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Indication: For the treatment of primary hyperoxaluria type 1 to lower urinary oxalate levels in pediatric and adult patients
CADTH recommends that Oxlumo be reimbursed by public drug plans for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in pediatric and adult patients if certain conditions are met.
Oxlumo should only be covered to treat those with a genetically confirmed diagnosis of PH1 and whose urine oxalate excretion is not normalized with standard of care therapy (including 3 to 6 months of vitamin B6).
Oxlumo should only be reimbursed if its cost is reduced and it is initially prescribed by a nephrologist or metabolic diseases specialist experienced in the diagnosis and management of PH1.
PH1 is caused by a genetic error that allows oxalate to build up in the body and form crystals, such as kidney stones, that are difficult for the kidneys to remove from the body. The accumulating oxalate crystals cause permanent damage to tissues, specifically the kidneys, leading to loss of function. Though prevalence in Canada is unknown, it is between 1 and 3 per million people in Europe.
Patients with PH1 need effective treatments that prevent further kidney damage, decrease oxalate accumulation throughout the body, and prevent the need for dialysis or organ transplant.
Treatment with Oxlumo is expected to cost approximately $581,132 for pediatric patients and $1,743,495 for adults in the first year, and $387,421 for pediatric patients and $1,162,263 for adults in subsequent years.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that lumasiran be reimbursed for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients only if the conditions listed in Table 1 are met.
One multicentre, double-blind (DB), phase III, randomized controlled trial (RCT) (ILLUMINATE-A; N = 39) that enrolled patients who had documented or confirmed PH1 who were 6 years or older, had a mean 24-hour urinary oxalate excretion of at least 0.70 mmol/24 hour/1.73 m2, and were on a stable dose of vitamin B6 demonstrated that, compared to placebo, 6 months of lumasiran was associated with a statistically significant reduction in 24-hour urinary oxalate levels, where the between-group difference from baseline to the average of months 3 to 6 was –53.55 mmol/24 hour/1.73 m2 (95% confidence interval [CI], –62.31 to –44.78 mmol/24 hour/1.73 m2). In addition, compared to placebo, lumasiran was associated with a statistically significant reduction in percent and absolute changes in plasma oxalate levels compared to the average in months 3 to 6. Moreover, 84% (95% CI, 64% to 95%) of patients in the lumasiran group had a 24-hour urine oxalate measure at month 6 that was at or less than 1.5 times the upper limit of normal [ULN] compared to no patients in the placebo group with a between-group difference in proportions of 0.84 (95% CI, 0.55 to 0.94; P < 0.001). Also, results from 2 multicentre, single-arm, phase III trials that enrolled patients with PH1 who were on a stable dose of vitamin B6 and were younger than 6 years with a urinary oxalate:creatinine ratio greater than the ULN based on age (ILLUMINATE-B; N = 18) or were any age with an estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m2 or lower with or without stable hemodialysis (ILLUMINATE-C; N = 21) were generally consistent with those observed in the ILLUMINATE-A trial for the outcomes of change from baseline in the 24-hour urine oxalate and plasma oxalate measures.
Patients identified a need for treatment options that effectively maintain kidney function; decrease the likelihood of kidney stones, oxalosis, and the need for renal dialysis and kidney and/or liver transplant; and improve the physical challenges and emotional burden of managing PH1. CDEC concluded that that the evidence for lumasiran appears to address some of the needs identified by patients; however, no definitive conclusions could be made regarding the effects of lumasiran on prevention of kidney stones, prevention of progression to ESKD, improvement of HRQoL, or preventing or delaying the need for organ transplant.
Using the sponsor-submitted price for lumasiran and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio for lumasiran was $2,165,926 per quality-adjusted life-year (QALY) gained compared with established clinical management. At this incremental cost-effectiveness ratio, lumasiran is not cost-effective at a $50,000 per QALY willingness-to-pay threshold for patients with PH1; a price reduction is required for lumasiran to be considered cost-effective at a $50,000 per QALY threshold.
Reimbursement Conditions and Reasons.
