Summary Basis of Decision for Oxlumo

As described above, the clinical review of the New Drug Submission for Oxlumo was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Lumasiran, the medicinal ingredient in Oxlumo, is a synthetic double-stranded small interfering ribonucleic acid (siRNA) that reduces the level of the enzyme glycolate oxidase (GO) by targeting hydroxyacid oxidase 1 (HAO1) messenger ribonucleic acid (mRNA) in hepatocytes through ribonucleic acid (RNA) interference. Decreased GO enzyme levels reduce the amount of available glyoxylate, a substrate for oxalate production. This results in a reduction of urinary and plasma oxalate levels, the underlying cause of disease manifestations in patients with primary hyperoxaluria type 1 (PH1).

Patients with PH1 have a deficiency of the alanine-glyoxylate aminotransferase (AGT) enzyme. As the GO enzyme is upstream of the AGT enzyme, the mechanism of action of lumasiran is independent of the underlying alanine-glyoxylate and serine-pyruvate aminotransferase (AGXT) gene mutation encoding AGT. Oxlumo is not expected to be effective in primary hyperoxaluria type 2 (PH2) or type 3 (PH3) because its mechanism of action does not affect the metabolic pathways causing PH2 and PH3.

The clinical pharmacology of Oxlumo in humans was evaluated in two studies (Study ALN-GO1-001 and Study ALN-GO1-002), and in pharmacometric analyses.

Study ALN-GO1-001 (Study 001) was a Phase I/II, randomized, single-blind, placebo-controlled, two-part study of subcutaneously administered lumasiran. The primary objective of the study was to evaluate the safety and tolerability of single- and multiple-ascending doses of lumasiran, in healthy adult volunteers and in patients with PH1, respectively. Part A (Study 001A) was conducted in 32 healthy volunteers (18 to 65 years of age), who received a single ascending dose of 0.3, 1.0, 3.0, or 6.0 mg/kg of lumasiran. Part B (Study 001B) was conducted in adult and pediatric patients with PH1 who were randomized 3:1 to receive multiple ascending doses of lumasiran (1.0 mg/kg monthly dosing [qm], 3.0 mg/kg qm, or 3.0 mg/kg quarterly dosing q3m) or placebo. All patients in Part B were permitted to enrol in the open-label extension Study ALN-GO1-002 (Study 002).

Study 002 was a Phase II, multi-center open-label, extension study to evaluate the long-term administration of lumasiran in PH1 patients. All patients from Study 001B were enrolled. The study population consisted of 20 patients with PH1 aged 6 to 65 years (mean age of 14 years), with relatively intact renal function (estimated glomerular filtration rate [eGFR] >45 mL/min/1.73m²). This population was considered appropriate for the purposes of this submission.

In Study 002, patients initially received subcutaneous lumasiran at the same dose and regimen as in Study 001B. Later in the study, those who were originally administered 1 mg/kg qm transitioned to 3.0 mg/kg q3m. The planned duration of treatment was 54 months, however, at the time of authorization, the study was ongoing. The mean duration of treatment at cut-off was 11.2 months (range: 7 to 17 months).

The primary endpoint for both Study 001 and Study 002 was the safety and tolerability of lumasiran. Additional end-points included efficacy, pharmacodynamic, and pharmacokinetic parameters. Antidrug antibodies were also examined to assess the immunogenicity of lumasiran.

The most common adverse events for lumasiran were the same as those observed in the Phase III studies (see the Clinical Safety section below). Study 001 was also used to assess cardiac safety as a thorough QT study was not conducted. The exposure-response analysis did not suggest a clinically significant prolongation of the QTc interval. This is acceptable in conjunction with the results from the in vitro and in vivo non-clinical studies.

In Study 001A, plasma glycolate concentrations increased dose-dependently with a median increase of 30 μmol/L. The mean percent increases at Day 57 were up to 730% at the 6 mg/kg dose. The time to glycolate recovery (plasma glycolate concentration ≤14 nmol/mL) ranged from 134 to 170 days. A rapid and sustained reduction of urinary oxalate levels was noted in PH1 subjects in Study 001B at all doses. The mean maximal reduction in body surface area (BSA)-corrected 24-hour urinary oxalate excretion was 74%. The 3.0 mg/kg qm dose resulted in a more rapid and larger reduction in 24-hour urinary oxalate, whereas the 3.0 mg/kg q3m dose showed sustained 24-hour urinary oxalate reduction.

