CADTH Reimbursement Review

Lumasiran (Oxlumo)

Sponsor: Alnylam Netherlands B.V.

Therapeutic area: Primary hyperoxaluria type 1

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Ethics Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Submitted for Review

NOC = Notice of Compliance.

Source: Sponsor’s submission package for review of lumasiran;¹ Oxlumo product monograph.²

Introduction

Primary hyperoxaluria type 1 (PH1) is an ultrarare, autosomal recessive metabolic condition caused by a pathogenic variant of the alanine:glyoxylate aminotransferase (AGT) gene.³ There is considerable heterogeneity with PH1 in the age of onset, severity of disease, residual enzyme activity, and genotype.⁴ The AGT enzyme catalyzes the conversion of glyoxylate to glycine in peroxisomes and without it (i.e., in patients with PH1), glyoxylate is converted to oxalate in the cytosol.³ Oxalate binds to calcium, producing insoluble calcium oxalate salts that are difficult for the body to eliminate. The clinical experts consulted by CADTH added that patients with PH1 are prone to kidney stone formation and recurrent episodes of renal colic. Once kidney function declines to an estimated glomerular filtration rate (eGFR) of less than 30 to 45 mL/min/1.73 m², the kidneys become unable to excrete excess oxalate.⁵ Plasma oxalate levels increase, leading to systemic oxalosis, in which oxalate builds up in tissues throughout the body (e.g., bone, skin, retina, and cardiovascular and nervous systems).^3,5 Patients often progress to end-stage kidney disease (ESKD), which, combined with complications of systemic oxalosis, results in early death.³ Laboratory tests showing urine oxalate levels consistently higher than 0.7 mmol/1.73 m²/day³ or 40 to 45 mg/day (500 µmol/day),⁵ elevated urine glycolate concentration, or plasma oxalate levels greater than 50 µmol/L when glomerular filtration rate (GFR) is less than 30 mL/min/1.73 m²³ also indicate PH1. To confirm the diagnosis, genetic testing is used to identify a pathogenic variant in the AGT gene.³ Due to the variable clinical presentation and age of onset as well as a limited awareness of PH1, it has been suggested that the disease is underdiagnosed.^3,6 The incidence of PH1 has been estimated to be between 0.4 and 1 per 100,000 live births in different populations.⁴ The prevalence has been estimated to be between 1 and 3 per million in European countries, with higher rates among countries with consanguinity.⁴ No Canadian data for prevalence or incidence have been identified from the literature.

Because hepatic overproduction of oxalate is the main cause of PH1, it is suggested that the best form of management is to reduce oxalate production, which can be further supported by increasing oxalate clearance by the kidneys, though the latter has limited effect.³ An estimated 30% of patients have a form of PH1 that is sensitive to high-dose vitamin B6 (a cofactor for AGT), which helps to ensure proper localization of the enzyme to the liver peroxisomes and may delay the onset of ESKD.^3,7 According to the literature and the clinical experts consulted by CADTH, vitamin B6 therapy may be able to lower oxalate levels in some patients; however, not all patients achieve normalization of oxalate levels.^7,8 Citrate supplementation to inhibit crystal formation and hyperhydration (2 to 3 L/m²/day) are also used to treat PH1 and preserve kidney function. Both citrate supplementation and hyperhydration can be burdensome for patients and are associated with compliance issues. Moreover, pediatric patients may require a gastrostomy tube to ensure adequate hydration throughout the day. It has been suggested that reducing dietary oxalate will have little effect because the main problem is endogenous overproduction.⁹ New therapeutics consisting of small interfering ribonucleic acid (siRNA) such as lumasiran and nedosiran have been developed to treat primary hyperoxaluria (PH).³ Patients may also undergo shockwave lithotripsy, ureteroscopy, or percutaneous nephrolithotomy to treat kidney stones. When kidney function declines to less than 30 mL/min/1.73 m², patients may require hemodialysis to remove oxalate that cannot be excreted through urine. The major limitation with dialysis is that oxalate production often exceeds clearance, and while hemodialysis can dramatically lower plasma oxalate levels, this effect is transient, with a return to supersaturated levels (i.e., greater than 30 to 45 µmol/L) within a few hours of completing each dialysis treatment.^3,9 The clinical experts consulted by CADTH stated that current standard-of-care treatments require lifelong adherence, are noncurative, and only partially alleviate the oxalate burden in patients. Liver-kidney transplant is considered the only cure for PH1 because it corrects AGT function (endogenous oxalate production is returned to normal levels) and restores kidney function, but is associated with high morbidity, mortality, and lifelong immunosuppression.^3,5,9

Lumasiran (Oxlumo) is indicated for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients.¹ The drug is available as a solution of 94.5 mg/0.5 mL lumasiran for subcutaneous injection with weight-based loading and maintenance dosing.² According to the product monograph, patients weighing less than 10 kg receive a loading dose of 6 mg/kg once monthly for 3 doses and a maintenance dose of 3 mg/kg once monthly, patients weighing 10 kg to less than 20 kg receive a loading dose of 6 mg/kg once monthly for 3 doses and a maintenance dose of 6 mg/kg once every 3 months (quarterly), and patients weighing 20 kg or more receive a loading dose of 3 mg/kg once monthly for 3 doses and a maintenance dose of 3 mg/kg once every 3 months (quarterly).²

The objective of the CADTH review is to perform a systematic review of the beneficial and harmful effects of lumasiran 94.5 mg/0.5 mL, subcutaneous, for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients.

Stakeholder Perspectives

The information in this section is a summary of input provided by patient groups that responded to CADTH’s call for patient input and from clinical experts consulted by CADTH for the purpose of this review.

Patient Input

Two patient groups (the Oxalosis and Hyperoxaluria Foundation and the Canadian Organization for Rare Disorders) provided input as a joint submission to the CADTH review of lumasiran for the treatment of PH1. The responses were collected through an online survey and a virtual focus group with caregivers and patients. In total, 43 respondents completed the entire survey (18.6% Canadian and 41.9% American). Of the 43 responders, one-third indicated they were patients with PH and two-thirds identified as caregivers. In addition, 3 Canadians, 7 Americans, 6 non–North Americans from the online survey, and 2 Canadian children from the focus group reported having experience with lumasiran.

Patients reported that the greatest burden of PH1 was the physical toll (e.g., frequent dialysis, multiple hospitalizations, fractures) and emotional stress (e.g., anxiety and/or depression over concerns about kidney failure, liver-kidney transplant, not having an approved treatment). Respondents also highlighted issues with receiving appropriate and timely care as well as misdiagnoses. Patients and caregivers described the challenges associated with treatment such as gastrostomy tube insertion for infants and children, ureteroscopy and/or surgery to remove stones, vitamin B6 losing efficacy over time, noncompliance, and intensive dialysis. Patients who have received lumasiran described experiencing an improvement in PH1 management and quality of life.

The survey participants responded that current treatments and dialysis are insufficient and that therapies that decrease the likelihood of kidney stones, need for kidney and/or liver transplant, kidney failure, oxalosis, and the amount of medication are critical. Patients and families said that they need access to treatments that improve physical well-being, thereby mitigating stress and anxiety for the entire family. The respondents described how the physical, emotional, and financial challenges associated with PH1 have profound effects on quality of life, which is further compounded by a lack of knowledge among clinicians as well as access to treatments and affordability issues.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The clinical experts consulted by CADTH emphasized the need for a therapy to treat PH1 that effectively lowers hepatic oxalate production, reduces kidney stone formation, and prevents the development of ESKD. The experts stated that current treatments are noncurative and do not lower hepatic oxalate production or total oxalate burden in patients. The clinical experts also noted that there is a small subset of patients whose PH1 is partially or completely vitamin B6 sensitive, but that vitamin B6 therapy only partially alleviates oxalate accumulation in these patients.

Two therapies, lumasiran and nedosiran, were identified by the clinicians as being possible pharmacotherapies for PH1. The experts expected lumasiran to cause a shift in the current treatment paradigm, becoming the first-line treatment for patients with PH1 and specifically for patients who are insensitive or only partially sensitive to vitamin B6 therapy. The clinicians noted that treatment with lumasiran is expected to be lifelong or until the patient receives a liver transplant. Further, the clinical experts stated the importance of continuing current standard-of-care treatments along with lumasiran.

As per the clinical experts, patients with PH1 would typically be identified based on clinical symptoms, laboratory testing of oxalate levels, and a diagnosis confirmed by genetic testing. Because there are hundreds of genetic variants currently identified¹⁰ as being related to PH1, 1 clinical expert noted that it may take time for new mutations to be accepted as pathogenic.

The clinical experts stated that patients would be candidates for lumasiran if they have genetically confirmed PH1 and are unable to normalize urine oxalate excretion. The clinicians were uncertain if or when lumasiran would be used for patients who are sensitive to vitamin B6 therapy and are able to normalize urine oxalate excretion but suggested it may be reasonable to begin treatment if these patients showed signs of disease progression. The experts felt that early intervention and treatment with lumasiran would be reasonable for all patients who still have kidney function and would not wait until GFR falls to 60 mL/min/1.73 m², given that starting treatment early would help reduce kidney stone formation and slow down the progression of kidney function impairment. The clinical experts indicated that patients with little or no urine oxalate excretion who are relying solely on dialysis to remove oxalate from the body are at a very high risk of systemic oxalosis and would benefit from lumasiran. They stated that hemodialysis only temporarily lowers plasma oxalate levels, which rise to predialysis levels within a few hours. The clinical experts noted that lumasiran may be effective in avoiding the need for liver transplant in patients with ESKD and that it would be reasonable to treat patients with lumasiran before and after a kidney transplant to lower both plasma and urine oxalate levels.

The clinical experts noted that urine oxalate excretion and plasma oxalate are surrogate markers for oxalate production in patients with PH1 and that there is no widely accepted method for measuring total body oxalate, making it difficult to assess how effective a treatment is. Per the clinical experts, patients in earlier stages of PH1 may be monitored for urine oxalate excretion, plasma oxalate levels, kidney function (eGFR), and nephrocalcinosis via radiological imaging. Because patients in later stages of PH1 and on dialysis would not have reliable urine oxalate measures, clinicians would instead measure predialysis plasma oxalate every 1 to 3 months. The clinical experts stated that patients who have received a kidney or combined liver-kidney transplant may have plasma oxalate levels measured initially on a daily basis, transitioning to weekly and then monthly frequency as levels stabilize. The clinicians expected that there would be a noticeable improvement after an initial 6-month treatment duration, but that this is unlikely to be long enough to see normalization of urine or plasma oxalate levels. The experts suggested that it is important to consider treatment success in light of how severe the patient’s disease is before treatment and that it might be reasonable to treat a patient for at least 12 months (total) before deciding to continue lumasiran or not. According to the clinical experts, renewal of lumasiran would depend on adequate response to treatment as well as an assessment of potential treatment issues (e.g., adverse events [AEs], antidrug antibodies [ADAs], or compliance).

The clinical experts stated that patients who have received a liver transplant would not be treated with lumasiran because the new liver has functional enzyme, and there would be no need for the drug. Other possible reasons for stopping treatment suggested by the clinicians were no response to treatment, or severe untreatable or intolerable AEs.

The clinical experts agreed that a specialist (e.g., nephrologist or metabolic physician) should monitor patients with PH1 and that lumasiran can be administered by a health care professional in a community setting. One clinical expert suggested the potential for the patient or caregiver to self-administer lumasiran at home because subcutaneous injections can be routinely performed for other medications; however, other clinicians did not expect lumasiran to be self-administered.

According to the experts, it is unlikely that treatment would exceed the Health Canada recommended dose for most patients, although a higher dose may be warranted in infants due to their larger liver surface area to body surface area (BSA) ratio or to overcome potential neutralizing ADAs. The latter was based on experience with other drugs and has been suggested in the literature,¹¹ though there is a lack of clinical evidence supporting higher doses of lumasiran at this time. The clinical experts identified the need for additional consideration of patients who have limited access to health care resources (e.g., living in remote areas, no primary care physician or access to specialists, and lack of health insurance). The clinical experts also indicated that other ethical issues were the burden of knowing there is a treatment for PH1 but not being able to access it, especially given the severity of the disease; the inadequacy of current treatments; and the overall burden of care on patients and families.

Drug Program Input

The drug programs described the lack of approved pharmacological treatments for PH1, different dosing for loading and maintenance, and dosing based on body mass. The drug programs also asked questions about the potential for newborn screening, the use of lumasiran in small infants, the relationship between trial outcomes and complications related to PH1, the likelihood of routine urine testing, identifying a loss of treatment response, prescribing and administration of lumasiran, and product wastage.

The clinical experts consulted by CADTH did not expect newborn screening to take place at this time and felt it would be reasonable to treat infants with PH1 who are aged less than 2 years and weigh less than 10 kg. The experts noted that the end points used in the ILLUMINATE trials are not perfect surrogates for PH1 complications but are satisfactory markers depending on how far a patient’s disease has progressed. The clinicians stated that 24-hour urine oxalate excretion is routinely measured for continent patients and spot oxalate:creatinine ratios for noncontinent children, which is considered an imperfect substitute and must be compared to normal ranges based on age. The clinical experts suggested that a loss of response would appear as a failure to show a progressive reduction in urine oxalate excretion over time in patients with preserved kidney function or failure to lower predialysis plasma oxalate in dialysis patients. A lack of response could also be due to patients not receiving treatment (e.g., missed dose), developing neutralizing ADAs; taking vitamin C, which increases oxalate production; or if GFR has declined, which would likely result in a rise in plasma oxalate. The clinical experts stated that it may be reasonable to stop lumasiran if there was documented failure to respond, serious untreatable or intolerable side effects, or the patient received a liver transplant. According to the experts, nephrologists or genetic/metabolic specialists would prescribe lumasiran while a health care professional, rather than the patient, would administer the drug, though the clinical experts had differing opinions on self-administration. The clinicians stated that a patient’s weight would be assessed at the time of the injection and the dose calculated based on the current weight (measured within 1 week for an infant, 2 weeks for a child, and 1 month for an adult). The clinical experts stated that product wastage would be inevitable given the current available formulation and weight-based dosing.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

The 3 included studies (ILLUMINATE-A, ILLUMINATE-B, and ILLUMINATE-C) are ongoing, phase III trials investigating the efficacy and safety of lumasiran in patients with PH1. All patients received study drug based on weight-based loading and maintenance-dosing schedules consistent with the Health Canada product monograph. The 3 trials were structured similarly with a 6-month primary analysis period followed by a 54-month extension period (3-month blinded extension and 51-month open-label extension [OLE] in the ILLUMINATE-A trial).

The ILLUMINATE-A trial (N = 39) is a placebo-controlled, double-blind (DB), randomized controlled trial (RCT) that included patients who were aged 6 years and older. Patients were randomized 2:1 to receive lumasiran or placebo. During the 6-month DB period, patients received study drug (lumasiran 3 mg/kg or matching placebo) administered as a subcutaneous injection once per month for the first 3 months (loading doses), followed by a single administration of study drug 1 month later (maintenance dose for the next 3 months). At month 6, patients entered the 3-month blinded treatment-extension period, in which all patients received active treatment (i.e., patients switched from placebo to lumasiran). At month 9, the 51-month OLE began, and all patients were on the maintenance-dosing schedule. The primary end point was percent change in 24-hour urinary oxalate excretion from baseline to month 6, corrected for BSA. The secondary end points were absolute change in urinary oxalate at month 6, percent change in urinary oxalate:creatinine ratio at month 6, percent and absolute changes in plasma oxalate at month 6, proportion of patients with urinary oxalate level near normal (at or below 1.5 times the upper limit of normal [ULN]) and normal (at or below the ULN) at month 6, and change in eGFR at month 6. At baseline, patients had a mean age of 18.1 years (standard deviation [SD] = █████ years; median = 14.0 years; range, 6 years to 60 years); 66.7% were male and 33.3% were female; and 76.9% were white, 15.4% were Asian, 5.1% were another race, and 2.6% identified as being of more than 1 race. Baseline mean 24-hour urine oxalate excretion corrected for BSA was 1.82 mmol/24 hour/1.73 m² (SD = 0.62 mmol/24 hour/1.73 m²).

The ILLUMINATE-B trial (N = 18) is a single-arm trial that included patients who were aged less than 6 years. The primary end point was percent change in urinary oxalate excretion from baseline to month 6. The secondary end points were proportion of patients with urinary oxalate near normal and normal, plasma oxalate, and eGFR levels. At baseline, patients had a mean age of ████ months (SD = █████ months; median = 50.1 months; range, 3 to 72 months); 55.6% were female and 44.4% were male; and 88.9% were white while 11.1% identified as another race. Baseline mean spot urine oxalate:creatinine ratio was 0.63 mmol/mmol (SD = 0.43 mmol/mmol).

