OXLUMO lumasiran 94.5 mg/.5mL Injection, Solution, 1 vial — NDC 71336-1002-1 (Billing 71336-1002-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Lumasiran reduces levels of glycolate oxidase (GO) enzyme by targeting the hydroxyacid oxidase 1 ( HAO1 ) 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 underlying AGXT gene 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.

12.2Pharmacodynamics The pharmacodynamic effects of OXLUMO have been evaluated in adult and pediatric patients with PH1 across a range of doses and dosing frequency. Dose-dependent reductions in urinary oxalate levels were observed, resulting in the selection of the recommended body weight-based loading and maintenance dosing regimens. With the recommended dosing regimens, onset of effect was observed within two weeks after the first dose and maximal reductions in urinary oxalate were observed by Month 2 and persisted with continued use of OXLUMO maintenance dosage [see Figures 1 and 2 in Clinical Studies (14.1, 14.2)] .

Cardiac Electrophysiology At the recommended dose, OXLUMO does not lead to clinically relevant QT interval prolongation.

12.3Pharmacokinetics The pharmacokinetic (PK) properties of OXLUMO were evaluated following administration of single and multiple dosages in patients with PH1 as summarized in Table 3. Table 3. Pharmacokinetic Parameters of Lumasiran Lumasiran General Information Steady-State Exposure C max [Median (Range)] 462 (38.5 to 1500) ng/mL AUC 0-last [Median (Range)] 6810 (2890 to 10700) ng∙h/mL Dose Proportionality Lumasiran exhibited an approximately dose proportional increase in plasma exposure following single subcutaneous doses ranging from 0.3 to 6 mg/kg.

Lumasiran exhibited time-independent pharmacokinetics with multiple doses of 1 and 3 mg/kg once monthly or 3 mg/kg quarterly. Accumulation No accumulation of lumasiran was observed in plasma after repeated monthly or quarterly dosing. Absorption T max [Median (Range)] 4 (0.5 to 12) hours Distribution Lumasiran distributes primarily to the liver after subcutaneous administration.

C max = maximum plasma concentration; AUC 0-last = area under the plasma concentration-time curve from time of administration (0) to the last measurable time point (last); T max = time to maximum concentration; Vd/F = apparent volume of distribution; CV = coefficient of variation; CL/F = apparent clearance. Estimated Vd/F

4.9L Protein Binding 85% Elimination Apparent Half-Life [Mean (%CV)] 5.2 (47%) hours Estimated CL/F

26.5L/hour Metabolism Primary Pathway Lumasiran is metabolized by endo- and exonucleases to oligonucleotides of shorter lengths. Excretion Primary Pathway Less than 26% of the administered dose of lumasiran is excreted unchanged into the urine within 24 hours with the rest excreted as inactive metabolite. Specific Populations No clinically significant differences in the pharmacokinetics or pharmacodynamics of lumasiran were observed based on age (4 months to <65 years old), sex, race/ethnicity, renal impairment, use of hemodialysis, or mild to moderate hepatic impairment (total bilirubin ≤ ULN and AST > ULN; or total bilirubin ≤ 3× ULN).

The effect of severe hepatic impairment on the pharmacokinetics of lumasiran is unknown. Body Weight In children <20 kg, lumasiran C max was twice as high due to the higher 6 mg/kg dose and faster absorption rate. At the approved recommended dosage, lumasiran AUC was similar across the 6.2 kg to 110 kg body weight range [see Dosage and Administration (2.1) ] .

Drug Interaction Studies Clinical Studies No clinical studies evaluating the drug interaction potential of lumasiran have been co… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Lumasiran reduces levels of glycolate oxidase (GO) enzyme by targeting the hydroxyacid oxidase 1 ( HAO1 ) 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 underlying AGXT gene 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.

12.3Pharmacokinetics The pharmacokinetic (PK) properties of OXLUMO were evaluated following administration of single and multiple dosages in patients with PH1 as summarized in Table 3. Table 3. Pharmacokinetic Parameters of Lumasiran Lumasiran General Information Steady-State Exposure C max [Median (Range)] 462 (38.5 to 1500) ng/mL AUC 0-last [Median (Range)] 6810 (2890 to 10700) ng∙h/mL Dose Proportionality Lumasiran exhibited an approximately dose proportional increase in plasma exposure following single subcutaneous doses ranging from 0.3 to 6 mg/kg.

Lumasiran exhibited time-independent pharmacokinetics with multiple doses of 1 and 3 mg/kg once monthly or 3 mg/kg quarterly. Accumulation No accumulation of lumasiran was observed in plasma after repeated monthly or quarterly dosing. Absorption T max [Median (Range)] 4 (0.5 to 12) hours Distribution Lumasiran distributes primarily to the liver after subcutaneous administration.

