustained reduction of Uox levels in children with PH1. These findings support nedosiran treatment in pediatric patients to reduce Uox and shows promise for limiting PH1-related complications.

Keywords: Chronic kidney disease; Gene expression; Hyperoxaluria; Pediatric nephrology; RNAi; Urology.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethical considerations: The PHYOX8 study was approved by the (local) IRB: Dubai Scientific Research Ethics Committee (DSREC; United Arab Emirates—DSREC-01/2023_07); Hamilton Integrated Research Ethics Board (Canada—REB-ProID_13895); Heidelburg University Ethics Committee of the Med. Faculty (Germany—AFmu-511/2021); Hospital Germans Trias i Pujol (Spain—AC-21–081-EXT-CEIM); South Central—Hampshire A Research Ethics Committee (England—21/SC/0222); Ospedale Pediatrico Bambino Gesu (Italy—2550–10/2021); Nagoya City University Institutional Review Board (Japan); Institutional Review Board Kurume University Hospital Clinical Trial Review Board (Japan—no specific approval number); Comité d’éthique Hôtel-Dieu de France (Lebanon—CEHDF 1860); Białystok Medical University (Poland—APK.002.316.2021), Gazi University Medical Faculty Clinical Trials Ethics Committee (Turkey—no specific approval number); Western-Copernicus Group (WCG; United States—21–005579). Competing interests: DJS has received research funding from Alnylam and Novo Nordisk and consulting fees from Advicenne Pharmaceuticals. SAB and VB have no conflict of interests. WH has received research funding from the National Institute for Health Research (NIHR) and honoraria from Alnylam. JZ and VR are employees and shareholders of Novo Nordisk. GA is a consultant for and has received honoraria from AstraZeneca Alexion, Recordati, Chiesi, Kyowa Kirin, and Advicenne; is a consultant for Novo Nordisk and Alnylam; and is a scientific advisor for AstraZeneca Alexion.

Figures

None
A higher resolution version of the Graphical abstract is available as Supplementary information
Fig. 1
Fig. 1
PHYOX8 study overview. Participant overview and study interventions. Physical examination included height/length, weight, inspection of injection site(s), and review of body systems. Vital signs on Day 1 and Day 30 were assessed pre-dose and at 6 h post-dose. On Days 1 and 30, ECG was performed pre-dose and at 6 h post-dose. Clinical laboratory included: hematology (e.g., platelet count), clinical chemistry (e.g., creatinine), coagulation, and urinalysis evaluations. Spot urine samples were collected for the determination of Uox and Ucr. At screening, 6 spot urine samples (3 of which were second morning voids) were collected over a 3-day period. On treatment, 4 spot urine samples (2 of which were second morning voids) were collected over a 2-day period monthly. Two-dimensional surface area of renal stones, measured via kidney ultrasound was performed at baseline and day 180. The kidneys were examined in the longitudinal (sagittal) and transverse scan planes, with images acquired in both the supine and prone positions. A linear array transducer with higher centre frequencies was used. Participants should have had a full bladder during image acquisition. Ultrasound data was transmitted to a standalone central imaging vendor, where qualified personnel performed central overread of all images. Abbreviations: PH1, primary hyperoxaluria type 1; PE, physical examination; ECG, electrocardiogram; PK, pharmacokinetics; EOS, end of study; Uox, urinary oxalate; Ucr, urinary creatinine
Fig. 2
Fig. 2
Percent change from baseline in spot Uox:Ucr ratio over time. Patients (N) represent the number of participants assessed at each time point. Abbreviations: SEM, standard error of the mean; EOS, end of study
Fig. 3
Fig. 3
Mean plot for spot Uox:Ucr ratio over time by age group. Patients (N) represent the number of participants assessed at each time point. Abbreviations: SEM, standard error of the mean; EOS, end of study
Fig. 4
Fig. 4
Percentage of participants with ≤ 1.0 × ULN or < 1.5 × ULN of Uox:Ucr excretion throughout the study. Data represent the average of 4 sample/visit. Abbreviations: ULN, upper limit of normal; SEM, standard error of the mean; EOS, end of study
See this image and copyright information in PMC

References

    1. Hoppe B (2012) An update on primary hyperoxaluria. Nat Rev Nephrol 8:467–475 - PubMed
    1. Cochat P, Hulton SA, Acquaviva C, Danpure CJ, Daudon M, De Marchi M, Fargue S, Groothoff J, Harambat J, Hoppe B, Jamieson NV, Kemper MJ, Mandrile G, Marangella M, Picca S, Rumsby G, Salido E, Straub M, van Woerden CS, OxalEurope (2012) Primary hyperoxaluria Type 1: indications for screening and guidance for diagnosis and treatment. Nephrol Dial Transplant 27:1729–1736 - PubMed
    1. Cochat P, Rumsby G (2013) Primary hyperoxaluria. N Engl J Med 369:649–658 - PubMed
    1. Edvardsson VO, Goldfarb DS, Lieske JC, Beara-Lasic L, Anglani F, Milliner DS, Palsson R (2013) Hereditary causes of kidney stones and chronic kidney disease. Pediatr Nephrol 28:1923–1942 - PMC - PubMed
    1. Garrelfs SF, Rumsby G, Peters-Sengers H, Erger F, Groothoff JW, Beck BB, Oosterveld MJS, Pelle A, Neuhaus T, Adams B, Cochat P, Salido E, Lipkin GW, Hoppe B, Hulton SA, OxalEurope Consortium (2019) Patients with primary hyperoxaluria type 2 have significant morbidity and require careful follow-up. Kidney Int 96:1389–1399 - PubMed

Publication types

MeSH terms

Supplementary concepts

LinkOut - more resources