The ILLUMINATE-C trial (N = 21) is a single-arm trial that included patients who had an eGFR of 45 mL/min/1.73 m² or lower and were either not receiving hemodialysis (Cohort A) or had begun stable hemodialysis (Cohort B). The primary end point was percent change in plasma oxalate from baseline to month 6 (predialysis for Cohort B). The secondary end points were plasma oxalate area under the curve (AUC) between dialysis sessions (Cohort B), urinary oxalate, urinary oxalate:creatinine ratio, Pediatric Quality of Life Inventory (PedsQL) and Kidney Disease Quality of Life Questionnaire (KDQOL) scores, and eGFR. At baseline, patients had a mean age of ████ years (SD = ████ years; median = 8.0 years; range, 0 to 59 years); 57.1% were male and 42.9% were female; and 76.2% were white, 19.0% were Asian, and 4.8% identified as another race. Mean baseline plasma oxalate was █████ μmol/L (SD = █████ μmol/L) for Cohort A and ██████ μmol/L (SD = █████ μmol/L) for Cohort B.

Efficacy Results

Statistical testing was conducted based on a gatekeeping procedure in the ILLUMINATE-A trial and the primary and secondary outcomes (except for eGFR) were controlled for multiplicity. Efficacy results are summarized in Table 2 for the ILLUMINATE-A trial and Table 3 for the ILLUMINATE-B and ILLUMINATE-C trials.

Kidney Function

During the 6-month DB period of the ILLUMINATE-A trial, eGFR declined from study baseline by a mean of 2.57 mL/min/1.73 m² (SD = 10.65 mL/min/1.73 m²) in the lumasiran group and 0.11 mL/min/1.73 m² (SD = 6.49 mL/min/1.73 m²) in the placebo group. Data at month 18 of extended lumasiran treatment showed that eGFR increased by a mean of ████ mL/min/1.73 m² (SD = ████ mL/min/1.73 m²) in the lumasiran followed by lumasiran treatment group and decreased by a mean of ████ mL/min/1.73 m² (SD = █████ mL/min/1.73 m²) in the placebo followed by lumasiran treatment group.

In the ILLUMINATE-B trial, eGFR declined from study baseline by a mean of 0.26 mL/min/1.73 m² (SD = 15.38 mL/min/1.73 m²) for all patients during the first 6 months of treatment. By month 12 of treatment on lumasiran, eGFR increased by a mean of █████ mL/min/1.73 m² (no SD) for 1 patient weighing less than 10 kg and decreased by a mean of ████ mL/min/1.73 m² (SD = █████ mL/min/1.73 m²) and mean of ████ mL/min/1.73 m² (SD = █████ mL/min/1.73 m²) in the groups of patients weighing between 10 and 20 kg and patients weighing more than 20 kg, respectively. In the ILLUMINATE-C trial, eGFR declined from study baseline by a mean of ████ mL/min/1.73 m² (SD = ████ mL/min/1.73 m²) for patients in Cohort A during the first 6 months of treatment.

Loss of kidney function over time and prevention of dialysis and/or liver-kidney transplant were not assessed in the trials.

Kidney Stone Events

During the DB period of the ILLUMINATE-A trial, 5 patients (19.2%) in the lumasiran group experienced 13 kidney stone events and 2 patients (15.2%) in the placebo group experienced 4 kidney stone events. Some events (████% for the lumasiran group and ████% for the placebo group) were graded as ████████ severity and the rest were ████. The rate of events was 0.30 and 0.18 events per 100 person-days for the lumasiran and placebo groups, respectively. The rate of events generally appeared to decrease in the lumasiran followed by lumasiran treatment group from 1.09 events per person-year (95% confidence interval [CI], 0.63 events to 1.88 events per person-year) between day 1 and month 6 to ████ events per person-year (95% CI, ████ to ████ events per person-year) between months 18 and 24 of lumasiran treatment. In the placebo followed by lumasiran treatment group, rates appeared to fluctuate over the same period and remained less than 1 event per person-year.

In the ILLUMINATE-B trial, █████████ had █ kidney stone █████ each (████████ from each weight group) and all events were graded as mild severity. The rate of events was 0.11 renal stone events per person-year for the whole group. In the ILLUMINATE-C trial, █████████ in Cohort A had a total of █ kidney stone events and all events were graded as ████████████. The rate of events was 1.52 renal stone events per person-year for Cohort A.

Health-Related Quality of Life

In the ILLUMINATE-A trial, results from the KDQOL, PedsQL, EuroQol-5 Dimensions-5 Levels (EQ-5D-5L), EuroQol-5 Dimensions-Youth (EQ-5D-Y), and visual analogue scale (VAS) generally showed ████████████ ███████ ████████ from baseline to month 6 and during extended lumasiran treatment. Data at month 18 showed mean scores ██████ ███████ ████ and were ██████ ███████ ██████ with the results from the DB period.

Health-related quality of life (HRQoL) was not assessed in the ILLUMINATE-B trial and results were very limited due to small patient numbers and short treatment duration in the ILLUMINATE-C trial.

Urine Oxalate Excretion Corrected for BSA

In the ILLUMINATE-A trial, the least squares mean (LSM) percent change from baseline to the average of months 3 to 6 for urine oxalate excretion was –65.39% (95% CI, –71.32% to –59.45%) for the lumasiran group and –11.84% (95% CI, –19.53% to –4.15%) for the placebo group. The treatment difference between groups was –53.55% (95% CI, –62.31% to –44.78%; P < 0.001). For absolute change, the LSM treatment difference between groups was –0.98 mmol/24 hour/1.73 m² (95% CI, –1.18 to –0.77 mmol/24 hour/1.73 m²; P < 0.001). For patients who achieved near normalization (at or below 1.5 times ULN), the difference in proportions was 0.84 (95% CI, 0.55 to 0.94; P < 0.001). For patients who achieved normalization (at or below ULN), the difference in proportions was 0.52 (95% CI, 0.23 to 0.70; P = 0.0010). Data from extended treatment on lumasiran indicated decreases in 24-hour urine oxalate at month 6 that appeared to be maintained for both lumasiran followed by lumasiran and placebo followed by lumasiran treatment groups to month 18.

Urine oxalate assessments were based on urine oxalate:creatinine ratios and are described later for the ILLUMINATE-B trial. In the ILLUMINATE-C trial, the LSM absolute change from baseline to the average of months 3 to 6 was –0.53 mmol/24 hour/1.73 m² (95% CI, –0.89 to –0.18 mmol/24 hour/1.73 m²). The LSM percent change from baseline to the average of months 3 to 6 was –10.56% (95% CI, –31.99% to 10.87%).

Plasma Oxalate

In the ILLUMINATE-A trial, for absolute change, the treatment difference between groups for plasma oxalate was –8.71 µmol/L (95% CI, –11.45 to –5.98 µmol/L; P < 0.001). For percent change, the treatment difference between groups was –39.48% (95% CI, –50.10% to –28.87%; P < 0.001).

In the ILLUMINATE-B trial, the mean absolute change from baseline was –5.03 µmol/L (SD = ████ µmol/L), while the mean percent change from baseline was –32.06% (SD = █████%) at month 6. Data from the extension period indicated that decreases in plasma oxalate at month 6 appeared to be ██████████ for patients ██████ ████████████ ████████████. In the ILLUMINATE-C trial, the LSM percent change from baseline to the average of months 3 to 6 was –33.33% (95% CI, –81.82% to 15.16%) for Cohort A and –42.43% (95% CI, –50.71% to –34.15%) for Cohort B. The LSM absolute change from baseline to the average of months 3 to 6 was –35.28 µmol/L (95% CI, –56.32 to –14.24 µmol/L) for Cohort A and –48.33 µmol/L (95% CI, –55.85 to –40.80 µmol/L) for Cohort B.

Urine Oxalate:Creatinine Ratio

In the ILLUMINATE-A trial, for percent change, the treatment difference between groups for urine oxalate:creatinine ratio was –51.77% (95% CI, –64.27% to –39.28%; P < 0.001). Data from extended treatment on lumasiran indicated that decreases at month 6 appeared to be maintained for both lumasiran followed by lumasiran and placebo followed by lumasiran treatment groups.

In the ILLUMINATE-B trial, the LSM percent change from baseline to the average of months 3 to 6 for all patients was –71.97% (95% CI, –77.52% to –66.42%). At month 6, 9 (50.0%) patients had achieved near normalization, while 1 (5.6%) patient had achieved normalization. Data from the extension period indicated decreases in spot urine oxalate:creatinine ratio by month 6 that appeared to be ██████████ for patients ██████████████████████████████. Additionally, ██ of the ██ patients who had data at that time point achieved near normalization and █ patients achieved normalization.

In the ILLUMINATE-C trial, the LSM absolute change from baseline to the average of months 3 to 6 was –0.19 mmol/mmol (95% CI, –0.23 to –0.15 mmol/mmol). The LSM percent change from baseline to the average of months 3 to 6 was –39.51% (95% CI, –64.13% to –14.90%).

Harms Results

Harms results are summarized in Table 2 for the ILLUMINATE-A trial and Table 3 for the ILLUMINATE-B and ILLUMINATE-C trials.

Table 2: Summary of Key Results From the ILLUMINATE-A Trial

ADA = antidrug antibody; AE = adverse event; BSA = body surface area; CI = confidence interval; DB = double-blind; eGFR = estimated glomerular filtration rate; FAS = full analysis set; LSM = least squares mean; SAE = serious adverse events; SD = standard deviation; SEM = standard error of the mean; ULN = upper limit of normal; WDAE = withdrawal due to adverse events.

^aThe eGFR is calculated from serum creatinine based on the Modification of Diet in Renal Disease formula for patients at least 18 years of age and the Schwartz Bedside Formula for patients aged younger than 18 years at screening.

^bRate is calculated as total number of renal stone events divided by total person-days at risk, defined as time from first dose to end of the DB period.

^cBased on Mixed-Effect Model Repeated Measures model with the corresponding value at baseline as a continuous fixed covariate, visit, and treatment as fixed effects, and patient as a random effect. Visit is fitted as a categorical variable, and the variance-covariance matrix is assumed to be unstructured. Satterthwaite approximation is used to estimate denominator degrees of freedom. A difference less than 0 represents a favourable outcome for lumasiran.

^dP value has been adjusted for multiple testing (i.e., the type I error rate has been controlled).

^eClopper Pearson exact confidence interval.

^fCalculated using the Newcombe method based on the Wilson score.

^gP value is based on Cochran-Mantel-Haenszel test stratified by baseline 24-hour urine oxalate corrected for BSA (less than or equal to 1.70 vs. greater than 1.70 mmol/24 hour/1.73 m²).

Source: ILLUMINATE-A Clinical Study Report.¹²

Table 3: Summary of Key Results From the ILLUMINATE-B and ILLUMINATE-C Trials

ADA = antidrug antibody; AE = adverse event; BSA = body surface area; CI = confidence interval; eGFR = estimated glomerular filtration rate; FAS = full analysis set; LSM = least squares mean; MMRM = Mixed-Effect Model Repeated Measures; NA = not applicable; NR = not reported; REML = restricted maximum likelihood; SAE = serious adverse events; SD = standard deviation; SEM = standard error of the mean; ULN = upper limit of normal; WDAE = withdrawal due to adverse events.

^aILLUMINATE-B analysis population was the efficacy analysis set.

^bILLUMINATE-C analysis population was the FAS.

^cThe eGFR is calculated based on the Schwartz Bedside Formula in patients aged at least 12 months at the time of the assessment.

^dRate is calculated as total number of renal stone events divided by total person-years during lumasiran treatment. The 95% CI for the event rate was obtained using a generalized linear model for a Poisson distribution unless the rate was 0, in which case the upper bound of the 95% CI was calculated using the exact Poisson method.

^eBased on REML-based MMRM model to test against the null hypothesis of mean change from baseline outcome being equal to 0. The model includes scheduled visits and baseline 24-hour urine oxalate corrected for BSA (mmol/24 hour/1.73 m²) as fixed effects and patient as a random factor. Autoregressive (1) was used to model the within-patient variability.

^fP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

^gBased on REML-based MMRM model to test against the null hypothesis of mean change from baseline outcome being equal to 0. The model includes scheduled visits and baseline plasma oxalate (μmol/L) as fixed effects and patient as a random factor. Autoregressive (1) was used to model the within-patient variability.

^hBased on REML-based MMRM model to test against the null hypothesis of mean percent change from baseline output being equal to 0. The model includes fixed effects of scheduled visits and baseline spot urine oxalate:creatinine ratio value (mmol/mmol), including patient as a random factor. Autoregressive (1) was used to model the within-patient error.

ⁱBased on REML-based MMRM model to test against the null hypothesis of mean change from baseline outcome being equal to 0. The model includes scheduled visits and baseline spot urine oxalate:creatinine ratio as fixed effects and patient as a random factor. Autoregressive (1) was used to model the within-patient variability.

Source: ILLUMINATE-B Clinical Study Report,¹³ ILLUMINATE-C Clinical Study Report.¹⁴

During the primary analysis period, in the ILLUMINATE-A trial, a larger proportion of patients in the lumasiran group reported an AE compared to the placebo group (84.6% versus 69.2%). All patients in the ILLUMINATE-B trial reported at least 1 AE. In the ILLUMINATE-C trial, the percentage of patients reporting an AE was similar between the groups (83.3% for no dialysis and 86.7% for dialysis). The most frequently reported AEs were injection site reaction (the ILLUMINATE-A and ILLUMINATE-C trials), headache (the ILLUMINATE-A trial), and pyrexia (the ILLUMINATE-B and ILLUMINATE-C trials) with injection site reaction occurring only among patients treated with lumasiran. During the overall period of receiving lumasiran treatment, injection site reaction (██████████), abdominal pain (█████████), and headache (█████████) were the most frequently reported AEs in the ILLUMINATE-A trial. In the ILLUMINATE-B trial, pyrexia (8 patients) and vomiting (5 patients) were the most frequently reported AEs.

During the primary analysis period, there were no serious adverse events (SAEs) in the ILLUMINATE-A trial. One patient weighing more than 20 kg (33.3%) in the ILLUMINATE-B trial reported a viral infection SAE. In the ILLUMINATE-C trial, 9 patients reported an SAE: 1 (16.7%) patient not on dialysis and 8 (53.3%) patients on dialysis. ███████████████████████ and device-related infection were reported in 2 patients for each SAE (all patients were on dialysis). All other SAEs were single-patient events. During the overall period of receiving lumasiran treatment, █████████ reported SAEs of █████████████, urosepsis, and ██████████████████████████ in the ILLUMINATE-A trial, while 1 patient reported viral infection in the ILLUMINATE-B trial.

During the primary analysis period, 1 patient receiving lumasiran in the ILLUMINATE-A trial stopped treatment due to an AE (fatigue and disturbance in attention) while ████████████ ███████ in the ILLUMINATE-C trial ████████ ███ ██████████████ ██████ █████████████████. There were no new reports of patients stopping treatment due to AEs during the extended treatment for either the ILLUMINATE-A or ILLUMINATE-B trials. No deaths were reported for any patients during the 6-month primary analysis period for any of the 3 studies or during the extension periods up to the data cut-off dates.

Notable Harms

Complications from systemic oxalosis were not reported in the clinical study reports at the given cut-off dates.

Injection site reactions were reported among 6 patients receiving lumasiran in the ILLUMINATE-A trial, 3 patients (2 patients weighing between 10 kg and 20 kg, 1 patient weighing more than 20 kg) in the ILLUMINATE-B trial, and 5 patients (4 patients on dialysis, 1 patient not on dialysis) in the ILLUMINATE-C trial. During the overall period of receiving lumasiran treatment, █████████ in the ILLUMINATE-A trial and 3 patients in the ILLUMINATE-B trial reported an injection site reaction, with the most common symptom being erythema.

Kidney stone events were captured as an efficacy outcome and were not reported as harms. All renal events were single-patient events and were generally infrequent: █████████ in the ILLUMINATE-A trial, ████████ in the ILLUMINATE-B trial, and █████████ in the ILLUMINATE-C trial. During the overall period of receiving lumasiran treatment, █████████ in the ILLUMINATE-A trial reported renal events, with the most frequent events being ███████ (█████████) and █████████ (█████████). In the ILLUMINATE-B trial, ████████ reported █████████.

Six patients reported headache in the ILLUMINATE-A trial (3 patients each on placebo and lumasiran) and 2 patients in the ILLUMINATE-B trial (███████████████████). No patients reported headache in the ILLUMINATE-C trial. During the overall period of receiving lumasiran treatment, █████████ in the ILLUMINATE-A trial and █████████ in the ILLUMINATE-B trial reported headache.

Four patients reported rhinitis in the ILLUMINATE-A trial (2 patients each on placebo and lumasiran) and 4 patients in the ILLUMINATE-B trial (1 patient weighing less than 10 kg and 3 patients weighing between 10 kg and 20 kg). No patients reported rhinitis in the ILLUMINATE-C trial. During the overall period of receiving lumasiran treatment, █████████ in the ILLUMINATE-A trial and █████████ in the ILLUMINATE-B trial reported rhinitis.

Four patients reported upper respiratory infection in the ILLUMINATE-A trial (2 patients each on placebo and lumasiran), 4 patients in the ILLUMINATE-B trial (1 patient less than 10 kg, 2 patients weighing between 10 kg and 20 kg, and 1 patient weighing more than 20 kg), and █████████ in the ILLUMINATE-C trial (████████ each not receiving dialysis and on dialysis). During the overall period of receiving lumasiran treatment, 4 patients reported upper respiratory infection each in the ILLUMINATE-A and ILLUMINATE-B trials.

One patient receiving lumasiran in the ILLUMINATE-A trial reported a hypersensitivity reaction. Hypersensitivity reactions were not reported in the ILLUMINATE-B or ILLUMINATE-C trials. There were no additional reports in the ILLUMINATE-A trial during extended lumasiran treatment.

One patient tested positive for ADAs in the ILLUMINATE-A trial, while 3 patients tested positive for ADAs in the ILLUMINATE-B trial. The sponsor concluded that the ADAs did not appear to affect efficacy or safety results for these patients. No patients tested positive for ADAs in the ILLUMINATE-C trial. During the overall period of receiving lumasiran treatment, in the ILLUMINATE-A trial, 1 patient originally randomized to placebo tested positive for ADAs. There were no additional reports of patients testing positive for ADAs in the ILLUMINATE-B trial during extended lumasiran treatment.

Critical Appraisal

The ILLUMINATE-A trial appeared to have appropriate methods for blinding of treatment assignment, randomization, and adequate power, and the primary and secondary outcomes (except eGFR) were controlled for multiplicity. The primary and key secondary outcomes were objective in nature, centrally assessed, relevant to PH1, and supported by regulatory agencies, which reduce bias in the results.^12,15 The ILLUMINATE-B and ILLUMINATE-C sample sizes were based on feasibility considerations rather than power calculations, were single-arm trials, and end points were not controlled for multiplicity. The sponsor noted that patient heterogeneity, disease heterogeneity, rarity of PH1, lack of available approved therapies, objectively measured end points, and the sponsor’s feasibility results justified the use of a single-arm trial design.^13,14 Baseline characteristics were mostly balanced in the ILLUMINATE-A trial, suggesting that randomization was generally successful, and it is possible that the imbalances were due to the small patient numbers. There were imbalances in sex; race; patients’ medical history, specifically for PH1-related symptoms; and vitamin B6 use, which may have introduced bias, though the magnitude or direction of the bias is uncertain. More specifically, the proportion of patients using vitamin B6 varied among treatment groups in the trials and, because it may also lower oxalate levels, it is unclear how much of the treatment effect could be attributed to vitamin B6 compared to lumasiran. Subgroup analyses of baseline vitamin B6 use (yes versus no) did not indicate a clear difference between the groups, though limitations of the subgroup analyses prevent firm conclusions from being made. Because patients in the ILLUMINATE-B and ILLUMINATE-C trials were not randomized to their treatment group, but rather were categorized based on body mass and use of dialysis, respectively, imbalances between groups are likely to occur. During the 6-month primary analysis periods, few patients discontinued lumasiran during the trials and few withdrew from the trials, suggesting there was little risk of attrition bias. Due to the small amount of missing data among the 3 trials and sensitivity analyses supporting the primary outcomes, the risk of bias due to missing data appears to be low.

One of the main limitations is the small number of patients in each trial (N = 39, 18, and 21 in the ILLUMINATE-A, ILLUMINATE-B, and ILLUMINATE-C trials, respectively), though consideration must be given for the rarity of PH1. The small number of patients in each treatment group makes it challenging to interpret the results and to estimate how meaningful they are. Although there are data for up to 24 months of lumasiran treatment in the ILLUMINATE-A trial, a second major limitation is the relatively short duration of evidence available, given that the clinical experts expect lumasiran to be a lifelong treatment or until liver transplant occurs. The short duration makes it difficult to be certain if the efficacy and safety results will persist long-term. A third limitation is the lack of minimal important differences (MIDs) for patients with PH1 identified from the literature for all outcomes in the trials. Without published MIDs, there is uncertainty around how meaningful the absolute and percent changes from baseline were. The sponsor performed analyses for the proportion of patients who achieved near normalization or normalization for 24-hour urine oxalate in the ILLUMINATE-A trial and spot urine oxalate:creatinine ratio in the ILLUMINATE-B trial, but not for plasma oxalate in the ILLUMINATE-C trial. According to the clinical experts, normalization of elevated oxalate levels may result in clinical benefits, but it is unclear if achieving near normalization prevents long-term kidney outcomes, and long-term evidence will be needed to support this.

Given the lack of details for screening failures for all 3 trials, it is unknown if this biased results or how this limits the generalizability to the entire population of patients who could receive lumasiran. Patients enrolled in the 3 ILLUMINATE trials included both adult and pediatric patients (age range, 0 to 60 years) with a range of kidney function (eGFR range, 8.61 to 174.06 mL/min/1.73 m² and included patients on dialysis) and presenting symptoms related to PH1. Patients with possible hepatic impairment (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] reading greater than 2 times ULN for age or total bilirubin greater than 1.5 times ULN), history of kidney transplant, evidence of systemic oxalosis (in the ILLUMINATE-A or ILLUMINATE-B trials), or receiving peritoneal dialysis (in the ILLUMINATE-C trial) were excluded. Thus, treatment with lumasiran is uncertain in patients with these characteristics. Aside from these limitations, the clinical experts generally felt that the trial results could be generalized to the Canadian population with PH1. The clinical experts confirmed that the trial outcomes, all of which are surrogate measures, were typical measures used when assessing and managing patients with PH1. However, it is unclear how the main outcomes of the trials lead to treatment goals such as prevention of kidney stones and progression to ESKD, and the clinical experts emphasized the need for long-term data to better understand how the surrogate outcomes are related to clinical benefit.

Other Relevant Evidence

Description of Studies

The ALN-GO1 to 001 trial was a phase I/II study conducted in 2 parts: single ascending dose (Part A) in 32 healthy adult volunteers aged between 18 and 64 years and multiple ascending dose (Part B) in 20 patients with PH1 who were aged at least 6 years and had relatively preserved kidney function (eGFR at least 45 mL/min/1.73m²). The ALN-GO1 to 002 trial is a phase II, multicentre, open-label, extension study to evaluate the long-term safety and efficacy of lumasiran in patients with PH1 who have completed Part B of the ALN-GO1 to 001 trial. Patients received lumasiran according to their initiation-dosing regimen in Part B of the ALN-GO1 to 001 trial for up to 54 months.

Efficacy Results

Results are presented for the baseline for Part B of the ALN-GO1 to 001 trial and postbaseline for the ALN-GO1 to 002 trial. Mean eGFR was 77.34 mL/min/1.73 m² (SD = 22.11 mL/min/1.73 m²) at baseline and █████ mL/min/1.73 m² (SD = █████ mL/min/1.73 m²) at month 30, and appeared to be stable throughout the study. Three (15%) patients had at least 1 kidney stone event during the study period and the rate of kidney stone events per person-year during treatment was 0.06 (95% CI, ████ to ████). No data on HRQoL were reported in the clinical study reports. Mean 24-hour urinary oxalate corrected for BSA was 2.24 mmol/24 hour/1.73 m² (SD = ████ mmol/24 hour/1.73 m²) at baseline, ████ mmol/24 hour/1.73 m² (SD = ████ mmol/24 hour/1.73 m²) at month 30, and appeared to be stable after the first 6 months. At any postbaseline visit, 100% and ██% of patients achieved near-normal and normal 24-hour urinary oxalate corrected for BSA levels, respectively. Mean plasma oxalate level was 15.28 µmol/L (SD = ████ µmol/L) at baseline, ████ µmol/L (SD = ████ µmol/L) at month 30, and appeared to be stable after the first 6 months. Mean 24-hour urinary oxalate:creatinine ratio was 0.28 mmol/mmol (SD = ████ mmol/mmol) at baseline and ████ mmol/mmol (SD = ████ mmol/mmol) at month 30, and appeared to be stable after the first 6 months.

Harms Results

All patients in the ALN-GO1 to 002 trial experienced at least 1 AE. The most commonly reported AEs were injection site reaction (40%), vomiting (20%), headache (15%), limb injury (15%), and oropharyngeal pain (15%). Four (20%) patients reported SAEs of blood creatinine increase, pyelonephritis, renal colic, and ureterolithiasis. One patient experienced 2 SAEs, a craniocerebral injury and bone (rib) contusion, from road traffic accidents. There were no withdrawals due to AEs (WDAEs), no patients discontinued treatment due to AEs, and no deaths reported during the study.

Of the notable harms identified in the CADTH systematic review protocol, 40% of patients reported injection site reaction. Three (15%) patients experienced kidney and urinary disorders, such as nephrolithiasis, renal colic, and ureterolithiasis. Headache, ██████ ██████████████ ██████████, and ████████ were reported by 3, █, and █ patients, respectively. Complications caused by systemic oxalosis and hypersensitivity were not reported during the study period. ██ ████████ █████ █████████ █████████████████ ███████████████████████ ███████████ █████ █████ ██████ ██ █ █ █████ █████████ ███████.

Critical Appraisal

The limitations for the ALN-GO1 to 002 trial are similar to those for the ILLUMINATE trials. The ALN-GO1 to 002 trial was a phase II, OLE study, and statistical analyses, adjustments for multiplicity, and imputations for missing data points were not performed. Because vitamin B6 may help to reduce oxalate levels, it is unclear how much of the effect seen in this trial could be attributed to the concomitant treatment. The sample size was not determined using a power calculation and was likely too small to make definitive conclusions about safety and efficacy. Considering the wide range of clinical manifestations with PH1, it is uncertain if the sample population adequately represents patients with PH1 living in Canada, which limits generalizability of the results. Additionally, none of the trial sites were in Canada. The follow-up time may be sufficient for observing an immediate treatment effect (mean duration of exposure was 28.8 months) because the clinical experts stated that 2 to 3 years are deemed appropriate in a kidney disease–related clinical trial setting. However, it is unlikely that the duration of exposure is long enough to draw long-term conclusions for lumasiran treatment given that it is expected to be a lifelong treatment. Although the safety data suggest that lumasiran is safe for the first 30 months of treatment, the clinical experts emphasized that longer-term data for efficacy and safety are warranted.

Conclusions

The ILLUMINATE-A, ILLUMINATE-B, and ILLUMINATE-C trials are ongoing trials that have provided evidence of the efficacy and safety of lumasiran in patients with PH1 who were aged 6 years and older, younger than 6 years, and any age with an eGFR at or below 45 mL/min/1.73 m² (receiving dialysis or not), respectively. Lumasiran demonstrated improvements in urine oxalate corrected for BSA, plasma oxalate, and urine oxalate:creatinine ratio in the 3 trials. In the DB, placebo-controlled ILLUMINATE-A trial, all primary and key secondary outcomes were for objective measures, controlled for multiplicity (except eGFR), and most were deemed clinically meaningful (except eGFR) based on clinical expert opinion because there were no MIDs identified from the literature. Results for single-arm ILLUMINATE-B and ILLUMINATE-C trials were generally consistent with those observed in the ILLUMINATE-A trial, which the clinical experts agreed were also meaningful for those populations. Changes in eGFR and HRQoL were numerically small, the latter outcome was not controlled for multiplicity, and conclusions could not be drawn about whether lumasiran had an impact on these outcomes due to the small number of patients and short treatment duration of the trials so far.

Efficacy results for up to 30 months on lumasiran in the ALN-GO1 to 002 study indicated similar findings as the ILLUMINATE trials, although the same limitations apply to these longer-term data. The clinical experts had no major concerns with the harms profile and there were few SAEs, WDAEs, and no deaths reported. Lumasiran treatment for up to 30 months in the ALN-GO1 to 002 trial showed a similar harms profile as the ILLUMINATE trials, with no new safety signals identified. In the ILLUMINATE trials, there were no patients aged 60 years or older patients were excluded if they had a history of kidney transplant or had hepatic impairment (ALT or AST greater than 2 times ULN for age or total bilirubin greater than 1.5 times ULN).

Therefore, further research showing adequate efficacy and safety is needed to inform broader treatment with lumasiran. According to the clinical experts, given the meaningful reductions in urine and plasma oxalate levels compared to placebo for up to 24 months of treatment, acceptable safety profile so far, lack of other effective treatments, and easy administration, lumasiran appears to be an important treatment option for patients with PH1. The experts and CADTH review team agreed that long-term efficacy and safety data will be necessary to confirm the findings in the ILLUMINATE trials and to better understand how the main trial outcomes translate to improved long-term outcomes of maintained lowering of hepatic oxalate production, prevention of kidney stones, and prevention of progression to ESKD.

Introduction

Disease Background

PH1 is an ultrarare, autosomal recessive metabolic condition caused by a pathogenic variant of the AGT gene.³ There is considerable heterogeneity with PH1 in the age of onset, severity of disease, residual enzyme activity, and genotype.⁴ It has been estimated that there are about 200 genetic variants of the AGT gene¹⁰ and that the genotype does not reliably predict the phenotype.³ Further, the level of enzyme function may not be indicative of disease severity because some patients may have functional enzyme that is incorrectly localized to mitochondria rather than peroxisomes in the liver.^3,4 The enzyme catalyzes the conversion of glyoxylate to glycine in peroxisomes and without it (i.e., in patients with PH1), glyoxylate is converted to oxalate in the cytosol.³ Oxalate binds to calcium, producing insoluble calcium oxalate salts that are difficult for the body to eliminate. The clinical experts stated that PH1 usually manifests with the formation of kidney stones. Once kidney function declines to an eGFR of less than 30 to 45 mL/min/1.73 m², the kidneys become unable to excrete excess oxalate.⁵ Plasma oxalate levels increase, leading to systemic oxalosis in which oxalate builds up in tissues throughout the body (e.g., bone, skin, retina, and cardiovascular and nervous systems).^3,5 Patients often progress to ESKD, which, combined with complications of systemic oxalosis, results in early death.³

Due to the variable clinical presentation and age of onset as well as a limited awareness of PH1, it has been suggested that the disease is underdiagnosed.^3,6 The incidence of PH1 has been estimated to be between 0.4 and 1 per 100,000 live births in different populations.⁴ The prevalence has been estimated to be between 1 and 3 per million in European countries, with higher rates among countries with consanguinity.⁴ Patient survival has been estimated in a study¹⁶ of 155 patients of families from Western Europe, North Africa, and the Middle East to be 95%, 86%, and 74% at 10, 30, and 50 years of age, respectively, and based on a European study¹⁷ of 526 patients to be 95%, 93%, 85%, and 74% at 5, 10, 30, and 50 years of age, respectively. No Canadian data for prevalence, incidence, or survival have been identified from the literature.

There is notable heterogeneity in the presentation of PH1 and Milliner et al. described 5 groups of patients who are differentiated by kidney manifestations.³ Approximately 10% of patients show early nephrocalcinosis and kidney failure in infancy or early childhood. Most patients present with recurrent nephrolithiasis and progressive kidney failure in childhood to mid-adulthood. About 10% of patients are diagnosed after ESKD based on oxalate deposits from kidney biopsy, recurrent oxalate nephropathy after kidney transplant, or systemic oxalosis with chronic dialysis. Less than 10% of patients are considered late-onset and have occasional kidney stones in adulthood. Finally, less than 10% of patients are diagnosed presymptomatically based on family screening and having a close relative with PH1. The median age for symptom onset has been reported to be about 4 to 6 years (ranging from infancy to 60 years of age) and can be higher (i.e., 25 years) for patients who are diagnosed after ESKD.³

Symptoms suggestive of PH1 in pediatric patients consist of recurrent kidney stones, nephrocalcinosis, oxalate deposits in tissues, or impaired kidney function leading to failure to thrive.³ Laboratory tests showing urine oxalate levels consistently higher than 0.7 mmol/1.73 m²/day³ or 40 to 45 mg/day (500 µmol/day),⁵ elevated urine glycolate concentration, or plasma oxalate levels greater than 50 µmol/L when GFR is less than 30 mL/min/1.73 m²³ also indicate PH1. It is recommended, both in the literature and by the clinical experts consulted by CADTH, that 24-hour urine collection corrected for BSA be used over spot urine analyses, where possible, and assessments such as that for oxalate:creatinine ratio be interpreted with an age-related reference.¹⁸ The clinical experts CADTH consulted stated that patients suspected of having PH1 (who do not yet have ESKD) will have urine biochemistry testing with a hyperoxaluria panel. Then, to confirm a diagnosis, genetic testing is used to identify a pathogenic variant in the AGT gene.³ Of the 3 types of PH, PH1 makes up approximately 80%.¹⁰ The types can be differentiated from each other based on genetic testing: AGT gene for PH1, glyoxylate reductase/hydroxypyruvate reductase (GRHPR) gene for PH2, and 4-hydroxy-2-oxoglutarate aldolase (HOGA1) gene for PH3.³ Additionally, PH2 and PH3 have a less severe phenotype than PH1.³ It has also been recommended that siblings of a proband be screened even if they are asymptomatic because their clinical course can be similar and they may benefit from early treatment.¹⁹

