Lumasiran (Oxlumo)

Number: 0983

Policy

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 (866) 267-3277.

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.

Aetna considers lumasiran (Oxlumo) medically necessary for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in adult and pediatric members who meet both of the following criteria:

1. Member has a documented diagnosis of PH1 confirmed by a molecular genetic test showing a mutation in the alanine:glyoxylate aminotransferase (AGXT) gene or liver enzyme analysis demonstrating absent or significantly reduced alanine:glyoxylate aminotransferase (AGT) activity; and

2. Member has a pre-treatment estimated glomerular filtration rate (eGFR) of greater than or equal to 30 ml/min/1.73 m²

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

Aetna considers lumasiran (Oxlumo) experimental/investigational for all other indications.

Dosing Recommendations

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)

Background

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 oxalate levels in pediatric and adult patients.

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, 2020).

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 normalFootnote1* (13/25 patients or 52 %; p = 0.001) and at or below 1.5 x upper limit of normalFootnote2** (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 m²)

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 m²)

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 m² 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.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
J0224	Injection, lumasiran, 0.5 mg
ICD-10 codes covered if selection criteria are met:
E72.53	Primary hyperoxaluria

The above policy is based on the following references: