Lumasiran for Primary Hyperoxaluria Type 1 - CAM 50137

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 glyoxalate 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 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.

Summary of Evidence
For individuals with primary hyperoxaluria type 1 with preserved kidney function, the evidence includes 1 phase 3 randomized controlled trial (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 (estimated glomerular filtration rate (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% confidence interval [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 the 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.

Additional Information
Not applicable 

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 glyoxalate aminotransferase, which converts glyoxalate into pyruvate and glycine.2 Absent or deficient levels lead to accumulation of oxalate and its deposition as calcium oxalate.

Table 1. Primary Hyperoxaluria Types1
PH Type Genea Affected Enzyme Prevalence Distinctive Diagnostic Features
Type 1 AGXT Alanine glyoxalate aminotransferase 80% of cases
  • Elevated urinary glycolate excretion.
  • Definitive diagnosis testing that demonstrates a variant in the AGXT gene.
  • If no variant detected, liver biopsy demonstrating absent or significantly reduced AGT activity.3
Type 2 GRHPR Glycolate reductase hydroxy pyruvate reductase 10% of cases
  • Elevated urinary oxalate and L-glycerate (> 28 mmol/mol creatinine), which is pathognomonic for type 2 disease.4
  • Definite diagnosis by genetic testing. First step involves sequence analysis of exons 2 and 4 to detect the 2 most common mutations, c.103delG (40%) in exon 2 and c.403_405+2 del AAGT (16%) in exon 4. If these variants are not detected, complete sequencing is performed.5
Type 3 HOGA1 4-hydroxy 2-ketoglutarate aldolase 10% of cases
  • Elevated urinary hydroxy-oxo-glutarate.

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 infants6 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 Age6,7
Type Average age of onset (range)a Clinical Presentation Prevalence
Early onset 5.5 months (3 weeks to 9 months) Majority of infants present with failure to thrive because of renal failure 26% of cases
Pediatric onset 7.9 years (1 to 17 years) High variability in presentation. Recurrent symptomatic nephrolithiasis with a normal to moderate decline in kidney function 30% of cases
Adult onset 29.4 years (19 to 45 years) Majority of patients experience recurrent kidney stones for years before diagnosis 21% of cases

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 1a

  Per Million in the US/EU Total Number in the US/EUb
Variant Prevalence8 ~ 4.3 ~ 3,600
Diagnosed Prevalence10,11,12 ~ 1.5 to 2.5 ~ 1,300 to 2,100
Diagnosed and Non Transplanted ~ 1.2 to 2.0 ~ 1,000 to 1,700

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 mper day or 45 mg/1.73 mper 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 patients15,16 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 oxalate18,19 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 (e.g., infections or adverse drug effects), secondary malignancy, and failure of allograft.

Regulatory Status
On Nov. 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.

Policy
Initial Treatment
Lumasiran may be considered MEDICALLY NECESSARY when ALL of the following are met:

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

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

    1. Elevated urine oxalate excretion (body surface area-normalized daily urine oxalate excretion output ≥ 0.5 to 0.7 mmol/1.73 m2 or > 61.6 mg/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

    4. Serum creatinine value above age-specific upper limit of normal for patients < 1 year of age

  3. Individual has not received a liver or kidney transplant

  4. The estimated glomerular filtration rate is > 30 mL/min/1.73m2

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

  6. Initial approval is for 6 months, limited to the United States Food and Drug Administration approved dosing.

Continuation of Treatment
Incremental reauthorization for lumasiran for 1 year may be considered MEDICALLY NECESSARY when ALL of the following are met:

  1. Individual was previously approved for lumasiran based on criteria cited above

  2. Documented evidence to support clinically meaningful response to therapy from pre-treatment baseline (e.g., decreased urinary oxalate concentrations, decreased urinary oxalate:creatinine ratio, decreased plasma oxalate concentrations)

  3. Individual has not received a liver or kidney transplant

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

Lumasiran is considered investigational and/or unproven and therefore NOT MEDICALLY NECESSARY for all other indications.

Policy Guidelines
Lumasiran
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)

Policy Guidelines
Coding 
See the Codes table for details.

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Rationale 
This evidence review was created in April 2021 with searches of the PubMed database. The most recent literature update was performed through April 8, 2021.

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 uses 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.

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 question addressed in this evidence review is: Does treatment with lumasiran improve the net health outcome in individuals with primary hyperoxaluria type 1 with preserved renal function?

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, an investigational 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 (e.g., 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

Outcome Description Relevance
Kidney stones
  • Kidney stone event rates can be measured in multiple ways including visits to a healthcare provider because of a renal stone, medications for renal colic, stone passage, macroscopic hematuria due to renal stones, development of new stones, and change in the size or shape of existing stones.
  • Kidney stone events may be considered a direct health outcome measure as it is a direct reflection of underlying disease pathophysiology.
Nephrocalcinosis
  • Nephrocalcinosis is characterized by the deposition of calcium in the kidney parenchyma and tubules.
  • It can be graded on a standardized 4-point scale by renal ultrasound as grade 0, no echogenicity; grade 1, mild echogenicity around medullary pyramid borders; grade 2, moderate echogenicity around and inside pyramids; and grade 3, severe echogenicity of entire pyramids.22
  • Outcomes were categorized as bilateral improvement, unilateral improvement, stabilized, or worsened in the clinical trials of lumasiran.
  • Outcomes related to the severity of nephrocalcinosis may be considered a direct health outcome measure as it is a direct reflection of underlying disease pathophysiology.
Urinary oxalate excretion
  • Urinary oxalate excretion is considered a surrogate measure. It may not be useful in CKD stage 3b to 5 as kidney function declines, urine oxalate excretion decreases, and the urinary oxalate estimation becomes inaccurate.
  • It is typically measured from a 24-hour urine sample. Normal urinary oxalate excretion: < 0.5 mmol/1.73 m2 per day.13 Levels
    > 1 mmol/1.73 m2 per day are indicative of PH1. Some patients excrete as much as 1.5 to 3 mmol/1.73 m2 per day.15
    In younger patients, obtaining a 24-hour urine collection is difficult, especially in infants and small children who are not toilet trained. An alternative measure is molar oxalate:creatinine ratio in spot urine samples.
  • Normative values for spot oxalate:creatinine (mmol/mmol) vary by age and the assay method, the generally acceptable normal values based on age used to screen for hyperoxaluria are:13,15 A retrospective analysis of registry data of 297 patients that included all types of primary hyperoxaluria (65% PH1) showed that patients with higher baseline urine oxalate excretion were at the highest risk of developing kidney failure. The hazard ratio for kidney failure was 3.4 (95% CI, 1.4 to 7.9) for patients with an oxalate excretion rate in the highest 4th quartile compared to those in quartiles 1 to 3. The 20-year kidney survival was 96% for those with an oxalate excretion rate of 1.11 mmol/1.73 m2 per 24 hours in contrast to 42% for those with excretions ≥ 2.45 mmol/1.73 m2 per 24 hours at the time of diagnosis. Further, the risk of kidney failure increases with increasing urine oxalate levels with a hazard ratio of 1.8 (95% CI, 1.2 to 2.5) per 1 mmol/1.73 m2 per 24-hour increase.23
    • < 6 months: < 0.32 to 0.36
    • 6 months and 2 years: < 0.13 to 0.17
    • 2 and 5 years: < 0.098 to 0.1
    • 6 and 12 years: < 0.07 to 0.08
  •  
  • The optimal target would be close to normal levels (i.e., < 0.5 mmol/1.73m2).
Plasma oxalate levels
  • Plasma oxalate level is considered a surrogate measure.
  • Plasma oxalate concentration remains normal as long as the GFR is higher than 40 mL/min per 1.73 m2. Plasma oxalate levels may be more accurate in patients with advanced CKD.24,14
  • When GFR is well preserved (>60 ml/min per 1.73m2), plasma oxalate levels are normal/modestly increased (2 – 10 mmol/L; normal is 1 – 3 mmol/L with most assays). In patients with CKD stage 5, they increase markedly (> 90 to 100 mmol/L).9,15,25
    Plasma oxalate concentrations that exceed the supersaturation threshold for calcium oxalate are typically observed in patients with primary hyperoxaluria with a GFR ≤30 to 40 ml/min per 1.73m2 (CKD 3b to 5).25,26
  • In patients with preserved GFR (CKD 1 to 3a), the role of plasma oxalate in disease progression has not been studied due to the small number of laboratories performing plasma oxalate measurements, differences in measurement methods, and infrequent measurement of plasma oxalate in earlier stages of CKD.12
  • Evidence relating to a decrease in plasma oxalate reducing the risk or severity of subsequent systemic oxalosis is limited to anecdotal experience with intensive dialysis regimens and the resolution of disease manifestations after transplantation. Plasma oxalate has been shown to decrease rapidly after liver transplantation,21 with gradual resolution of oxalosis.27
  • Studies of treatment response to plasma oxalate reduction in patients with primary hyperoxaluria who have CKD stages 1 to 3a are lacking. The magnitude of change in plasma oxalate in CKD stages 3b to 5 likely to predict clinical benefit requires further study.12