Standards of Therapy

Because hepatic overproduction of oxalate is the main cause of PH1, it is suggested that the best form of management is to reduce oxalate production, which can be further supported by increasing oxalate clearance, though the latter has limited effect.³ An estimated 30% of patients have a form of PH1 that is sensitive to high-dose vitamin B6 (a cofactor for AGT), which helps to ensure proper localization of the enzyme to the liver peroxisomes and may delay the onset of ESKD.^3,7 According to the literature and the clinical experts consulted by CADTH, vitamin B6 therapy may be able to lower oxalate levels in some patients; however, not all patients achieve normalization of oxalate levels.^7,8 Citrate supplementation to inhibit crystal formation and hyperhydration (2 to 3 L/m²/day) are also used to treat PH1 and preserve kidney function. Both citrate supplementation and hyperhydration can be burdensome for patients and are associated with compliance issues. Moreover, pediatric patients may require a gastrostomy tube to ensure adequate hydration throughout the day. It has been suggested that reducing dietary oxalate will have little effect because the main problem is endogenous overproduction.⁹ New therapeutics consisting of siRNA, such as lumasiran and nedosiran, have been developed to treat PH.³ Patients may also undergo shockwave lithotripsy, ureteroscopy, or percutaneous nephrolithotomy to treat kidney stones. When kidney function declines to less than 30 mL/min/1.73 m², patients may require hemodialysis to remove oxalate that cannot be excreted through urine. The major limitation with dialysis is that oxalate production often exceeds clearance and intensive hemodialysis (consisting of many hours per day and multiple days per week) only reduces plasma oxalate levels transiently for a few hours before returning to supersaturated levels (i.e., greater than 30 to 45 µmol/L).^3,9 The clinical experts consulted by CADTH noted that current standard-of-care treatments require lifelong adherence, are noncurative, and only partially alleviate the oxalate burden in patients. Liver-kidney transplant and complete removal of the non-functional liver is considered the only cure for PH1 because it corrects AGT function (endogenous oxalate production is returned to normal levels) and restores kidney function, but is associated with high morbidity, mortality, and lifelong immunosuppression.^3,5,9 It has been estimated that 5-year survival is higher with dual-organ transplant compared to isolated kidney transplant at 67% versus 45%, respectively, in adults²⁰ and 76% versus 14%, respectively, in children.²¹ After liver-kidney transplant, systemic oxalosis may be reversible, but the resolubilization of oxalate from tissues can put the new kidneys at risk of nephrocalcinosis and can take years to completely clear oxalate stores.^3,9,18 Hemodialysis may also be used as a bridge to organ transplant and can be continued posttransplant in some patients to clear systemic stores of calcium oxalate and limit damage to the transplanted kidney.^9,18

Milliner et al. suggested monitoring patients with PH1 based on kidney function.³ For example, patients with preserved function (GFR at least 60 mL/min/1.73 m²) may have regular kidney ultrasounds, fundoscopic eye exams for oxalate deposition, and urinalysis for oxalate and creatinine measures. In patients with reduced renal function (GFR less than 60 mL/min/1.73 m²) plasma oxalate may be included with the previously listed assessments. Those with greatly reduced renal function (GFR less than 30 mL/min/1.73 m²) or rapid deterioration of function may have bone X-rays, anemia testing, electrocardiogram for conduction abnormalities, echocardiogram for oxalate cardiomyopathy, and imaging for tissue calcification, along with the previously listed assessments.

The clinical experts consulted by CADTH stated that the current goals of therapy are to lower hepatic oxalate production, reduce kidney stone formation, and prevent the development of ESKD.

Drug

Lumasiran (Oxlumo) is indicated for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients.¹ The drug is available as a solution of 94.5 mg/0.5 mL lumasiran for subcutaneous injection with weight-based loading and maintenance dosing.² According to the product monograph, patients weighing less than 10 kg receive a loading dose of 6 mg/kg once monthly for 3 doses and a maintenance dose of 3 mg/kg once monthly, patients weighing 10 kg to less than 20 kg receive a loading dose of 6 mg/kg once monthly for 3 doses and a maintenance dose of 6 mg/kg once every 3 months (quarterly), and patients weighing 20 kg or more receive a loading dose of 3 mg/kg once monthly for 3 doses and a maintenance dose of 3 mg/kg once every 3 months (quarterly).²

Lumasiran is a double-stranded siRNA that targets hydroxyacid oxidase 1 (HAO1) messenger RNA (mRNA) in hepatocytes and reduces glycolate oxidase (GO) levels through RNA interference.² Lower GO levels reduce the amount of glyoxylate available for oxalate production, which results in a reduction of urine and plasma oxalate levels, the underlying cause of disease manifestations in patients with PH1. Since GO is upstream of AGT, the deficiency of which causes PH1, the mechanism of action of lumasiran is independent of the underlying gene mutation encoding AGT. Lumasiran is not expected to be effective in PH2 or PH3 because its mechanism of action does not affect the metabolic pathways causing PH2 and PH3.

Lumasiran underwent a priority review at Health Canada and was issued a Notice of Compliance on March 7, 2022. The sponsor has requested reimbursement as per the approved Health Canada indication.¹ Lumasiran has not been previously reviewed by CADTH.

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by 1 patient group. The full original patient input received by CADTH has been included in the stakeholder section at the end of this report.

About the Patient Groups and Information Gathered

Two patient groups provided input as a joint submission to the CADTH review of lumasiran for the treatment of PH1. The Oxalosis and Hyperoxaluria Foundation is the first patient advocacy organization in the world dedicated to finding treatments, and ultimately a cure, for hyperoxaluria and is the largest private funder of hyperoxaluria research in the world. The Canadian Organization for Rare Disorders is Canada’s national network for organizations representing those with rare disorders. The network advocates for health policy and a health care system that is supportive of rare disorders and works with stakeholders to promote research, diagnosis, treatment, and services for all rare disorders in Canada.

The responses have been collected through an online survey (Survey Monkey, available from May 19, 2022, to May 31, 2022) and a virtual focus group (3 Canadian caregivers for children less than 12 years old diagnosed with PH1 and 1 Canadian patient diagnosed with PH1). In total, 43 respondents completed the entire survey (18.6% Canadian from Alberta, British Columbia, Ontario, and Yukon; 41.9% American). Of the 43 responders, one-third indicated that they were patients with PH and two-thirds identified as caregivers. In addition, 3 Canadians, 7 Americans, 6 non–North Americans from the online survey, and 2 Canadian children from the focus group reported having experience with lumasiran.

Disease Experience

Patients reported that the greatest burden of PH1 was the physical toll and emotional stress. Physical burdens included frequent dialysis, multiple hospitalizations, or emergency visits to remove stones and manage pain, fractures, repeated urinary or kidney infections, delayed development, infertility, and many systemic symptoms including nausea, stomach pain, and headaches. Emotional stress included anxiety and/or depression, concerns about kidney failure, liver-kidney transplant, disease prognosis, pregnancy, dying at a younger age, not having an approved treatment, and not being able to live as 1 wishes. Younger patients felt additional emotional stress because they wondered why they have the disease or why they are different. Also, responders highlighted the complexity of diagnosis for PH — for example, the time it took to get appropriate care and the preceding years of misdiagnoses. Responders cited challenges associated with treatment that included gastrostomy tube insertion for some infants and children, ureteroscopy and/or surgery to remove stones, loss of efficacy over time with vitamin B6, noncompliance, and intensive dialysis. Patients who have received lumasiran described experiencing an improvement in PH1 management and quality of life.

Improved Outcomes

The participants responded that current treatments and dialysis are insufficient and that therapies that decrease the likelihood of kidney stones, need for kidney and/or liver transplant, kidney failure, oxalosis, and the amount of medication are critical. Patients and families said they need access to treatments that improve physical well-being, thereby mitigating stress and anxiety for the entire family.

The respondents described the many physical, emotional, and financial challenges associated with PH1 having profound impacts on the quality of life of patients, caregivers, and families. These are compounded by a lack of knowledge among clinicians as well as access and affordability issues to treatments. One respondent stated, “There is a lack of clinical expertise within Canada that creates additional barriers to diagnosis and treatment. Just getting to a diagnosis has been a painful and exhausting marathon.”

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). In addition, as part of the lumasiran review, a panel of 4 clinical experts from across Canada was convened to characterize unmet therapeutic needs, assist in identifying and communicating situations in which there are gaps in the evidence that could be addressed through the collection of additional data, promote the early identification of potential implementation challenges, gain further insight into the clinical management of patients living with a condition, and explore the potential place in therapy of the drug (e.g., potential reimbursement conditions). The following is a summary of this panel discussion.

Unmet Needs

The clinical experts consulted by CADTH emphasized the need for a therapy to treat PH1 that effectively lowers hepatic oxalate production, reduces kidney stone formation, and prevents the development of ESKD. The experts stated that current treatments, such as hyperhydration, oxalate crystal inhibitors, and dialysis, are noncurative and do not lower hepatic oxalate production or the total oxalate burden in patients. The clinical experts also noted that there is a small subset of patients whose PH1 is partially or completely vitamin B6 sensitive, but who may still progress to ESKD. One expert stated that administration of vitamin B6 in patients with pyridoxine-sensitive mutations only sometimes partially alleviates oxalate accumulation in these patients.

Place in Therapy

According to the clinical experts, a liver transplant is currently considered the only cure for PH1, but this is associated with high morbidity and lifelong immunosuppression. Two therapies, lumasiran and nedosiran, were identified by the clinicians as being possible pharmacotherapies for PH1. The experts expected lumasiran to cause a shift in the current treatment paradigm, becoming the first-line treatment for patients with PH1 and specifically for patients who are insensitive or only partially sensitive to vitamin B6 therapy. The clinicians noted that treatment with lumasiran is expected to be lifelong or until the patient receives a liver transplant. Long-term safety and efficacy data are limited, and it is uncertain what long-term outcomes or potential side effects there could be with lumasiran. Further, the clinical experts stated the importance of continuing current standard-of-care treatments along with lumasiran, particularly post–kidney transplant or when on dialysis, at least until there is normalization of urine oxalate excretion and plasma oxalate levels.

Patient Population

As per the clinical experts, patients with PH1 would typically be identified based on clinical symptoms, laboratory testing of oxalate levels, and a diagnosis confirmed by genetic testing. The clinicians suggested that a diagnosis could be missed if clinical signs were not further investigated, such as kidney stones in adults, which are more common than in children and do not immediately indicate PH1. Otherwise, the experts indicated that a diagnosis of PH1 is unlikely to be missed with genetic testing, which is generally not difficult to access, and which drug companies may subsidize. One clinical expert noted that it may take time for mutations that have not been previously documented to be accepted as being pathogenic, which may occur more frequently in underrepresented ethnic groups.

As noted earlier, the clinical experts stated that patients would be candidates for lumasiran if they have genetically confirmed PH1 and are unable to normalize urine oxalate excretion. The clinicians were uncertain if or when lumasiran would be used for patients who are sensitive to vitamin B6 therapy and are able to normalize urine oxalate excretion. The experts suggested that it may be reasonable to treat these latter patients with lumasiran if, despite adequate standard of care, they experience any of the following: inability to maintain normalized urine oxalate excretion, elevated plasma oxalate levels, progressive nephrocalcinosis, ongoing kidney stone formation, or decline in GFR (to less than 60 mL/min/1.73 m²). The clinicians explained that patients with normal renal function but who have evidence of nephrocalcinosis or elevated plasma oxalate levels may benefit from lumasiran because it is very unlikely these patients will maintain normal kidney function long-term. The experts felt that early intervention and treatment with lumasiran would be reasonable for patients who still have kidney function, rather than waiting until GFR falls to 60 mL/min/1.73 m². As PH1 progresses and GFR declines, the clinical experts stated that lumasiran could reduce urine oxalate excretion and plasma oxalate levels and prevent systemic oxalosis.

One expert explained that patients with limited kidney function may have low urine oxalate excretion, though this is not indicative of the extent of disease and the urine oxalate level is inaccurate in patients who have ESKD. The clinical experts indicated that patients with little or no urine oxalate excretion and who rely solely on dialysis to remove oxalate from the body are at very high risk of systemic oxalosis with clinical deterioration and would benefit from lumasiran. The experts stated that hemodialysis only temporarily lowers plasma oxalate levels, with a typical drop of 50% in a 2.5-hour dialysis, after which plasma oxalate rises to predialysis levels within minutes to hours. Moreover, an expert emphasized that daily dialysis is insufficient to remove the daily production of oxalate, resulting in persistent tissue deposition of oxalate. Currently, there is a lack of long-term data in patients on dialysis who have been treated with lumasiran.

The clinical experts noted that lumasiran may be effective in avoiding the need for liver transplant in patients with ESKD and identified some evidence²² for treating pediatric patients with ESKD or with markedly reduced GFR (e.g., less than 30 mL/min/1.73 m²) with lumasiran and kidney-only transplants. The experts explained that it would be reasonable to treat patients with lumasiran before and after a kidney transplant to lower plasma and urine oxalate levels and prevent damage to the transplanted kidney from oxalate deposition as well as reduce stored oxalate that is excreted post–kidney transplant. One expert noted that patients who receive a kidney-only transplant would be required to continue lumasiran treatment indefinitely because the allograft would be otherwise damaged by endogenous oxalate overproduction.

Assessing Response to Treatment

The clinical experts noted that urine oxalate excretion and plasma oxalate are surrogate markers for oxalate production in patients with PH1 and that there is no widely accepted method for measuring total body oxalate, making it difficult to assess how effective a treatment is. The expert also stated that in patients with ESKD who receive dialysis, predialysis oxalate levels would be measured to assess adequate suppression of oxalate production, which should slowly decline, indicating effective treatment, but may take time because dialysis is continually removing stored oxalate from the body.

The clinicians expected that there would be a noticeable improvement after an initial treatment duration of lumasiran for 6 months, but that this is unlikely to be long enough to see a lowering of urine or plasma oxalate to normal levels, especially in patients on dialysis or with advanced chronic kidney disease (CKD). The experts suggested that successful treatment must consider how progressed a patient is before treatment; for example, a patient with established kidney failure and on dialysis will not see normalization of oxalate levels very quickly. A clinician indicated that if no observable changes occurred during the first 6 months of treatment, it might be reasonable to treat a patient for 12 months (total) before deciding to continue lumasiran or not.

Per the clinical experts, patients in earlier stages of PH1 may be monitored for urine oxalate excretion (24-hour urine preferred over spot urine sampling depending on the patient’s age), plasma oxalate levels, kidney function (eGFR), and nephrocalcinosis via radiological imaging. Because patients in later stages of PH1 and on dialysis would not have reliable urine oxalate measures, clinicians would instead measure predialysis plasma oxalate every 1 to 3 months to assess response to therapy. The clinical experts stated that patients who have received a kidney or combined liver-kidney transplant may have plasma oxalate levels measured initially on a daily basis, transitioning to weekly and then monthly frequency as levels stabilize.

The clinicians noted that a 30% reduction in urine oxalate excretion may not be sufficient to declare successful treatment and would rather see normalization of urine and plasma oxalate for a full response. Clinicians of patients with systemic oxalosis would want to see an improvement in symptoms such as clearance of skin deposits, normal cardiac ejection fraction, and improvement in musculoskeletal and vascular issues. The experts described how patients (post–liver transplant or on lumasiran) with substantial systemic oxalate burden may require years to normalize urinary excretion because the body is slowly clearing stored oxalate.

According to the clinical experts, renewal of lumasiran would depend on adequate response to treatment as well as an assessment of potential treatment issues (e.g., AEs, ADAs, compliance). The clinicians indicated that it would be important to have urine and plasma measurements at least 2 times per year and to see patients in the clinic at least annually.

Discontinuing Treatment

The clinical experts stated that patients who have received a liver transplant would not be treated with lumasiran because the new liver has functional enzyme and there would be no need for the drug. Other possible reasons for stopping treatment suggested by the clinicians were no response to treatment, or severe untreatable or intolerable adverse effects.

Prescribing Conditions

The clinical experts agreed that a specialist (e.g., nephrologist or metabolic physician) should monitor patients with PH1, depending on who is available to the patient in their area. The experts also stated that lumasiran can be administered by a health care professional, such as by a nurse, in a community setting. One clinical expert suggested the potential for the patient or caregiver to self-administer lumasiran at home because subcutaneous injections can be routinely performed for other medications, but other clinicians did not expect lumasiran to be self-administered.

According to the experts, it is unlikely that treatment would exceed the Health Canada recommended dose for most patients. The clinicians suggested that a higher dose may be used in infants due to their larger liver surface area to BSA ratio and that a higher dose might overcome neutralization occurring in patients who have measurable neutralizing ADAs. This was based on experience with other drugs and has been suggested in the literature,¹¹ although there is a lack of clinical evidence supporting higher doses of lumasiran at this time.

Additional Considerations

The clinical experts identified the need for additional consideration of patients who have limited access to health care resources (e.g., individuals living in remote areas, who do not have a primary care physician or access to specialists, and who lack health insurance or a means to afford treatments). The clinicians also noted that access to pediatric hemodialysis is limited to major cities across Canada (e.g., Vancouver, Calgary, Edmonton, Winnipeg, London, Hamilton, Toronto, Ottawa, Montreal, and Halifax), requiring patients and families to relocate to access treatment. The experts stated that lowering hepatic oxalate production with medications such as lumasiran would potentially allow treatment of ESKD with peritoneal dialysis, preventing the need for relocation to access pediatric hemodialysis. The clinical experts also indicated that other ethical issues were the burden of knowing there is a treatment for PH1, but not being able to access it, especially given the severity of the disease, inadequacy of current treatments, and overall burden of care on patients and families.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

ADA = antidrug antibody; BSA = body surface area; CDEC = CADTH Canadian Drug Expert Committee; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; GFR = glomerular filtration rate; PH1 = primary hyperoxaluria type 1.

