RARE DISEASE
Primary hyperoxaluria type 1
Primary hyperoxaluria type 1
Primary hyperoxaluria type 1
Synonyms: Glycolic aciduria, Peroxisomal alanine-glyoxylate aminotransferase deficiency
Synonyms: Glycolic aciduria, Peroxisomal alanine-glyoxylate aminotransferase deficiency
Synonyms: Glycolic aciduria, Peroxisomal alanine-glyoxylate aminotransferase deficiency
Drug discovery
6
drugs
With orphan designations
Overview
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder caused by mutations in the AGXT gene, leading to deficient alanine-glyoxylate aminotransferase activity. This results in hepatic overproduction of oxalate, causing recurrent calcium oxalate kidney stones, nephrocalcinosis, and progressive chronic kidney disease. Over 70% of patients develop end-stage renal disease (ESRD), often requiring dialysis or transplantation. Systemic oxalosis occurs when glomerular filtration rate drops below 30–45 mL/min, depositing oxalate in bones, retina, and cardiovascular tissues [1][2][6][11].
Population
Burden
Clinical: Median 12.8 lifetime hospital days, 3.6 hospitalizations, and 5+ urologic procedures (ureteroscopy/PCNL) [4][9].
Economic: Annual healthcare costs 6.5× higher vs matched controls, driven by dialysis ($4,530) and outpatient care ($13,894) [9].
Mortality: Up to 50% mortality within 5 years of ESRD without transplantation [4][10].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare ophthalmic disorders, rare renal diseases, rare transplant-related disorders
Research Papers
597 drug discovery papers about Primary hyperoxaluria type 1, with 3 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
597 drug discovery papers about Primary hyperoxaluria type 1, with 3 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-01 | A Case Report of Primary Hyperoxaluria Type 1 Diagnosed in a Geriatric Patient on Dialysis: Unique Clinical Course With Lumasiran
Primary hyperoxaluria (PH) is a group of rare autosomal recessive disorders of impaired hepatic glyoxylate metabolism. Primary hyperoxaluria type 1 (PH1), the most common and severe phenotype, results in incident kidney failure in most patients by young adulthood (1). The majority of PH1 patients are diagnosed around age 10 years, though a significant delay in diagnosis is common (2). Preventative treatment options have historically been limited to robust fluid intake, crystallization inhibitors, and pyridoxine.
2026-07-03 | Primary hyperoxaluria type 1-current practice in the siRNA era: an ERA Genes & Kidney Working Group survey.
Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder leading to the formation of kidney stones, nephrocalcinosis, and kidney failure. Besides, PH1 poses the risk of developing systemic oxalosis, a life-threatening condition with oxalate deposits in multiple organ systems. The rarity of the disorder combined with recent major additions to therapeutic options based on small interfering RNA (siRNA) therapeutics make a formal assessment of current practice and implementation of treatment recommendations an important asset. An international questionnaire survey was conducted among medical doctors involved in the treatment of patients with chronic kidney disease. The survey included 32 questions addressing demographics, diagnostics and therapeutics, and educational needs related to the care for PH1 patients. 176 participants from 43 countries completed the survey, the majority of them were from Europe. The results indicate clear shortcomings in the availability of recommended diagnostics, especially with regards to plasma oxalate. Genetic testing strategies often do not include patients who may have PH1, e.g. when the underlying cause of kidney failure is unknown or in patients with nephrolithiasis or nephrocalcinosis. Treatment modalities are only partly harmonized and intensified dialysis is not fully implemented across centers. Strategies toward combination of conventional therapeutics such as hyperhydration and pyridoxine with new siRNA therapeutics depend on the treating physician's expertise. The survey identifies clear needs regarding implementation of current treatment recommendations as well as important educational gaps. The advent of targeted treatment opportunities for PH1 comes with an increased need to provide guidance to the field. Filling the existing gaps will ensure that a growing number of patients get access to optimal care and novel life-changing therapies.
