U.S. Food and Drug Administration (FDA)-Approved Indications

Lumasiran (Oxlumo) is indicated for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary and plasma oxalate levels in pediatric and adult patients.

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

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

Primary Hyperoxaluria Type 1 (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. Patients with PH1 produce excessive oxalate, which can combine with calcium to cause kidney stones and deposits in the kidneys. Patients 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 patients 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 patient, 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 acts by lowering oxalate production. It was examined in 2 studies in patients with PH1: a randomized, placebo-controlled trial in patients 6 years and older and an open-label study in patients younger than 6 years. Patients ranged in age from 4 months to 61 years at the 1st dose. In the first study, 26 patients received a monthly injection of Oxlumo followed by a maintenance dose every 3 months; 13 patients received placebo injections. The primary end-point was the amount of oxalate measured in the urine over 24 hours. In the Oxlumo group, patients had, on average, a 65 % reduction of oxalate in the urine, compared to an average 12 % reduction in the placebo group. By the 6th month of the study, 52 % of patients treated with Oxlumo reached a normal 24-hour urinary oxalate level; no patients treated with the placebo did. In the 2nd study, 16 patients younger than 6 years all received Oxlumo. Using another measure of oxalate in the urine, the study showed, on average, a 71 % decrease in urinary oxalate by the 6th month of the study.

On November 23, 2020, the Food and Drug Administration (FDA) approved Oxlumo (lumasiran) as the 1st treatment for PH1; Oxlumo received orphan drug designation. The FDA approval was based on the positive findings from 2 clinical trials in patients with PH1 -- the ILLUMINATE-A and ILLUMINATE-B phase-III studies. ILLUMINATE-A was a randomized (2:1; drug to placebo), double-blind, placebo-controlled, multi-national study. It enrolled 39 patients with PH1, aged 6 and above, with relatively preserved renal function (an estimated glomerular filtration rate [eGFR] of greater than or equal to 30 ml/min/1.73 m2), at 16 study sites, in 8 countries around the world. Oxlumo achieved the ILLUMINATE-A primary end-point of % change from baseline, relative-to-placebo, in 24-hour urinary oxalate excretion averaged across months 3 to 6 and corrected for body surface area (BSA). Specifically, treatment with Oxlumo resulted in a 65 % mean reduction in urinary oxalate relative to baseline versus 12 % reduction reported in response to placebo, resulting in a mean treatment difference of 53 % relative to placebo (p = 1.7 x 10-14). At month 6, all tested secondary end-points were met, including the proportion of patients treated with Oxlumo achieving at or below the upper limit of normal

Footnote1 *

(13/25 patients or 52 %; p = 0.001) and at or below 1.5 x upper limit of normal

Footnote2 **

(21/25 patients or 84 %; p = 8.3 x 10-7) levels of urinary oxalate, compared to none (0/13) of the patients receiving placebo. No serious or severe adverse events (AEs) were reported. Injection site reactions (ISRs) were the most common drug-related adverse reaction, reported in 10 out of 26 (38 %) of patients receiving Oxlumo. No ISRs were reported in patients receiving placebo; and ISRs occurred throughout the study period and included erythema, pain, pruritus, and swelling. These symptoms were generally mild and resolved within 1 day of the injection and did not lead to discontinuation of treatment.

Footnote1

* Normalization was defined as urinary oxalate levels of less than or equal to upper limit of normal (0.514 mmol/24 hour/1.73 m

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)

Footnote2

** Near-normalization was defined as urinary oxalate levels of less than or equal to 1.5 x the upper limit of normal (0.771 mmol/24 hour/1.73 m

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)

ILLUMINATE-B was an open-label, single-arm, multi-national pediatric study. The approval was based on an interim analysis, which included 16 of 18 PH1 patients enrolled in the study; patients were under the age of 6 with an eGFR of greater than or equal to 45 ml/min/1.73 m

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or normal serum creatinine, if less than 12 months old. The primary end-point of the study was the % change from baseline to month 6 in spot urinary oxalate:creatinine ratio averaged across months 3 to 6. In the interim analysis (n = 16), patients treated with Oxlumo attained a 71 % mean reduction in spot urinary oxalate:creatinine ratio from baseline (95 % CI: 65 to 77). In the 6-month primary analysis (n = 18), patients treated with Oxlumo attained a 72 % mean reduction in spot urinary oxalate:creatinine ratio from baseline. The overall safety and tolerability profile of Oxlumo was consistent with that observed in the ILLUMINATE-A pivotal study.