PH1 is a rare, autosomal recessive metabolic condition caused by a pathogenic variant of the AGT gene. There is considerable heterogeneity with PH1 in the age of onset, severity of disease, residual enzyme activity, and genotype. Oxalate binds to calcium-producing insoluble calcium oxalate salts that are difficult for the body to eliminate. Once kidney function declines to an eGFR of less than 30 mL/min/1.73 m2 to 45 mL/min/1.73 m2, the kidneys become unable to excrete excess oxalate. Elevated plasma oxalate levels lead to systemic oxalosis where oxalate builds up in tissues throughout the body. Patients often progress to ESKD, which, combined with complications of systemic oxalosis, results in early death. The incidence of PH1 has been estimated to be between 0.4 and 1 per 100,000 live births in different populations. The prevalence has been estimated to be between 1 and 3 per million in European countries with higher rates among countries with consanguinity. No Canadian data for prevalence or incidence have been identified from the literature. It is suggested that the best form of management is to reduce hepatic oxalate production as this is the main cause of PH1. An estimated 30% of patients have a form of PH1 that is sensitive to high-dose vitamin B6, though while therapeutic doses of vitamin B6 may be able to lower oxalate levels in some patients, not all patients achieve normalization of oxalate levels. Citrate supplementation to inhibit crystal formation and hyperhydration (2 L/m2 per day to 3 L/m2 per day) are also used to treat PH1 and preserve kidney function, but both 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. Patients may also undergo medical procedures to treat kidney stones. New therapeutics consisting of a small interfering ribonucleic acid, such as lumasiran and nedosiran, have been developed to treat types of primary hyperoxaluria. While hemodialysis can remove oxalate from the blood, oxalate production often exceeds clearance and plasma oxalate levels may only be lowered transiently, with a return to supersaturated levels within a few hours of dialysis treatment. 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 as it corrects AGT function and restores kidney function; however, it is associated with high morbidity, mortality, and lifelong immunosuppression.
Lumasiran is a small interfering ribonucleic acid that has been approved by Health Canada for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients. It is available as a solution of 94.5 mg lumasiran/0.5 mL for subcutaneous injection with weight-based loading and maintenance dosing. The product monograph recommends a loading dose of 6 mg/kg once monthly for 3 doses and a maintenance dose of 3 mg/kg once monthly for patients weighing less than 10 kg; a loading dose of 6 mg/kg once monthly for 3 doses and a maintenance dose of 6 mg/kg once every 3 months for patients weighing 10 kg to less than 20 kg; and a loading dose of 3 mg/kg once monthly for 3 doses and a maintenance dose of 3 mg/kg once every 3 months for patients weighing 20 kg or more.
To make its recommendation, the committee considered the following information:
Two patient groups (OHF 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, while 16 individuals from the online survey and 2 children from the focus group reported having experience with lumasiran. Patients reported the greatest burden of PH1 being the physical toll (e.g., frequent dialysis, multiple hospitalizations, fractures) and emotional stress (e.g., worry over kidney failure, liver-kidney transplant, no approved treatment). Respondents also highlighted issues with getting 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, surgery to remove kidney stones, vitamin B6 losing effect over time, noncompliance, and intensive dialysis. Patients who have received lumasiran described experiencing an improvement in PH1 management and quality of life. Survey participants responded that current treatments and dialysis are insufficient and therapies that decrease the likelihood of kidney stones, need for kidney and/or liver transplant, kidney failure, and oxalosis are critical. Patients and their families emphasized the need for access to treatments that improve physical well-being, which would also mitigate stress and anxiety for the entire family. The respondents described how the physical, emotional, and financial challenges associated with PH1 have profound impacts on their quality of life, which are further compounded by a lack of knowledge among clinicians as well as access and affordability issues to treatments.
The clinical experts consulted by CADTH emphasized the need for a PH1 treatment 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 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; they also stated the importance of continuing current standard of care treatments along with lumasiran. 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 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 indicated that they would not wait for eGFR to decline as early treatment would help reduce kidney stone formation and slow 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. 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 levels are surrogate markers for oxalate production in patients with PH1 and there is no widely accepted method for measuring total body oxalate, which makes 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. As patients in later stages of PH1 and on dialysis would not have reliable urine oxalate measures, clinicians would instead measure predialysis plasma oxalate levels 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, then monthly as levels stabilize. The clinicians expected that there would be a noticeable improvement after an initial 6-month treatment duration, but this is unlikely to be long enough to see normalization of oxalate levels. The experts suggested that treatment success must take into account disease severity before treatment and that it might be reasonable to treat a patient for at least 12 months (total) before deciding to whether to continue lumasiran. 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], compliance). The clinical experts stated that patients who have received a liver transplant would not be treated with lumasiran as the new liver has functional enzyme. Other possible reasons for stopping treatment were a lack of treatment response 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 given that subcutaneous injections can be routinely performed for other medications, but the other clinical experts 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 but a higher dose may be warranted in infants due to their larger liver surface area to BSA ratio or to overcome potential neutralizing ADAs. The latter was based on experience with other drugs and has been suggested in the literature, though there is a lack of clinical evidence to support 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., those living in remote areas, those with no primary care physician or access to specialists, and those lacking 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, inadequacy of current treatments, and overall burden of care on patients and families.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for lumasiran:
The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs, these are presented in Table 2.
