Infantile Primary Hyperoxaluria Type 1 Treated With Lumasiran in Twin Males

Aldabek, Khaled; Grossman, Oulimata K; Alomar, Osama; Fox, Janelle; Moritz, Michael L.

doi:10.7759/cureus.21673

Cited by 7 publications

(15 citation statements)

References 11 publications

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“…Lumasiran has shown promising clinical benefits in PH1 with sustained lowering of oxalate levels, acceptable safety, and encouraging results on clinical outcomes in clinical trials 28−31 and also benefits for management of PH1 in small infants 32 and twins 33 in the postmarketing studies.…”

Section: Acs Pharmacology and Translational Sciencementioning

confidence: 99%

Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies

Liu

Zhao

Shah

et al. 2022

ACS Pharmacol. Transl. Sci.

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Due to the lack of treatment options for the genetic disease primary hyperoxaluria (PH), including three subtypes PH1, PH2, and PH3, caused by accumulation of oxalate forming kidney stones, there is an urgent need for the development of a drug therapy aside from siRNA drug lumasiran for patients with PH1. After the recent success of drug therapies based on small interfering RNA (siRNA), nedosiran is currently being developed for the treatment of three types of PH as a siRNA-based modality. Through specific inhibition of lactate dehydrogenase enzyme, the key enzyme in biosynthesis of oxalate in liver, phase 1, 2, and 3 clinical trials of nedosiran have achieved the desired primary end point of reduction of urinary oxalate levels in patients with PH1. More PH2 and PH3 patients need to be tested for efficacy. It has also produced a favorable secondary end point on safety and toxicity in PH patients. In addition to common injection site reactions that resolved spontaneously, no severe nedosiran treatment-associated adverse events were reported. Based on the positive results in the clinical studies, nedosiran is a candidate siRNA drug to treat PH patients.

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Section: Acs Pharmacology and Translational Sciencementioning

confidence: 99%

Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies

Liu

Zhao

Shah

et al. 2022

ACS Pharmacol. Transl. Sci.

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“…So far, experiences with Oxlumo ® treatment (outside long-term studies from the company itself) have been reported only in ten PH1 cases, both children (n = 7) [85][86][87][88] and adults (n = 3) [89-91] (Table 3) with the time under treatment reported as from 1 to 18 months. Good tolerance, reduced urinary oxalate/creatinine ratio, and stability (or even slight improvement) of renal function were reported only in the children treated.…”

Section: Substrate Reduction Therapies: the Expensive Approachmentioning

confidence: 99%

“…Glycolate not measured >5 months Fourth dose injected 3 months after third dose + B6 + citrate + hyperhydration Slight elevation of GGT and alkaline phosphatase. Developed non-anion gap metabolic acidosis (HCO 3 - 14 mmol/L and anion gap 8mmol/L) after HD discontinuation due to elevated glycolate Sodium bicarbonate resolved the metabolic acidosis 2 [ 87 ] Male Twin A 11 months old (p.Gly161Cys p.Gly170Arg) Passed stones at 6 weeks old. Kidney stone (100% CaOx) at 9 months old, bilateral UL and bilateral double-J stent.…”

Section: Current Treatment Optionsmentioning

confidence: 99%

“…Well tolerated Preeclampsia at week 31. B6 and citrate discontinued when lumasiran started 3 [ 87 ] Male Twin B 11 months old p.Gly161Cys p.Gly170Arg (assumed from dizygotic twin A) At 10 months old, bilateral renal (non-obstructive) and bladder calculi + B6 + citrate 12 months old Lumasiran Prior: Scr 0.31 mg/dl Follow up: Scr 0,12 mg/dl Prior: Uox/cr 0,125 mg/mg After: n/a Glycolate not measured 8 months 6 mg/kg monthly for 3 months, 3 mg/kg monthly thereafter Stopped crying episodes. No new stone formation.…”

Section: Current Treatment Optionsmentioning

confidence: 99%

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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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“…The role of lumasiran in the treatment of the infantile form of PH1 still needs to be completely clarified and widely evaluated, however, there are some case reports in the literature that show evidence of lumasiran’s efficacy in improving clinical manifestations and quality of life in infantile forms. 56 …”

Section: Lumasiran: Current Clinical Evidencementioning

confidence: 99%

Lumasiran in the Management of Patients with Primary Hyperoxaluria Type 1: From Bench to Bedside

D’Ambrosio¹,

Ferraro²

2022

IJNRD

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Primary hyperoxaluria (PH) is a rare genetic disease caused by excessive hepatic production and elevated urinary excretion of oxalate that leads to recurrent nephrolithiasis, nephrocalcinosis and, eventually, kidney failure. As glomerular filtration rate declines, oxalate accumulates leading to systemic oxalosis, a debilitating condition with high morbidity and mortality. Although PH is usually diagnosed during infancy, it can present at any age with different phenotypes, ranging from mild symptoms to extremely debilitating manifestations. PH is an autosomal recessive disorder and, to date, three types have been identified: PH1, PH2 and PH3. PH1 is the most common and most aggressive type, accounting for almost 80% of primary hyperoxaluria diagnoses. Until 2020, general treatment for PH1 consisted mainly in high fluid intake, urine alkalization, surgical management of recurrent nephrolithiasis and eventually, if and when kidney failure occurred, intensive dialysis regimens and transplantation strategies (simultaneous or sequential liver-kidney transplant or isolated liver/kidney transplant in carefully selected patients). Specific treatment did and still consists in administration of pyridoxine hydrochloride, although it is only effective in a subset of PH1 patients. Lumasiran, a novel biological drug based on mRNA interference that has been recently approved in the US and European Union, showed promising results and is set to be a turning point in the management of PH1. This literature review aims to summarize the available evidence on PH1 treatment with lumasiran, in order to provide both pediatric and adult nephrologists and clinicians with the knowledge for the identification and management of PH1 patients suitable for treatment.

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Infantile Primary Hyperoxaluria Type 1 Treated With Lumasiran in Twin Males

Cited by 7 publications

References 11 publications

Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies

Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies

Improving Treatment Options for Primary Hyperoxaluria

Lumasiran in the Management of Patients with Primary Hyperoxaluria Type 1: From Bench to Bedside

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