Medical Policy                                                                                                          

Policy Num:       M5.001.016
Policy Name:     Lumasiran for Primary Hyperoxaluria Type 1
Policy ID:          [M5.001.016] [Ac / Mg / M+ / P + ][0.00.00]

Last Review:       May 10, 2024
Next Review:      May 20, 2025
 

Related Policies: None

Lumasiran for Primary Hyperoxaluria Type 1

Summary

Description

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.

OBJECTIVE

The objective of this evidence review is to assess whether treatment with lumasiran improves the net health outcome in patients with primary hyperoxaluria type 1.

COVERAGE INDICATIONS, LIMITATIONS, AND/OR MEDICAL NECESSITY

Initial Treatment

Lumasiran may be considered medically necessary if all of the following conditions are met:

1. Diagnosis of primary hyperoxaluria type 1 confirmed by identification of biallelic pathogenic variants in alanine:glyoxylate aminotransferase (AGT or AGXT) gene OR liver biopsy demonstrating AGT deficiency.

2. Presence of 1 of the following clinical signs or symptoms of primary hyperoxaluria type 1:

   1. Elevated urine oxalate excretion (body surface area-normalized daily urine oxalate excretion output ≥0.7 mmol/1.73 m²)

   2. Elevated plasma oxalate concentration >20 μmol/L or >1.76 mg/L

   3. Urine oxalate excretion:creatinine ratio above age-specific upper limit of normal.

3. Individual has not received a liver transplant.

4. Prescribed by or in consultation with a nephrologist, urologist, geneticist, or any healthcare provider with expertise in treating primary hyperoxaluria type 1.

Initial authorization period is for 6 months.

Continuation of Treatment

Incremental reauthorization for lumasiran may be considered medically necessary if the following conditions are met:

1. Individual continues to meet the initial treatment criteria cited above.

2. Documented evidence to support clinically meaningful response to therapy from pre-treatment baseline (eg, decreased urinary oxalate concentrations, decreased urinary oxalate:creatinine ratio, decreased plasma oxalate concentrations, improvement, stabilization or slowed worsening of nephrocalcinosis, renal stone events, renal impairment or systemic calcinosis).

3. Does not exceed United States Food and Drug Administration approved maintenance dose.

Reauthorization period is for 12 months.

Lumasiran is considered investigational when the above criteria are not met.

Lumasiran is considered investigational for all other indications.

BENEFIT APPLICATION

BACKGROUND

Primary Hyperoxaluria

Primary hyperoxaluria is a rare disorder of glyoxylate metabolism characterized by the overproduction of oxalate, which is poorly soluble and deposited as calcium oxalate in the kidneys and urinary tract, leading to 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.

There are 3 types of primary hyperoxaluria. Each of these is caused by a defect in a gene that governs the production of a different hepatic enzyme, and each results in the overproduction of oxalate by the liver. The 3 types are summarized in Table 1. Type 1 is the most common type, which accounts for approximately 80% of cases^1,. Homozygous or compound heterozygous alanine:glyoxylate aminotransferase (AGXT) variants lead to hepatic deficiency of alanine glyoxylate aminotransferase, which converts glyoxylate into pyruvate and glycine.^2, Absent or deficient levels lead to accumulation of oxalate and its deposition as calcium oxalate.

Table 1. Primary Hyperoxaluria Types.^1,

a Approximately 5 percent of patients with primary hyperoxaluria do not have identifiable genetic mutations of the AGXT, GRHPR, or HOGA1 gene.

Primary hyperoxaluria type 1 is a heterogeneous disorder with high variability in age and severity of symptoms at the time of presentation. Kidney stones are the most common manifestation that lead to the diagnosis of primary hyperoxaluria type 1. Patients can present from birth to adulthood with clinical presentation ranging from kidney stones to end stage renal disease (ESRD). A summary from 2 case series comprising 78 infants^6, and 155 patients (from 129 unrelated families)^7, diagnosed with primary hyperoxaluria type 1 is presented in Table 2. Young patients present with more severe complications than adults as they have premature kidneys and develop rapid progression to ESRD.^2, An analysis of 247 patients with primary hyperoxaluria type 1 from the Rare Kidney Stone Consortium Registry showed that 20% of patients developed ESRD by approximately age 20 while 50% developed ESRD by age 35. By age 60, nearly 90% of all patients progressed to ESRD.^8,

Table 2. Clinical Manifestations of Primary Hyperoxaluria Type 1 by Age^6,7,

a Approximately 10 percent of patients were diagnosed on post-transplant recurrence of kidney stones and 13% were diagnosed during family screening.