Responses to Questions From the Drug Programs.
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 the study drug based on weight-based loading and maintenance dosing schedules that are 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 in ILLUMINATE-A).
ILLUMINATE-A (N = 39) is a placebo-controlled, DB, RCT that included patients who were 6 years and older. Patients were randomized 2:1 to receive lumasiran or placebo. During the 6-month DB period, patients received the study drug (lumasiran 3 mg/kg or matching placebo) as a subcutaneous injection once per month for the first 3 months (loading doses) followed by a single administration of the study drug 1 month later (maintenance dose for the next 3 months). At month 6, patients entered the 3-month blinded treatment extension period where all patients received active treatment (i.e., patients switched from placebo to lumasiran). At month 9, the 51-month open-label extension 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 levels at month 6, proportion of patients with urinary oxalate level near normal (at or below 1.5 times the 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) and most were male (66.7%) and white (76.9%). 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).
ILLUMINATE-B (N = 18) is a single-arm trial that included patients who were younger 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 levels, and eGFR levels. At baseline, patients had a mean age of |||| months (SD = ||||| months; median = 50.1 months; range, 3 months to 72 months) and most were female (55.6%) and white (88.9%). Baseline mean spot urine oxalate:creatinine ratio was 0.63 mmol/mmol (SD = 0.43 mmol/mmol).
ILLUMINATE-C (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 levels from baseline to month 6 (predialysis for cohort B). The secondary end points were plasma oxalate level area under the curve between dialysis sessions (cohort B), urinary oxalate excretion, urinary oxalate:creatinine ratio, pediatric quality of life (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 years to 59 years) and most were male (57.1%) and white (76.2%). Mean baseline plasma oxalate levels were ||||| μmol/L (SD = ||||| μmol/L) for cohort A and |||||| μmol/L (SD = ||||| μmol/L) for cohort B. Median baseline plasma oxalate levels were 57.9 μmol/L (range = 22.7 μmol/L to 134.0 μmol/L) for cohort A and 103.7 μmol/L (range = 56.3 μmol/L to 167.0 μmol/L) for cohort B.
Statistical testing was conducted based on a gate-keeping procedure in the ILLUMINATE-A trial and the primary and secondary outcomes (except for eGFR) were controlled for multiplicity.
During the 6-month DB period of the ILLUMINATE-A study, 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 from the study baseline 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 from study baseline 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 the 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 with 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 kg and 20 kg and those weighing more than 20 kg, respectively.
In the ILLUMINATE-C trial, eGFR declined from the 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.
During the DB period of the ILLUMINATE-A trial, 5 (19.2%) and 2 (15.4%) patients in the lumasiran and placebo groups experienced 13 and 4 kidney stone events, respectively. 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% CI, 0.63 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 (placebo to lumasiran) and 24 (lumasiran to lumasiran) of lumasiran treatment. In the placebo followed by lumasiran treatment group, rates appeared to fluctuate over the same period and remained fewer 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 ||||||||||||. 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.
In the ILLUMINATE-A trial, results from the KDQOL, PedsQL, 5-level EQ-5D 5 Levels, EQ-5D Youth, and visual analogue scale generally showed ||||||||||||||||||||||||||| from baseline to month 6 and during extended lumasiran treatment. Data at month 18 showed mean scores ||||||||||||||||| and were ||||||||||||||||||||||| the results from the DB period.
HRQoL was not assessed in the ILLUMINATE-B study and results were very limited due to small patient numbers and short treatment duration in the ILLUMINATE-C study.
In the ILLUMINATE-A trial, the 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 mmol/24 hour/1.73 m2 to –0.77 mmol/24 hour/1.73 m2; P < 0.001). For patients who achieved near normalization (at or below 1.5 times the 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 the 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 excretion at month 6, which appeared to be maintained for both the lumasiran followed by lumasiran and placebo followed by lumasiran treatment groups to month 18.