C max = maximum plasma concentration; AUC 0-last = area under the plasma concentration-time curve from time of administration (0) to the last measurable time point (last); T max = time to maximum concentration; Vd/F = apparent volume of distribution; CV = coefficient of variation; CL/F = apparent clearance. Estimated Vd/F

4.9L Protein Binding 85% Elimination Apparent Half-Life [Mean (%CV)] 5.2 (47%) hours Estimated CL/F

26.5L/hour Metabolism Primary Pathway Lumasiran is metabolized by endo- and exonucleases to oligonucleotides of shorter lengths. Excretion Primary Pathway Less than 26% of the administered dose of lumasiran is excreted unchanged into the urine within 24 hours with the rest excreted as inactive metabolite. Specific Populations No clinically significant differences in the pharmacokinetics or pharmacodynamics of lumasiran were observed based on age (4 months to <65 years old), sex, race/ethnicity, renal impairment, use of hemodialysis, or mild to moderate hepatic impairment (total bilirubin ≤ ULN and AST > ULN; or total bilirubin ≤ 3× ULN).

The effect of severe hepatic impairment on the pharmacokinetics of lumasiran is unknown. Body Weight In children <20 kg, lumasiran C max was twice as high due to the higher 6 mg/kg dose and faster absorption rate. At the approved recommended dosage, lumasiran AUC was similar across the 6.2 kg to 110 kg body weight range [see Dosage and Administration (2.1) ] .

Drug Interaction Studies Clinical Studies No clinical studies evaluating the drug interaction potential of lumasiran have been conducted. Concomitant use of pyridoxine (vitamin B6) did not influence the pharmacodynamics or pharmacokinetics of lumasiran. In Vitro Studies In vitro studies indicate that lumasiran is not a substrate or an inhibitor of cytochrome P450 (CYP) enzymes.

Lumasiran is not expected to induce CYP enzymes or modulate the activities of drug transporters.

12.2Pharmacodynamics The pharmacodynamic effects of OXLUMO have been evaluated in adult and pediatric patients with PH1 across a range of doses and dosing frequency. Dose-dependent reductions in urinary oxalate levels were observed, resulting in the selection of the recommended body weight-based loading and maintenance dosing regimens. With the recommended dosing regimens, onset of effect was observed within two weeks after the first dose and maximal reductions in urinary oxalate were observed by Month 2 and persisted with continued use of OXLUMO maintenance dosage [see Figures 1 and 2 in Clinical Studies (14.1, 14.2)] .

Cardiac Electrophysiology At the recommended dose, OXLUMO does not lead to clinically relevant QT interval prolongation.

14 CLINICAL STUDIES

14.1ILLUMINATE-A 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 m 2 (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 [see Dosage and Administration (2.1) ] . 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 m 2 , the median plasma oxalate level was 13.1 µmol/L, 33% of patients had eGFR ≥90 mL/min/1.73 m 2 , 49% had eGFR of 60 to <90 mL/min/1.73 m 2 , and 18% had eGFR 30 to <60 mL/min/1.73 m 2 , 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 m 2 ) 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.

Figure 1

14.2ILLUMINATE-B ILLUMINATE-B was a single-arm study in 18 patients <6 years of age with PH1 and an eGFR >45 mL/min/1.73 m 2 for 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 [see Dosage and Administration (2.1) ] . 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 Figure 2

14.3ILLUMINATE-C 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 m 2 in 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 [see Dosage and Administration (2.1) ]. Patients requiring peritoneal dialysis were excluded.

The median age of patients at first dose was 9… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies were conducted in Tg-rasH2 mice and Sprague Dawley rats. Lumasiran was not carcinogenic in transgenic Tg-rasH2 mice following monthly subcutaneous administration of lumasiran for 26 weeks at doses of 150, 500, or 1500 mg/kg. In a 2-year carcinogenicity study, lumasiran was not carcinogenic up to the highest dose tested.

Sprague Dawley rats were administered subcutaneous doses of 20, 55, or 110 mg/kg lumasiran once every 4 weeks (3, 9, or 18 times the normalized maintenance MRHD, based on body surface area). Lumasiran was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, in the in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, or the in vivo micronucleus assay in rats. Administration of lumasiran by weekly subcutaneous doses of 0, 5, 15, and 50 mg/kg in male and female rats prior to and during mating and continuing in females once on Day 6 of presumed gestation resulted in no adverse effects upon the male or female fertility endpoints evaluated.