Primary hyperoxaluria type 1 is considered a rare disease with an estimated prevalence of 1 to 3 patients per million people worldwide (mainly based on estimates from Europe).^9, The incidence in Europe has been estimated at 1 in 120,000 live births per year. ^9, Estimating the prevalence and incidence is difficult owing to the wide variability in its clinical presentation and age of clinical onset. Patients often experience a considerable diagnostic delay; approximately 20 to 50% of patients have advanced chronic kidney disease, or even ESRD at the time of diagnosis.^9, Data regarding prevalence and incidence is summarized in Table 3.

Table 3. Estimated United States and European Union Prevalence of Primary Hyperoxaluria Type 1^a

a Assumed indication is for the treatment of primary hyperoxaluria type 1 in pediatric and adult patients regardless of stage of disease.b United States population= 328 million; European Union population including the United Kingdom= 513 million.

Diagnosis

Diagnosis of primary hyperoxaluria type 1 is often delayed because of the rarity of the condition and general lack of awareness of the disease. Diagnosis generally involves 3 steps:

1. Clinical suspicion based on symptoms and radiographic features such as recurrent renal stones, nephrocalcinosis associated with decreased glomerular filtration rate (GFR), renal failure of unknown cause, presence of oxalate crystals in any biological fluid or tissue.
2. Metabolic screening for urinary oxalate levels. Normal urinary oxalate excretion is less than 0.5 mmol/1.73 m² per day or 45 mg/1.73 m² per day.^13, Levels greater than this are strongly supportive of the diagnosis of primary hyperoxaluria type 1.
3. Diagnosis is confirmed by molecular genetic testing that demonstrates a variant of the AGXT gene.

Current Treatment

The initial medical management approaches, which are aimed to delay progressive renal decline, include use of pyridoxine, calcium oxalate crystallization inhibitors, hyperhydration, and dietary restrictions.

Treatment with pyridoxine (vitamin B6) has been shown to decrease urine oxalate excretion in about 10 to 30% of patients, particularly those with homozygous p.Gly170Arg or p.Phe152lle variants.^14, As a result, a trial of pyridoxine that lasts at least 3 months is warranted in all patients with type 1 primary hyperoxaluria.^15, A positive response is defined as a reduction greater than 30% in urinary oxalate excretion. Observational data suggest that in patients who are responsive to pyridoxine, continued treatment is beneficial in most patients^15,16, and should be continued indefinitely or until liver transplantation is performed. Large doses of pyridoxine may induce sensory neuropathy.

Certain medication such as potassium citrate, orthophosphates, and thiazides prevent crystallization of calcium oxalate in the kidneys.^14, Hyperhydration (fluid intake greater than 3 L/day per 1.73 m²) is an effective therapy to decrease tubular fluid oxalate concentration and diminish intratubular oxalate deposition. However, it is problematic in young children, as a gastric tube or a percutaneous gastrostomy may be necessary to maintain this high urine flow around the clock including both day and nighttime. While avoidance of foods with high oxalate content, such as tea, chocolate, spinach, and rhubarb is generally advocated, most oxalate is of an endogenous source and as such dietary measures are of little help.^17,

As the disease progresses, individuals may require interventions for renal stone removal, dialysis, and renal/liver transplant. However, with conventional hemodialysis and peritoneal dialysis, the rate of oxalate removal is often less than the endogenous production of oxalate^18,19, and plasma oxalate returns to 80% of the predialysis value within 24 hours and 95% within 48 hours after dialysis.^20, As a consequence, despite standard maintenance dialysis therapy, plasma oxalate typically exceeds the supersaturation threshold of 30 micromol/L during a substantial amount of time between dialysis treatments, thereby increasing the risk and progression of systemic oxalosis.