In the ILLUMINATE-B trial, urine oxalate assessments were based on urine oxalate:creatinine ratios and are described in a later section. In cohort A of 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 mmol/24 hour/1.73 m2 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%).
In the ILLUMINATE-A trial , for absolute change, the treatment difference between groups for plasma oxalate level was –8.71 µmol/L (95% CI, –11.45 µmol/L to –5.98 µmol/L; P < 0.001) for the DB period. For percent change, the treatment difference between groups was –39.48% (95% CI, –50.10% to –28.87%; P < 0.001) for the DB period.
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. In the ILLUMINATE-B trial, the LSM absolute change from baseline to the average of months 3 to 6 was –5.2 μmol/L (95% CI, –6.2 µmol/L to –4.2 μmol/L), while the LSM percent change was –31.7% (95% CI, –39.5% to –23.9%). 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 µmol/L to –14.24 µmol/L) for cohort A and –48.33 µmol/L (95% CI, –55.85 µmol/L to –40.80 µmol/L) for cohort B.
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 the 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 mmol/mmol 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%).
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 (in the ILLUMINATE-A and ILLUMINATE-C trials), headache (in the ILLUMINATE-A trial), and pyrexia (in 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 (defined by system organ class and preferred term) (||||||||||), 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 who weighed more than 20 kg (33.3%) in the ILLUMINATE-B trial reported a viral infection SAE. In the ILLUMINATE-C trial, |||||||| reported an SAE: ||| (||||%) ||||||| not on dialysis and ||| (||||%) |||||||| 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 a viral infection in the ILLUMINATE-B trial.
During the primary analysis period, 1 patient who was 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 period for either of 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.
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), 2 patients reported headache in the ILLUMINATE-B trial (||||||||||||||||||||), and no patients reported headache in the ILLUMINATE-C trial. During the overall period of receiving lumasiran treatment, |||||||| in ILLUMINATE-A and |||||||| in the ILLUMINATE-B trial reported headache.
Four patients reported rhinitis in the ILLUMINATE-A trial (2 patients each on placebo and lumasiran), 4 patients reported rhinitis in the ILLUMINATE-B trial (1 patient weighing less than 10 kg and 3 patients weighing between 10 kg and 20 kg), and no patients reported rhinitis in the ILLUMINATE-C trial. During the overall period of receiving lumasiran treatment, 4 patients in the ILLUMINATE-A trial and 4 patients in the ILLUMINATE-B trial reported rhinitis.
Four patients reported upper respiratory tract infection in the ILLUMINATE-A trial (2 patients each on placebo and lumasiran), 4 patients reported upper respiratory tract infection in the ILLUMINATE-B trial (1 patient weighing 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 reported upper respiratory tract infection (|||||||| each not receiving dialysis and on dialysis). During the overall period of receiving lumasiran treatment, 4 patients reported upper respiratory tract 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 and 3 patients tested positive for ADAs in the ILLUMINATE-B trial. The sponsor concluded that the ADAs did not appear to impact 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.
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 reduces bias in the results. The ILLUMINATE-B and ILLUMINATE -C trials’ sample sizes were based on feasibility considerations rather than power calculations, they were single-arm trials, and their 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. Baseline characteristics were mostly balanced in the ILLUMINATE-A trial, which suggests that randomization was generally successful, and it is possible that the imbalances were due to the small number of patients included. 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 and direction of the bias are 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. As patients in the ILLUMINATE-B and ILLUMINATE-C trials were not randomized to their treatment group (rather, they 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, which suggests 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 (unless 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 for patients with PH1 identified from the literature for all outcomes in the trials. Without published minimal important differences, 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 levels in the ILLUMINATE-A trial and spot urine oxalate:creatinine ratio in the ILLUMINATE-B trial, but not for plasma oxalate levels 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 damage, 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 in Canada who could receive lumasiran. Patients enrolled in the 3 ILLUMINATE trials included both adult and pediatric patients (age range, 0 years to 60 years) with a range of kidney function (eGFR range, 8.61 mL/min/1.73 m2 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 or aspartate aminotransferase readings greater than 2 times the ULN for age or total bilirubin greater than 1.5 times the 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 population of people in Canada 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.