Lumasiran administered by subcutaneous injection into the abdomen, upper arm, or thigh was rapidly absorbed with a median time to reach maximum plasma concentration of 4.0 hours (range: 0.5 to 12.0 hours) with first-order absorption process. Lumasiran is moderately to highly bound to plasma proteins (77 to 85%) at clinically relevant concentrations. Lumasiran is an N-acetylgalactosamine (GalNAc) conjugated siRNA, and following absorption, it is preferentially taken up by the liver via asialoglycoprotein (ASGR) receptors. The mean (percent coefficient of variation [%CV]) terminal plasma half-life of lumasiran is approximately 5.2 hours (47.0%); however, plasma concentrations of lumasiran do not reflect the extent or duration of its pharmacodynamic activity. In the liver, lumasiran exhibits a long half-life leading to maintenance of a pharmacodynamic effect over the monthly or quarterly dosing interval. The volume of distribution of lumasiran in humans was extrapolated from intravenous non-clinical data to be 4.9 L in a typical 70 kg adult. Lumasiran is metabolized in the liver by endo- and exonucleases. The total plasma clearance (CL_P) is the sum of two elimination pathways: hepatic uptake clearance (CL_H) and renal clearance (CL_R). The primary driver of lumasiran clearance from plasma is CL_H which accounts for about 80% of CL_P, whereas CL_R is a minor route of elimination accounting for about 20% of CL_P in patients with normal renal function.

The pharmacometric analyses included population pharmacokinetic analysis, as well as pharmacokinetic/pharmacodynamic modelling. The population pharmacokinetic dataset for lumasiran was constructed by pooling plasma pharmacokinetic data from Studies 001, 002, 003, and 004. These data were obtained from 99 subjects (24 healthy adult volunteers and 75 patients with PH1). Covariate analysis showed no significant effects of age (2 to <65 years of age), sex, race (Caucasian, Asian), and disease status. Weight was identified as an important factor and weight adjusted dosing was proposed.

The pharmacokinetic/pharmacodynamic modeling was also used to provide information on the use of lumasiran in patients with mild to moderate renal impairment as dedicated studies were not conducted. It was concluded these subjects do not require dose adjustments. The effect of lumasiran on patients with severe or end-stage renal impairment or those on hemodialysis is unknown.

Limited data were available in patients with mild and moderate hepatic impairment. Based on pharmacokinetic/pharmacodynamic modelling, it was concluded that no dose adjustment is required in these patients. The effect of severe hepatic impairment on the pharmacokinetics and pharmacodynamics of lumasiran is unknown.

Across all clinical studies in the Oxlumo development program, including patients with PH1 and healthy volunteers dosed with Oxlumo, 6 of 100 (6%) of lumasiran-treated individuals tested positive for antidrug antibodies (ADA). Antidrug antibody titers were low and generally transient. The presence of ADA did not have an effect on the safety of lumasiran and all patients continued to receive Oxlumo in ongoing studies.

The clinical pharmacology data support the use of Oxlumo for the recommended indication. For further details, please refer to the Oxlumo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy for the recommended indication of Oxlumo was supported by two pivotal Phase III studies: Study ALN-GO1-003 (ILLUMINATE-A, Study 003) and Study ALN-GO1-004 (ILLUMINATE-B, Study 004). 

Study ALN-GO1-003 (ILLUMINATE-A, Study 003)

Study ALN-GO1-003 (ILLUMINATE-A, Study 003) is a Phase III, multinational, multi-centered, randomized, double-blind, placebo-controlled study with an extension period, designed to evaluate the efficacy and safety of Oxlumo in adults and children ≥6 years of age with PH1. This study was ongoing at the time of authorization. Study 003 builds on results from the Phase I/II Study 001, in which the therapeutic hypothesis for Oxlumo was confirmed.