Liver transplantation is the only curative intervention as it corrects the underlying enzymatic defect due to mutations of the AGXT gene. In patients with significant chronic renal disease, renal transplant may also be required. Currently, multiple transplantation strategies are in use and include combined liver-renal transplantation, sequential liver and renal transplantation, isolated liver transplantation, and isolated renal transplantation. However, the optimal transplantation type or sequence remains uncertain.^21, Complications include those due to immunosuppressive therapy (eg, infections or adverse drug effects), secondary malignancy, and failure of allograft.

REGULATORY STATUS

On November 23, 2020, lumasiran (Oxlumo) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of primary hyperoxaluria type 1 to lower urinary oxalate levels in pediatric and adult patients.

On October 6, 2022, the U.S. FDA approved a new label expansion to lower urinary oxalate and plasma oxalate levels in pediatric and adult patients. The approval was based on the results of the ILLUMINATE-C phase 3 trial in patients with severe renal impairment, including individuals on hemodialysis.

Rationale

This evidence review was created in April 2021 with searches of the PubMed database. The most recent literature update was performed through April 11, 2023.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1 

Primary Hyperoxaluria Type 1

Clinical Context and Therapy Purpose

The purpose of lumasiran in individuals who have primary hyperoxaluria type 1 is to provide a treatment option that is an improvement on existing therapies. Potential benefits of this therapy may include the following:

• A novel mechanism of action or approach that provides an additional treatment option for many individuals who have failed or have yielded a sub-optimal response to existing treatments.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with primary hyperoxaluria type 1 with preserved renal function.

Interventions

The therapy being considered is lumasiran, a RNA interference (RNAi) therapy. It silences the HAO1 gene that encodes for the enzyme glycolate oxidase. Decreased production of glycolate oxidase reduces hepatic oxalate production. Treatment is administered in an outpatient setting. The recommended dose of lumasiran is weight-based and given as a subcutaneous injection. All maintenance doses begin 1 month after the last loading dose.

• For individuals weighing less than 10 kg: Loading dose is 6 mg/kg once monthly for 3 doses followed by a maintenance dose of 3 mg/kg once monthly.

• For individuals weighing 10 kg to less than 20 kg: Loading dose is 6 mg/kg once monthly for 3 doses followed by a maintenance dose of 6 mg/kg once every 3 months (quarterly)

• For individuals weighing 20 kg and above: Loading dose is 3 mg/kg once monthly for 3 doses followed by a maintenance dose of 3 mg/kg once every 3 months (quarterly)

Comparators

The following therapies are currently being used to manage individuals with primary hyperoxaluria type 1.

The initial medical management approaches, which are aimed to delay progressive renal decline, include use of pyridoxine, calcium oxalate crystallization inhibitors, hyperhydration, and dietary restrictions. As the disease progresses, individuals may require interventions for renal stone removal, dialysis, and renal/liver transplant. Despite standard maintenance dialysis therapy, plasma oxalate typically exceeds the supersaturation threshold of 30 micromol/L during a substantial amount of time between dialysis treatments, thereby increasing the risk and progression of systemic oxalosis. Liver transplantation is the only curative intervention as it corrects the underlying enzymatic defect due to mutations of the AGXT gene. In patients with significant chronic renal disease, renal transplant may also be required. Currently, multiple transplantation strategies are in use and include combined liver-renal transplantation, sequential liver and renal transplantation, isolated liver transplantation, and isolated renal transplantation. However, the optimal transplantation type or sequence remains uncertain.^21, Complications include those due to immunosuppressive therapy (eg, infections or adverse drug effects), secondary malignancy, and failure of allograft.

Outcomes

The general outcomes of interest are quality of life, disease-specific survival, change in disease status, resource utilization, treatment-related mortality, and treatment-related morbidity. Relevant outcome measures in alphabetical order are summarized in Table 4.

