A year of change for PH1:
from long-term RNAi data to real-world evidence
One year has passed since the 2024 overview on advances in Primary Hyperoxaluria Type 1 (PH1), and the field has continued to evolve.
In the past twelve months, new clinical data, real-world evidence, and mechanistic insights have deepened our understanding of how RNA interference (RNAi) and related therapies can reshape the management and outcomes of PH1 patients.
From long-term follow-up confirming the durability of RNAi, to real-world evidence validating its safety and efficacy, 2025 has brought a wealth of information, confirming RNAi as a powerful and durable approach and opening new perspectives for precision and early intervention significantly improving patients’ lives.
Once again, Professor Jun Oh, as special correspondent, has gathered
the most relevant discoveries and clinical highlights of 2025 and interviewed three leading experts to explore the new burning questions in PH1.
Read how RNA interference therapy
is emerging as a real game changer in PH1.
As a rare and often under-recognized condition, PH1 has long been associated with significant diagnostic delays.
Over the past five years, growing awareness among clinicians and broader access to genetic testing have dramatically changed this picture, halving the time to diagnosis and enabling earlier access to effective therapies1.
Within this evolving landscape, RNAi therapies are emerging as true game changers, able to transform the quality of life of both patients and caregivers, marking a new era in the management of PH1.
LUMASIRAN
Five years after the approval of lumasiran in 2020, long-term data continue to support its sustained efficacy and safety in PH1.
The ILLUMINATE-A, -B and -C phase 3 studies, together with their 60-month extensions, currently represent the most extensive longitudinal dataset for any RNAi therapy in this disease. Across pediatric and adult populations, lumasiran consistently reduced urinary and plasma oxalate by approximately 65–70%, with stable or improved eGFR and marked regression of nephrocalcinosis2.
- In ILLUMINATE-A, patients aged ≥6 years maintained preserved kidney function and low rates of stone events throughout five years of follow-up2.
- ILLUMINATE-B extended these findings to infants and young children, demonstrating sustained biochemical control, normal growth trajectories, and almost no stone recurrences (0–1 events over five years) with medullary nephrocalcinosis improving in the majority of patients3.
- ILLUMINATE-C further confirmed robust plasma oxalate reduction (≈60% at 24 months) and favorable safety even in individuals with advanced kidney disease or dialysis dependence4.
Additionally, pooled five-year analyses from ILLUMINATE-A and -B showed that most patients developed no new stones and several achieved complete resolution of medullary nephrocalcinosis, reinforcing the durability of RNAi therapy5. Likewise, the Phase 2 open-label extension now provides the longest published follow-up (up to 54 months) and confirms durable biochemical response, stable renal function, and no emergent safety concerns6. A post-hoc pooled analysis across Phase 2, ILLUMINATE-A and -B further demonstrated sustained oxalate reduction and stable eGFR across all AGXT genotypes, indicating that lumasiran efficacy is genotype-independent7.
Real-world data corroborate trial results. The French Daily LUMA cohort, covering more than 90% of treated PH1 patients in France, confirmed stable renal function and excellent tolerability over two years8. Similarly, Saffe et al. reported favorable clinical outcomes despite some variability in biochemical response, reflecting differences in disease stage, genotype and laboratory methodologies9.
These findings confirm lumasiran’s effectiveness in managing PH1 after symptom onset. But what if lumasiran were initiated at birth? Could we prevent PH1 manifestations before they ever emerge?
Although lumasiran had already been administered in infants with genetically confirmed PH110, available data in this age group remain limited. In 2025, the first case report describing lumasiran administration within hours after birth was published, providing novel insight into its potential use in the immediate neonatal period. The child remained asymptomatic over 24 months with no safety concerns, suggesting that treatment begun at birth may prevent nephrocalcinosis and reshape the natural course of the disease11.
NEDOSIRAN
Nedosiran is currently under advanced clinical evaluation, and new data are expanding our understanding of its efficacy in PH1.
The PHYOX8 Phase 2 trial evaluated monthly nedosiran in 15 children (2–11 years) with preserved renal function. After six months, urinary oxalate decreased by ~64%, plasma oxalate by 39%, and eGFR increased slightly (+2.5%), with no treatment-related serious adverse events12.