ALN-GO1-001 was a phase I and II study conducted in 2 parts: single ascending dose (part A) in 32 healthy adult volunteers who were between 18 and 64 years of age and multiple ascending dose (part B) in 20 patients with PH1 who were at least 6 years of age and had relatively preserved kidney function (eGFR at least 45 mL/min/1.73m2). ALN-GO1-002 is a phase II, multicentre, open-label extension study meant to evaluate the long-term safety and efficacy of lumasiran in patients with PH1 who have completed part B of the ALN-GO1-001 trial. Patients received lumasiran according to their initiation dosing regimen in part B of the ALN-GO1-001 trial for up to 54 months.
Results are presented for baseline of the ALN-GO1-001B trial and postbaseline for the ALN-GO1-002 trial. Mean eGFR was 77.34 mL/min/1.73 m2 (SD = 22.11 mL/min/1.73 m2) at baseline, ||||| 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.
All patients in the ALN-GO1-002 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 increased blood creatinine, pyelonephritis, renal colic, and ureterolithiasis (1 event for each patient). One patient experienced 2 SAEs, a craniocerebral injury and bone (i.e., rib) contusion from road traffic accidents. There were no withdrawals due to AEs, no patients discontinued treatment due to AEs, and there were 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. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The limitations for the ALN-GO1-002 trial are similar to those for the ILLUMINATE trials. ALN-GO1-002 was a phase II, open-label extension study and statistical analyses, with adjustments for multiplicity, and imputations for missing data points were not performed. As 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 conclusion 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 in Canada, which limits the 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 (the mean duration of exposure was 28.8 months) as the clinical experts stated that 2 to 3 years are deemed appropriate in kidney disease–related clinical trial settings. 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.
Cost and Cost-Effectiveness.
CADTH identified the following key limitations with the sponsor’s budget impact analysis: the total number of patients with PH1 eligible for funding of lumasiran is unknown, and the sponsor-estimated proportion of pediatric patients is likely an overestimate and would underestimate the 3-year budget impact of reimbursing lumasiran; the expected market share of lumasiran was underestimated; and the use of treatment adherence rate to estimate the lumasiran drug cost is inappropriate. The CADTH reanalysis updated the market shares for lumasiran to reflect an update of 80%, 85%, and 88% in year 1, year 2, and year 3, respectively, and used a treatment adherence rate of 100%. In the CADTH base case, the budget impact of reimbursing lumasiran is expected to be $46,922,574 in year 1, $36,344,252 in year 2, and $38,660,077 in year 3. The 3-year total budget impact was $121,926,903.
Patient, clinical expert, and drug program input gathered for the CADTH review, as well as relevant literatures were reviewed to identify ethical considerations relevant to the use of lumasiran for the treatment of PH1 in pediatric and adult patients.
Ethical considerations in the context of PH1 included challenges of diagnosis for this rare disease, as well as equity and access challenges related to diagnosis and treatment. The severity of PH1 was noted, as was the burdensome nature of current treatment options. Given the ongoing need for liver and kidney transplants for the treatment of PH1, considerations arise related to the allocation of scarce organs.
Ethical considerations arising in the evidence used to support lumasiran indicated that several evidentiary uncertainties exist, particularly related to the long-term safety and efficacy of this drug, and the use of surrogate end points in clinical trials, as well as their representativeness of this population in Canada.
Patients and clinical experts reported improvements in PH1 with the use of lumasiran, but uncertainties remain about efficacy and challenges in prescribing and dispensing.
Ethical considerations for health systems related to the implementation of lumasiran included the challenges of funding decisions, population screening, and issues related to high-cost drugs for rare diseases.
The sponsor filed a request for minor reconsideration for the draft recommendation for lumasiran for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients, in which they requested the following:
In the meeting to discuss the sponsor’s request for minor reconsideration, CDEC committee subpanel considered the following information:
All stakeholder feedback received in response to the draft recommendation from the patient group and the public drug programs is available on the CADTH website.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed
Meeting date: September 28, 2022
Regrets: Two expert committee members did not attend.
Conflicts of interest: None
Minor reconsideration CDEC Committee Subpanel meeting date: January 25, 2023
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Indication: For the treatment of primary hyperoxaluria type 1 to lower urinary oxalate levels in pediatric and adult patients
Sponsor: Alnylam Netherlands B.V.
Recommendation: Reimburse with conditions
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