Lumasiran 94.5mg/0.5ml solution for injection vials

Background: Primary hyperoxaluria is a rare genetic disorder of hepatic oxalate over production. Standard of care was largely supportive with hyperhydration, urinary alkalinization and pyridoxine. RNA interference therapies have recently shown promising results. Material and Methods: The systematic review was prospectively registered with PROSPERO and followed PRISMA guidelines. Pubmed, EMBASE and CENTRAL were searched from January 1974 to July 2024 for randomized controlled trials and single arm intervention studies on use of RNAi therapies in primary hyperoxaluria. Results: We found 127 records across the databases, with 12 of them included in the final analysis. A total of 140 patients were enrolled in Lumasiran (9 trials) and Nedosiran (3 trials). Most studies demonstrated a significant reduction in the oxalate burden. Injection site reaction was the most common adverse event with a largely acceptable safety profile. Quality of studies assessed through ROB-2 and ROBINS-I showed a low risk of bias. Conclusion: This systematic review emphasizes the effectiveness and safety of RNA interference therapies, Lumasiran and Nedosiran, in treating primary hyperoxaluria by lowering urinary and plasma oxalate levels.

Abstract licence: CC BY-NC

Lumasiran (Oxlumo®), a first-in-class synthetic, double-stranded, ribonucleic acid (RNA) interference molecule targeting glycolate oxidase through silencing HAO1 mRNA, is approved in several countries for patients of any age and stage of kidney function with primary hyperoxaluria type 1 (PH1). Approval was based on results from the phase III ILLUMINATE trials. In the double-blind, placebo-controlled, ILLUMINATE-A trial, subcutaneous lumasiran was significantly more effective than placebo in reducing 24-h urinary oxalate excretion in patients aged ≥ 6 years with PH1; this effect was sustained for ≥ 36 months in ongoing longer-term analyses. In the single-arm ILLUMINATE-B trial, lumasiran reduced urinary oxalate:creatinine ratios and plasma oxalate levels in patients aged < 6 years with PH1. In the single-arm ILLUMINATE-C trial, lumasiran reduced plasma oxalate levels in patients with PH1 receiving dialysis as well as those not receiving dialysis. In secondary and exploratory analyses of these trials, nephrocalcinosis grade, kidney stone event rates and estimated glomerular filtration rates were either stable or improved with lumasiran. Lumasiran had an acceptable tolerability profile that remained consistent in longer-term analyses; the most common adverse events were mild and transient injection-site reactions. Thus, lumasiran is an effective treatment option, with an acceptable tolerability profile, in patients with PH1. Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder that leads to excess oxalate in urine or plasma requiring removal by the kidneys. This overproduction is damaging and can lead to kidney failure. Management of PH1 is typically not curative, eventually ending in kidney and/or liver transplantation. Lumasiran (Oxlumo®) is the first medicine to be approved in several countries for use in patients with PH1, regardless of their age or level of kidney function. It reduces liver oxalate production, lessening damage to the kidneys and potentially reducing the need for organ transplantation. In clinical trials, lumasiran was effective in reducing oxalate levels (in urine and/or plasma) in patients of all ages with PH1, and irrespective of whether they were receiving dialysis or not. Lumasiran either improved or stabilized the severity of calcium deposition in the kidneys, number of kidney stone events and kidney function. Lumasiran had an acceptable tolerability profile; the most common side effects were mild injection-site reactions that resolved quickly. Thus, lumasiran is an effective treatment option, with an acceptable tolerability profile, in patients with PH1.

Abstract licence: CC BY-NC 4.0

BackgroundPrimary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by excessive oxalate production that leads to nephrocalcinosis or nephrolithiasis and progressive kidney failure, associated with systemic oxalosis that is not reversed by dialysis. Pharmacological treatment is limited. Combined or sequential liver and kidney transplant is standard of care for PH1. Recently approved RNA-interference (RNAi) therapy with lumasiran or nedosiran targeting glycolate oxidase and lactate dehydrogenase A, respectively, reduces hepatic oxalate synthesis. This makes kidney-only (isolated) transplantation (iKT) a potentially successful, novel approach for managing PH1 patients with advanced kidney disease combined with hyperhydration, urine alkalinization, and vitamin B6 (where applicable).MethodsWe analyzed the course of a young PH1 kidney transplant recipient at our institution and performed a literature review of patients with small interfering RNA-enabled iKT.Case presentationA patient with PH1 due to a homozygous, pathogenic variant in AGXT exon 1 (c.121G>A; p.Gly41Arg) received a deceased donor kidney transplant after 6.5 years of hemodialysis and 4.3 years of RNAi therapy with lumasiran. He maintained good kidney allograft function 9 months post-transplant despite the occurrence of an asymptomatic calyceal stone within the graft prior to transition to adult nephrology care. At 14 months, he experienced a T cell-mediated rejection, associated with a rise in serum creatinine and plasma oxalate, and a partially obstructing stone. A review of all 10 accessible cases of RNAi-supported iKT, including our own, revealed several instances of kidney stone formation (20%), stent obstruction (20%), and mild, mostly transient crystal deposition in the graft (37.5%).ConclusionsThis report enriches the limited experience of RNAi-enabled kidney-only transplantation in PH1. RNA interference therapy has the potential to challenge the current standard of dual liver and kidney transplantation in children and young adults with this devastating disease but requires uninterrupted access to the drug with individualized, eGFR and oxalate level adjusted dosing, continued vigilance, and reporting of long-term outcomes.

Abstract licence: CC BY-NC-ND