LEQVIO inclisiran 284 mg/1.5mL Injection, Solution, 1 syringe — NDC 0078-1000-60 (Billing 00078-1000-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Inclisiran is a double-stranded small interfering ribonucleic acid (siRNA), conjugated on the sense strand with triantennary N-Acetylgalactosamine (GalNAc) to facilitate uptake by hepatocytes. In hepatocytes, inclisiran utilizes the RNA interference mechanism and directs catalytic breakdown of mRNA for PCSK9. This increases LDL-C receptor recycling and expression on the hepatocyte cell surface, which increases LDL-C uptake and lowers LDL-C levels in the circulation.

12.2Pharmacodynamics Following a single subcutaneous administration of 284 mg of inclisiran, LDL-C reduction was apparent within 14 days post dose. Mean reductions of 38% to 51% for LDL-C were observed 30 to 180 days post dose. At Day 180, LDL-C levels were still reduced by approximately 53%.

Following a dose at Day 1 and Day 90 of 284 mg of inclisiran, mean serum PCSK9 levels were reduced by approximately 75% and 69% at Day 120, and Day 180, respectively. In the clinical trials, following four doses of LEQVIO at Day 1, Day 90 (3 months), Day 270 (~6 months) and Day 450 (~12 months), LDL-C, total cholesterol, ApoB, and non-HDL-C were reduced [see Clinical Studies (14)] . Cardiac Electrophysiology At a dose 3 times the maximum recommended dose, inclisiran does not prolong the QT interval to any clinically relevant extent.

12.3Pharmacokinetics Absorption Following a single subcutaneous administration, systemic exposure to inclisiran increased in a linear and dose proportional manner over a range from 25 mg to 800 mg of inclisiran sodium. At the recommended dosing regimen of 284 mg of LEQVIO, plasma concentrations reached peak in approximately 4 hours post dose with a mean C max of 509 ng/mL. Concentrations reached undetectable levels after 24 to 48 hours post dosing.

The mean area under the plasma concentration-time curve from dosing extrapolated to infinity was 7,980 ng*h/mL. Pharmacokinetic findings following multiple subcutaneous administrations of LEQVIO were similar to single-dose administration. Distribution Inclisiran is 87% protein bound in vitro at the relevant clinical plasma concentrations.

Following a single subcutaneous 284 mg dose of LEQVIO to healthy adults, the apparent volume of distribution is approximately 500 L. Inclisiran has been shown to have high uptake into, and selectively for the liver, the target organ for cholesterol lowering. Elimination The terminal elimination half-life of LEQVIO is approximately 9 hours, and no accumulation occurs with multiple dosing.

Metabolism Inclisiran is primarily metabolized by nucleases to shorter nucleotides of varying length. Inclisiran is not a substrate for CYP450 or transporters. Excretion Approximately 16% of LEQVIO is cleared through the kidney.

Specific Populations Male and Female Patients and Racial or Ethnic Groups A population pharmacodynamic analysis was conducted on data from 4,328 patients. Age, body weight, gender, race, and creatinine clearance were found not to significantly influence inclisiran pharmacokinetics. Pediatric Patients The pharmacokinetics of LEQVIO were evaluated in pediatric patients aged 12 years and older with HeFH (Trial 4) or HoFH (Trial 5) [see Use in Specific Populations (8.4), Clinical Studies (14)] .

Inclisiran plasma concentrations in pediatric patients at the clinically recommended dose were similar to adults. Patients with Renal Impairment Pharmacokinetic analysis of data from a dedicated renal impairment study reported increases in inclisiran C max and AUC of approximately 2.3 to 3.3-fold and 1.6 to 2.3-fold, respectively, in patients with mild, moderate or severe renal impairment, relative to patients with normal renal function. Despite the higher plasma exposures, reductions in LDL-C were similar across all groups based on renal function.

Patients with Hepatic Impairment Pharmacokinetic analysis of data from a dedicated hepatic impairment study reported increases in inclisiran C max and AUC of approximately 1.1- t… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Inclisiran is a double-stranded small interfering ribonucleic acid (siRNA), conjugated on the sense strand with triantennary N-Acetylgalactosamine (GalNAc) to facilitate uptake by hepatocytes. In hepatocytes, inclisiran utilizes the RNA interference mechanism and directs catalytic breakdown of mRNA for PCSK9. This increases LDL-C receptor recycling and expression on the hepatocyte cell surface, which increases LDL-C uptake and lowers LDL-C levels in the circulation.

12.3Pharmacokinetics Absorption Following a single subcutaneous administration, systemic exposure to inclisiran increased in a linear and dose proportional manner over a range from 25 mg to 800 mg of inclisiran sodium. At the recommended dosing regimen of 284 mg of LEQVIO, plasma concentrations reached peak in approximately 4 hours post dose with a mean C max of 509 ng/mL. Concentrations reached undetectable levels after 24 to 48 hours post dosing.

