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PRIMARY HYPEROXALURIA TYPE1 (PH1)

Primary hyperoxalurias (PHs) are rare inborn errors of glyoxylate metabolism characterized by the over-production of oxalate, which is poorly soluble and is deposited as calcium oxalate in various organs (including the bones, eyes, heart, and kidney).  Primary hyperoxaluria is caused by mutations in 1 of the 3 genes that encode enzymes involved in glyoxylate metabolism.  Primary hyperoxaluria type 1 (PH1; about 80 % of cases) is due to mutations of hepatic peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT); it is the most common and severe type affecting an estimated 1 to 3 individuals per million in Europe and North America.  As oxalate is primarily excreted in the urine, the kidney is the prime target for oxalate deposition, which leads to end-stage renal disease (ESRD) in many cases.  Individuals with PH1 produce excessive oxalate, which can combine with calcium to cause kidney stones and deposits in the kidneys.  Individuals can experience progressive kidney damage, which can lead to kidney failure and the need for dialysis.  As kidney function worsens, oxalate can build up and damage other organs (Cochat and Rumsby, 2013; Niaudet, 2022).

Liebow and associates (2017) stated that PH1 arises from mutations in the enzyme AGT; and the resulting deficiency in this enzyme leads to abnormally high oxalate production resulting in calcium oxalate crystal formation and deposition in the kidney and many other organs, with systemic oxalosis and ESRD being common outcomes.  Although a small subset of individuals can manage the disease with vitamin B6 treatments, the only effective treatment for most is a combined liver-kidney transplant.  These researchers discussed the development of ALN-GO1, an investigational RNA interference (RNAi) therapeutic targeting glycolate oxidase, to deplete the substrate for oxalate synthesis.  Subcutaneous administration of ALN-GO1 resulted in potent, dose-dependent, and durable silencing of the mRNA encoding glycolate oxidase and increased serum glycolate concentrations in wild-type mice, rats, and non-human primates.  Furthermore, ALN-GO1 increased urinary glycolate concentrations in normal non-human primates and in a genetic mouse model of PH1.  Notably, ALN-GO1 reduced urinary oxalate concentration up to 50 % following a single-dose in the genetic mouse model of PH1, and up to 98 % after multiple doses in a rat model of hyperoxaluria.  The authors concluded that these findings showed the ability of ALN-GO1 to reduce oxalate production in pre-clinical models of PH1 across multiple species and provided a clear rationale for clinical trials with this compound.

McGregor and colleagues (2020) noted that by sequencing autozygous human populations, these researchers identified a healthy adult woman with lifelong complete knockout of HAO1 (expected about 1 in 30 million outbred people).  HAO1 (glycolate oxidase) silencing is the mechanism of lumasiran, an investigational RNAi therapeutic for PH1.  Lumasiran acts by lowering oxalate production.  Her plasma glycolate levels were 12 times, and urinary glycolate 6 times, the upper limit of normal observed in healthy reference individuals (n = 67).  Plasma metabolomics and lipidomics (1,871 biochemicals) revealed 18 markedly elevated biochemicals (greater than 5 standard deviations outliers versus n = 25 controls) suggesting additional HAO1 effects.  Comparison with lumasiran pre-clinical and clinical trial data suggested she had less than 2 % residual glycolate oxidase activity.  Cell line p.Leu333SerfsTer4 expression showed markedly reduced HAO1 protein levels and cellular protein mis-localization.  The authors concluded that in this individual, lifelong HAO1 knockout is safe and without clinical phenotype, de-risking a therapeutic approach and informing therapeutic mechanisms.  Unlocking evidence from the diversity of human genetic variation can facilitate drug development.

LUMASIRAN

Lumasiran, a HAO1-directed small interfering ribonucleic acid (siRNA), is available as the brand Oxlumo (Alnylam Pharmaceuticals, Inc.). Per the label for Oxlumo, lumasiran reduces levels of glycolate oxidase (GO) enzyme by targeting the hydroxyacid oxidase 1 (HAO1) messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference. Decreased GO enzyme levels reduce the amount of available glyoxylate, a substrate for oxalate production. As the GO enzyme is upstream of the deficient alanine:glyoxylate aminotransferase (AGT) enzyme that causes PH1, the mechanism of action of lumasiran is independent of the underlying AGXT gene mutation. Oxlumo is not expected to be effective in primary hyperoxaluria type 2 (PH2) or type 3 (PH3) because its mechanism of action does not affect the metabolic pathways causing hyperoxaluria in PH2 and PH3 (Alnylam, 2022).

The most common adverse reaction (reported in 20% or more of individuals) is injection site reactions.

Lumasiran acts by lowering oxalate production.  It was examined in 2 studies in individuals with PH1: a randomized, placebo-controlled trial in individuals 6 years and older and an open-label study in individuals younger than 6 years.​

CLINICAL STUDIES

ILLUMINATE-A

ILLUMINATE-A was a randomized, double-blind trial comparing lumasiran and placebo in 39 individuals 6 years of age and older with PH1 and an eGFR ≥30 mL/min/1.73 m2 (ILLUMINATE-A; NCT03681184). Individuals received 3 loading doses of 3 mg/kg OXLUMO (N=26) or placebo (N=13) administered once monthly, followed by quarterly maintenance doses of 3 mg/kg OXLUMO or placebo.

The median age was 15 years (range 6 to 61 years), 67% were male, and 77% were White. At baseline, the median 24-hour urinary oxalate excretion corrected for body surface area (BSA) was 1.7 mmol/24 h/1.73 m2, the median plasma oxalate level was 13.1 µmol/L, 33% of individuals had eGFR ≥90 mL/min/1.73 m2, 49% had eGFR of 60 to <90 mL/min/1.73 m2, and 18% had eGFR 30 to <60 mL/min/1.73 m2, 56% were on pyridoxine, and 85% reported a history of symptomatic kidney stone events.