In a multicenter, single-arm, cohort study (ILLUMINATE-C), 21 patients with PH1 and an eGFR less than or equal to 45 mL/min/1.73 m

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(12 months of age and older or who had an elevated serum creatinine for age in patients less than 12 months of age), including patients on hemodialysis, were treated with the recommended dosing regimen of lumasiran based on body weight. Patients requiring peritoneal dialysis were excluded. The primary endpoint was the percent change in plasma oxalate from baseline to Month 6 for Cohort A (N = 6) and the percent change in pre-dialysis plasma oxalate from baseline to Month 6 (average from Month 3 to Month 6) for Cohort B(N = 15). The percent change from baseline to Month 6 in plasma oxalate levels in Cohort A was an LS mean difference of -33% (95% CI: -82, 15) and in Cohort B was -42% (95% CI: -51, -34). Mean plasma oxalate decreased from 65 µmol/L (95% CI: 21, 108) at baseline to 33 µmol/L (95% CI: 10, 56) at Month 6 in Cohort A, and from 108 µmol/L (95% CI: 92, 125) at baseline to 62 µmol/L (95% CI: 51, 72) at Month 6 in Cohort B (Alnylam, 2022).

No dose adjustment is necessary in patients with renal impairment including patients with kidney failure treated with hemodialysis (Alnylam, 2022).

Garrelfs et al (2021) noted that PH1 is a rare genetic disease caused by hepatic overproduction of oxalate that results in formation of kidney stones, nephron-calcinosis, kidney failure, and systemic oxalosis. In a double-blind, phase-III clinical trial, these researchers randomly assigned (in a 2:1 ratio) patients with PH1 aged 6 years or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary endpoint was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary endpoints included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6. A total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference (LSMD) in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was -53.5 percentage points (p < 0.001), with a reduction in the lumasiran group of 65.4 % and an effect observed as early as month 1. The between-group differences for all hierarchically tested secondary endpoints were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was -39.5 percentage points (p < 0.001). In the lumasiran group, 84 % of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0 % in the placebo group (p < 0.001). Mild, transient injection-site reactions were reported in 38 % of lumasiran-treated patients. The authors concluded that lumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal range of urinary oxalate levels after 6 months of treatment.

The authors stated that one drawback of this study was that patients younger than 6 years of age and patients with an eGFR of less than 30 ml/min per 1.73 m2 were excluded. Two additional, ongoing phase-III clinical trials are being carried out to comprehensively examine the effect of lumasiran in patients with PH1 across the full spectrum of age and disease severity. In ILLUMINATE-B, the safety and effectiveness of lumasiran in patients younger than 6 years of age who have relatively preserved kidney function are being examined.

Hayes et al (2022) stated that lumasiran showed safety and effectiveness in the 6-month primary analysis period of the open-label, single-arm, multi-center, phase-III clinical trial (the ILLUMINATE-B Trial) of infants and children 6 years old or younger with PH1. These investigators reported the outcomes in the ILLUMINATE-B extension period (EP) for patients who completed 12 months or longer. Of the 18 patients enrolled in the 6-month primary analysis period, all entered the EP and completed 6 or more additional months of lumasiran treatment (median (range) duration of total exposure, 17.8 (12.7 to 20.5) months). Lumasiran treatment was previously reported to reduce spot urinary oxalate:creatinine ratio by 72 % at month 6, which was maintained at 72 % at month 12; mean month 12 reductions in pre-specified weight sub-groups were 89 %, 68 %, and 71 % for patients weighing less than 10 kg, 10 to less than 20 kg, and 20 kg or more, respectively. The mean reduction from baseline in plasma oxalate (POx) level was reported to be 32 % at month 6, and this improved to 47 % at month 12. Additional improvements were also observed in nephron-calcinosis grade, and kidney stone event rates remained low. The most common lumasiran-related AEs were mild, transient injection-site reactions (3 patients (17 %)). The authors concluded that lumasiran treatment provided sustained reductions in UOx and POx through month 12 across all weight sub-groups, with an acceptable safety profile, in infants and young children with PH1.

