Regulatory Decision Summary for Oxlumo

This Supplement to a New Drug Submission (SNDS) was filed by Alnylam Netherlands B.V. to update the Product Monograph (PM) of Oxlumo (lumasiran) with new clinical data from Study ALN-GO1-005 that was conducted in pediatric and adult patients with primary hyperoxaluria type 1 (PH1) who have advanced renal disease, including patients on hemodialysis, and to provide updated efficacy and safety data from the extension period of the 2 pivotal studies ALN-GO1-003 & ALN-GO1-004.

To better reflect the totality of evidence, the Sponsor-proposed indication for Oxlumo was revised to: “for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary and plasma oxalate levels in pediatric and adult patients.”

Oxlumo (lumasiran) was originally approved for the treatment of primary hyperoxaluria (PH) to lower urinary oxalate in pediatric and adult patients with relatively preserved renal function. The approval was based on the data from the primary analysis period (6 months) of 2 pivotal Phase 3 studies: Study ALN-GO1-003 (Study 003; ILLUMINATE-A), in patients with PH1 older than 6 years of age, and Study ALN-GO1-004 (Study 004; ILLUMINATE B), in PH1 patients up to 6 years of age. In Study 003, the primary endpoint was the percent change in urinary oxalate at Month 6 compared to baseline, whereas in Study 004, the primary endpoint was the percent change in spot urinary oxalate:creatinine ratio at Month 6 compared to baseline.

With this submission, the indication for lumasiran was amended to include a statement that lumasiran is for the treatment of PH1 to lower urinary and plasma oxalate levels in pediatric and adult patients. The primary data is from the primary analysis period of pivotal Phase 3 study, ALN-GO1-005 (Study 005; ILLUMINATE-C), a multinational, multi-centered, randomized, single-arm uncontrolled study with a primary analysis period of 6 months, and an extension period of up to 54 months, designed to evaluate the efficacy and safety of Oxlumo in adults and children with PH1 and End-stage Renal Disease (ESRD), including patients on hemodialysis. This study included 2 cohorts: Cohort A consisted of 6 patients who did not require hemodialysis at the time of study enrollment and Cohort B consisted of 15 patients who were on a stable regimen of hemodialysis. Patients received subcutaneously the recommended dosing regimen of Oxlumo based on body weight. The median age of patients at first dose was 8.9 years (range 0 to 59 years), 57.1% were male, and 76.2% were White. For Cohort A patients, the median plasma oxalate level was 57.94 µmol/L. For Cohort B patients, the median plasma oxalate level was 103.65 µmol/L at baseline.

The primary endpoint of the study was the percent change in plasma oxalate from baseline to Month 6 for Cohort A and the percent change in pre-dialysis plasma oxalate from baseline to Month 6 for Cohort B. Patients in both cohorts had a reduction in plasma oxalate as early as Month 1; the percent reduction from baseline to Month 6 in plasma oxalate levels for Cohort A was -33.3% (95% CI: -15.2, 81.8) and for Cohort B it was -42.4% (95% CI: -34.2, -50.7). This primary endpoint is acceptable as a surrogate endpoint in patients with PH1 and ESKD since the increased oxalate production by the liver cannot be compensated by increased urinary oxalate excretion due to the presence of ESRD. The primary analysis period of 6 months was also appropriate since it was aligned with pivotal studies 003 and 004. The secondary endpoints of absolute change in plasma oxalate, change in plasma oxalate AUC, reductions in 24-hour urinary oxalate excretion corrected for BSA and in spot urinary oxalate:creatinine ratios for patients who were not anuric, support the primary efficacy results.

The efficacy data from all 3 pivotal studies demonstrate that the benefits of lumasiran treatment extend across patients with PH1, including those with ESRD, and patients on hemodialysis. Reduction of hepatic oxalate production with lumasiran treatment has the potential to reduce plasma and urinary oxalate levels in ESRD patient populations. The efficacy results support the indication of lumasiran for the treatment of PH1 to lower urinary and plasma oxalate levels in pediatric and adult patients. Furthermore, since the renal pathway is a minor elimination route for lumasiran, the same weight-based dosing regimen can be used regardless of the degree of renal impairment in patients with PH1.

The Sponsor has also provided information to update the efficacy and safety of lumasiran in PH1 patients with relatively preserved kidney function for up to 24 months from Study 003, and for up to 12 months from Study 004. The data from the extensions in Studies 003 and 004 demonstrate that reductions in plasma and urinary oxalate are maintained with long-term treatment with lumasiran. Continued treatment with lumasiran was accompanied by an increase in the number of patients with improvement in medullary nephrocalcinosis and a decrease in renal stone events from baseline to Month 12 and beyond in both Study 003 and Study 004. The mean eGFR remained stable following long-term treatment with lumasiran.

The Sponsor has provided safety data from 98 patients with PH1, including 71 pediatric patients, and 15 patients on hemodialysis. Adverse events (AEs) were reported in 92.9% of patients, most of which were mild or moderate in severity, with only 8 (8.2%) reporting severe AE. Adverse events reported in ≥10% of patients included pyrexia, injection site reaction, and diarrhea. There were no drug-related deaths. Serious AEs were reported in 16 (16.3%) patients none of which were considered related to study drug. Most of these occurred in patients from Study 005, who had ESRD. Three (3.1%) patients discontinued treatment due to an AE. Adverse drug reactions associated with lumasiran treatment include injection site reactions (ISRs), presenting as erythema, pain, swelling, pruritus, discoloration, and hematoma, and abdominal pain. Most of the adverse reactions of abdominal pain were mild in severity, transient and none led to the discontinuation of treatment. Both ISRs and abdominal pain are included in the current Product Monograph for Oxlumo and can be managed. Hepatic events were infrequent during the lumasiran clinical development program. Most renal events were mild or moderate in severity and did not lead to changes in study drug dosing.

Overall, the updated safety data from the pooled experience of lumasiran in Studies 002, 003, 004, and 005 demonstrate a similar safety profile as previously described with no additional safety concerns with longer term treatment in adult and pediatric patients, including patients with advanced PH1, patients with ESRD, and patients on dialysis. The additional data from ongoing studies continue to support the favorable benefit/risk profile of lumasiran in the treatment of pediatric and adult patients with PH1. The risk management plan (RMP) version 2.0 and the Canadian Addendum v2.0 submitted by the sponsor are considered acceptable.

The proposed product labelling has been updated to reflect the increased cumulative exposure to lumasiran. Based on the totality of evidence across the clinical development program, lumasiran, at the recommended dosing regimen, has a favorable benefit/risk profile in adult and pediatric patients with PH1.