Long-term findings from the PHYOX3 extension (42 months) confirmed a >60% sustained reduction in urinary oxalate, stable kidney function (mean eGFR 71–81 mL/min/1.73 m2), and halved stone-event rates compared to baseline13.
Population pharmacokinetic and pharmacodynamic modeling validated a 3.5 mg/kg monthly dose as optimal for children aged 2–11 years, achieving exposure and efficacy comparable to adults14.
OTHER THERAPIES IN PIPELINE
Lanthanum carbonate, a phosphate-binder with strong oxalate affinity, achieved normalization of urinary oxalate in small proof-of-concept cohorts, with excellent tolerability, representing a cost-effective adjunct potentially usable worldwide15.
Oxalobacter formigenes, a gut bacterium that metabolizes oxalate, achieved stable colonization and reduced urinary oxalate by ~14 % in healthy volunteers, suggesting future microbiome-based applications16.
Gene therapy: mRNA-based Alanine–Glyoxylate Aminotransferase (AGT) replacement demonstrated a 70 % urinary-oxalate reduction in preclinical PH1 models after a single dose, marking the next frontier in gene-replacement and protein-restoration therapy17.
References
- Cabezas et al. Improvement Of diagnostic delay of PH. ERA poster Preprint at (2025).
- Saland, J. M. et al. Long-Term Efficacy and Safety of Lumasiran in Patients With Primary Hyperoxaluria Type 1 in a Final Analysis of the ILLUMINATE-A Trial; Oral Presentation at: Pediatric Academic Societies (PAS) 2025.
- Sellier-Leclerc, A.-L. et al. Long-Term Efficacy, Safety, and Growth Outcomes in the Phase 3 ILLUMINATE-B Trial of Lumasiran for Primary Hyperoxaluria Type 1 in Infants and Young Children; Oral Presentation at: ESPN Congress 2025.
- Sellier-Leclerc, A.-L. et al. Efficacy and Safety of Lumasiran for Advanced Primary Hyperoxaluria Type 1: 24-Month Follow-up of the Phase 3 ILLUMINATE-C Trial. American Journal of Kidney Diseases 86, 285–288 (2025).
- Tasian, G. et al. Long-Term Effects of Lumasiran on Kidney Stones and Nephrocalcinosis in Patients With Primary Hyperoxaluria Type 1; Oral presentation at: ESPU 2025.
- Frishberg, Y. et al. Long-term Lumasiran Therapy Final Results from a Phase 2 Open-label Extension Study in primary hyperoxaluria. Nephrol Dial Transplant (2025).
- Sas, D. J. Lumasiran for Primary Hyperoxaluria Type 1: Analysis of Urinary Oxalate and Estimated Glomerular Filtration Rate Over Time in Patients by Genotype; Oral Presentation at IPNA 2025.
- Sellier-Leclerc, A. L. et al. Real-Life Data of 2-Year Lumasiran Use in the DAILY-LUMA Cohort. Kidney Int Rep 10, 1020–1036 (2025).
- Saffe, S. et al. Variable treatment response to lumasiran in pediatric patients with primary hyperoxaluria type 1. Pediatric Nephrology 40, 1929–1937 (2025).
- Méaux MN et al. The effect of lumasiran therapy for primary hyperoxaluria type 1 in small infants. Pediatr Nephrol. 37, 907–911 (2022).
- Peruzzi, L. & Leporati, M. Lumasiran at birth changes the trajectory of primary hyperoxaluria type 1: same disease, different outcomes in two affected siblings. J Nephrol Nov;38(8):2417-2422 (2025).
- Sas, D. J. et al. Nedosiran in pediatric patients with PH1 and relatively preserved kidney function, a phase 2 study (PHYOX8). Pediatric Nephrology 40, 1939–1948 (2025).
- Lieske, J. C. et al. PHYOX3: Nedosiran Long-Term Safety and Efficacy in Patients With Primary Hyperoxaluria Type 1. Kidney Int Rep 10, 1993–2002 (2025).
- Zhang, S., Gamallo, P. & Rawson, V. Population Pharmacokinetic and Pharmacodynamic Modelling and Simulation for Nedosiran Clinical Development and Dose Guidance in Pediatric Patients with Primary Hyperoxaluria Type 1. Clin Pharmacokinet 64, 1395–1411 (2025).