The mean area under the plasma concentration-time curve from dosing extrapolated to infinity was 7,980 ng*h/mL. Pharmacokinetic findings following multiple subcutaneous administrations of LEQVIO were similar to single-dose administration. Distribution Inclisiran is 87% protein bound in vitro at the relevant clinical plasma concentrations.

Following a single subcutaneous 284 mg dose of LEQVIO to healthy adults, the apparent volume of distribution is approximately 500 L. Inclisiran has been shown to have high uptake into, and selectively for the liver, the target organ for cholesterol lowering. Elimination The terminal elimination half-life of LEQVIO is approximately 9 hours, and no accumulation occurs with multiple dosing.

Metabolism Inclisiran is primarily metabolized by nucleases to shorter nucleotides of varying length. Inclisiran is not a substrate for CYP450 or transporters. Excretion Approximately 16% of LEQVIO is cleared through the kidney.

Specific Populations Male and Female Patients and Racial or Ethnic Groups A population pharmacodynamic analysis was conducted on data from 4,328 patients. Age, body weight, gender, race, and creatinine clearance were found not to significantly influence inclisiran pharmacokinetics. Pediatric Patients The pharmacokinetics of LEQVIO were evaluated in pediatric patients aged 12 years and older with HeFH (Trial 4) or HoFH (Trial 5) [see Use in Specific Populations (8.4), Clinical Studies (14)] .

Inclisiran plasma concentrations in pediatric patients at the clinically recommended dose were similar to adults. Patients with Renal Impairment Pharmacokinetic analysis of data from a dedicated renal impairment study reported increases in inclisiran C max and AUC of approximately 2.3 to 3.3-fold and 1.6 to 2.3-fold, respectively, in patients with mild, moderate or severe renal impairment, relative to patients with normal renal function. Despite the higher plasma exposures, reductions in LDL-C were similar across all groups based on renal function.

Patients with Hepatic Impairment Pharmacokinetic analysis of data from a dedicated hepatic impairment study reported increases in inclisiran C max and AUC of approximately 1.1- to 2.1-fold and 1.3- to 2.0-fold, respectively, in patients with mild and moderate hepatic impairment, relative to patients with normal hepatic function. Despite the higher plasma inclisiran exposures, reductions in LDL-C were similar between the groups of patients administered inclisiran with normal hepatic function and mild hepatic impairment.

In patients with moderate hepatic impairment, baseline PCSK9 levels were lower and reductions in LDL-C were less than those observed in patients with normal hepatic function. LEQVIO has not been studied in patients with severe hepatic impairment. Drug Interaction Studies No formal clinical drug interaction studies have been performed.

The components of LEQVIO are not substrates, inhibitors or inducers of cytochrome P450 enzymes or transporters. In a population pharmacokinetic analysis, concomitant use of inclisiran did not have a clinically significant impact on atorvastatin or rosuvastatin concentrations. LEQVIO is not expected to cause drug-drug interactions or to be affected by inhibitors or inducers of cytochrome P450 enzymes or transporters.

12.2Pharmacodynamics Following a single subcutaneous administration of 284 mg of inclisiran, LDL-C reduction was apparent within 14 days post dose. Mean reductions of 38% to 51% for LDL-C were observed 30 to 180 days post dose. At Day 180, LDL-C levels were still reduced by approximately 53%.

Following a dose at Day 1 and Day 90 of 284 mg of inclisiran, mean serum PCSK9 levels were reduced by approximately 75% and 69% at Day 120, and Day 180, respectively. In the clinical trials, following four doses of LEQVIO at Day 1, Day 90 (3 months), Day 270 (~6 months) and Day 450 (~12 months), LDL-C, total cholesterol, ApoB, and non-HDL-C were reduced [see Clinical Studies (14)] . Cardiac Electrophysiology At a dose 3 times the maximum recommended dose, inclisiran does not prolong the QT interval to any clinically relevant extent.

14 CLINICAL STUDIES Adults with Primary Hypercholesterolemia or HeFH The efficacy of LEQVIO was investigated in three randomized, double-blind, placebo-controlled trials that enrolled 3,660 adults with HeFH, clinical ASCVD, or increased risk for ASCVD, who were taking maximally tolerated statin therapy and who required additional LDL-C lowering. Demographics and baseline disease characteristics were balanced between the treatment arms in all trials. Adults with Primary Hypercholesterolemia Trial 1 (ORION-10, NCT03399370) was a multicenter, double-blind, randomized, placebo-controlled 18-month trial in which 1,561 adults with ASCVD were randomized 1:1 to receive subcutaneous injections of either LEQVIO 284 mg (n = 781) or placebo (n = 780) on Day 1, Day 90, Day 270, and at Day 450.

