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Pharmacodynamics: Following a single subcutaneous administration of 284 mg of inclisiran, LDL-C reduction was apparent within 14 days post-dose. Mean reductions of 49%-51% for LDL-C were observed 30 to 60 days post-dose. At Day 180, LDL-C levels were still reduced by approximately 53%.
In the Phase III studies, following four doses of inclisiran at Day 1, Day 90 (~3 months), Day 270 (~6 months) and Day 450 (~12 months), LDL-C, total cholesterol, apolipoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), and lipoprotein(a) (Lp(a)) were reduced.
Cardiac Electrophysiology: In a randomized, double-blind, placebo-controlled, active-comparator, 3-way crossover trial, 48 healthy subjects were administered an 852 mg subcutaneous dose of inclisiran (3 times the maximum recommended dose), moxifloxacin, and placebo. No increase in QTc or any other ECG parameter was observed with the supratherapeutic dose of inclisiran.
Clinical Studies: The safety and efficacy of Inclisiran (Sybrava) was evaluated in three 18-month, Phase III, randomized, double-blind, placebo-controlled trials in patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or heterozygous familial hypercholesterolemia (HeFH).
Patients were taking a maximally tolerated dose of statins with or without other lipid-modifying therapy (such as ezetimibe), and required additional LDL-C reduction. Approximately 17% of patients were statin-intolerant. Patients were administered subcutaneous injections of 284 mg of inclisiran or placebo on Day 1, Day 90 (~3 months), Day 270 (~9 months) and Day 450 (~15 months). Patients were followed until Day 540 (~18 months).
Phase III Pooled Analysis: In the Phase III pooled analysis, inclisiran administered subcutaneously lowered LDL-C between 50% and 55% as early as Day 90 (Figure 1), which was maintained during long-term therapy. Maximal LDL-C reduction was achieved at Day 150 following a second administration. Small but statistically significant increased LDL-C reductions up to 65% were associated with lower baseline LDL-C levels (approximately <2 mmol/L [77 mg/dL]), higher baseline PCSK9 levels, and higher statin doses and statin intensity.
Reduction in LDL-C was observed across all subgroups, including age, race, gender, region, body mass index, National Cholesterol Education Program risk, current smoking status, baseline coronary heart disease (CHD) risk factors, family history of premature CHD, glucose tolerance status (i.e. diabetes mellitus type 2, metabolic syndrome, or neither), hypertension, and baseline triglycerides.
Inclisiran also reduced non-HDL-C, Apo B, total cholesterol, and Lp(a) in patients with primary hypercholesterolemia and mixed dyslipidemia. There were no clinically significant changes in high-density lipoprotein cholesterol (HDL-C) and triglycerides. (See Figure 1.)
Click on icon to see table/diagram/imageTwo studies were conducted in patients with ASCVD and ASCVD Risk Equivalents (ORION-10 and ORION-11).
The co-primary endpoints in each study were the percentage change in LDL-C from baseline to Day 510 relative to placebo, and the time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 to estimate the integrated effect on LDL-C over time.
Key secondary endpoints were the absolute change in LDL-C from baseline to Day 510, the time-adjusted absolute change in LDL-C from baseline after Day 90 and up to Day 540, and the percentage change from baseline to Day 510 in PCSK9, total cholesterol, Apo B, and non-HDL-C. Additional secondary endpoints included the individual responsiveness to inclisiran, and the proportion of patients attaining global lipid targets for their level of ASCVD risk.
ORION-10 was a multicenter, double-blind, randomized, placebo-controlled 18-month trial conducted in 1,561 patients with ASCVD. Patients were taking a maximally tolerated dose of statins with or without other lipid modifying therapy, such as ezetimibe, and required additional LDL-C reduction. Patients were administered subcutaneous injections of 284 mg of inclisiran or placebo on Day 1, Day 90 (~3 months), Day 270 (~9 months) and Day 450 (~15 months).
The mean age at baseline was 66 years (range: 35 to 90 years), 60% were ≥65 years old, 31% were women, 86% were White, 13% were Black, 1% were Asian, and 14% identified as Hispanic or Latino ethnicity. The mean baseline LDL-C was 2.7 mmol/L (105 mg/dL). Sixty-nine percent (69%) were taking high-intensity statins, 19% were taking medium-intensity statins, 1% were taking low-intensity statins, and 11% were not on a statin. The most commonly administered statins were atorvastatin and rosuvastatin.
Inclisiran significantly reduced the mean percentage change in LDL-C from baseline to Day 510 by 52% compared to placebo (95% CI: -56%, -49%; p<0.0001) (Table 1 and Figure 2).
Inclisiran also significantly reduced the time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 by 54% compared to placebo (95% CI: -56%, -51%; p<0.0001). For additional results, see Table 1. (See Table 1 and Figure 2.)
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Click on icon to see table/diagram/imageAt Day 510, the LDL-C target of <1.8 mmol/L (70 mg/dL) was achieved by 84% of inclisiran-treated patients with ASCVD compared to 18% of placebo-treated patients.
