Oxlumo

Lumasiran reduces levels of glycolate oxidase (GO) enzyme by targeting the hydroxyacid oxidase 1 (

) messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference. Decreased GO enzyme levels reduce the amount of available glyoxylate, a substrate for oxalate production. As the GO enzyme is upstream of the deficient alanine: glyoxylate aminotransferase (AGT) enzyme that causes PH1, the mechanism of action of lumasiran is independent of the underlyinggene mutation. 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 hyperoxaluria in PH2 and PH3.

ILLUMINATE-A was a randomized, double-blind trial comparing lumasiran and placebo in 39 patients 6 years of age and older with PH1 and an eGFR ≥30 mL/min/1.73 m²(ILLUMINATE-A; NCT03681184). Patients received 3 loading doses of 3 mg/kg OXLUMO (N=26) or placebo (N=13) administered once monthly, followed by quarterly maintenance doses of 3 mg/kg OXLUMO or placebo

. After six months, all patients received OXLUMO.

The median age of patients at first dose was 15 years (range 6 to 61 years), 67% were male, and 77% were White. At baseline, the median 24-hour urinary oxalate excretion corrected for body surface area (BSA) was 1.7 mmol/24 h/1.73 m², the median plasma oxalate level was 13.1 µmol/L, 33% of patients had eGFR ≥90 mL/min/1.73 m², 49% had eGFR of 60 to <90 mL/min/1.73 m², and 18% had eGFR 30 to <60 mL/min/1.73 m², 56% were on pyridoxine, and 85% reported a history of symptomatic kidney stone events.

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 LS mean percent change from baseline in 24-hour urinary oxalate in the OXLUMO group was -65% (95% CI: -71, -59) compared with -12% (95% CI: -20, -4) in the placebo group, resulting in a between-group LS mean difference of 53% (95% CI: 45, 62; p<0.0001) [Figure 1].

Abbreviation: CI ꞊ Confidence Interval. Results are plotted as mean (95% CI) of percent change from baseline.

Figure 1. ILLUMINATE-A: Percent Change from Baseline in 24-hour Urinary Oxalate by Month

By Month 6, 52% (95% CI: 31, 72) of patients treated with OXLUMO achieved a normal 24-hour urinary oxalate corrected for BSA (≤0.514 mmol/24 hr/1.73 m²) compared to 0% (95% CI: 0, 25) placebo-treated patients (p=0.001). Reduced urinary oxalate levels were maintained through Month 24 in patients treated with OXLUMO.

ILLUMINATE-B was a single-arm study in 18 patients <6 years of age with PH1 and an eGFR >45 mL/min/1.73 m²for patients ≥12 months of age or a normal serum creatinine for patients <12 months of age (ILLUMINATE-B; NCT03905694). Dosing was based on body weight

.

The median age of patients at first dose was 51 months (range 4 to 74 months), 56% were female, and 88% were White. Three patients were less than 10 kg, 12 were 10 kg to <20 kg, and 3 were ≥20 kg. 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. Patients treated with OXLUMO achieved a reduction in spot urinary oxalate: creatinine ratio from baseline of 72% (95% CI: 66, 78) (Figure 2). The reduction in urinary oxalate excretion was maintained with continued OXLUMO treatment through Month 12.

Abbreviation: CI ꞊ Confidence Interval. Results are plotted as mean (95% CI) of percent change from baseline.

Figure 2. ILLUMINATE-B: Percent Change from Baseline in Spot Urinary Oxalate: Creatinine Ratio by Month

A total of 21 patients were enrolled and treated with OXLUMO in a multi-center, single-arm study in patients with PH1 and an eGFR ≤45 mL/min/1.73 m²in patients 12 months of age and older or an elevated serum creatinine for age in patients less than 12 months of age, including patients on hemodialysis. ILLUMINATE-C included 2 cohorts. Cohort A included 6 patients who did not require dialysis at the time of study enrollment. Cohort B included 15 patients who were on a stable regimen of hemodialysis; the hemodialysis regimen was to remain stable in these patients for the first 6 months of the study. Patients received the recommended dosing regimen of OXLUMO based on body weight

Patients requiring peritoneal dialysis were excluded.

The median age of patients at first dose was 9 years (range 0 to 59 years), 57% were male, and 76% were White. For Cohort A, the median plasma oxalate level was 58 µmol/L. For Cohort B, the median pre-dialysis plasma oxalate level was 104 µmol/L.

The primary endpoint was the percent change in plasma oxalate from baseline to Month 6 (average from Month 3 to Month 6) for Cohort A (N=6) and the percent change in pre-dialysis plasma oxalate from baseline to Month 6 (average from Month 3 to Month 6) for Cohort B (N=15). The percent change from baseline to Month 6 in plasma oxalate levels in Cohort A was an LS mean difference of -33% (95% CI: -82, 15) and in Cohort B was -42% (95% CI: -51, -34).

Mean plasma oxalate decreased from 65 µmol/L (95% CI: 21, 108) at baseline to 33 µmol/L (95% CI: 10, 56) at Month 6 in Cohort A, and from 108 µmol/L (95% CI: 92, 125) at baseline to 62 µmol/L (95% CI: 51, 72) at Month 6 in Cohort B. The time course for changes in plasma oxalate is shown in Figure 3.

Abbreviation: CI ꞊ Confidence Interval. Results are plotted as mean (95% CI) of actual values. For Cohort A, the baseline is defined as the mean of all plasma oxalate samples collected prior to the first dose of lumasiran; for Cohort B, the baseline is defined as the last four pre-dialysis plasma oxalate samples collected prior to the first dose of lumasiran. In Cohort B, only pre-dialysis samples are utilized.

Figure 3. ILLUMINATE-C: Plasma Oxalate Levels (µmol/L) during the Primary Analysis Period by Month