The primary objective of Study 003 is to evaluate the effect of Oxlumo on the percent reduction in urinary oxalate excretion. The study is being conducted in two parts. The first part is a 6-month, placebo-controlled, double-blind (DB) treatment period (referred to as the DB Period). The second part is an extension period composed of a 3-month blinded treatment extension period and an open-label extension (OLE) period of up to 51 months.

The primary endpoint of Study 003 is to evaluate the effect of Oxlumo versus placebo on urinary oxalate through Month 6. This was chosen based on the pathophysiology of PH1, which manifests from excessive oxalate production by the liver. It was therefore expected that a reduction in hepatic oxalate production, the mechanism of action of Oxlumo, would confer clinical benefit in the PH1 population.

The study population includes patients 6 years of age or older with documented or confirmed PH1 as determined by genetic analysis prior to randomization. Patients had a mean 24-hour urinary oxalate excretion from the first two valid 24-hour urine collections ≥0.70 mmol/24hr/1.73m². If taking pyridoxine (vitamin B6) for the treatment of PH1, patients were required to have been on a stable regimen for at least 90 days before randomization, and to be willing to remain on this stable regimen for 12 months from first study drug administration.

A total of 39 patients with PH1 were randomized 2:1 to receive subcutaneous doses of Oxlumo or placebo during the 6-month double-blind, placebo-controlled period. Patients 6 years and older with an eGFR ≥30 mL/min/1.73 m² were enrolled and received three loading doses of 3 mg/kg Oxlumo or placebo administered once monthly, followed by quarterly maintenance doses of 3 mg/kg Oxlumo or placebo. After the 6-month double-blind treatment period, patients, including those originally assigned to placebo, entered an extension period with administration of Oxlumo.

During the 6-month double-blind, placebo-controlled period, 26 patients received Oxlumo, and 13 received placebo. The median age of patients at first dose was 14.9 years (range: 6.1 to 61.0 years), 66.7% were male, and 76.9% were White. The median 24-hour urinary oxalate excretion corrected for BSA at baseline was 1.72 mmol/24 hr/1.73 m². The median spot urinary oxalate:creatinine ratio at baseline was 0.21 mmol/mmol. The median plasma oxalate level at baseline was 13.1 µmol/L. Overall, 33.3% of patients had normal renal function (eGFR ≥90 mL/min/1.73 m²), 48.7% had mild renal impairment (eGFR of 60 to <90 mL/min/1.73 m²), and 18% had moderate renal impairment (eGFR of 30 to <60 mL/min/1.73 m²). The Oxlumo and placebo arms were balanced at baseline with respect to age, urinary oxalate level, and eGFR.

The primary endpoint was the percent reduction from baseline in 24-hour urinary oxalate excretion corrected for BSA averaged over Months 3 through 6. The primary endpoint was met as Oxlumo was associated with a clinically meaningful least square (LS) mean percent reduction from baseline in 24-hour urinary oxalate of 65.4% (95% confidence interval [CI] 59.5, 71.3), compared with 11.8% (95% CI: 4.1, 19.5) in the placebo group. This resulted in a statistically significant between-group LS mean difference of -53.5% (95% CI: -62.31%, -44.78%; p<0.0001) change in 24-hour urinary oxalate excretion corrected for BSA in the Oxlumo group compared to the placebo group from baseline to Month 6 (average of Month 3 to Month 6). The reductions in urinary oxalate observed in patients treated with Oxlumo were rapid and sustained.

The robustness of the primary endpoint was confirmed by two sensitivity analyses which were conducted to evaluate the estimated treatment effect using the assumption that the treatment effect reaches steady state at Month 3 and is maintained through Month 6. The treatment effect was consistent across all subgroups analyzed including: age, gender, baseline 24-hour urinary oxalate, baseline vitamin B6 use, renal function, and geographical region.

There was a continued treatment effect during the extension period with a mean percent change reduction from baseline in 24-hour urinary oxalate corrected for BSA at Month 12 of 64.1% (standard error of the mean [SEM] = 3.3%) in the group who continued Oxlumo treatment in the extension period.