Table 4. Health Outcome Measures Relevant to Primary Hyperoxaluria Type 1

CI: confidence interval; CKD: chronic kidney disease; GFR: glomerular filtration rate; PH1; primary hyperoxaluria type 1.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

The clinical development program for lumasiran includes 3 prospective trials. These trials enrolled patients with primary hyperoxaluria type 1 with varying levels of renal function, with age groups ranging from infant to adult. ILLUMINATE-A (NCT03681184) enrolled patients aged 6 years and older with an estimated glomerular filtration rate [eGFR] ≥30 mL/min/1.73 m², ILLUMINATE-B (NCT03905694) enrolled patients aged less than 6 years old with an eGFR >45 mL/min/1.73 m² (if ≥12 months old) and ILLUMINATE-C (NCT04152200) enrolled patients with advanced primary hyperoxaluria type 1 irrespective of age with an eGFR ≤30 mL/min/1.73 m². A dose-finding phase-I first-in-human study (NCT02706886) was not included in the review of evidence.^28,

Randomized Controlled Trials

ILLUMINATE-A is the pivotal phase 3 randomized, double-blind, placebo-controlled trial.^29, The study consists of 2 parts: an initial 6-month, double-blind treatment period followed by a 54-month extension period in which placebo patients had an option to switch to lumasiran. The study characteristics are summarized in Table 5. Results with 6-months follow-up are available and summarized in Table 6. At 6 months, the percent change in 24-hour urinary oxalate excretion from baseline to month 6 in the lumasiran group was -65% compared to -12% in the placebo group, resulting in a between-group least square (LS) mean difference of 53% (95% confidence interval [CI]: 45 to 62; p<0.0001). The proportion of patients who achieved a 24-hour urinary oxalate level at or below the upper limit of normal (ULN) at month 6 was 52% in the lumasiran group versus 0% in the placebo group (p=0.001). The absolute change in 24-hour urinary oxalate levels in the lumasiran group was -1.24 (95% CI, -1.37 to -1.12) compared to -0.27 (95% CI, -0.44 to -0.10) in the placebo group with a difference of -0.98 (95% CI, -1.18 to -0.78) mmol/24 hr/1.73 m².^30,Urinary oxalate excretion is a surrogate health outcome and, while it is directly related to the pathophysiology of the disease, ILLUMINATE-A was not powered to assess hard endpoints associated with hyperoxaluria such as renal stones, nephrocalcinosis, and renal failure. Renal stone events was a composite outcome and included at least 1 of the following: visit to healthcare provider because of a renal stone, medication for renal colic, stone passage, or macroscopic hematuria due to a renal stone. Overall, 8 patients (31%) in the lumasiran group and 3 (23%) in the placebo group experienced stone events during the 6-month, placebo-controlled period (13 vs 4 stone events, respectively). Evidence of a treatment effect on kidney stone events was not expected given that calcium oxalate stones are slow to form and pass. The proportion of patients with self-reported stone events at baseline was greater in the lumasiran group versus placebo (89% vs 77%).

Table 5. Summary of ILLUMINATE-A Characteristics

AGXT: alanine glyoxylate aminotransferase; DBRCT: double-blind randomized controlled trial; eGFR: estimated glomerular filtration rate; HIV: human immunodeficiency virus; PH1: primary hyperoxaluria type 1.a Treatment arms were stratified at randomization based upon mean 24hr urinary oxalate from the first 2 valid samples collected during screening (≤1.70 mmol/24hr/1.73m2 vs >1.70 mmol/24hr/1.73m2).

Table 6. Summary of ILLUMINATE-A Results

BSA: body surface area; CI: confidence interval; LSM: least square mean.a 24-hr urinary oxalate levels were measured as mmol/24hr/1.73m2. b A renal stone event was defined as an event that includes at least 1 of the following: visit to healthcare provider because of a renal stone, medication for renal colic, stone passage, or macroscopic hematuria due to a renal stone. Randomization was not stratified by renal stone events at baseline.c Patient reported history of renal stone events.