Clinical Evidence

The clinical evidence included in the review of lumasiran (Oxlumo) is presented in 3 sections. The first section, the Systematic Review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of lumasiran 94.5 mg/0.5 mL, subcutaneous, for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 5: Inclusion Criteria for the Systematic Review

ADA = antidrug antibody; AE = adverse event; eGFR = estimated glomerular filtration rate; HRQoL = health-related quality of life; RCT = randomized controlled trial; SAE = serious adverse event; WDAE = withdrawal due to adverse events.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.²³

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in EndNote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s Medical Subject Headings, and keywords. The main search concepts were Oxlumo (lumasiran). Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, the WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on June 9, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on September 28, 2022.

Grey literature (i.e., literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.²⁴ Included in this search were the websites of regulatory agencies (US FDA and the European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the sponsor of the drug was contacted for information regarding unpublished studies.

Findings From the Literature

A total of 3 reports from 2 studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of Included Studies

ADA = antidrug antibody; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; AUC = area under the curve; BSA = body surface area; DB = double-blind; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; INR = international normalized ratio; KDQOL = Kidney Disease Quality of Life Questionnaire; MCS = mental component summary; NA = not applicable; OLE = open-label extension; PCS = physical component summary; PedsQL = Pediatric Quality of Life Inventory; PH1 = primary hyperoxaluria type 1; PK = pharmacokinetic; RCT = randomized controlled trial; SF-12 = Short Form-12; ULN = upper limit of normal; VAS = visual analogue scale.

^aeGFR calculated by the Modification of Diet in Renal Disease formula if aged at least 18 years, or Schwartz Bedside Formula if aged at least 12 months to less than 18 years, or patients aged less than 12 months with serum creatinine that was considered elevated for age at consent.

Source: ILLUMINATE-A Clinical Study Report,¹² ILLUMINATE-B Clinical Study Report,¹³ ILLUMINATE-C Clinical Study Report.¹⁴

Description of Studies

All 3 trials were ongoing at the time of the CADTH review of lumasiran.

ILLUMINATE-A Trial

The ILLUMINATE-A trial is a phase III, DB, RCT investigating the efficacy and safety of lumasiran in patients with PH1 who were aged 6 years and older. The trial took place at 16 study centres in 8 countries and screening for eligibility occurred within 60 days of the first administration of the study drug. Overall, 39 patients were randomized 2:1 to receive lumasiran or placebo. Randomization was conducted using an interactive response system and treatment patients were stratified by mean urine oxalate excretion (greater than versus less than or equal to 1.70 mmol/24 hour/1.73 m²). Patients received study drug based on weight-based loading and maintenance-dosing schedules. During the 6-month primary analysis period (DB period), patients received study drug (lumasiran 3 mg/kg or matching placebo) administered as a subcutaneous injection once per month for the first 3 months (loading dose at day 1, month 1, and month 2) followed by a single administration of study drug 1 month later (maintenance dose for the next 3 months at month 3). At month 6, patients entered the 3-month blinded treatment-extension period in which all patients received active treatment. Patients randomized to lumasiran continued the maintenance-dosing schedule, consisting of a single administration of lumasiran and matching placebo for the next 2 injections to maintain treatment blinding (referred to as lumasiran followed by lumasiran). Patients randomized to placebo started receiving active treatment and began the loading dose schedule (lumasiran 3 mg/kg each month; referred to as placebo followed by lumasiran). At month 9, the 51-month OLE began, and all patients were on the maintenance-dosing schedule. Efficacy and safety assessments were conducted every month through month 9, then every 3 months through month 24 and every 6 months until month 60 at the end of the trial. Data are available from primary analysis safety and efficacy results with an interim data cut-off date of November 6, 2019.

Urine and plasma oxalate testing was performed by a central laboratory and the investigator was blinded to the results from the first dose to unblinding (when the last patient completed month 9 assessments). If laboratory measurements were taken locally as part of routine clinical care, steps were taken to avoid informing the patient and site personnel of the result until unblinding occurred.

The baseline for the DB period was based on the last valid measurements before the first dose of study drug. For the all lumasiran–treated set, baseline for patients randomized to lumasiran was the same as described for the DB period. For patients randomized to placebo and crossed over to lumasiran, baseline was defined as the last valid measurement before the first dose of lumasiran (i.e., month 6).

Protocol amendment 2 contained changes that lowered the exclusion threshold for GFR from at or below 45 mL/min/1.73 m² to less than 30 mL/min/1.73 m², moved the evaluation of long-term plasma oxalate measures from exploratory to secondary end points, and clarified that specific study assessments may be performed outside of the trial centre by a home health care professional. As a result of the first amendment, the subgroup analysis by baseline eGFR changed from at or below versus greater than 60 mL/min/1.73 m² to less than versus at least 60 mL/min/1.73 m².

ILLUMINATE-B Trial

The ILLUMINATE-B trial is a phase III, single-arm trial investigating the efficacy and safety of lumasiran in patients with PH1 who were aged younger than 6 years. The trial took place at 9 study centres in 5 countries and screening for eligibility was similar to ILLUMINATE-A. At screening, for those who were able to comply, patients had a 24-hour urine collection to establish baseline urine oxalate excretion. Otherwise, where allowed and at the discretion of the investigator and patient’s guardian, baseline and month 6 measures may have been taken using a single catheterized 24-hour collection. Due to the challenges of pediatric patients providing 24-hour urine samples, single-void urine samples were collected throughout the trial. Overall, 18 patients were included in the trial. Patients received the study drug based on weight-based loading and maintenance-dosing schedules. Efficacy and safety assessments were conducted every 2 weeks for the first month and every month for the rest of the 6-month primary analysis period. During the 54-month long-term extension period, assessments occurred at least once every 3 months until the end of the trial. Data are available from primary analysis safety and efficacy results with an interim data cut-off date of June 30, 2020.

As a single-arm trial, there was no blinding of treatment assignments. All efficacy and pharmacodynamic (PD) analyses were performed centrally, and data were distributed to study sites only after the last patient had completed the month 6 visit.

Protocol amendment 1 contained changes that increased the sample size to 20 patients, due to a lower-than-expected screening failure rate; moved the evaluation of plasma oxalate from exploratory to secondary end points; included the percentage of time that the spot urine oxalate:creatinine ratio was at or below 1.5 times ULN, as a secondary end point in the extension period; and clarified that specific study assessments might be performed outside of the trial centre by a home health care professional and that specific laboratory tests could be performed locally, with abnormalities being confirmed by a central laboratory.

An interim analysis was conducted based on data available up to October 25, 2019, with an updated report dated March 9, 2020, for regulatory submission purposes. Analyses were descriptive and did not contain formal hypothesis testing.

ILLUMINATE-C Trial

The ILLUMINATE-C trial is a phase III, single-arm trial investigating the efficacy and safety of lumasiran in patients with PH1 who had an eGFR of 45 mL/min/1.73 m² or lower and were either not receiving hemodialysis (Cohort A) or had begun hemodialysis (Cohort B). The trial took place at 13 study centres in 10 countries and screening for eligibility occurred within 120 days of the first administration of the study drug. Overall, 21 patients were included in the trial. Patients received the study drug based on weight-based loading and maintenance-dosing schedules. Dose administration and efficacy and safety assessment scheduling were similar to the ILLUMINATE-B trial. Data are available from primary analysis safety and efficacy results with an interim data cut-off date of May 20, 2021.

Similar to the ILLUMINATE-B trial, there was no blinding of treatment assignments and data were not distributed until after the last patient’s month 6 visit.

Cohort A included patients who did not require hemodialysis, while Cohort B included those who did. Patients in Cohort A who began requiring hemodialysis due to progressive renal impairment could cross over to Cohort B. At the time of the data cut-off for the primary analysis, no patients had crossed over to Cohort B. According to the study protocol and at the sponsor’s discretion, patients may have been replaced if they discontinued the study drug or stopped participating before month 6, or if patients crossed over from Cohort A to Cohort B. Patients who discontinued study drug or participation after month 6 were not replaced.

Protocol amendment 1 increased the sample size from 16 to 20 patients.

An interim analysis was conducted based on plasma oxalate data available up to May 14, 2021, from 4 patients in Cohort B to support responses directed to questions from a health agency. Analyses were descriptive.

Populations

Inclusion Criteria

All patients included in the 3 trials must have had documented or confirmed diagnosis of PH1 by genetic testing and, if taking therapeutic vitamin B6, were on a stable regimen for at least 90 days before screening and maintained the regimen for at least 6 months during the trial. The ILLUMINATE-A trial included patients who were aged 6 years or older with a mean 24-hour urine oxalate excretion of at least 0.70 mmol/24 hour/1.73 m² based on 24-hour urine collections. The ILLUMINATE-B trial included patients who were aged younger than 6 years with a urine oxalate:creatinine ratio greater than the ULN based on age. The ILLUMINATE-C trial included patients of any age who had an eGFR at or below 45 mL/min/1.73 m² and plasma oxalate of at least 20 μmol/L. Patients on hemodialysis (Cohort B) must have had a stable regimen for at least 4 weeks before screening and maintained this regimen through the month 6 visit.

Exclusion Criteria

Patients in the 3 trials were not eligible if they had an ALT or AST reading greater than 2 times ULN for age or total bilirubin greater than 1.5 times ULN. Of note, individuals were excluded from the ILLUMINATE-A or ILLUMINATE-B trials if they had an eGFR less than 30 mL/min/1.73 m² or 45 mL/min/1.73 m² and lower, respectively; had clinical evidence of extrarenal systemic oxalosis, past liver or kidney transplant, or anticipated a liver transplant within 6 months. Individuals were excluded from the ILLUMINATE-C trial if they had a condition other than PH1 that resulted in renal insufficiency, were receiving peritoneal dialysis, had a history of liver transplant or kidney transplant and were receiving immunosuppression for it, or anticipated a liver transplant within 6 months.

Baseline Characteristics

Baseline characteristics are summarized in Table 7. Due to the different eligibility criteria and data reported for each trial, meaningful comparisons between trials could not be made.

ILLUMINATE-A Trial

The mean age of patients was 18.1 years (SD = █████ years; median = 14.0 years; range, 6 years to 60 years); 66.7% were male and 33.3% were female; and 76.9% were white, 15.4% were Asian, 5.1% were another race, and 2.6% identified as being of more than 1 race. The mean age at diagnosis was ███ years (SD = █████ years). Patients had a mean 24-hour urine oxalate excretion corrected for BSA of 1.82 mmol/24 hour/1.73 m² (SD = 0.62 mmol/24 hour/1.73 m²) and mean plasma oxalate of 15.01 μmol/L (SD = 7.44 μmol/L). Most patients had an eGFR of at least 60 mL/min/1.73 m² (82.0%), while fewer had an eGFR between 45 and 60 mL/min/1.73 m² (███%) or between 30 and 45 mL/min/1.73 m² (████%). In general, baseline characteristics appeared to be balanced between lumasiran and placebo groups.

A higher percentage of patients in the lumasiran group had history of kidney stones (88.5% versus 76.9% in placebo), whereas a higher percentage of patients in the placebo group had history of vitamin B6 use (69.2% versus 50.0% in lumasiran), pyelonephritis (38.5% versus 19.2% in lumasiran), and nephrocalcinosis (69.2% versus 46.2% in lumasiran). At diagnosis, a higher percentage of patients in the lumasiran group reported presenting symptoms of kidney stones (80.8% versus 53.8% in placebo), whereas a higher percentage of patients in the placebo group reported presenting with nephrocalcinosis (53.8% versus 38.5% in lumasiran) or were asymptomatic (23.1% versus 7.7% in lumasiran).

ILLUMINATE-B Trial

The mean age of patients was ████ months (SD = █████ months; median = 50.1 months; range, 3 months to 72 months); 55.6% were female and 44.4% were male; and 88.9% were white while 11.1% identified as another race. The mean age at diagnosis was ████ months (SD = █████ months). Patients had a mean spot urine oxalate:creatinine ratio of 0.63 mmol/mmol (SD = 0.43 mmol/mmol) and mean plasma oxalate of 13.24 μmol/L (SD = 6.50 μmol/L). The mean eGFR was 112.80 mL/min/1.73 m² (SD = 27.63 mL/min/1.73 m²). Due to the small number of patients in each group and because treatment groups were differentiated by body mass, which is related to age, some baseline characteristics did not appear balanced. There were more females than males in the 10 kg to 20 kg group and all patients in the 20 kg or more group were male. One-third of patients in the 10 kg or less group and all patients in the 10 kg or more group were white. Mean spot urine oxalate:creatinine ratio, plasma oxalate measures, and eGFR were highest in the 10 kg or less group.

Mean plasma oxalate was higher in the less than 10 kg group compared to the other treatment groups. More than half of patients in each weight category reported using vitamin B6 (66.7%, 58.3%, and 66.7% by increasing weight category, respectively). A larger percentage of patients in the 20 kg or more group reported a history of kidney stone events (33.3% versus 16.7%) and nephrocalcinosis (███% versus ████%) compared to the group of patients weighing between 10 kg and 20 kg. At diagnosis, a larger proportion of patients weighing less than 10 kg were identified through familial screening (66.7%) compared to the other groups. A higher percentage of patients in the 20 kg or more group presented with nephrocalcinosis (66.7%) compared to the other groups.

ILLUMINATE-C Trial

The mean age of patients was ████ years (SD = ████ years; median = 8.0 years; range, 0 years to 59 years); 57.1% were male and 42.9% were female; and 76.2% were white, 19.0% were Asian, and 4.8% identified as another race. The mean age at diagnosis was ████ years (SD = ████ years). Patients had a mean plasma oxalate of █████ μmol/L (SD = █████ μmol/L). The mean eGFR was 19.85 mL/min/1.73 m² (SD = 9.64 mL/min/1.73 m²) for Cohort A and eGFR was not available for Cohort B. In general, baseline characteristics appeared to be balanced between cohorts A and B. Urinary measures were not available for most patients in Cohort B.

Mean plasma oxalate was higher in Cohort B compared to Cohort A. A larger proportion of patients in Cohort A had a history of kidney stone events (█████ versus ████ in Cohort B) and vitamin B6 use (66.7% versus 46.7% in Cohort B), while a larger proportion of patients in Cohort B had a history of pyelonephritis (████% versus ████% in Cohort A). At diagnosis, a higher percentage of patients presented with nephrocalcinosis (████% versus ████%), ESKD (███% versus ████%), and other symptoms (████% versus ████%) in Cohort B versus Cohort A. A larger proportion of patients in Cohort A presented with kidney stones (████% versus ████% in Cohort B) or were asymptomatic at diagnosis (████% versus █% in Cohort B).

Table 7: Summary of Baseline Characteristics, Safety Analysis Set

BSA = body surface area; CKD = chronic kidney disease; DB = double-blind; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; NA = not applicable; NR = not reported; SD = standard deviation.

^aAge is in years for ILLUMINATE-A, months for ILLUMINATE-B, and years for ILLUMINATE-C.

^bData presented are from patients who could complete testing (e.g., 24-hour urine oxalate was evaluated in a limited subset of patients who were able to complete a 24-hour urine collection). Percentages are based on the number of patients in each treatment group for whom data are available.

^cMinimum reflects 1 patient with a prebirth diagnosis.

^dIncludes all symptoms that a patient experienced before diagnosis. A patient may check more than 1 category; therefore, percentages may exceed 100%.

^eIncluded metabolic acidosis, weight loss, whewellite crystals in urine, acute renal injury, and urinary tract infection.

^fIdentified by CADTH and clinical experts consulted by CADTH as being potentially important.

Note: Percentages are based on the number of patients in each treatment group for whom data are available.

Source: ILLUMINATE-A Clinical Study Report,¹² ILLUMINATE-B Clinical Study Report,¹³ ILLUMINATE-C Clinical Study Report.¹⁴

Interventions

For all 3 trials, lumasiran for subcutaneous injection (189 mg/mL concentration of lumasiran in sterile solution) was the active treatment. In the ILLUMINATE-A trial, placebo was sterile saline solution for subcutaneous injection, and site pharmacists covered syringes in yellow transparent film to mask the identity of the treatment being administered. Preferred injection site was the abdomen, with optional injection in the upper arms or thighs.

Doses and scheduling were based on results from the phase I/II study ALN-GO1 to 001, with consideration for the younger age, lower body weight, and physiologic differences between children and adults for pediatric patients in the ILLUMINATE-B and ILLUMINATE-C trials. Dose administration was based on total body weight, which was measured within 3 months of dosing or collected on the day of dosing (ILLUMINATE-A trial), or within 7 days for patients weighing less than 20 kg (ILLUMINATE-B trial) or aged younger than 6 years (ILLUMINATE-C trial). For the ILLUMINATE-C trial, the sponsor noted that preclinical and clinical data indicated that renal impairment did not affect the systemic exposure, PD, or safety of siRNA compounds; thus, weight-based dosing was used.