The study met all of its secondary endpoints. The proportion of patients achieving near normalization (≤1.5x the upper limit of normal [ULN]) or normalization (<ULN) were considered to be the key secondary endpoints of most clinical relevance. A statistically significant and clinically meaningful higher proportion of Oxlumo-treated patients achieved near normalization (84%; 95% CI: 55%, 95%; p <0.0001) and normalization (52%; 95% CI: 23%, 70%; p = 0.0010) of 24-hour urinary oxalate levels at Month 6 compared to no patients in the placebo group.

Of the patients who continued Oxlumo treatment in the extension period, 87.5% (21/24) maintained near normalization at Month 12 and 37.5% (9/24) maintained normalization. For patients who received placebo in the first part of the study but crossed over to receive Oxlumo for the extension period, 76.9% (10/13) achieved near normalization of 24-hour urinary oxalate corrected for BSA at Month 12. Estimated glomerular filtration rate was assessed through the double-blind and extension periods for a total of 12 months and remained stable in patients administered Oxlumo.

Study ALN-GO1-004 (ILLUMINATE-B, Study 004)

Study ALN-GO1-004 (ILLUMINATE-B, Study 004) is a Phase III, multinational, multi-centered, single-arm study designed to evaluate the efficacy and safety of Oxlumo in infants and children <6 years of age with PH1. The study was ongoing at the time of authorization.

The primary objective of the study is to evaluate the effect of Oxlumo on urinary oxalate excretion. This study is being conducted in two parts: a 6-month, single-arm, primary analysis period followed by a long-term extension period (up to 54 months). During the 6-month primary analysis period, patients undergo efficacy and safety assessments every 2 weeks for the first month and monthly thereafter. During the long-term extension period of up to 54 months, dosing continues and visits occur at least once every 3 months.

A total of 18 patients were enrolled and treated with Oxlumo in Study 004. All enrolled patients were less than 6 years of age with an eGFR >45 mL/min/1.73 m² in patients 12 months of age and older, and normal serum creatinine in patients less than 12 months of age.

At the time of the first dose, three patients were <10 kg, 12 were 10 kg to <20 kg, and three were >20 kg. Patients <10 kg received 6 mg/kg Oxlumo once monthly for 3 months, followed by monthly maintenance doses of 3 mg/kg of Oxlumo. Patients 10 to <20 kg received 6 mg/kg Oxlumo once monthly for 3 months, followed by quarterly maintenance doses of 6 mg/kg of Oxlumo. Finally, patients >20 kg received 3 mg/kg once monthly for 3 months, followed by quarterly maintenance doses of 3 mg/kg of Oxlumo. The median age of patients at first dose was 51.4 months (range 4 to 74 months), 55.6% were female, and 88.9% were White. The median spot urinary oxalate:creatinine ratio at baseline was 0.47 mmol/mmol.

The primary endpoint was the percent reduction from baseline in spot urinary oxalate:creatinine ratio (averaged over Months 3 through 6). The primary endpoint was met as the results demonstrated a clinically meaningful LS mean reduction of 72.0% (95% CI: 77.5%, 66.4%) from baseline to Month 6 (average from Month 3 to Month 6) in spot urinary oxalate:creatinine ratio. The observed reduction in urinary oxalate excretion was consistent with data from Study 003.

Oxlumo was associated with rapid and sustained reductions in spot urinary oxalate:creatinine ratio, which were similar across all weight strata. Both the sensitivity analysis, which accounted for the impact of natural decline in spot urinary oxalate:creatinine ratio with age, and the subgroup analysis based on age and weight supported the primary endpoint. One of the key secondary endpoints showed that at Month 6, 9 out of 18 (50%) of patients achieved near normalization (≤1.5 × ULN) in spot urinary oxalate:creatinine ratio level, including one patient who achieved normalization (≤ULN). The eGFR remained relatively stable throughout the study.

Indication

The New Drug Submission for Oxlumo was filed by the sponsor with the following indication:

Oxlumo is indicated for the treatment of primary hyperoxaluria type 1 (PH1) in pediatric and adult patients.

To support safe and effective use of the product, Health Canada approved the following indication:

Oxlumo is indicated for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients.