Single Arm Prospective Trials

ILLUMINATE-B is the pivotal single-arm trial in infants and children younger than 6 years. The study consists of 2 parts: (a 6-month primary analysis period followed by a 54-month extension period). The study characteristics and results are summarized in Tables 7 and 8 with 6-months follow-up.^32, At 6 months, the percent change in spot urinary oxalate:creatinine ratio from baseline was -72% in lumasiran-treated patients. When stratified by weight, the percent reduction was 84%, 67%, and 71% among patients <10 kg (n=3), 10 to <20 kg (n=11), and ≥20 kg (n=2), respectively. While ILLUMINATE-B lacked a concurrent control, the magnitude of reduction in urinary oxalate and time course were generally consistent with the findings in ILLUMINATE-A.

ILLUMINATE-C is the pivotal single-arm trial in pediatric and adult patients with moderately or severely reduced GFR (eGFR ≤45 mL/min/1.73 m² or pediatric patients <12 months of age with serum creatinine above the ULN for age) including patients with kidney failure on hemodialysis. The primary endpoint was the percent change in plasma oxalate levels from baseline to month 6. The study consisted of 2 cohorts: cohort A included 6 patients who did not require dialysis at the time of study enrollment while cohort B included 15 patients who were on a stable regimen of hemodialysis; the hemodialysis regimen was to remain stable in these patients for the first 6 months of the study. The study characteristics and results are summarized in Tables 7 and 8 with 6-month follow-up. At 6 months, the percent change from baseline in plasma oxalate levels in cohort A was a LS mean difference of -33% (95% CI, -82% to 15%) and in cohort B was -42% (95% CI, -51% to -34%).^31,33,

Safety

A safety analysis included pooled data from 77 patients (including 56 pediatric patients) from placebo-controlled and open-label clinical studies. Patients ranged in age from 4 months to 61 years at first dose. The median duration of exposure was 9.1 months (range, 1.9 to 21.7 months). Overall, 58 patients were treated for at least 6 months, and 18 patients for at least 12 months. In ILLUMINATE-A, the most common (≥20%) adverse reaction reported was injection site reaction. Injection site reactions 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. The safety profile in ILLUMINATE-B was similar to that seen in ILLUMINATE-A. As with all oligonucleotides, there is a concern for development of anti-drug antibodies that may neutralize the therapeutic effect of a drug. As per FDA data analysis from across all clinical studies in the lumasiran development program, including patients with primary hyperoxaluria type 1 and healthy volunteers dosed with lumasiran, 6 of 100 (6%) lumasiran-treated individuals with a mean follow-up duration of 8.9 months tested positive for anti-drug antibodies. No clinically significant differences in the safety, pharmacokinetic, or pharmacodynamic profiles of lumasiran were observed in patients who tested positive for an anti-lumasiran antibody.

Table 7. Summary of ILLUMINATE-B Characteristics

AGXT: alanine glyoxylate aminotransferase; DBRCT: double-blind randomized controlled trial; eGFR: estimated glomerular filtration rate; PH1: primary hyperoxaluria type 1; UOx:Cr: urinary oxalate creatinine ratio.a Treatment arms were stratified at randomization based upon mean 24hr urinary oxalate from the first 2 valid samples collected during screening (≤1.70 mmol/24hr/1.73m2 vs >1.70 mmol/24hr/1.73m2).

Table 8. Summary of ILLUMINATE-B Results

CI: confidence interval; LS: least squares.a For Cohort A, the baseline is defined as the mean of all plasma oxalate samples collected prior to the first dose of lumasiran.b For Cohort B, the baseline is defined as the last 4 pre-dialysis plasma oxalate samples collected prior to the first dose of lumasiran. In Cohort B, only pre-dialysis samples were utilized.

The purpose of limitations tables is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement. Identified limitations in study relevance and study design/conduct are summarized in Tables 9 and 10. The major limitation is the lack of data on clinical outcomes, such as nephrolithiasis and related complications and loss of kidney function, and patient reported outcomes such as quality of life. Given the rarity of the disease and its slow progression, it would be challenging to detect treatment effects on clinical events in a clinical trial. Use of urinary oxalate as a surrogate for clinical outcomes in the pivotal trials can 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. Epidemiologic data demonstrates an association between urinary oxalate and loss of kidney function, particularly in patients with high levels of urinary oxalate.^8,23,33, Further observational data from patients treated with pyridoxine or a liver transplant show associations between reductions in urinary oxalate and preservation of kidney function.^27,34,35,Further, the consistency and size of treatment effect (more than half of patients receiving lumasiran achieved normal urinary oxalate levels at 6 months of treatment in ILLUMINATE-A) in clinical trials are indicative of the potential for a clinical benefit over the long term. Lastly, while lumasiran was generally well-tolerated in ILLUMINATE-A and -B, the safety database was small and limited in duration.