The primary endpoint was the percent reduction from baseline in 24-hour urinary oxalate excretion corrected for BSA averaged over Months 3 through 6. The LS mean percent change from baseline in 24­hour urinary oxalate in the OXLUMO group was -65% (95% CI: -71, -59) compared with -12% (95% CI: -20, -4) in the placebo group, resulting in a between-group LS mean difference of 53% (95% CI: 45, 62; p<0.0001). By Month 6, 52% (95% CI: 31, 72) of individuals treated with OXLUMO achieved a normal 24-hour urinary oxalate corrected for BSA (≤0.514 mmol/24 hr/1.73 m2) compared to 0% (95% CI: 0, 25) placebo-treated individuals (p=0.001).

ILLUMINATE-B

ILLUMINATE-B was a single-arm study in 18 individuals <6 years of age with PH1 and an eGFR >45 mL/min/1.73 m2 for individuals ≥12 months of age or a normal serum creatinine for individuals <12 months of age (ILLUMINATE-B; NCT03905694). Efficacy analyses included the first 16 individuals who received 6 months of treatment with OXLUMO. Dosing was based on body weight.

The median age was 47 months (range 4 to 74 months), 56% were female, and 88% were White. Three individuals were less than 10 kg, 11 were 10 kg to < 20 kg, and 2 were ≥ 20 kg. The median spot urinary oxalate:creatinine ratio at baseline was 0.47 mmol/mmol. The primary endpoint was the percent reduction from baseline in spot urinary oxalate:creatinine ratio averaged over Months 3 through 6. Individuals treated with OXLUMO achieved a reduction in spot urinary oxalate:creatinine ratio from baseline of 71% (95% CI: 65, 77).

SUMMARY

Primary hyperoxalurias are a group of rare genetic diseases. There are 3 subtypes each resulting in the overproduction of oxalate by the liver. Type 1 is the most common type, which accounts for approximately 80% of cases and occurs as a result of a genetic defect in the alanine:glyoxylate aminotransferase (AGXT) gene that encodes the enzyme alanine glyoxylate aminotransferase. Defect in the enzyme results in overproduction of oxalate, which leads to deposition of calcium oxalate crystals in the kidneys and urinary tract. The result is the formation of painful and recurrent nephrolithiasis (renal stones), nephrocalcinosis, and renal failure. Compromised renal function exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation and crystallization in bones, eyes, skin, and heart, leading to severe illness and death. Lumasiran is a subcutaneously administered RNA interference (RNAi) therapeutic that silences the HAO1 gene, which encodes for a glycolate oxidase enzyme. By silencing the HAO1 gene, levels of glycolate oxidase are depleted, decreasing production of oxalate, the metabolite that directly contributes to the pathophysiology of primary hyperoxaluria type 1.

For individuals with primary hyperoxaluria type 1, evidence includes 1 phase 3 randomized controlled trial (RCT) (ILLUMINATE-A) in individuals 6 years and older and 2 single arm prospective studies (ILLUMINATE-B and ILLUMINATE-C). Relevant outcomes are symptoms, quality of life, disease-specific survival, change in disease status, treatment-related morbidity, and treatment-related mortality. In ILLUMINATE-A and ILLUMINATE-B, individuals with preserved renal function were enrolled (estimated glomerular filtration rate [eGFR] >30 mL/min/1.73 m2) while in ILLUMINATE-C, individuals with moderately or severely reduced GFR including individuals with kidney failure on hemodialysis were enrolled. In ILLUMINATE-A, 39 individuals were randomized 2:1 to lumasiran or placebo for 6 months. The primary endpoint was the percent change in 24-hour urinary oxalate excretion from baseline to month 6. The percent reduction in 24-hour urinary oxalate from baseline to month 6 was -65% and -12% in the lumasiran and placebo groups, respectively, with a between-group mean difference of 53% (95% confidence interval [CI], 45% to 62%; p<.0001). A similar effect was seen in individuals with high baseline urinary oxalate values, and approximately half of individuals who received lumasiran achieved normal urinary oxalate values by month 6. In ILLUMINATE-B, 18 individuals were treated with lumasiran. The primary endpoint was the percent change in spot urinary oxalate-to-creatinine ratio from baseline to month 6. Lumasiran demonstrated a percent reduction in spot urinary oxalate-to creatinine ratio from baseline of -71% (95% CI, -77% to -65%) at 6 months. Results at 1 year follow-up showed that treatment effects were sustained. The magnitude of the reduction and the time course were consistent with findings in ILLUMINATE-A. In ILLUMINATE-C, 21 individuals were treated with lumasiran. The primary endpoint was the percent change in plasma oxalate levels from baseline to month 6. Lumasiran demonstrated a percent reduction in plasma oxalate levels of -33% (95% CI, -82% to 15%) and -42% (95% CI, -51% to -34%) in individuals who did not require dialysis at the time of study enrollment and individuals who were on a stable regimen of hemodialysis. The major limitation is the lack of data on health outcomes such as renal stones, nephrocalcinosis, and renal failure since neither trial was powered to assess these health outcomes. However, use of urinary oxalate as a surrogate for health outcomes in the pivotal trials may be justified based on the knowledge of the pathophysiology of the disease and the causal role of urinary oxalate in kidney stone formation, nephrocalcinosis, and loss of kidney function. Further, the consistency and size of treatment effect across 3 trials are indicative of the potential for a clinical benefit over the long term. Lumasiran was generally well-tolerated in all 3 studies.