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) > 45 mL/min/1.73 m2, ILLUMINATE-B (NCT03905694) enrolled patients aged less than 6 years old with an eGFR >30 mL/min/1.73 m(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. None of these trials have been published and information was obtained from the prescribing label28 and FDA review documents.29

Randomized Controlled Trials
ILLUMINATE-A is the pivotal phase 3 randomized, double-blind, placebo-controlled trial.30 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 m2.29 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 health care 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

Study Study Type Country Dates Participants Treatment Follow-Up
ILLUMINATE-A29,28 DBRCT Global 2018 – ongoing Inclusion criteria
  • Patients with PH1 aged 6 years and older
  • Confirmed AGXT gene variants
  • eGFR ≥ 30 mL/min/1.73 m2
  • Urinary oxalate excretion ≥ 0.7 mmol/24hr/1.73m2
Exclusion criteria
  • History of kidney or liver transplant
  • History of alcohol abuse; hepatitis B or C, or HIV
Patient characteristics
  • Median age: 15 years (range 6 to 61)
  • Male: 67%
  • Pyridoxine use: 56%
  • Nephrocalcinosis grade 1: 78%
  • Lifetime history of renal stones: 85%
  • History of renal stones in last 12 months: 39%
  • 6-month double-blind treatment perioda
  • Lumasiran/placebo every month for first 3 months then every 3 monthsa
  • Lumasiran (n = 26)
  • Placebo (n = 13)
60 months (results at 6 months are reported)

AGXT: alanine glyoxalate 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

Study LSM % Change in 24 hr Urinary Oxalate Excretiona % of Patients With Normal 24 hr Urinary Oxalate Excretion Corrected for BSA (≤0.514 mmol/24 hr/1.73 m2) Renal Stones Eventsn/N(%)
ILLUMINATE-A29,30 N = 39 N = 39 N = 39
6 months      
Lumasiran -65% (95% CI: -71 to -59) 52% (95% CI: 31 to 72)
  • Overall: 8/26 (31%)
  • In patients without event in preceding year: 1/15 (7%)
  • In patients with event in preceding year: 7/11 (64%)c
  • Number of stone events: 13
Placebo -12% (95% CI: -20 to -4) 0% (95% CI: 0 to 25)
  • Overall: 3/13 (23%)
  • In patients without event in preceding year: 1/9 (11%)
  • In patients with event in preceding year: 2/4 (50%)c
  • Number of stone events: 4
Between Group LSM Difference 53% (95% CI: 45 to 62; p<0.0001) p=0.001 -

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 health care 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.28,29 At 6 months, the % change in spot urinary oxalate:creatinine ratio from baseline to month 6 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.