Table 9. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 10. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: Primary Hyperoxaluria Type 1

The evidence for lumasiran for individuals with primary hyperoxaluria with preserved renal function consists of 1 phase 3 RCT (ILLUMINATE-A) in patients 6 years and older and 1 single arm prospective study (ILLUMINATE-B) in patients 6 years and younger. In both studies, patients with preserved renal function were enrolled (eGFR >30 mL/min/1.73 m²). In ILLUMINATE-A, 39 patients 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 group, respectively, with a between-group mean difference of 53% (95% CI: 45 to 62%; p<0.0001). A similar effect was seen in patients with high baseline urinary oxalate values, and approximately half of patients receiving lumasiran achieved normal urinary oxalate values by month 6. In ILLUMINATE-B, 18 patients 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). The magnitude of the reduction and the time course were consistent with findings in ILLUMINATE-A. The major limitation is the lack of data on clinical outcomes such as renal stones, nephrocalcinosis, and renal failure as both trials were not powered to assess these clinical endpoints. However, use of urinary oxalate as a surrogate for clinical 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 (more than half of patients receiving lumasiran achieved normal urinary oxalate levels at 6 months of treatment in ILLUMINATE-A) in clinical trials are indicative of the potential for a clinical benefit over the long term. Lastly, while lumasiran was generally well-tolerated in ILLUMINATE-A and -B, the safety database was small and limited in duration. The most common treatment-related adverse events were injection site reactions, which were mild and transient and included erythema, pain, pruritus, or swelling at the injection site.

For individuals with primary hyperoxaluria type 1 with preserved kidney function, the evidence includes 1 phase 3 RCT (ILLUMINATE-A) in patients 6 years and older and 1 single arm prospective study (ILLUMINATE-B) in patients 6 years and younger. Relevant outcomes are symptoms, quality of life, disease-specific survival, change in disease status, treatment-related morbidity, and treatment-related mortality. In both studies, patients with preserved renal function were enrolled (eGFR >30 mL/min/1.73 m²). In ILLUMINATE-A, the percent reduction in 24-hour urinary oxalate from baseline to month 6 was -65% and -12% in the lumasiran and placebo group, respectively, with a between-group mean difference of 53% (95% CI: 45 to 62%; p<0.0001). A similar effect was seen in patients with high baseline urinary oxalate values, and approximately half of patients receiving lumasiran achieved normal urinary oxalate values by month 6. In ILLUMINATE-B, lumasiran demonstrated a percent reduction in spot urinary oxalate-to creatinine ratio from baseline of -71% (95% CI -77 to -65). The magnitude of the reduction and the time course were consistent with findings in ILLUMINATE-A. The major limitation is the lack of data on clinical outcomes such as nephrolithiasis (renal stones), nephrocalcinosis, and renal failure as both trials were not powered to assess these clinical endpoints. However, use of urinary oxalate as a surrogate for clinical 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 (more than half of patients receiving lumasiran achieved normal urinary oxalate levels at 6 months of treatment in ILLUMINATE-A) in clinical trials are indicative of the potential for a clinical benefit over the long term. Lumasiran was generally well-tolerated in ILLUMINATE-A and -B. However, the safety database was small and limited in duration. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

European Hyperoxaluria Consortium

Clinical practice recommendations for primary hyperoxaluria were published by a workgroup comprising members from OxalEurope (a network of European scientists and physicians who specialize in primary hyperoxaluria) and and the metabolic workgroup of the European Rare Kidney Disease Reference Network.^38, The group formulated and graded statements relating to the management of primary hyperoxaluria on the basis of existing evidence. Recommendations are summarized in Table 11 and 12.