2026-06-16 | In Vivo Genome Editing Approach to Disrupt Hydroxyacid Oxidase 1 for the Treatment of Primary Hyperoxaluria Type 1.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder that leads to kidney and liver failure. PH1 is caused by a mutation in the alanine glyoxylate aminotransferase (AGXT) gene, which encodes a key metabolic enzyme that converts glyoxylate to glycine in the liver. Inability to metabolize glyoxylate leads to oxalate overproduction, yielding insoluble calcium oxalate crystals; accumulation of these crystals leads to progressive organ failure. Here, we used a novel, minimally disruptive genome-editing approach to disrupt the mechanism of action of hydroxyacid oxidase 1 (HAO1), an upstream enzyme in the glyoxylate metabolic pathway. Successful gene editing and disruption of the HAO1 gene is expected to increase levels of glycolate, a harmless intermediate of the glycine metabolic pathway, thereby preventing the formation of calcium oxalate crystals. We intravenously administered an adeno-associated virus (AAV) vector expressing the M1HAO1 meganuclease to both wild-type and Agxt-/- mice, a mouse model of PH1. We observed >30% editing of HAO1 in Agxt-/- mice, correlating with a dose-dependent increase in serum glycolate levels. At the highest dose tested, urine glycolate levels increased by 79%, with a concomitant 75% decrease in urine oxalate levels. We also evaluated in vivo targeting in rhesus macaques injected with AAV expressing two different versions of the HAO1 meganuclease. Dose-dependent editing of hepatic DNA and RNA was achieved, and serum glycolate levels changed in a manner consistent with successful liver editing; additionally, the treatment was well tolerated. Our results indicate that AAV-delivered meganucleases can effectively target HAO1 in mice and nonhuman primates to achieve high levels of HAO1 gene editing. Moreover, increased glycolate levels in serum indicate that this intervention significantly impacts the HAO1-mediated glycolate-to-glyoxylate pathway. These data suggest that this approach may represent an effective treatment for PH1.
2026-06-08 | From recurrent flank pain to systemic oxalosis: a case of primary hyperoxaluria type 1 requiring dual organ transplantation.
Primary hyperoxalurias (PH) are rare autosomal recessive inherited disorders that disrupt the metabolism of glyoxylate and oxalate. The most common type, primary hyperoxaluria type 1 (PH1), is caused by a deficiency in the liver enzyme alanine-glyoxylate aminotransferase (AGT), leading to the overproduction and excessive urinary excretion of oxalate. On routine evaluation, the patient presented with deranged renal function and echogenic kidneys. Imaging via KUB X-ray revealed radio-opaque kidney stones, small shrunken kidneys, and nephrocalcinosis, indicating progression to end-stage kidney disease (ESKD). Additional systemic manifestations included increased lumbar bone density and pulmonary fibrosis. Diagnosis was definitively confirmed through elevated 24-hour urinary oxalate levels and genetic screening showing an AGXT gene mutation. This necessitated combined liver-kidney transplantation (CLKT): the liver graft provides the missing AGT enzyme to stop oxalate production, while the kidney graft replaces damaged organs and discontinues chronic dialysis. PH1 must be suspected in pediatric patients presenting with recurrent urolithiasis or nephrocalcinosis, especially in clinical cases of consanguinity. Early interventions - high fluid intake, crystallization inhibitors, and pyridoxine - can help preserve kidney function. For patients reaching ESKD, combined transplantation is the most effective approach to correct the underlying metabolic error and stop oxalate accumulation. This case highlights the diagnostic challenge of PH1, where the initial presentation with flank pain and urinary symptoms may mimic a urinary tract infection, placing the patient at potential risk of urosepsis if misdiagnosed or untreated. CLKT remains the definitive treatment in advanced disease.
2026-05-27 | Targeting the Highly Deleterious G161C and Y260C SNP Variants of the AGXT Protein Involved in Glyoxylate Metabolism Using Tauroursodeoxycholic Acid: A Computational Study.
Hyperoxaluria Type 1 (PH1) is a rare autosomal recessive metabolic disorder caused by mutations in the AGXT gene, leading to impaired glyoxylate metabolism and excessive oxalate accumulation, resulting in nephrolithiasis, nephrocalcinosis, and end-stage renal disease. As a rare and often neglected disease, PH1 poses a significant challenge to modern healthcare systems due to its progressive nature and limited therapeutic options. In this study, an integrated in silico approach was employed to identify pathogenic single-nucleotide polymorphisms (SNPs) and evaluate potential therapeutic candidates. Computational analyses using ConSurf, Align-GVGD, INPS-MD, CUPSAT, and iStable identified G161C and Y260C as highly deleterious variants affecting protein stability. Virtual screening, followed by ADME and toxicity assessments, identified Tauroursodeoxycholic acid (TUDCA) as a promising candidate with favorable pharmacokinetic and safety profiles. Molecular docking revealed that TUDCA exhibited higher binding affinity than the reference drug pyridoxine across native and SNP variants of AGXT proteins. Molecular dynamics simulations (300 ns) demonstrated enhanced structural stability of TUDCA-bound complexes, indicated by reduced RMSD and RMSF, improved compactness, and sustained hydrogen bonding. Furthermore, free energy landscape (FEL) and dynamic cross-correlation matrix (DCCM) analyses confirmed improved conformational stability and coordinated residue motions in SNP variant structures. Overall, these findings suggest that TUDCA may effectively stabilize structural alterations induced by pathogenic AGXT variants, highlighting its potential as a precision medicine-based therapeutic strategy for PH1.