- De Broe, M. E. et al. A Targeted Release Capsule of Lanthanum Carbonate: a New Efficient Cheap Treatment for Primary Hyperoxalurias. Kidney Int Rep 10, 503–515 (2025).
- Fargue, S. et al. Inducing Oxalobacter formigenes Colonization Reduces Urinary Oxalate in Healthy Adults. Kidney Int Rep 10, 1518–1528 (2025).
- Yang, T. et al. Preclinical Evaluation of AGT MRNA Replacement Therapy for Primary Hyperoxaluria Type I Disease. Sci. Adv vol. 11 (2025).
BURNING QUESTIONS
Watch the Expert Insights and Perspectives
Professor Jun Oh is Professor of Paediatrics and the Head of the Department of Paediatric Nephrology, Ped. Gastroenterology and Ped. Transplantation at the Medical Center of the University Hamburg/Eppendorf
Professor Justine Bacchetta is Professor of Paediatrics, Head of the Paediatric Nephrology Unit, and Vice Chair of the Department of Paediatrics at Femme Mère Enfant Hospital, Lyon Bron, France.
Professor Jaap Groothoff is professor of Paediatrics, with a focus on Paediatric Nephrology, at the University of Amsterdam’s Faculty of Medicine (AMC-UvA).
Michael J.G. Somers is Associate Professor of Paediatrics at Harvard Medical School, Nephrologist in the Division of Nephrology, Director of Clinical Services in the Division of Nephrology and Medical Director of the Renal Dialysis Unit at Boston Children’s Hospital.
Explore how recent studies are guiding clinicians toward safer and biomarker-driven transplant decisions.
Before the advent of RNAi therapies, the only curative option for patients with PH1 was isolated kidney (IKT) or combined liver–kidney transplantation (CLKT). The introduction of RNAi has dramatically changed this landscape, offering new possibilities for patients previously bound to high-risk surgical approaches.
As shown by Tan et al. registry data revealed a sharp decline in liver transplant listings for PH1 following RNAi approval, reflecting how RNAi therapy now offers the possibility for many patients to avoid transplantation1.
The goal now is no longer to replace organs reactively, but to restore metabolic balance proactively, preserving native kidney function for as long as possible. Today, the metabolic control achieved with RNAi therapy allows IKT in a broader population, not only in those with pyridoxine-responsive AGXT variants, as previously required2.
But how can we be sure that when transplantation is needed, it occurs at the right time, in the right patient, and with the right biomarker profile? To ensure optimal outcomes, robust biomarkers such as plasma oxalate (POx) are essential to evaluate treatment efficacy and guide transplant timing. The study by Makosso Afiavi et al.3 explored the importance of precise oxalate monitoring in pediatric patients.
But is POx the only biomarker guiding transplant decisions?
In a 2025 case report2, a patient was listed for IKT on the basis of the elevated plasma glycolate (pGly) levels after lumasiran, combined with significant POx reduction, introducing pGly as an additional indicator of RNAi efficacy. Similarly, in the largest cohort to date, Martin-Higueras et al.4 analyzed 17 PH1 patients receiving various RNAi regimens. Four underwent IKT, two with successful long-term outcomes and two with recurrence, demonstrating that transplant results depend on systemic oxalate load, B6 responsiveness, and RNAi response, rather than POx alone.
Rescue cases further highlight the potential of RNAi in post-transplant management. As reported by Bahbah et al.5, a patient diagnosed with PH1 after kidney transplantation recovered graft function through intensive dialysis and lumasiran, underscoring the drug’s efficacy even in late or misdiagnosed disease.
Finally, a post-hoc analysis by Somers et al.6 combined data from the Phase 2 and Phase 3 ILLUMINATE trials with up to 60 months of follow-up. Results confirmed long-term renal stabilization across age groups and CKD stages. In ILLUMINATE-C, five dialysis patients (4 pediatrics, 1 adult) underwent IKT after sustained POx reduction: all remained dialysis-free, continued lumasiran, and showed no graft oxalate nephropathy. Patient-reported outcomes showed 15–43% improvements in physical, emotional, and social well-being, demonstrating that lumasiran not only preserves kidney function but also enhances quality of life.