Table 11. Recommendations for Management of Patients With or Suspected to Have Primary Hyperoxaluria

CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate; PH: primary hyperoxaluria; RNAi: RNA interference.Grading of recommendations was based on the American Academy of Pediatrics.39,

Table 12. Recommended Management and Monitoring of Patients with Primary Hyperoxaluria on RNA Interference Therapy

CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate (units: ml/min/1.73 m2); PH: primary hyperoxaluria; Pox: plasma oxalate; RNAi: RNA interference; SAE: severe adverse event; UL: upper level reference value; Uox: urinary oxalate excretion; VB6: vitamin B6 (also known as pyridoxine).a Groups are defined as follows:Group A patients are defined as patients of any age with (genetically established) PH1; and biochemically established non-responsiveness to pyridoxine therapy or with mutation consistent with pyridoxine unresponsiveness; and urinary oxalate excretion >1.5 times the upper reference limit (based on at least 2 samples); and a clinical phenotype of PH1, characterized by active stone disease and/or nephrocalcinosis and/or renal impairment (but with eGFR >30 mL/min/1.73 m2). Group B patients are defined as patients of any age with genetically established PH1; and biochemically established partial responsiveness to pyridoxine therapy (that is, urinary oxalate level 1.0 to 1.5 times the upper reference limit of normal while on pyridoxine treatment); and a clinical phenotype of PH1, characterized by active stone disease and/or nephrocalcinosis and/or renal impairment (but with eGFR >30 mL/min/1.73 m2).Group C patients are defined as patients of any age with genetically established PH1; and a mutation consistent with pyridoxine unresponsiveness and eGFR <30 mL/min/1.73 m2.Group D patients are defined as patients of any age with genetically established PH1; and a mutation consistent with pyridoxine responsiveness and eGFR <30 mL/min/1.73 m2.Group E patients are defined as patients with clinically suspected PH1 with stage 5 CKD based on elevated plasma oxalate levels (>80 μmol/L in those with stage 5D CKD; >10 μmol/L in patients not on dialysis) and plasma glycolate levels, but awaiting genetic confirmation.Group F patients are defined as patients of any age with genetically established PH1; and biochemically established non-responsiveness to pyridoxine therapy or with a mutation consistent with pyridoxine non-responsiveness; and urinary oxalate excretion >1.5 times the upper reference limit (based on at least 2 samples); and no ongoing clinical disease.Group G patients are defined as patients of any age with genetically established PH1; and biochemically established full pyridoxine responsiveness (urinary oxalate less than the upper reference limit of normal while on pyridoxine treatment); and a clinical phenotype of PH1, characterized by active stone disease and/or nephrocalcinosis and/or renal impairment (but eGFR >30 mL/min/1.73 m2).b Urinary oxalate excretion per 24 h or urinary oxalate excretion-to-creatinine ratio.c Deterioration should be evaluated in the context of the individual patient; recurrent attacks due to pre-existing stones are not a criterion for failure. Only consider serious adverse events that are potentially related to lumasiran.d Evaluated in patients on a stable dialysis regimen or in pre-dialysis patients with a stable eGFR; otherwise discussion.e In patients who do not undergo kidney transplantation during therapy course. In patients who do undergo kidney transplantation, evaluate the response to RNAi therapy on plasma oxalate levels, taking into account the expected reduction in relation to eGFR and estimation of stored oxalate. High urinary oxalate levels after kidney transplantation may be the result of oxalate release from bone.f In patients who have not undergone kidney transplantation; in patients who do undergo kidney transplantation, consider stopping lumasiran 3 months after kidney transplantation if urinary oxalate levels is normalized; repeat measurement of urinary oxalate levels every month and restart lumasiran if urinary oxalate increases >1 UL.

U.S. Preventive Services Task Force Recommendations

Not applicable

Medicare Coverage

There was no LCD, NDC identified for PR region

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 13.

Table 13. Summary of Key Trials

NCT: national clinical trial.a Denotes industry-sponsored or cosponsored trial.

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