In primary hyperoxaluria, calcium oxalate crystals form in the kidney and other organs. These can lead to renal insufficiency and even failure of renal function. In an international study involving the University of Bern, researchers demonstrated the efficacy and tolerability of lumasiran for the treatment of primary hyperoxaluria type 1. Recently, Swissmedic approved this active substance, which belongs to the group of small interfering RNAs, thus reaching an important milestone for patients.
Primary hyperoxaluria is a rare genetic disorder of glyoxylate metabolism that leads to increased endogenous production of oxalate, resulting in extremely increased renal excretion of oxalic acid [1]. Today, three autosomal recessive inherited forms of the disease are known. By far the most common is primary hyperoxaluria type 1, in which the mutation affects the peroxisomal liver enzyme alanine glyoxylate aminotransferase. In type 2, the genetic defect is due to a mutation in the ubiquitous glyoxylate reductase/hydroxypyruvate reductase, and in type 3, it is due to mutations in the HOGA1 gene, which encodes 2-keto-4-hydroxyglutarate aldolase. Primary hyperoxaluria type 1 occurs in different age groups and is considered to be significantly underdiagnosed. Epidemiological studies estimate the population-dependent incidence to be approximately 1:100 000 to 1:250 000 [5].
Drug treatment as an alternative to transplantation
The main symptoms of primary hyperoxaluria are recurrent urolithiasis and/or progressive nephrocalcinosis [1]. Especially in type 1, early renal failure and associated systemic deposition of calcium oxalate crystals often develop as a result. This makes primary hyperoxaluria a multisystem disease. Often, the diagnosis is made late, in about one third of those affected only in the phase of terminal kidney failure. Until now, the only possible measures were an extremely increased daily fluid intake and drugs that increase the solubility of oxalate in the urine or a liver-kidney transplant. With lumasiran, a causal therapy option is now available for the first time. Efficacy and safety of this substance, which belongs to the group of small interfering RNA (siRNA), were tested in the international randomized, placebo-controlled double-blind study “ILLUMINATE-A” [3,4]. Results published in the New England Journal of Medicine indicate that primary hyperoxaluria type 1 can be successfully treated with lumasiran (Oxlumo®).
Lumasiran reduces glycolate oxidase in liver cells.
Through RNA interference, lumasiran causes a reduction in the concentration of the enzyme glycolate oxidase in liver cells. This increases the available amount of glyoxylate – a substrate for the formation of oxalate -.
reduced. In the ILLUMINATE-A study, a total of 39 patients with primary hyperoxaluria were randomized 2:1 to receive lumasiran (n=26) or placebo (n=13) subcutaneously for 6 months. Of the patients enrolled in the study, 84.6% reported symptomatic kidney stones and 53.8% reported a history of nephrocalcinosis at baseline. Other important patient characteristics at baseline are described in Table 1 presented [3].
Subjects received three initial doses of 3 mg/kg lumasiran or placebo once monthly during the six-month treatment period, followed by two maintenance doses at months 3 and 6. Lumasiran-treated patients experienced a rapid and sustained reduction in oxalate excretion in 24-hour urine collection [3]. (Fig. 1). The reduction in oxalate corrected for body surface area in 24-hour collected urine was 65.4% with lumasiran versus 11.8% with placebo*. [3,4]. This corresponds to a highly significant difference of 53.5% (95% CI: 44.8; 62.3; p<0.0001). Thus, the primary endpoint of the study was met. After six months, the lumasiran arm showed a 60.5% reduction in the oxalate/creatinine ratio in spontaneous urine, compared to an 8.5% increase in the placebo arm. The reduction in oxalate corrected for body surface area in 24-hour collected urine proved to be sustained over the six months. Subsequently, patients, including participants initially assigned to placebo, were enrolled in an extension phase of lumasiran administration as part of ILLUMINATE-B.
* Values averaged over months 3-6
Conclusion: Oxlumo® is very effective and generally well tolerated
The results of the pivotal ILLUMINATE-A trial can be considered groundbreaking in that for the first time a causal, effective and well-tolerated therapy is available [2]. Lumasiran has already been approved for the treatment of primary hyperoxaluria in the U.S. and EU since November 2020 and now also in Switzerland since December 31, 2021. Several patients, including two children, were successfully treated with lumasiran at the Inselspital Bern. Prof. Daniel Fuster, MD, Chief Physician, Inselspital, University Hospital Bern, explains: “The very good tolerability and the extent of oxalic acid reduction were very positive. No serious side effects occurred, and most patients had normal oxalic acid levels in blood and urine after six months with Lumasiran.” [2,3]. Diagnosis and therapy require a lot of experience and a specialized, interdisciplinary team. Only a few centers are available internationally that are capable of meeting the high requirements. Education and training will be necessary to prepare all partners for the specific requirements. Due to their participation in the ILLUMINATE-A study and the related experience with lumasiran therapy, the specialists at the Inselspital of the University Hospital Bern are well equipped to do so.
Literature:
- Hoppe B: Primary hyperoxaluria. Nephrologist 2014; 9: 204212.
- “Hyperoxaluria: therapy against rare metabolic disease”, University of Bern, May 11, 2021.
- Garrelfs FS, et al: Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1. N Engl J Med 2021; 384: 1216-1226.
- Drug Information: Oxlumo®, www.swissmedicinfo.ch, (last accessed Feb. 15, 2022).
- Zarbock R: Hyperoxaluria. www.medizinische-genetik.de/diagnostik/humangenetik/erkrankungen/syndrome/nierenerkrankungen/hyperoxalurie (last call 02/15/2022)
HAUSARZT PRAXIS 2022; 17(3): 48-50
CARDIOVASC 2022; 21(2): 29