References
- Tan, E. & et al. The evolving role of liver transplantation as enzyme replacement therapy in the era of RNA nanotherapies. Am J Transplant. (2025).
- Moretti, M. I. et al. Plasma Glycolate Levels Contribute to Drive the Decision of Isolated Kidney Transplantation in Dialyzed Patients with End-Stage Kidney Disease due to Primary Hyperoxaluria Type 1 Treated with Lumasiran: A Case Report. Case Rep Nephrol Dial 141–149 (2025).
- Makosso Afiavi MC, et al. Fine-tuning circulating oxalate levels to improve transplant strategies in primary hyperoxaluria: what is the ideal threshold in pediatrics? Nephrol Ther. 21, 31–35 (2025).
- Martin-Higueras C & et al. RNA interference medication and transplantation procedures in patients with primary hyperoxaluria type 1 (PH1), Nephrology Dialysis Transplantation. Nephrology Dialysis Transplantation (2025).
- Bahbah H & et al. Hidden in CAKUT: Post-Transplant Diagnosis of Primary Hyperoxaluria Type 1 and Rescue Management Using Lumasiran. Pediatr Transplant. 29, (2025).
- Somers M. Kidney-Function,-Isolated-Kidney-Transplant,-and-Health-Related-Q uality-of-Life-Outcomes-in-Primary-Hyperoxaluria-Type-1-Treated-Wit h-Long-term-Lumasiran. Poster at ESPN 2025.
BURNING QUESTIONS
Watch the Expert Insights and Perspectives
Professor Jun Oh is Professor of Paediatrics and the Head of the Department of Paediatric Nephrology, Ped. Gastroenterology and Ped. Transplantation at the Medical Center of the University Hamburg/Eppendorf
Professor Justine Bacchetta is Professor of Paediatrics, Head of the Paediatric Nephrology Unit, and Vice Chair of the Department of Paediatrics at Femme Mère Enfant Hospital, Lyon Bron, France.
Professor Jaap Groothoff is professor of Paediatrics, with a focus on Paediatric Nephrology, at the University of Amsterdam’s Faculty of Medicine (AMC-UvA).
Michael J.G. Somers is Associate Professor of Paediatrics at Harvard Medical School, Nephrologist in the Division of Nephrology, Director of Clinical Services in the Division of Nephrology and Medical Director of the Renal Dialysis Unit at Boston Children’s Hospital.
PH1 management in the RNAi era:
discover how early diagnosis and equitable
access are now imperative.
The advent of RNAi therapies has profoundly reshaped the management of PH1. Historically, treatment relied on conservative measures and combined liver–kidney transplantation strategies which were associated with high morbidity and mortality. Pre-RNAi outcome analyses show the severity of late-stage disease. In a retrospective analysis of historical cohorts, Lieske et al.1 documented progressive systemic oxalosis and high mortality in PH1 patients despite transplantation, with dialysis unable to sufficiently eliminate oxalate. These data reinforce a central principle: metabolic control must be initiated before irreversible organ injury occurs.
Real-world evidence now confirms this. The BONAPH1DE global registry2 showed that earlier therapeutic intervention correlates with superior renal preservation, emphasizing timing as a critical determinant of clinical outcomes. However, despite therapeutic innovation, delayed diagnosis remains a major barrier to optimal care of a disease that is more frequent than expected. A genomic prevalence analysis by Mandrile et al.3 estimated the true global frequency of PH at approximately 1 in 59,000 individuals, significantly exceeding known clinical incidence. Mild or atypical phenotypes and limited access to molecular diagnostics contribute to underrecognition, highlighting the need for proactive diagnostic strategies.
What strategies can we adopt to further improve early diagnosis of PH1, despite the growing awareness among clinicians and expanded access to genetic testing having already halved the time to diagnosis4? Routine genetic testing and newborn screening are emerging as essential public-health strategies to identify patients before irreversible kidney damage occurs. Hoppe et al. 5 demonstrated the feasibility and diagnostic yield of neonatal screening for PH1 and PH3, enabling pre-symptomatic initiation of care and facilitating cascade testing within affected families. As sequencing costs decline, integration of PH gene panels into national screening programs becomes increasingly realistic. Advances in variant interpretation further refine diagnostic precision. Ruta et al.6 reported that pathogenicity of selected AGXT variants, including p.I279T, is modulated by haplotype context. Incorporating haplotype-resolved molecular testing enhances classification accuracy and supports individualized prognostication, essential steps in precision nephrology.