In an open-label, single-arm, multi-center, phase-III clinical trial (the ILLUMINATE-C Trial), Michael et al (2022) examined the safety, effectiveness, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease. This study enrolled patients with PH1 of all ages, eGFR of 45 or less ml/min/1.73m2 (if age of 12 months or older) or elevated serum creatinine (if age was less than 12 months), and POx of 20 or higher μmol/L at screening, including patients with or without systemic oxalosis. Lumasiran was administered subcutaneously; 3 monthly doses followed by monthly or quarterly weight-based dosing. Primary endpoint included percent change in POx from baseline to Month 6 (Cohort A; not receiving hemodialysis at enrollment) and percent change in pre-dialysis POx from baseline to Month 6 (Cohort B; receiving hemodialysis at enrollment). Pharmacodynamic secondary endpoints included percent change in POx area under the curve (AUC) between dialysis sessions (Cohort B only); absolute change in POx; percent and absolute change in spot urinary oxalate:creatinine ratio, and 24-hour urinary oxalate (UOx) corrected for BSA. All patients (n = 21; 43 % female; 76 % white) completed the 6-month primary analysis period. Median age at consent: 8 (range of 0 to 59) years. For the primary endpoint, LSM reduction in POx in Cohort A (n = 6) was 33.3 % (95 % CI: -15.2 % to 81.8 %) and in Cohort B (n = 15) was 42.4 % (95 % CI: 34.2 % to 50.7 %). Improvements were also observed in all pharmacodynamic secondary endpoints. Most AEs were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related AEs were injection-site reactions, all mild and transient. The authors concluded that lumasiran resulted in substantial reductions in POx with acceptable safety in patients with PH1 who have advanced kidney disease, supporting its safety and effectiveness in this patient population.

Note

: Requires Precertification:

Precertification of lumasiran (Oxlumo) is required of all Aetna participating providers and members in applicable plan designs. For precertification of lumasiran (Oxlumo), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see

Specialty Pharmacy Precertification . Note

: Site of Care Utilization Management Policy applies. For information on site of service for lumasiran (Oxlumo), see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

Criteria for Initial Approval

Aetna considers lumasiran (Oxlumo) medically necessary for the treatment of primary hyperoxaluria type 1 (PH1) when the member has a documented diagnosis of primary hyperoxaluria type 1 (PH1) confirmed by

either

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Molecular genetic test showing a mutation in the alanine:glyoxylate aminotransferase (AGXT) gene;

or

Liver enzyme analysis demonstrating absent or significantly reduced alanine:glyoxulate aminotransferase (AGT) activity.

Aetna considers all other indications as experimental and investigational.

Continuation of Therapy

Aetna considers continuation of lumasiran therapy medically necessary for members who meet all initial authorization criteria and the member’s urinary and/or plasma oxalate has decreased or normalized since initiation of therapy.

Dosage and Administration

Lumasiran is available as Oxlumo and supplied as 94.5 mg/0.5 mL in a single-dose vial. Oxlumo is intended for subcutaneous use and should be administered by a healthcare professional.

The recommended dose of lumasiran (Oxlumo) by subcutaneous injection is based on body weight.

Table: Oxlumo Weight-Based Dosing Regimen Body Weight Loading Dose Maintenance Dose (begin 1 month after the last loading dose) Less than 10 kg 6 mg/kg once-monthly for 3 doses 3 mg/kg once-monthly 10 to less than 20 kg 6 mg/kg once-monthly for 3 doses 6 mg/kg once every 3 months (quarterly) 20 kg and above 3 mg/kg once-monthly for 3 doses 3 mg/kg once every 3 months (quarterly)

Source: Alnylam, 2022