Is stiripentol truly effective for treating primary hyperoxaluria?

Martín-Higueras, Cristina; Feldkötter, Markus; Höppe, Bernd

doi:10.1093/ckj/sfaa068

Cited by 15 publications

(6 citation statements)

References 4 publications

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“…In another report of an 18-month-old patient with PH1 characterized by a pyridoxine-responsive mutation, administration of stiripentol led to a significant reduction in urinary oxalate level to normal values 113 . However, other case reports -albeit in patients with advanced kidney failure -found no benefit of stiripentol therapy 114,115 . A trial is currently underway to determine the efficacy of stiripentol as monotherapy in patients aged >6 months with PH1-3 and an eGFR of >45 ml/min/1.73 m 2 (ref.…”

Section: Stiripentolmentioning

confidence: 95%

Clinical practice recommendations for primary hyperoxaluria: an expert consensus statement from ERKNet and OxalEurope

et al. 2023

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Primary hyperoxaluria (PH) is an inherited disorder that results from the overproduction of endogenous oxalate, leading to recurrent kidney stones, nephrocalcinosis and eventually kidney failure; the subsequent storage of oxalate can cause life-threatening systemic disease. Diagnosis of PH is often delayed or missed owing to its rarity, variable clinical expression and other diagnostic challenges. Management of patients with PH and kidney failure is also extremely challenging. However, in the past few years, several new developments, including new outcome data from patients with infantile oxalosis, from transplanted patients with type 1 PH (PH1) and from patients with the rarer PH types 2 and 3, have emerged. In addition, two promising therapies based on RNA interference have been introduced. These developments warrant an update of existing guidelines on PH, based on new evidence and on a broad consensus. In response to this need, a consensus development core group, comprising (paediatric) nephrologists, (paediatric) urologists, biochemists and geneticists from OxalEurope and the European Rare Kidney Disease Reference Network (ERKNet), formulated and graded statements relating to the management of PH on the basis of existing evidence. Consensus was reached following review of the recommendations by representatives of OxalEurope, ESPN, ERKNet and ERA, resulting in 48 practical statements relating to the diagnosis and management of PH, including consideration of conventional therapy (conservative therapy, dialysis and transplantation), new therapies and recommendations for patient follow-up. SectionsUnanswered questions and research agenda Conclusions

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Section: Stiripentolmentioning

confidence: 95%

Clinical practice recommendations for primary hyperoxaluria: an expert consensus statement from ERKNet and OxalEurope

et al. 2023

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“…Stiripentol significantly reduced Uox in one patient with PH1 with good kidney function after 10 weeks of treatment. However, in patients with PH1 with CKD or ESKD, this medication did not produce a significant decline in Uox or Pox [ 103 , 104 ]. Currently, a pivotal study is ongoing for all types of PH, for which recruitment has been finished (NCT03819647).…”

Section: Current Treatment Optionsmentioning

confidence: 99%

Improving Treatment Options for Primary Hyperoxaluria

Höppe¹,

Martín-Higueras

2022

Drugs

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The primary hyperoxalurias are three rare inborn errors of the glyoxylate metabolism in the liver, which lead to massively increased endogenous oxalate production, thus elevating urinary oxalate excretion and, based on that, recurrent urolithiasis and/or progressive nephrocalcinosis. Frequently, especially in type 1 primary hyperoxaluria, early end-stage renal failure occurs. Treatment possibilities are scare, namely, hyperhydration and alkaline citrate medication. In type 1 primary hyperoxaluria, vitamin B 6 , though, is helpful in patients with specific missense or mistargeting mutations. In those vitamin B 6 responsive, urinary oxalate excretion and concomitantly urinary glycolate is significantly decreased, or even normalized. In patients non-responsive to vitamin B 6 , RNA interference medication is now available. Lumasiran ® is already available on prescription and targets the messenger RNA of glycolate oxidase, thus blocking the conversion of glycolate into glyoxylate, hence decreasing oxalate, but increasing glycolate production. Nedosiran blocks liver-specific lactate dehydrogenase A and thus the final step of oxalate production. Similar to vitamin B 6 treatment, where both RNA interference urinary oxalate excretion can be (near) normalized and plasma oxalate decreases, however, urinary and plasma glycolate increases with lumasiran treatment. Future treatment possibilities are on the horizon, for example, substrate reduction therapy with small molecules or gene editing, induced pluripotent stem cell-derived autologous hepatocyte-like cell transplantation, or gene therapy with newly developed vector technologies. This review provides an overview of current and especially new and future treatment options. Key PointsPrimary hyperoxaluria is a rare metabolic disorder, with often a fatal outcome if not treated.New medications based on RNA interference are available but need adequate adjustment into the current therapeutic approaches.Future treatment options are on the horizon.