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

Study Study Type Country Dates Participants Treatment Follow-Up
ILLUMINATE-B29,28 Single arm prospective cohorta Global 2019 – ongoing Inclusion criteria
  • Infants and children with PH1 aged 6 years and younger
  • Confirmed AGXT gene variants
  • eGFR > 45 mL/min/1.73 m2 if ≥ 12 months old; non elevated serum creatinine if < 12 months old
Exclusion criteria
  • Abnormal serum creatinine levels at screening for infants who are less than 1 year old
  • Does not have relatively preserved kidney function
  • Clinical evidence of systemic oxalosis
  • History of kidney or liver transplant
Patients characteristics
  • Median age: 47 months (4 to 74)
  • Male: 44%
  • Mean spot UOx:Cr ratio, mmol/mmol: 0.47
Weight based dosing lumasiran (n = 18)
  • < 10 kg: 6.0 mg/kg every month for 3 months followed by 3.0 mg/kg every month
  • ≥ 10 kg to <20 kg: 6.0 mg/kg every month for 3 months followed by 6.0 mg/kg every 3 months
  • ≥ 20 kg: 3.0 mg/kg every month for 3 month followed by 3.0 mg/kg every 3 months
60 months (results at 6 months are reported)

AGXT: alanine glyoxalate 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

Study % Reduction in Spot Urinary Oxalate: Creatinine Ratio
ILLUMINATE-B29,28 N = 18
6 months  
Lumasiran 71% (95% CI: 65 to 77)

CI: confidence interval.

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.8,23,31 Further observational data from patients treated with pyridoxine or a liver transplant show associations between reductions in urinary oxalate and preservation of kidney function.27,32,33 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
Study Populationa Interventionb Comparatorc Outcomesd Duration of Follow-upe
ILLUMINATE-A29,30       2. Physiologic measures (oxalate levels), not validated surrogates
  1. Not sufficient duration for benefits
  2. Not sufficient duration for harms
ILLUMINATE-B29,28       2. Physiologic measures (oxalate levels), not validated surrogates
  1. Not sufficient duration for benefits
  2. Not sufficient duration for harms

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations 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
Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
ILLUMINATE-A29,30            
ILLUMINATE-B29,28
  1. Participants not randomly allocated
  2. Allocation not concealed
  3. Allocation concealment unclear
  1. Not blinded to treatment assignment
       

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
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.
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.

Summary of Evidence
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.

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 U.S. professional society, an international society with U.S. 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
Recommendations for screening, diagnosis, and management of primary hyperoxaluria type 1 were published on behalf of OxalEurope in 2012.24 These guidelines do not include lumasiran as they were published prior to the FDA approval.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 11.

Table 11. Summary of Key Trials
NCT No. Trial Name Planned Enrollment Completion Date
Ongoing      
NCT03350451 An Extension Study of an Investigational Drug, Lumasiran (ALN-GO1), in Patients With Primary Hyperoxaluria Type 1 (ALN-GO1-002) 20 Jun 2023
NCT04152200 A Study to Evaluate Lumasiran in Patients With Advanced Primary Hyperoxaluria Type 1 (ILLUMINATE-C) 20 Jul 2023
Unpublished      
NCT02706886 Study of Lumasiran in Healthy Adults and Patients With Primary Hyperoxaluria Type 1 (ALN-GO1-001) 52 Jan 2019

NCT: national clinical trial.

a Denotes industry-sponsored or cosponsored trial.

References:

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Coding Section 

Codes Number Description
CPT N/A  
HCPCS C9074 Injection, lumasiran, 0.5 mg (eff 04/01/2021)
ICD10 CM E72.53 Primary hyperoxaluria
Place of Service Outpatient/ Professional  
Type of Service Drugs

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2021 Forward     

05/18/2022 

Annual review, no change to policy intent. 

06/01/2021

NEW POLICY

 

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