Pediatrics (<18 years): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of Oxlumo in pediatric patients has been established. Therefore, Health Canada has authorized an indication for pediatric use. Limited data is available for patients <2 years of age and weighing <10 kg. 

The efficacy of Oxlumo in PH1 patients <6 years of age was based on a single-arm trial.

Geriatrics (≥65 years): Clinical studies of Oxlumo did not include patients over the age of 65 years.

For more information, refer to the Oxlumo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Oxlumo was evaluated based on safety data obtained from the pivotal, Phase III, placebo-controlled Study 003 and the overall pooled safety data from pivotal Studies 003 and 004 and Study 002. A total of 77 patients from these three studies contributed data for the evaluation of the clinical safety, including 39 patients from Study 003, 18 patients from Study 004, and 20 patients from Study 002. All patients received at least one dose of Oxlumo. The pivotal studies 003 and 004 are described above in the Clinical Efficacy section.

The median duration of drug exposure to Oxlumo in the overall pooled safety data was 9.1 months (range of 1.9 to 21.7 months) with an overall cumulative drug exposure of 60.9 person-years. The cumulative total number of doses received was 501 doses. The study population was representative of the target population. Of the 77 patients, 56 (72.7%) were pediatric patients (less than 18 years of age) and 21 (27.3%) were adult patients (≥18 years of age). Four of the pediatric patients in Study 004 were less than 2 years of age. Treatment compliance was high with only three patients missing one dose of Oxlumo and no patients missing more than one dose.

The most common adverse event (AE), occurring in ≥10% of all patients in the overall pooled safety data, was injection site reaction (ISR). Injection site reactions and abdominal pain were reported in 32.5% and 15.6% of patients, respectively. Injection site reactions were considered to be related to study drug by the investigator with the most commonly reported symptoms being erythema, pain, pruritus, swelling, discomfort, and discoloration. All ISRs were transient, mild in severity, and none led to drug discontinuation or study withdrawal. There were no patterns observed in the frequency or severity of ISRs over time.

Adverse events of abdominal pain, which included abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort and abdominal tenderness, were not considered to be drug related by the investigators. Most of these AEs were mild in severity, transient, and none led to drug discontinuation or study withdrawal.

Serious AEs and severe AEs occurred with low frequency (5.2% and 1.3%, respectively) and none were considered to be related to the study drug by the investigator.

Hepatic and renal events occurred in low frequency (3.9% and 9.1%, respectively). All events were non-serious, mild in severity, and did not result in dose modifications or withdrawal from the study. There were no notable changes in liver function tests or renal function parameters related to Oxlumo.

Mean values and changes from baseline in vital signs remained stable across the three studies. There were no reported clinically significant changes from baseline in electrocardiogram (ECG) results. Most patients did not exhibit any meaningful shifts in hematology, chemistry or coagulation parameters. Apart from a single transient Grade 3 shift in a chemistry value (post-baseline potassium of 6.2 mmol/L) in Study 002, there were no Grade 3 or higher abnormalities in hematology, chemistry and coagulation parameters across all studies.  

There were no drug discontinuations or study withdrawals due to drug-related AEs. No deaths or malignancies were reported.

Oxlumo caused a chronic stable increase in plasma glycolate levels. The risk of metabolic acidosis in patients with severe and or end-stage renal disease and the risk of teratogenicity associated with prolonged exposure to higher levels of plasma glycolate is unknown. From the non-clinical studies and literature reviews, the suspected risks of metabolic acidosis in patients with ESRD and of teratogenicity associated with prolonged exposure to higher levels of plasma glycolate were considered a concern for possible harm to humans. However, the mechanism remained unknown for teratogenicity, and it was not possible to associate the abnormalities observed in the non-clinical studies to either Oxlumo or plasma glycolate. Revised statements were included in the Oxlumo Product Monograph advising to monitor for signs and symptoms of metabolic acidosis in patients with ESRD. This is also reflected in the Risk Management Plan. 

Appropriate warnings and precautions are in place in the approved Oxlumo Product Monograph to address the identified safety concerns. For more information, refer to the Oxlumo Product Monograph, approved by Health Canada and available through the Drug Product Database.