For patients weighing less than 10 kg, the loading dose was lumasiran 6.0 mg/kg for 3 months followed by the maintenance dose of lumasiran 3.0 mg/kg monthly. For patients weighing 10 kg to less than 20 kg, the loading dose was lumasiran 6.0 mg/kg for 3 months followed by the maintenance dose of lumasiran 6.0 mg/kg every 3 months. For patients weighing 20 kg or more, the loading dose was lumasiran 3.0 mg/kg for 3 months followed by the maintenance dose of lumasiran 3.0 mg/kg every 3 months. In the ILLUMINATE-B and ILLUMINATE-C trials, patients whose weight increased past the next weight-based dose threshold continued with the increased dose during the study (i.e., patients did not return to a lower weight-based dose if their weight decreased). Monthly doses were required to be administered at least 21 days apart. In the ILLUMINATE-C trial, lumasiran was required to be administered within 120 minutes after dialysis.

Due to the COVID-19 pandemic restricting patient and health care professional travel, the study drug may have been administered at home by the patient’s caregiver after adequate training, under the oversight of the investigator, in consultation with the medical monitor, and where local regulations and infrastructure allowed. In the ILLUMINATE-A trial, patients who demonstrated tolerability could begin receiving at-home administration starting at month 15, while those in the ILLUMINATE-B and ILLUMINATE-C trials must have tolerated at least 1 dose of lumasiran in the clinic.

Standard-of-care therapies for PH1 (e.g., hyperhydration, vitamin B6, crystallization inhibitors) were continued throughout month 6 (ILLUMINATE-B and ILLUMINATE-C) or month 12 (ILLUMINATE-A) of the trial. Patients using vitamin B6 for the treatment of PH1 must have been on a stable regimen for at least 9 months before the trial and continue for at least 6 months (ILLUMINATE-B and ILLUMINATE-C) or 12 months (ILLUMINATE-A) from the start of the trial. Other restrictions on concomitant treatments included not applying topical steroids near the injection site, avoiding high doses of vitamin C 4 days before oxalate measures, and not injecting concomitant subcutaneous medications in the same site within 7 days of the study drug.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 8. These end points are further summarized subsequently. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

Most biochemical assessments and collections were made before the study drug was administered. Sponsor-developed assays for urine and plasma oxalate assessments had characteristics that met FDA and European Medicines Agency guidance and were validated early on during the trial at QPS Holdings LLC, a sponsor contract research organization partner. Randomization was stratified in the ILLUMINATE-A trial based on 24-hour urine oxalate measures. Initially, the measures were based on a clinical assay (Mayo Clinical Laboratories), and included the first 5 patients, before assessments were transitioned to the validated PD assay (QPS). Once the QPS assay was validated and available, patient screening and stratification were performed based on both assays. During the trial, 24-hour urine oxalate samples were analyzed using the QPS assay and plasma oxalate samples were analyzed using both assays.

Table 8: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

eGFR = estimated glomerular filtration rate; HRQoL = health-related quality of life; NR = not reported.

The sponsor noted that all urine oxalate and creatinine samples were analyzed within established long-term stability limits (i.e., for storage). Seven and 5 plasma oxalate samples in the ILLUMINATE-A and ILLUMINATE-B trials, respectively, were analyzed outside of the established stability limit. In the ILLUMINATE-C trial, all plasma oxalate samples were analyzed within the established stability limit. The Clinical Study Report presented efficacy and PD data using the QPS assays.

Kidney Function

Serum creatinine from blood samples was measured and eGFR (mL/min/1.73 m²) was calculated to assess kidney function. The Modification of Diet in Renal Disease method was used for patients aged 18 years and older while the Schwartz Bedside Formula was used for patients aged 12 months to 18 years. In the ILLUMINATE-B trial, eGFR was calculated for patients aged at least 12 months. In the ILLUMINATE-C trial, eGFR was calculated for patients in Cohort A.

According to the Kidney Disease Improving Global Outcomes guideline, CKD is defined as abnormalities in kidney function or structure that have been present for at least 3 months.²⁸ For patients with kidney damage, GFR (mL/min/1.73 m²) maps to levels of kidney function as follows: GFR of at least 90 is normal or high, 60 to 89 is mildly decreased relative to young adult level, 45 to 59 is mildly to moderately decreased, 30 to 44 is moderately to severely decreased, 15 to 29 is severely decreased, and less than 15 is kidney failure.²⁸

Loss of kidney function over time and prevention of dialysis and/or liver-kidney transplant were identified as important outcomes in the CADTH review of lumasiran but were not assessed in the trials.

Kidney Stone Events

A kidney stone event was defined as having at least 1 of the following occur:

• visit to health care provider (e.g., outpatient clinic, urgent care, emergency department, or procedure) due to a kidney stone

• medication taken for renal colic

• stone passage

• macroscopic hematuria due to a kidney stone.

All events were assessed by the investigator.

Health-Related Quality of Life

In the ILLUMINATE-A and ILLUMINATE-C trials, adult patients (aged 18 years or older) completed the KDQOL-36 while pediatric patients (aged 2 to 18 years) completed the PedsQL, including the generic and end-stage renal disease (ESRD) modules. Both parent- and self-report versions were available for pediatric patients in the trials. Adult patients also completed the EQ-5D-5L and VAS, while pediatric patients completed the EQ-5D-Y and VAS. HRQoL was not assessed in the ILLUMINATE-B trial.

The KDQOL-36 is a self-reported questionnaire made up of 36 items in 5 scales: Physical component summary (PCS), mental component summary (MCS), burden of kidney disease, symptoms and problems with kidney disease, and effects of kidney disease.^29,30 Although the instrument was intended to assess HRQoL in patients on dialysis, patients who have had a transplant and/or are at the predialysis stage can also complete it by excluding 2 items asking about access and catheter sites.³¹ Scores are transformed into a scale from 0 to 100,³² with higher scores representing better HRQoL. The instrument has been shown to have adequate construct validity supported by moderate to strong correlations³³ (r = 0.40 to 0.52) between the SF-12 (PCS and MCS) scores and the kidney-specific subscale scores as well as statistically significant differences (P < 0.001 to 0.05) between distinct patient groups.²⁹ Internal consistency (alpha = 0.83 to 0.85) and dialysis facility-level reliability (alpha = 0.72 to 0.83) were acceptable (alpha > 0.7).^29,34 Most items within each scale demonstrated acceptable internal consistency (alpha = 0.31 to 0.73).²⁹ No MID was identified from the literature.

The PedsQL survey consists of 23 items from the 4.0 Generic Core Scales and 34 items from the 3.0 ESRD Module for measuring HRQoL in healthy and/or pediatric patient populations using a Likert scale for each item.³⁵ Raw scores are transformed to a scale of 0 to 100, with higher scores indicative of better HRQoL.³⁵ The Psychosocial Health Summary Score consists of the emotional, social, and school functioning scores. For the Generic Core Scales, construct validity has been demonstrated using the known-groups approach: healthy versus acutely ill versus chronically ill children,³⁶ no chronic illness versus complex or noncomplex chronic illness,³⁷ and healthy children versus children with ESRD.³⁸ Internal consistency for total scale scores was acceptable: self-report (alpha = 0.88) and proxy-report (alpha = 0.90) in pediatric population (healthy, acutely or chronically ill pediatric population),³⁶ alpha was about 0.9 in pediatric patients who are healthy and/or have ESRD.³⁸ Also, a strong correlation (Pearson r = 0.6) was found between patient self-report and parent-proxy report of patients on dialysis.³⁹ Evidence for responsiveness to change was identified from pediatric patients admitted to hospital: total score changed from upon admission to during follow-up (mean difference = 22.1; SD = 22.7).³⁷ No MID was identified from the literature.

For the PedsQL 3.0 ESRD Module, content validity was assessed using focus groups, cognitive interviews, pretesting, and field-testing protocols in population of children with ESRD.³⁸ Internal consistency was acceptable in most of the self-report and parent-proxy report scales, though child self-reports tended to show lower reliability.³⁸ Moderate agreements (intraclass correlation [ICC] = 0.41 to 0.60) between child self-reports and parent-proxy reports were found in 7 of 10 scales and fair agreements (ICC = 0.21 to 0.40) were found in 3 of 10 scales of PedsQL 4.0 Generic Core Scales and 3.0 ESRD Module. No MID was identified from the literature.

The EQ-5D-5L is a generic, preference-based HRQoL measure consisting of descriptive questions and a VAS.⁴⁰ The descriptive questions cover 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) in which each dimension is divided into 5 levels (no, slight, moderate, severe, and extreme) of perceived problems.^41,42 Higher scores indicate worse quality of life in individual scores and better quality of life in population index scores. The VAS records the patient’s self-rated health on a 10 cm scale with end points 0 to 100 labelled “the worst health you can imagine” and “the best health you can imagine,” respectively.^40,42 Validity, reliability, and responsiveness to change have not been studied in patients with kidney disease or PH1. No MID was identified from the literature.

The EQ-5D-Y is a generic, preference-based HRQoL measure with child-friendly wording intended for younger populations.⁴³ Self-completion (ages 8 to 15 years) and proxy (ages 4 to 7 years) versions are available. Like the EQ-5D questionnaire, the descriptive system comprises the same 5 dimensions, with each dimension having 3 levels (no problems, some problems, and a lot of problems) with wording that is more child-appropriate.^43,44 The VAS is the same as that for the EQ-5D. Scoring is consistent with the EQ-5D and VAS. Validity, reliability, and responsiveness to change have not been studied in pediatric patients with kidney disease or PH1. No MID was identified from the literature.

Urine Oxalate Levels

In the ILLUMINATE-A trial, 24-hour urine samples were collected to assess urine oxalate excretion corrected for BSA (mmol/24 hour/1.73 m²). To be a valid collection, the sample must have been between 22 and 26 hours in duration, no voids were missed between start and end times (based on patient collection diary), and the 24-hour creatinine content was at least 10 mg/kg, as determined by the central laboratory. A sample was not collected if it was within 14 days after a dialysis session.

In the ILLUMINATE-B trial, 24-hour urine collections could not be collected by all patients and single-void urine samples were collected instead. A noncatheterized 24-hour urine collection was valid if the samples were between 18 and 26 hours in duration, no voids were missed between start and end times, and the 24-hour creatinine content was at least 5 mg/kg, as determined by the central laboratory.

In the ILLUMINATE-C trial, some patients were anuric (unable to produce more than 100 mL/day) and did not require collection assessments. Otherwise, 24-hour samples were collected from patients who were not anuric, or single-void urine samples were collected from those who could not comply with 24-hour collections. Urine oxalate excretion was assessed for patients who provided 24-hour collections. A urine sample was valid if collected between 18 and 26 hours in duration, no missed voids, and, for Cohort A, 24-hour creatinine was at least 5 mg/kg for patients aged younger than 6 years or weighing at least 10 mg/kg for patients aged 6 years and older as determined by the central laboratory. Patients in Cohort B did not have a minimum creatinine threshold to be considered valid.

Urine oxalate excretion is thought to be in the causal pathway to stone formation and kidney damage in CKD (especially stages 1 to 3a) and is a surrogate outcome to measure total body oxalate in patients with PH1.⁴⁵ Analysis of data from the Rare Kidney Stone Consortium PH registry of 297 patients with all types of PH (65% of whom had PH1) demonstrated that kidney outcomes were correlated with baseline urine oxalate excretion stratified by quartile, with a kidney failure hazard ratio for quartile 4 (Q4) versus Q1 to Q3 of 3.4 (95% CI, 1.4 to 7.9).⁴⁶ Based on the literature, normal values for urine oxalate from 24-hour urine samples are less than 0.50 mmol or less than 45 mg/1.73 m²/day, although readings may vary based on laboratory or methods of analysis used.³ Further, oxalate excretion results should be corrected to a BSA of 1.73 m² in children to be properly interpreted.⁴⁵ It has been suggested that PH1 should be suspected in an individual with elevated urine oxalate excretion persistently greater than 0.7 mmol/1.73 m²/day.⁴⁷ The magnitude of reduction needed for clinical benefit is uncertain.³

Plasma Oxalate Levels

In the ILLUMINATE-A and ILLUMINATE-B trials, blood samples were collected post–drug administration for plasma oxalate measures (µmol/L).

In the ILLUMINATE-C trial, blood samples were collected pre–drug administration and predialysis for patients in Cohort B. Up to 8 samples were collected over a 24-hour period to produce plasma oxalate profiles and calculate AUC between dialysis sessions and may have been taken before, during, or after dialysis.

Similar to urine oxalate excretion, plasma oxalate is a surrogate measure for total body oxalate in patients with PH1.⁴⁵ It has been suggested that plasma oxalate may not correlate well with the loss of kidney function at higher eGFR levels (greater than 45 mL/min/1.73 m²) because of the kidney’s ability to excrete excess oxalate, and therefore measures in patients with advanced CKD may be more accurate.⁴⁵ A study noted that plasma oxalate increased as eGFR fell and plasma oxalate exceeded 35 to 40 μmol/L (threshold for supersaturation) in samples from patients with PH almost universally when eGFR fell to less than 10 mL/min/1.73m².⁴⁸ These results are supported in a recent study that found a moderate to strong inverse correlation between eGFR and plasma oxalate levels for patients with CKD stages 1 to 3b, though the relationship is nonlinear across eGFR values.⁴⁹ Normal plasma oxalate levels are about 1 to 3 µmol/L,⁴⁵ while normative plasma oxalate values range from less than 50.0 µmol/L^50-55 to 89.9 µmol/L.⁵⁶

Urine Oxalate:Creatinine Measures

In the trials, 24-hour and spot urine samples were collected for oxalate:creatinine measures (mmol/mmol). When available, 24-hour urine samples were collected for oxalate excretion corrected by BSA and oxalate:creatinine ratios.

Similar to urine oxalate excretion, urine oxalate:creatinine ratio is a surrogate measure for total body oxalate in patients with PH1.⁴⁵ As noted by the sponsor, although 24-hour urine collections are the preferred method for assessing urine oxalate excretion, many pediatric patients were not able to comply with 24-hour urine collection procedures. Therefore, in the ILLUMINATE-B and ILLUMINATE-C trials, multiple spot urine samples were collected to calculate the oxalate:creatinine ratio (mmol/mmol). The sponsor identified literature that indicated spot urine oxalate:creatinine measures were an appropriate alternative for 24-hour urine oxalate measures. Data from individuals (N = 5,580) with and without PH showed a moderate correlation between spot urine oxalate:creatinine ratios and 24-hour urine oxalate (R² = 0.63),⁵⁷ though there were notable limitations (described in Appendix 4). These results were consistent with a small population (N = 94) of groups of children aged 5 to 14 years without PH (R² = 0.75).⁵⁸ A cross-sectional study found a weak correlation between 24-hour urine oxalate excretion and spot urine oxalate:creatinine (Spearman correlation r = 0.289, P < 0.005) in 62 patients with a history of kidney stones and it was concluded that a random spot urine test could not replace the 24-hour urine oxalate estimation in patients with urolithiasis.⁵⁹ Based on the literature, normal values for urine oxalate:creatinine ratio in spot urine samples are less than 325 to 360 mmol/mol for individuals aged 0 to 6 months, 132 to 174 mmol/mol for individuals aged 7 to 24 months, less than 98 to 101 mmol/mol for individuals aged 2 to 5 years, 70 to 82 mmol/mol for individuals aged 5 to 14 years, and less than 40 mmol/mol for individuals aged greater than 16 years.³ Again, measurements are expected to vary based on laboratory, methods of analysis used, or literature reference, which was confirmed by the clinical experts consulted by CADTH. It was also noted that values are inconsistent before 5 years of age and differ based on sex,^45,57 and the clinical experts stated that there is a gradual decline in the oxalate:creatinine ratio with age.

Harms

Incidence and seriousness of AEs, WDAEs, and deaths were reported for the safety population during the primary analysis and extension period of the 3 trials. AEs, SAEs, and protocol-defined notable harms were described based on preferred term and associated system organ class. Notable harms from the CADTH systematic review protocol included injection site reactions, renal events, complications from systemic oxalosis, headache, rhinitis, upper respiratory infection, hypersensitivity reactions, and ADAs. Kidney stone events were considered an efficacy outcome and were not captured as an AE or SAE. Blood samples were collected before study drug administration to assess ADAs using a validated enzyme-linked immunosorbent assay.

Statistical Analysis

The statistical analysis of efficacy end points conducted in the trials is summarized in Table 9.

Primary Outcome

In the ILLUMINATE-A trial, the percent change from baseline to month 6 for 24-hour urine oxalate corrected for BSA (mmol/24 hour/1.73 m²) was the primary end point and was estimated based on the mean percent change from baseline across months 3 to 6 (when treatment was expected to have reached a steady state). The primary analysis used a restricted maximum likelihood (REML)–based Mixed-Effect Model Repeated Measures (MMRM) method. The LSM treatment differences (lumasiran – placebo), standard errors of the mean (SEMs), 95% CIs, and P values have been reported.

In the ILLUMINATE-B trial, the percent change from baseline to month 6 for spot urine oxalate:creatinine ratios (mmol/mmol) was the primary end point and was based on the mean percent change from baseline across months 3 to 6. The primary analysis used a REML-based MMRM method. Because the sample size was small for this trial, an autoregressive (1) covariance structure was used to model the within-patient error. If the autoregressive (1) covariance structure matrix failed to converge, an analysis of covariance (ANCOVA) model with covariate of baseline spot urine oxalate:creatinine ratio value was used. The LSM treatment averaged from months 3 to 6, SEMs, 95% CIs, and P values has been reported.