2026-08-01 | A Case Report of Primary Hyperoxaluria Type 1 Diagnosed in a Geriatric Patient on Dialysis: Unique Clinical Course With Lumasiran
Primary hyperoxaluria (PH) is a group of rare autosomal recessive disorders of impaired hepatic glyoxylate metabolism. Primary hyperoxaluria type 1 (PH1), the most common and severe phenotype, results in incident kidney failure in most patients by young adulthood (1). The majority of PH1 patients are diagnosed around age 10 years, though a significant delay in diagnosis is common (2). Preventative treatment options have historically been limited to robust fluid intake, crystallization inhibitors, and pyridoxine.
2026-07-03 | Primary hyperoxaluria type 1-current practice in the siRNA era: an ERA Genes & Kidney Working Group survey.
Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder leading to the formation of kidney stones, nephrocalcinosis, and kidney failure. Besides, PH1 poses the risk of developing systemic oxalosis, a life-threatening condition with oxalate deposits in multiple organ systems. The rarity of the disorder combined with recent major additions to therapeutic options based on small interfering RNA (siRNA) therapeutics make a formal assessment of current practice and implementation of treatment recommendations an important asset. An international questionnaire survey was conducted among medical doctors involved in the treatment of patients with chronic kidney disease. The survey included 32 questions addressing demographics, diagnostics and therapeutics, and educational needs related to the care for PH1 patients. 176 participants from 43 countries completed the survey, the majority of them were from Europe. The results indicate clear shortcomings in the availability of recommended diagnostics, especially with regards to plasma oxalate. Genetic testing strategies often do not include patients who may have PH1, e.g. when the underlying cause of kidney failure is unknown or in patients with nephrolithiasis or nephrocalcinosis. Treatment modalities are only partly harmonized and intensified dialysis is not fully implemented across centers. Strategies toward combination of conventional therapeutics such as hyperhydration and pyridoxine with new siRNA therapeutics depend on the treating physician's expertise. The survey identifies clear needs regarding implementation of current treatment recommendations as well as important educational gaps. The advent of targeted treatment opportunities for PH1 comes with an increased need to provide guidance to the field. Filling the existing gaps will ensure that a growing number of patients get access to optimal care and novel life-changing therapies.
2026-06-16 | In Vivo Genome Editing Approach to Disrupt Hydroxyacid Oxidase 1 for the Treatment of Primary Hyperoxaluria Type 1.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder that leads to kidney and liver failure. PH1 is caused by a mutation in the alanine glyoxylate aminotransferase (AGXT) gene, which encodes a key metabolic enzyme that converts glyoxylate to glycine in the liver. Inability to metabolize glyoxylate leads to oxalate overproduction, yielding insoluble calcium oxalate crystals; accumulation of these crystals leads to progressive organ failure. Here, we used a novel, minimally disruptive genome-editing approach to disrupt the mechanism of action of hydroxyacid oxidase 1 (HAO1), an upstream enzyme in the glyoxylate metabolic pathway. Successful gene editing and disruption of the HAO1 gene is expected to increase levels of glycolate, a harmless intermediate of the glycine metabolic pathway, thereby preventing the formation of calcium oxalate crystals. We intravenously administered an adeno-associated virus (AAV) vector expressing the M1HAO1 meganuclease to both wild-type and Agxt-/- mice, a mouse model of PH1. We observed >30% editing of HAO1 in Agxt-/- mice, correlating with a dose-dependent increase in serum glycolate levels. At the highest dose tested, urine glycolate levels increased by 79%, with a concomitant 75% decrease in urine oxalate levels. We also evaluated in vivo targeting in rhesus macaques injected with AAV expressing two different versions of the HAO1 meganuclease. Dose-dependent editing of hepatic DNA and RNA was achieved, and serum glycolate levels changed in a manner consistent with successful liver editing; additionally, the treatment was well tolerated. Our results indicate that AAV-delivered meganucleases can effectively target HAO1 in mice and nonhuman primates to achieve high levels of HAO1 gene editing. Moreover, increased glycolate levels in serum indicate that this intervention significantly impacts the HAO1-mediated glycolate-to-glyoxylate pathway. These data suggest that this approach may represent an effective treatment for PH1.
2026-06-08 | From recurrent flank pain to systemic oxalosis: a case of primary hyperoxaluria type 1 requiring dual organ transplantation.