However, also complementary diagnostic tools retain an important role. When biochemical and imaging findings are inconclusive, renal biopsy remains a crucial confirmatory modality. The Tunisian experience7 showed that biopsy can differentiate primary from secondary hyperoxaluria and trigger timely genetic evaluation.
The clinical implications of delayed recognition are profound. In case report a 46-year-old woman was diagnosed with PH1 only after kidney transplantation, when graft biopsy revealed oxalate deposits. Although harboring a pyridoxine-responsive AGXT mutation, she did not receive RNAi therapy due to prohibitive cost, resulting in only partial renal recovery8. This case illustrates the dual burden of late diagnosis and inequitable therapeutic access. Indeed, global disparities in PH1 care are significant. A multinational survey reported that genetic testing is accessible in 82% of high-income settings, compared with 55% in low-income regions. RNAi therapy was available in only 53% of surveyed countries, predominantly in higher-resource settings, with access gaps persisting even within Europe9.
In conclusion, cumulative findings from 2025 studies indicate that RNAi is a game changer in PH1 management. Achieving its full benefit, however, requires coordinated efforts to ensure early detection and equitable treatment availability across healthcare systems.
References
- Lieske, J. C. et al. Natural History of Advanced Primary Hyperoxaluria Type 1: A Retrospective Study. Kidney Med 101115 (2025).
- Efrat Ben-Shalom & et al. Descriptive Analysis of Real-World Enrollment Data of Pediatric and Adult Patients From a Global Primary Hyperoxaluria Type 1 Registry (BONAPH1DE). Poster at ESPN 2025.
- Mandrile, G. et al. Global genetic prevalence estimates of primary hyperoxaluria are greater than previously reported. Clin Kidney J 18, (2025).
- Cabezas et al. Improvement Of diagnostic delay of PH. ERA poster Preprint at (2025).
- Hoppe, B. et al. Effective Newborn Screening for Type 1 and 3 Primary Hyperoxaluria. Kidney Int Rep 10, 177–183 (2025).
- Ruta, L. et al. A Minor Haplotype Variant Determines the Pathogenicity of the p.Ile279Thr Substitution in the Primary Hyperoxaluria Type 1 Gene, AGXT. J Inherit Metab Dis 48, (2025).
- Hajji, M. et al. Renal Biopsy: A Key Tool for Diagnosing Hyperoxaluria. Nephrology Dialysis Transplantation 40, (2025).
- Sobczyńska K, et al. Primary hyperoxaluria type 1-an unexpected diagnosis after kidney transplantation. Kidney Blood Press Res
- Deesker, L. J. et al. Global access to management of primary hyperoxaluria: A survey on behalf of OxalEurope, G&K Working Group of the ERA and ESPN. Nephrology Dialysis Transplantation 40, 1688–1697 (2025).
BURNING QUESTIONS
Watch the Expert Insights and Perspectives
Professor Jun Oh is Professor of Paediatrics and the Head of the Department of Paediatric Nephrology, Ped. Gastroenterology and Ped. Transplantation at the Medical Center of the University Hamburg/Eppendorf
Professor Justine Bacchetta is Professor of Paediatrics, Head of the Paediatric Nephrology Unit, and Vice Chair of the Department of Paediatrics at Femme Mère Enfant Hospital, Lyon Bron, France.
Professor Jaap Groothoff is professor of Paediatrics, with a focus on Paediatric Nephrology, at the University of Amsterdam’s Faculty of Medicine (AMC-UvA).
Michael J.G. Somers is Associate Professor of Paediatrics at Harvard Medical School, Nephrologist in the Division of Nephrology, Director of Clinical Services in the Division of Nephrology and Medical Director of the Renal Dialysis Unit at Boston Children’s Hospital.
This program is supported by Alnylam Pharmaceuticals in the form of an unrestricted financial support.
The scientific program has not been influenced in any way by its sponsor.