In the ILLUMINATE-C trial, the percent change from baseline to month 6 for plasma oxalate (μmol/L; Cohort A) or predialysis plasma oxalate (Cohort B) was the primary end point and was based on the mean percent change from baseline across months 3 to 6. The primary analysis used a REML-based MMRM method. Similar to the ILLUMINATE-B trial, an autoregressive (1) covariance structure and ANCOVA model with covariate of baseline plasma oxalate (predialysis for Cohort B) was used. The LSM treatment averaged from months 3 to 66, SEMs, 95% CIs, and P values have been reported.

Sample Size and Power Calculation

In the ILLUMINATE-A trial, patients were randomized 2:1 to lumasiran or placebo. The power calculation was based on an assumption that the placebo group would have a mean reduction from baseline to month 6 in 24-hour urine oxalate corrected for BSA of 17% and both treatment groups would have an SD of 25%. The sponsor determined that 24 patients would be required to provide 90% power to detect a treatment difference of 37% at a 2-sided 5% significance level, or a 54% reduction in the lumasiran group. Enrolment of up to 30 patients was planned to account for potential dropouts.

In the ILLUMINATE-B trial, the sample size was based on feasibility considerations rather than power calculations. The sponsor planned to enrol 8 patients based on the original trial protocol and, as outlined in protocol amendment 1, the number was increased to 20 patients (with at least 1 patient aged younger than 12 months and weighing less than 10 kg) due to a lower-than-expected screening failure rate.

In the ILLUMINATE-C trial, the sample size was based on feasibility considerations, as in the ILLUMINATE-B trial. The sponsor planned to enrol at least 20 patients with at least 6 patients in each cohort, 4 patients aged younger than 6 years, and 2 patients aged between 6 and 18 years.

Statistical Testing

In the ILLUMINATE-A trial, a gatekeeping testing strategy was used to control for overall type I error rate for primary and secondary end points. The primary end point (percent change in 24-hour urine oxalate from baseline to month 6) was compared between treatment groups at a 2-sided significance level of 0.05. Subsequent testing proceeded only if the previous test was statistically significant at the 0.05 level. Change in eGFR was a secondary end point, but not included in the hierarchy because it was not expected that a significant difference would occur within 6 months.²⁵ Tests for secondary outcomes were conducted in the following order:

• absolute change in 24-hour urinary oxalate from baseline to month 6 (full analysis set [FAS])

• percent change in 24-hour urinary oxalate:creatinine ratio from baseline to month 6 (FAS)

• percent change in plasma oxalate from baseline to month 6 (plasma oxalate analysis set)

• proportion of patients with 24-hour urinary oxalate at or below 1.5 times ULN at month 6 (FAS)

• proportion of patients with 24-hour urinary oxalate at or below ULN at month 6 (FAS)

• absolute change in plasma oxalate from baseline to month 6 (plasma oxalate analysis set)

In the ILLUMINATE-B and ILLUMINATE-C trials, there was no formal hypothesis testing and no control for multiplicity.

Data Imputation

In the ILLUMINATE-A trial, data missing for the primary end point were imputed by treatment group using the Markov Chain Monte Carlo method, assuming data were missing at random, with adjustments for baseline 24-hour urine oxalate level and visit. After imputation, data were analyzed using an ANCOVA model.

In the ILLUMINATE-B trial, data missing for 24-hour urine oxalate and 24-hour urine oxalate:creatinine ratio values were imputed using spot urine oxalate:creatinine ratio measures. Imputation was applied for patients who had valid baseline values only; patients with missing baseline values were not included in the analysis. This method for imputing values was deemed to be valid by the sponsor based on 156 paired samples and 16 patients from a phase I study of lumasiran (ALN-GO1 to 001) demonstrating correlation between time-matched oxalate:creatinine ratios from spot urine samples and oxalate excretion from 24-hour urine collections (Pearson correlation coefficient = ████; 95% CI, ████ to ████). Like the ILLUMINATE-A trial, data were analyzed using an ANCOVA model.

In the ILLUMINATE-C trial, linear interpolation or extrapolation may have been used for missing plasma oxalate AUC values, if appropriate. Imputation of missing data was not further described.

Sensitivity Analyses

In the ILLUMINATE-A trial, 2 sensitivity analyses were performed to estimate the treatment effect of the primary end point without assuming an equal treatment effect across months 3 to 6. The first sensitivity analysis includes the interaction of visit and treatment to the primary MMRM model. The second sensitivity analysis includes all postbaseline data, such as that from months 1 and 2.

In the ILLUMINATE-B trial, 3 sensitivity analyses were performed to estimate the treatment effect of the primary end point by visits for the efficacy analysis set, from months 3 to 6 for the safety analysis set, and for the percent change from baseline in ULN ratio (ratio of measured spot urine oxalate:creatinine to ULN) from months 3 to 6 for the efficacy analysis set.

In the ILLUMINATE-C trial, 1 sensitivity analysis was performed to estimate the treatment effect of the primary end point by cohorts in the safety analysis set, which included patients who lacked plasma oxalate assessments at month 3 or after.

Subgroup Analyses

In the ILLUMINATE-A trial, prespecified subgroups included age (6 to younger than 12 years, versus 12 to younger than 18 years, versus 18 years and older), sex (male versus female), race (white versus any other race), baseline 24-hour urine oxalate corrected for BSA (at or below versus greater than 1.70 mmol/24 hour/1.73 m²), baseline eGFR (less than versus at least 60 mL/min/1.73 m²), history of renal stones (yes versus no), baseline vitamin B6 use (yes versus no), region 1: North America (Canada and US) versus other (outside of North America), and region 2: Europe versus other (outside of Europe). When there were fewer than 5 patients in a subgroup treatment group, only descriptive statistics were presented. These analyses were not controlled for multiplicity.

In the ILLUMINATE-B trial, prespecified subgroups included age (0 to younger than 1 year versus 1 to younger than 6 years) and weight-based dosing categories (less than 10 kg, versus 10 to less than 20 kg, versus 20 kg or more).

In the ILLUMINATE-C trial, prespecified subgroups included age (younger than 2 years, versus 2 to younger than 6 years, versus 6 to 18 years, versus 18 years or older) and weight-based dosing categories (same as the ILLUMINATE-B trial).

The CADTH review team and clinical experts identified subgroups based on age, kidney function, baseline urine and/or plasma oxalate levels, and genetic status as being relevant.

Secondary Outcomes

In the ILLUMINATE-A trial, secondary outcomes of absolute change in 24-hour urine oxalate, percent change in 24-hour urine oxalate:creatinine ratio, percent change in plasma oxalate, and absolute change in plasma oxalate from baseline to month 6 were analyzed using a similar MMRM model as the primary end point. The proportion of patients with 24-hour urine oxalate at or below 1.5 times ULN and at or below ULN at month 6 were analyzed using a Cochran-Mantel-Haenszel test stratified by baseline urine oxalate (at or below versus greater than 1.70 mmol/24 hour/1.73 m²). The number and percentage of patients, odds ratio, 95% CI, and P values were reported. The differences in proportion of responders and their 95% CIs, which were calculated using the Newcombe method based on the Wilson score, were reported. Continuous data were presented using descriptive statistics, LSMs, and SEs. Reporting for the extension period end points was limited by the data available at the cut-off date for the Clinical Study Report.

In the ILLUMINATE-B trial, the secondary outcome for the extension period (month 6 to end of study) was the percent change in spot urine oxalate:creatinine ratio from baseline for all post–month 6 visits using the efficacy analysis set. For the entire duration of study (baseline to end of study), the secondary outcomes included absolute change in spot urine oxalate:creatinine ratio and percent and absolute change in plasma oxalate from baseline for the efficacy analysis set. Descriptive statistics were presented for eGFR and the percentage of time a patient met the 1.5 times ULN threshold during the study. Counts and percentages were presented for the number of patients with urine oxalate excretion at or below 1.5 times ULN and at or below ULN.

In the ILLUMINATE-C trial, the secondary outcome for percent change from baseline in plasma oxalate AUC_{0 to 24 hours} was calculated using the linear-trapezoidal method and the LSM and 95% CI were estimated using an MMRM model. Absolute change from baseline to month 6 for plasma oxalate, percent and absolute change from baseline to month 6 for 24-hour urine oxalate, and percent and absolute change for spot urine oxalate:creatinine ratio were analyzed using a REML-based MMRM method. Results for HRQoL instruments were summarized. The number of patients with kidney stone events, total events, and rate were calculated and reported. Continuous data were presented using descriptive statistics and categorical data were presented using counts and percentages.

Table 9: Statistical Analysis of Efficacy End Points

AUC = area under the curve; BSA = body surface area; CMH = Cochran-Mantel-Haenszel; MMRM = Mixed-Effect Model Repeated Measures; REML = restricted maximum likelihood; ULN = upper limit of normal.

Source: ILLUMINATE-A Clinical Study Report,¹² ILLUMINATE-B Clinical Study Report,¹³ ILLUMINATE-C Clinical Study Report.¹⁴

Analysis Populations

ILLUMINATE-A Trial

The FAS included all randomized patients who received any study drug and was used to assess efficacy end points during the DB period. Patients were analyzed according to the treatment to which they were randomized.

The safety analysis set included all patients who received any study drug and was used to assess safety end points. Patients were analyzed according to the treatment they received.

The PK analysis set included all patients who received any study drug and have at least 1 PK concentration measurement and was used to assess PK end points.

The all lumasiran–treated set included all patients who received any lumasiran (both patients randomized to lumasiran and patients who crossed over from placebo to lumasiran). Long-term efficacy and safety were assessed using the all lumasiran–treated set.

The plasma oxalate analysis set included all patients who received any study drug and had a baseline plasma oxalate level of at least 1.5 times the lower limit of quantitation (LLOQ; 5.55 μmol/L) and was used to assess plasma oxalate end points.

ILLUMINATE-B Trial

The efficacy analysis set included all patients who received any lumasiran and have at least 1 valid spot urine oxalate:creatinine value at baseline and from assessments at months 3 to 6.

The PK analysis set included all patients who received a full dose of lumasiran and have at least 1 postdose blood sample for PK parameters and have evaluable PK data.

The safety analysis set included all patients who received any lumasiran and was used to assess safety end points.

ILLUMINATE-C Trial

The FAS included all randomized patients who received any lumasiran, have at least 1 evaluable plasma oxalate value (predialysis in Cohort B) at baseline, and have at least 1 evaluable plasma oxalate value from assessments at months 3 through 6. The FAS was used to assess efficacy end points.

The safety analysis set included all patients who received any lumasiran. The safety analysis set was used to assess safety end points and the sensitivity analysis of efficacy.

The PK analysis set included all patients who received any lumasiran, have at least 1 postdose blood sample for PK parameters, and have evaluable PK data. The PK analysis set was used to assess PK end points.

Results

Patient Disposition

Patient disposition is summarized in Table 10.

In the ILLUMINATE-A trial, 52 individuals were screened, of whom 13 were screened out based on eligibility criteria and withdrawal by the individual. The resulting 39 patients were randomized to lumasiran (N = 29) or placebo (N = 13). All but 1 patient in the lumasiran group (96.2%) and all patients in the placebo group completed the month 6 visit. Two (7.7%) patients in the lumasiran group discontinued the study drug due to fatigue and disturbance in attention and parent/caregiver choice. One (3.8%) patient withdrew from the study due to parent/caregiver choice. All but 2 patients (92.3%) in the lumasiran group and all patients in the placebo group entered the OLE.

In the ILLUMINATE-B trial, the number of individuals screened was not reported, although 18 patients participated: 3 weighing less than 10 kg, 12 weighing between 10 and 20 kg, and 3 weighing more than 20 kg. All patients completed the month 6 visit and entered the OLE. There were no discontinuations or withdrawals from the 6-month primary analysis period.

Similarly, in the ILLUMINATE-C trial, the screening numbers were not reported but 21 patients participated: 6 in Cohort A (no dialysis) and 15 in Cohort B (on dialysis). All patients completed the month 6 visit and entered the OLE. ███ (████%) patients discontinued treatment and █ (███%) withdrew from the study, all due to █████████ ██████████ █████, which was considered an AE.

Table 10: Patient Disposition

FAS = full analysis set; NA = not applicable; NR = not reported; OLE = open-label extension; PK = pharmacokinetic.

^aIn ILLUMINATE-A, patients were randomized 2:1 to receive either lumasiran or placebo.

^bIn ILLUMINATE-A, patients randomized to placebo began lumasiran treatment after the 6-month DB primary analysis period.

Source: ILLUMINATE-A Clinical Study Report,¹² ILLUMINATE-B Clinical Study Report,¹³ ILLUMINATE-C Clinical Study Report.¹⁴

Exposure to Study Treatments

Exposure to study treatments is summarized in Table 11.

In the ILLUMINATE-A trial, the mean duration of treatment was ████ months (range, ███ to ████ months) in the lumasiran group and ████ months (range, ████ to ████ months) in the placebo group. Most patients (████%) had at least 18 months of treatment on lumasiran and █ patients (████%) had at least 24 months of exposure.

In the ILLUMINATE-B trial, the mean duration of treatment was about ████ months for all weight groups (range, ████ to ████ months). ████ of the patients had at least 18 months of treatment on lumasiran.

In the ILLUMINATE-C trial, the mean durations of treatment were ███ months (range, ███ to ███ months) for Cohort A and █████ months (range ███ to ████ months) for Cohort B. Most patients (████%) had at least 6 months of treatment on lumasiran and █ (████%) patients had at least 12 months of exposure.

Table 11: Overall Treatment Exposure — ILLUMINATE-A, ILLUMINATE-B, and ILLUMINATE-C Trials

SD = standard deviation.

^aIndividual duration of exposure (months) = individual duration of treatment (days) / 30.44. Study visits and drug administration were scheduled based on 28-day intervals (e.g., month 3 visit corresponds to 85 days or 2.8 months).

Source: ILLUMINATE-A Clinical Study Report,¹² ILLUMINATE-B Clinical Study Report,¹³ ILLUMINATE-C Clinical Study Report.¹⁴

Protocol Deviations

In the ILLUMINATE-A trial, 5 major protocol deviations were reported for 4 patients: █████████ in the lumasiran group and ████████ in the placebo group. These were related to study procedures or assessments (24-hour urine sample not valid or not collected and signed consent not properly collected) and concomitant medication (pause in stable vitamin B6 regimen [2 events for 1 patient]).

In the ILLUMINATE-B trial, █ major protocol deviations were reported for █ patients related to study procedures or assessments (signed consent not properly collected) and concomitant medication (pause in stable vitamin B6 regimen).

In the ILLUMINATE-C trial, █ major protocol deviations were reported for █ patients in Cohort B (failure to collect blood samples for plasma oxalate assessment).

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported in the sections that follow. Refer to Appendix 3 for detailed efficacy data.

Kidney Function

ILLUMINATE-A Trial

Change from baseline in eGFR during the DB and extension periods were secondary outcomes and are summarized in Table 12 and Table 37, respectively. During the 6-month DB period, eGFR declined from study baseline by a mean of 2.57 mL/min/1.73 m² (SD = 10.65 mL/min/1.73 m²) in the lumasiran group and 0.11 mL/min/1.73 m² (SD = 6.49 mL/min/1.73 m²) in the placebo group. Data at month 18 of lumasiran treatment showed that eGFR increased by a mean of ████ mL/min/1.73 m² (SD = ████ mL/min/1.73 m²) in the lumasiran group and decreased by a mean of ████ mL/min/1.73 m² (SD = █████ mL/min/1.73 m²) in the placebo group.

The shift from baseline eGFR to worst postbaseline eGFR during the DB period is summarized in Table 38 and during the overall period of receiving lumasiran treatment in Table 39. During the DB period, █████████ in the placebo group decreased 1 step in eGFR category (e.g., from at least 90 mL/min/1.73 m² at baseline to between 60 and less than 90 mL/min/1.73 m²) whereas ████████ increased 1 step during that time. In the lumasiran group, ██ patients decreased 1 step in eGFR category. During the overall period of receiving lumasiran treatment, █ patients in the placebo followed by lumasiran treatment group decreased 1 step in eGFR category while ██ decreased 1 step and █ patients decreased 2 steps in the lumasiran followed by lumasiran treatment group.

ILLUMINATE-B Trial

Change from baseline in eGFR during the study was a secondary outcome and is summarized in Table 13. By month 12 of treatment on lumasiran, eGFR increased by a mean of █████ mL/min/1.73 m² (no SD) for 1 patient weighing less than 10 kg and decreased by a mean of ████ mL/min/1.73 m² (SD = █████ mL/min/1.73 m²) and mean of ████ mL/min/1.73 m² (SD = █████ mL/min/1.73 m²) in the groups of patients weighing between 10 and 20 kg and patients weighing greater than 20 kg, respectively.

The shift from baseline eGFR to worst postbaseline eGFR during the overall period of receiving lumasiran treatment is summarized in Table 40. Overall, █████████ in the 10 to less than 20 kg group decreased 1 step in eGFR category, while ████████ decreased 1 step and ████████ decreased 2 steps in the 20 kg or more group.