Primary hyperoxalurias (PH) are rare autosomal recessive inherited disorders that disrupt the metabolism of glyoxylate and oxalate. The most common type, primary hyperoxaluria type 1 (PH1), is caused by a deficiency in the liver enzyme alanine-glyoxylate aminotransferase (AGT), leading to the overproduction and excessive urinary excretion of oxalate. On routine evaluation, the patient presented with deranged renal function and echogenic kidneys. Imaging via KUB X-ray revealed radio-opaque kidney stones, small shrunken kidneys, and nephrocalcinosis, indicating progression to end-stage kidney disease (ESKD). Additional systemic manifestations included increased lumbar bone density and pulmonary fibrosis. Diagnosis was definitively confirmed through elevated 24-hour urinary oxalate levels and genetic screening showing an AGXT gene mutation. This necessitated combined liver-kidney transplantation (CLKT): the liver graft provides the missing AGT enzyme to stop oxalate production, while the kidney graft replaces damaged organs and discontinues chronic dialysis. PH1 must be suspected in pediatric patients presenting with recurrent urolithiasis or nephrocalcinosis, especially in clinical cases of consanguinity. Early interventions - high fluid intake, crystallization inhibitors, and pyridoxine - can help preserve kidney function. For patients reaching ESKD, combined transplantation is the most effective approach to correct the underlying metabolic error and stop oxalate accumulation. This case highlights the diagnostic challenge of PH1, where the initial presentation with flank pain and urinary symptoms may mimic a urinary tract infection, placing the patient at potential risk of urosepsis if misdiagnosed or untreated. CLKT remains the definitive treatment in advanced disease.
2026-05-27 | Targeting the Highly Deleterious G161C and Y260C SNP Variants of the AGXT Protein Involved in Glyoxylate Metabolism Using Tauroursodeoxycholic Acid: A Computational Study.
Hyperoxaluria Type 1 (PH1) is a rare autosomal recessive metabolic disorder caused by mutations in the AGXT gene, leading to impaired glyoxylate metabolism and excessive oxalate accumulation, resulting in nephrolithiasis, nephrocalcinosis, and end-stage renal disease. As a rare and often neglected disease, PH1 poses a significant challenge to modern healthcare systems due to its progressive nature and limited therapeutic options. In this study, an integrated in silico approach was employed to identify pathogenic single-nucleotide polymorphisms (SNPs) and evaluate potential therapeutic candidates. Computational analyses using ConSurf, Align-GVGD, INPS-MD, CUPSAT, and iStable identified G161C and Y260C as highly deleterious variants affecting protein stability. Virtual screening, followed by ADME and toxicity assessments, identified Tauroursodeoxycholic acid (TUDCA) as a promising candidate with favorable pharmacokinetic and safety profiles. Molecular docking revealed that TUDCA exhibited higher binding affinity than the reference drug pyridoxine across native and SNP variants of AGXT proteins. Molecular dynamics simulations (300 ns) demonstrated enhanced structural stability of TUDCA-bound complexes, indicated by reduced RMSD and RMSF, improved compactness, and sustained hydrogen bonding. Furthermore, free energy landscape (FEL) and dynamic cross-correlation matrix (DCCM) analyses confirmed improved conformational stability and coordinated residue motions in SNP variant structures. Overall, these findings suggest that TUDCA may effectively stabilize structural alterations induced by pathogenic AGXT variants, highlighting its potential as a precision medicine-based therapeutic strategy for PH1.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
6 orphan drug designations for Primary hyperoxaluria type 1, including 1 approved therapy.
6 orphan drug designations for Primary hyperoxaluria type 1, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
5-[[trans-4-[(trifluoromethoxy)phenyl]cyclohexyl]oxy]-1H-1,2,3-triazole-4-carboxylic acid | small molecules | FDA | 2022-06-08 | — | BioMarin Pharmaceutical Inc. |
Bacillus subtilis oxalate decarboxylase | proteins | FDA | 2016-02-29 | — | Allena Pharmaceuticals, Inc. |
lumasiran [Oxlumo] | RNAs | FDA | 2016-02-08 | 2020-11-23 | Alnylam Pharmaceuticals |
Synthetic double-stranded RNA oligonucleotide specific to hydroxyacid oxidase 1 gene [DCR-PH1] | RNAs | EMA | 2015-07-28 | — | [INACTIVE] Dicerna EU Limited |
synthetic double-stranded (hybridized duplex) ribonucleic acid oligonucleotide specific to hydroxyacid oxidase 1 gene | RNAs | FDA | 2015-04-22 | — | Dicerna Pharmaceuticals, Inc. |
Adeno-associated viral vector serotype 5 containing the human AGXT gene | gene therapies | EMA | 2012-03-21 | — | uniQure Biopharma B.V |
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