Patients were taking a maximally tolerated dose of statin with or without other lipid modifying therapy and required additional LDL-C reduction. Patients were stratified by current use of statins or other lipid-modifying therapies. Patients taking PCSK9 inhibitors were excluded from the trial.

The mean age at baseline was 66 years (range: 35 to 90 years), 60% were ≥65 years old, 31% were female, 86% were White, 13% were Black or African American, 1% were Asian, and 14% identified as Hispanic or Latino ethnicity. Forty-five percent (45%) of patients had diabetes at baseline. The mean baseline LDL-C was 105 mg/dL.

At the time of randomization, 89% of patients were receiving statin therapy and 69% were receiving high-intensity statin therapy. The primary efficacy outcome measure in Trial 1 was the percent change from baseline to Day 510 in LDL-C. The difference between the LEQVIO and placebo groups in mean percentage change in LDL-C from baseline to Day 510 was -52% (95% CI: -56%, -49%; p < 0.0001).

For additional results, see Table 2 and Figure 1. Table 2: Changes in Lipid Parameters in Adults with Hypercholesterolemia and ASCVD on Maximally Tolerated Statin Therapy (Mean % Change from Baseline to Day 510 in Trial 1) Treatment Group LDL-C Total Cholesterol Non-HDL-C ApoB ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol a 11.5% of subjects on LEQVIO and 14.6% of subjects on placebo had missing LDL-C data at primary endpoint (Day 510).

Missing data were imputed using a modified control-based multiple imputation to account for treatment adherence. Percent change from baseline in LDL-C was analyzed using analysis of covariance (ANCOVA) with fixed effect for treatment group and baseline LDL-C as a covariate. Other endpoints were analyzed using a mixed-effect model for repeated measure (MMRM) with fixed effects for treatment group, visit, interaction between treatment and visit, and baseline value.

Missing data were imputed using a control-based pattern-mixture model approach. Day 510 (mean percentage change from baseline) a Placebo (n = 780) 1 0 0 -2 LEQVIO (n = 781) -51 -34 -47 -45 Difference from placebo (LS Mean) (95% CI) -52 (-56, -49) -33 (-35, -31) -47 (-50, -44) -43 (-46, -41) Figure 1: Mean Percent Change from Baseline in LDL-C Over 18 Months in Adults with Hypercholesterolemia and ASCVD on Maximally Tolerated Statin Therapy (Trial 1) Trial 2 (ORION-11, NCT03400800) was a multicenter, double-blind, randomized, placebo-controlled 18-month trial in which 1,617 adults with ASCVD or increased risk for ASCVD were randomized 1:1 to receive subcutaneous injections of either LEQVIO 284 mg (n = 810) or placebo (n = 807) on Day 1, Day 90, Day 270, and at Day 450.

Patients were taking a maximally tolerated dose of statin with or without other lipid modifying therapy and required additional LDL-C reduction. Patients were stratified by country and by current use of statins or other lipid-modifying therapies. Patients taking PCSK9 inhibitors were excluded from the trial.

The mean age at baseline was 65 years (range: 20 to 88 years), 55% were ≥65 years old, 28% were female,… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study, Sprague-Dawley rats were administered subcutaneous doses of 40, 95, or 250 mg/kg inclisiran once every 28 days (1, 3, or 8 times the MRHD, based on BSA comparison/dose). Inclisiran was not carcinogenic up to the highest dose tested. In a 26-week study in RasH2Tg mice, subcutaneous doses of 300, 600, or 1,500 mg/kg once every 28 days were administered.

Inclisiran was not carcinogenic up to the highest dose tested. Inclisiran was not mutagenic or clastogenic in a standard battery of genotoxicity tests, including a bacterial mutagenicity assay, an in vitro chromosome aberration assay using human peripheral lymphocytes, and an in vivo bone marrow micronucleus assay in rats. Fertility and early embryonic-development studies were conducted in male and female rats.

In male rats, inclisiran was administered subcutaneously at dose levels of 10, 50, and 250 mg/kg every 2 weeks for 4 weeks before cohabitation through mating, and until termination between Days 64 and 67. In female rats, inclisiran was administered subcutaneously at dose levels of 10, 50, and 250 mg/kg once every 4 days beginning 14 days prior to cohabitation and through mating, followed by 10, 50, or 150 mg/kg once daily during the gestation period up to Gestation Day 7. There were no adverse effects on fertility up to the highest dose examined, corresponding to 8 times the MRHD, based on BSA comparison/dose.