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“…Stiripentol, a pharmacological agent that inhibits LDH and is already approved for Dravet syndrome (a rare genetic epileptic encephalopathy) in the USA and Europe, appears a promising potential therapy for PH in both animal models and pilot human studies [ 19 ]. However, some authors have challenged this observation [ 20 , 21 ], and clinical trials are ongoing to prove its efficacy in PH1. Other small molecules are in the pipeline, including oral small molecule inhibitors to LDH or GO, or chaperones for misfolded enzymes to restore function, but these remain at the stage of pre-clinical experimentation [ 22 , 23 ].…”

Section: Other Therapeutic Perspectivesmentioning

confidence: 99%

Primary hyperoxaluria type 1: novel therapies at a glance

Bacchetta¹,

Lieske

2022

Clinical Kidney Journal

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Primary hyperoxaluria type 1 (PH1) is a rare and severe autosomal recessive disease of oxalate metabolism, resulting from a mutation in the AGXT gene that encodes the hepatic peroxisomal enzyme alanine–glyoxylate aminotransferase (AGT). Until recently, treatment of PH1 was supportive, consisting of intensive hyperhydration, use of crystallization inhibitors (citrate and neutral phosphorus), in a subset of responsive PH1 patients’ pharmacologic doses of vitamin B6 (pyridoxine), and kidney and liver transplantation when patients progressed to kidney failure. Treatment approaches have been similar for PH2 caused by mutations in hepatic glyoxylate reductase/hydroxypyruvate reductase (GR/HPR), although pyridoxine does not have any benefit in this group. PH3 is caused by mutations of mitochondrial 4-hydroxy-2-oxoglutarate aldolase (HOGA1) and was the most recently described. Kidney failure appears less common in PH3, although kidney stones occur as frequently as in PH1 and PH2. Oxalate metabolism in the liver is complex. Novel therapies based on RNA interference (RNAi) have recently emerged to modulate these pathways, designed to deplete substrate for enzymes upstream and decrease/avoid oxalate production. Two hepatic enzymes have been targeted to date in PH: glycolate oxidase (GO) with lumasiran and lactate dehydrogenase A (LDH-A) with nedosiran. Lumasiran was approved for the treatment of PH1 in 2020 by both the European Medicines Agency and the Food and Drug Administration, whilst clinical trials with nedosiran are ongoing. Results with the two RNAi therapies demonstrate a significant reduction of urinary oxalate excretion in PH1 patients, but long-term data on efficacy (preservation of kidney function, decreased stone events) and safety remain to be established. Nevertheless, the hepatically targeted RNAi approach represents a potential ‘game changer’ in the field of PH1, bringing hope to families and patients that they may be able to avoid liver and/or kidney transplantation in the future and suffer fewer stone events, perhaps with less strict therapeutic regimens. Pharmacological compounds directly inhibiting GO or LDH are also under development and could be of special interest in developing countries where RNAi therapies may not be readily available in the near future. Approaches to manipulate the intestinal microbiome with a goal to increase oxalate degradation or to stimulate secretion of oxalate into the intestine from plasma are also under development. Overall, we appear to be entering a new phase of PH treatment, with an array of promising approaches emerging that will need optimization and evaluation to establish long-term efficacy and safety.

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Is stiripentol truly effective for treating primary hyperoxaluria?

Cited by 15 publications

References 4 publications

Clinical practice recommendations for primary hyperoxaluria: an expert consensus statement from ERKNet and OxalEurope

Clinical practice recommendations for primary hyperoxaluria: an expert consensus statement from ERKNet and OxalEurope

Improving Treatment Options for Primary Hyperoxaluria

Primary hyperoxaluria type 1: novel therapies at a glance

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