ILLUMINATE-C Trial

Change from baseline in eGFR during the study was a secondary outcome and is summarized in Table 14. By month 6 of treatment on lumasiran, eGFR decreased by a mean of ████ mL/min/1.73 m² (SD = ████ mL/min/1.73 m²) in Cohort A.

The shift from baseline eGFR to worst postbaseline eGFR during the overall period of receiving lumasiran treatment is summarized in Table 41. Overall, █ patients in Cohort A decreased 1 step in eGFR category.

Table 12: Change From Baseline to Month 6 in eGFR During DB Period (Secondary Outcome): ILLUMINATE-A Trial, FAS

DB = double-blind; eGFR = estimated glomerular filtration rate; FAS = full analysis set; SD = standard deviation.

^aBaseline is the last assessment before the first dose of study drug (placebo or lumasiran) in the 6-month double-blind period.

Note: The eGFR is calculated from serum creatinine based on the Modification of Diet in Renal Disease formula for patients aged at least 18 years and the Schwartz Bedside Formula for patients aged less than 18 years at screening.

Source: ILLUMINATE-A Clinical Study Report.¹²

Table 13: Change From Baseline in eGFR (Secondary Outcome): ILLUMINATE-B Trial, Efficacy Analysis Set

eGFR = estimated glomerular filtration rate; NA = not applicable; SD = standard deviation.

^aBaseline is the last nonmissing value collected before the first dose of lumasiran.

Note: The eGFR is calculated based on the Schwartz Bedside Formula in patients aged at least 12 months at the time of the assessment.

Source: ILLUMINATE-B Clinical Study Report.¹³

Table 14: Change From Baseline in eGFR (Secondary Outcome): ILLUMINATE-C Trial, FAS

eGFR = estimated glomerular filtration rate; FAS = full analysis set; SD = standard deviation.

^aBaseline is defined as last nonmissing value collected before the first dose of lumasiran.

Note: The eGFR is calculated in patients aged at least 12 months at the time of the assessment.

Loss of kidney function over time and prevention of dialysis and/or liver-kidney transplant were not assessed in the trials.

Source: ILLUMINATE-C Clinical Study Report.¹⁴

Kidney Stone Events

ILLUMINATE-A Trial

Kidney stone events was an exploratory outcome and is summarized in Table 15 for the DB period. Five (19.2%) patients in the lumasiran group experienced 13 kidney stone events and 2 (15.2%) patients in the placebo group experienced 4 kidney stone events. Some events were graded as moderate severity (████% for the lumasiran group and ████% for the placebo group) and the rest were mild. The rate of events was 0.30 and 0.18 events per 100 person-days for the lumasiran and placebo groups, respectively.

Rates of kidney stone events per person-year by time period are summarized in Table 42. During the 12 months before informed consent, the rate was 3.19 events per person-year (95% CI, 2.57 to 3.96 events per person-year) for the lumasiran followed by lumasiran treatment group and 0.54 events per person-year (95% CI, 0.26 to 1.13 events per person-year) for the placebo followed by lumasiran treatment group. The rate of events generally appeared to decrease in the lumasiran followed by lumasiran treatment group from 1.09 events per person-year (95% CI, 0.63 to 1.88 events per person-year) between day 1 and month 6 to 0.63 events per person-year (95% CI, 0.30 to 1.33 events per person-year) between months 18 and 24 of lumasiran treatment. In the placebo followed by lumasiran treatment group, rates appeared to fluctuate over the same period and remained less than 1 event per person-year.

ILLUMINATE-B Trial

Kidney stone events was an exploratory outcome and is summarized in Table 16. In total, █ patients had 1 kidney stone event each (████ ████████████████████ ███) and ███ events were graded as mild severity. The rate of events was 0.11 renal stone events per person-year for the whole group.

ILLUMINATE-C Trial

Kidney stone events was a secondary outcome and is summarized in Table 17. ███ patients in Cohort A had a total of █ kidney stone events and ███ events were graded as mild severity. The rate of events was 1.52 renal stone events per person-year for Cohort A.

Table 15: Kidney Stone Events During DB Period (Exploratory Outcome): ILLUMINATE-A Trial, FAS

DB = double-blind; CI = confidence interval; FAS = full analysis set; NA = not applicable.

^aRate is calculated as total number of renal stone events divided by total person-days at risk, defined as time from first dose to end of the DB period.

Source: ILLUMINATE-A Clinical Study Report.¹²

Table 16: Kidney Stone Events During the Overall Period of Receiving Lumasiran Treatment (Exploratory Outcome): ILLUMINATE-B Trial, Efficacy Analysis Set

CI = confidence interval; NA = not applicable.

^aRate is calculated as total number of renal stone events divided by total person-years during the respective period. The 95% CI for the event rate was obtained using a generalized linear model for a Poisson distribution unless the rate was 0, in which case the upper bound of the 95% CI was calculated using the exact Poisson method.

Source: ILLUMINATE-B Clinical Study Report.¹³

Table 17: Kidney Stone Events During the Overall Period of Receiving Lumasiran Treatment (Secondary Outcome): ILLUMINATE-C Trial, FAS

CI = confidence interval; FAS = full analysis set; NA = not applicable.

^aRate is calculated as total number of renal stone events divided by total patient-years during the respective period. The 95% CI for the event rate was obtained using a generalized linear model for a Poisson distribution unless the rate was 0, in which case the upper bound of the 95% CI was calculated using the exact Poisson method.

Source: ILLUMINATE-C Clinical Study Report.¹⁴

Health-Related Quality of Life

ILLUMINATE-A Trial

The KDQOL and PedsQL results were captured for patients aged at least 18 years and younger than 18 years, respectively, and are summarized in Table 18 and Table 43 for the DB and extension periods, respectively. The EQ-5D-5L and EQ-5D-Y results (data not presented) were captured for the same age cut-offs, respectively, and the VAS results are summarized in Table 19 and Table 44 for the DB and extension periods, respectively. Results for HRQoL were exploratory outcomes.

Kidney Disease Quality of Life Questionnaire

During the DB period, mean scores on the SF-12 PCS █████████ from baseline by ████ points (SD = ████ points) by month 6 and █████████ by ████ points (SD = ████ points) for the lumasiran and placebo groups, respectively. Mean scores on the SF-12 MCS █████████ from baseline by ████ points (SD = █████ points) and █████████ by ████ points (SD = ████ points) for the lumasiran and placebo groups, respectively. Mean scores on the symptoms/problems subscale █████████ from baseline by █████ points (SD = █████ points) and █████████ by ████ points (SD = █████ points) for the lumasiran and placebo groups, respectively. Mean scores on the effects of kidney disease subscale █████████ from baseline by ████ points (SD = ████ points) and █████████ by ████ points (SD = █████ points) for the lumasiran and placebo groups, respectively. Mean scores on the burden of kidney disease (BKD) subscale █████████ from baseline by ████ points (SD = █████ points) and █████████ by ████ points (SD = █████ points) for the lumasiran and placebo groups, respectively.

Data at month 18 for the KDQOL showed mean scores for SF-12 PCS and MCS generally appeared to ████████ and kidney-specific subscales appeared to █████ ████████████████████ ██████ ███ ████. Mean scores at month 18 did not differ by more than ██ points between placebo followed by lumasiran and lumasiran followed by lumasiran treatment groups.

Pediatric Quality of Life Inventory

During the DB period, mean physical functioning scores █████████ from baseline by ████ points (SD = ████ points) and █████████ by ████ points (SD = █████ points) for the lumasiran and placebo groups, respectively. Mean psychosocial health summary scores █████████ from baseline by ████ points (SD = █████ points) and █████████ by ████ points (SD = ████ points) for the lumasiran and placebo groups, respectively. Mean total scores █████████ from baseline by ████ points (SD = █████ points) and █████████ by ████ points (SD = ████ points) for the lumasiran and placebo groups, respectively. Mean ESRD total score – patient █████████ from baseline by ███ points (SD = █████ points) and █████████ by ███ points (SD = ████ points) for the lumasiran and placebo groups, respectively. Mean ESRD total score – caregiver █████████ from baseline by ███ points (SD = █████ points) and █████████ by ████ points (SD = █████ points) for the lumasiran and placebo groups, respectively.

Data at month 18 for the PedsQL showed the mean physical functioning score generally seemed to █████ ███, Psychosocial Health Summary Score appeared to █████████ ██████████, and total score appeared to ██ ██████ ███████████ for the lumasiran followed by lumasiran treatment group and ████ ████████ for the placebo followed by lumasiran treatment group. The ESRD total score – patient seemed to ███ ████████████████ for the lumasiran followed by lumasiran treatment group and ███ █████ ████ for the placebo followed by lumasiran treatment group, while the ESRD total score – caregiver score generally appeared to ███████ for both groups. Only the mean ESRD total score – patient at month 18 differed by more than ██ points between placebo followed by lumasiran and lumasiran followed by lumasiran treatment groups.

EQ-5D-5L, EQ-5D-Y, and VAS

During the DB period, adults who completed the EQ-5D-5L ████ █████ ██████████████ ████████████████ ███ ████ █████████ ██████████████ ████ █████████ ████ ███ █ ███████ ████████████ ████████████ ██████ █████████ ██████████ ██████ ██ ██████████ ████████████ ████████████████ █████ █████████████████ ██████████ ████████ ███ ███████████ ██████ █████████ ██████████████████. Long-term results were consistent with those observed during the DB period.

During the DB period, most pediatric patients who completed the EQ-5D-Y █████ █████ ███████ ██████████ ███ █████ ██ ████ ███ ██████████ ██████ ██████████████ ██ ██████ █ █ ██████ █████ ████ ███ ███ ████████████ █ ███████████████ ███ ██ ████ █████████ █████████ ████ ██████ ██ ██ █████ ███ ███ ███████ █ ███████████ ██████ ████████████████ ███ █████ ████████████ ██ █████ ██████ █████ ██ █████████ ██████ ██ ██████████ ██████ ██████ ███ ████ █████ ████. Long-term results were generally consistent with those observed during the DB period.

During the DB period, VAS scores appeared to ████████ from baseline by ███ (SD = █████) in the lumasiran group and ████████ by ███ (SD = ████) in the placebo group. Data at month 18 showed that mean scores seemed to █████████ and were generally consistent with the results from the DB period. Results at month 18 appeared to be similar between groups.

ILLUMINATE-B Trial

HRQoL was not captured in the trial.

ILLUMINATE-C Trial

No information for HRQoL has been presented in the CADTH report due to the small number of patients who completed each questionnaire based on age and therefore meaningful conclusions could not be drawn from the results.

Table 18: Change in KDQOL and PedsQL During DB Period (Exploratory Outcome): ILLUMINATE-A Trial, FAS

DB = double-blind; ESRD = end-stage renal disease; FAS = full analysis set; KDQOL-36 = Kidney Disease Quality of Life Questionnaire-36; MCS = mental component summary; PCS = physical component summary; PedsQL = Pediatric Quality of Life Inventory; SD = standard deviation; SF-12 = Short Form-12.

Source: ILLUMINATE-A Clinical Study Report.¹²

Table 19: Change in EQ VAS During DB Period (Exploratory Outcome): ILLUMINATE-A Trial, FAS

DB = double-blind; EQ = EuroQol; FAS = full analysis set; SD = standard deviation; VAS = visual analogue scale.

Source: ILLUMINATE-A Clinical Study Report.¹²

Urine Oxalate Levels

ILLUMINATE-A Trial

Percent change from baseline to month 6 in 24-hour urine oxalate corrected for BSA was the primary outcome in the trial and is summarized in Table 20. The LSM percent change from baseline to the average of months 3 to 6 was –65.39% (95% CI, –71.32% to –59.45%) for the lumasiran group and –11.84% (95% CI, –19.53% to –4.15%) for the placebo group. The treatment difference between groups was –53.55% (95% CI, –62.31% to –44.78%; P < 0.001). The results of the 2 sensitivity analyses supported the primary outcome. Subgroup analyses for the primary outcome are summarized in Figure 2. Treatment estimates for subgroups of age, kidney function (baseline eGFR), and baseline urine oxalate level, which were identified as subgroups of interest in the CADTH systematic review protocol, indicated a benefit with lumasiran over placebo and were consistent with the overall analysis.

Absolute change from baseline to month 6 in 24-hour urine oxalate corrected for BSA was a secondary outcome in the trial and is summarized in Table 20. The LSM absolute change from baseline to the average of months 3 to 6 was –1.24 mmol/24 hour/1.73 m² (95% CI, –1.37 to –1.12 mmol/24 hour/1.73 m²) for the lumasiran group and –0.27 mmol/24 hour/1.73 m² (95% CI, –0.44 to –0.10 mmol/24 hour/1.73 m²). The treatment difference between groups was –0.98 mmol/24 hour/1.73 m² (95% CI, –1.18 to –0.77 mmol/24 hour/1.73 m²; P < 0.001).

The proportion of patients with 24-hour urine oxalate corrected for BSA at or less than 1.5 times ULN and at or less than the ULN at month 6 were secondary outcomes and are summarized in Table 21. In the lumasiran group, 84% (95% CI, 64% to 95%) of patients had a 24-hour urine oxalate measure at month 6 that was at or less than 1.5 times ULN, while no patients in the placebo group achieved this. The difference in proportions was 0.84 (95% CI, 0.55 to 0.94; P < 0.001). In the lumasiran group, 52% (95% CI, 31% to 72%) of patients had a 24-hour urine oxalate measure at month 6 that was at or less than the ULN, while no patients in the placebo group achieved this. The difference in proportions was 0.52 (95% CI, 0.23 to 0.70; P = 0.0010).

Absolute and percent change from baseline in 24-hour urine oxalate corrected for BSA were secondary outcomes for the extension period and are summarized in Table 45. Data from treatment on lumasiran indicated decreases in 24-hour urine oxalate at month 6 that appeared to be maintained for both lumasiran followed by lumasiran and placebo followed by lumasiran treatment groups to month 18.

ILLUMINATE-B Trial

Urine oxalate assessments were based on urine oxalate:creatinine ratios and are described later in the report.

ILLUMINATE-C Trial

Absolute and percent change from baseline in 24-hour urine oxalate corrected for BSA was a secondary outcome and is summarized in Table 22 for Cohort A. Patients who were anuric were not assessed. The LSM absolute change from baseline to the average of months 3 to 6 was –0.53 mmol/24 hour/1.73 m² (95% CI, –0.89 to –0.18 mmol/24 hour/1.73 m²). The LSM percent change from baseline to the average of months 3 to 6 was –10.56% (95% CI, –31.99% to 10.87%).

Table 20: Change From Baseline to Month 6 in 24-Hour Urine Oxalate Corrected for BSA (Primary and Secondary Outcomes): ILLUMINATE-A Trial, FAS

BSA = body surface area; CI = confidence interval; FAS = full analysis set; LSM = least squares mean; NA = not applicable; SEM = standard error of the mean.

^aBaseline is the median of all valid 24-hour urine assessments collected before the first dose date/time of study drug (lumasiran or placebo) without any nonprotocol-related sample issues.

^bBased on Mixed-Effect Model Repeated Measures model with the corresponding value at baseline as a continuous fixed covariate, visit, and treatment as fixed effects, and patient as a random effect. Visit is fitted as a categorical variable, and the variance-covariance matrix is assumed to be unstructured. Satterthwaite approximation is used to estimate denominator degrees of freedom. A difference less than 0 represents a favourable outcome for lumasiran.

^cP value has been adjusted for multiple testing (i.e., the type I error rate has been controlled).

Source: ILLUMINATE-A Clinical Study Report.¹²

Table 21: 24-Hour Urine Oxalate Corrected for BSA at Month 6 ≤ 1.5 × ULN or ≤ ULN (Secondary Outcome): ILLUMINATE-A Trial, FAS

BSA = body surface area; CI = confidence interval; FAS = full analysis set; ULN = upper limit of normal.

^aClopper Pearson exact confidence interval.

^bCalculated using the Newcombe method based on the Wilson score.

^cP value is based on the Cochran-Mantel-Haenszel test stratified by baseline 24-hour urine oxalate corrected for BSA (less than or equal to 1.70 vs. greater than 1.70 mmol/24 hour/1.73 m²).

^dP value has been adjusted for multiple testing (i.e., the type I error rate has been controlled).

Source: ILLUMINATE-A Clinical Study Report.¹²

Table 22: Change From Baseline in 24-Hour Urine Oxalate Corrected for BSA (Secondary Outcome): ILLUMINATE-C Trial, FAS

BSA = body surface area; CI = confidence interval; FAS = full analysis set; LSM = least squares mean; NA = not applicable; SD = standard deviation; SEM = standard error of the mean.

^aBaseline is defined as the median of all valid 24-hour urine assessments collected before the first dose date or time of lumasiran without any nonprotocol-related sample issues.

^bBased on the restricted maximum likelihood–based Mixed-Effect Model Repeated Measures model to test against the null hypothesis of mean change from baseline outcome being equal to 0. The model includes scheduled visits and baseline 24-hour urine oxalate corrected for BSA (mmol/24 hour/1.73 m²) as fixed effects and patient as a random factor. Autoregressive (1) was used to model the within-patient variability.

^cP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: ILLUMINATE-C Clinical Study Report.¹⁴