ORION-11 was an international, multicenter, double-blind, randomized, placebo-controlled 18-month trial which evaluated 1,617 patients with ASCVD or ASCVD risk equivalents (ASCVD risk equivalent was defined as those patients with type 2 diabetes mellitus, familial hypercholesterolemia, or 10-year risk of 20% or greater of having a cardiovascular event assessed by Framingham Risk Score or equivalent). More than 75% of patients were receiving a high-intensity statin background treatment, 87% of patients had ASCVD, and 13% were ASCVD risk equivalent. Patients were taking a maximally tolerated dose of statins with or without other lipid modifying therapy, such as ezetimibe, and required additional LDL-C reduction. Patients were administered subcutaneous injections of 284 mg of inclisiran or placebo on Day 1, Day 90 (~3 months), Day 270 (~9 months) and Day 450 (~15 months).
The mean age at baseline was 65 years (range: 20 to 88 years), 55% were ≥65 years old, 28% were women, 98% were White, 1% were Black, 1% were Asian, and 1% were Hispanic or Latino ethnicity. The mean baseline LDL-C was 2.7 mmol/L (105 mg/dL). Seventy-eight percent (78%) were taking high-intensity statins, 16% were taking medium-intensity statins, 0.4% were taking low-intensity statins, and 5% were not on a statin. The most commonly administered statins were atorvastatin and rosuvastatin.
Inclisiran significantly reduced the mean percentage change in LDL-C from baseline to Day 510 by 50% compared to placebo (95% CI: -53%, -47%; p<0.0001) (Table 2 and Figure 3).
Inclisiran also significantly reduced the time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 by 49% compared to placebo (95% CI: -52%, -47%; p<0.0001). For additional results, see Table 2. (See Table 2 and Figure 3.)
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Click on icon to see table/diagram/imageAt Day 510, the LDL-C target of <1.8 mmol/L (70 mg/dL) was achieved by 82% of Inclisiran (Sybrava)-treated patients with ASCVD compared to 16% of placebo-treated patients. In patients with an ASCVD risk equivalent, the LDL-C target of <2.6 mmol/L (100 mg/dL) was achieved by 78% of Inclisiran (Sybrava)-treated patients compared to 31% of placebo-treated patients.
In a pooled analysis of the two ASCVD studies (ORION-10 and -11), consistent and statistically significant (p<0.05) percentage change in LDL-C from baseline to Day 510 and time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 were observed. This was observed across all subgroups irrespective of baseline demographics, baseline disease characteristics (including gender, age, body mass index, race and baseline statin use), comorbidities, and geographic regions (Figure 4). (See Figure 4.)
Click on icon to see table/diagram/imageHeterozygous Familial Hypercholesterolemia (HeFH): ORION-9 was an international, multicenter, double-blind, randomized, placebo-controlled 18-month trial in 482 patients with heterozygous familial hypercholesterolemia (HeFH). All patients had HeFH, were taking maximally tolerated doses of statins with or without other lipid modifying therapy, such as ezetimibe, and required additional LDL-C reduction. The diagnosis of HeFH was made either by genotyping or clinical criteria ("definite FH" using either the Simon Broome or WHO/Dutch Lipid Network criteria).
The co-primary endpoints were the percentage change in LDL-C from baseline to Day 510 (~17 months) relative to placebo, and the time-adjusted percentage change in LDL-C from baseline after Day 90 (~3 months) and up to Day 540 (~18 months) to estimate the integrated effect on LDL-C over time. Key secondary endpoints were the absolute change in LDL-C from baseline to Day 510, the time-adjusted absolute change in LDL-C from baseline after Day 90 and up to Day 540, and the percentage change from baseline to Day 510 in PCSK9, total cholesterol, Apo B, and non-HDL-C. Additional secondary endpoints included the individual responsiveness to inclisiran, and the proportion of patients attaining global lipid targets for their level of ASCVD risk.
The mean age at baseline was 55 years (range: 21 to 80 years), 22% were ≥65 years old, 53% were women, 94% were White, 3% were Black, 3% were Asian, and 3% were Hispanic or Latino ethnicity. The mean baseline LDL-C was 4.0 mmol/L (153 mg/dL). Seventy-four percent (74%) were taking high-intensity statins, 15% were taking medium-intensity statins, and 10% were not on a statin. Fifty-two percent (52%) of patients were treated with ezetimibe. The most commonly administered statins were atorvastatin and rosuvastatin.
Inclisiran significantly reduced the mean percentage change in LDL-C from baseline to Day 510 by 48% compared to placebo (95% CI: -54%, -42%; p<0.0001) (Table 3 and Figure 5).
Inclisiran also significantly reduced the time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 by 44% compared to placebo (95% CI: -48%, -40%; p<0.0001). For additional results, see Table 3. (See Table 3 and Figure 5.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageAt Day 510, the LDL-C target of <1.8 mmol/L (70 mg/dL) was achieved by 53% of inclisiran-treated patients with ASCVD compared to 1% of placebo-treated patients. In patients with an ASCVD risk equivalent, the LDL-C target of <2.6 mmol/L (100 mg/dL) was achieved by 67% of inclisiran-treated patients compared to 9% of placebo-treated patients.
Consistent and statistically significant (p<0.05) percentage change in LDL-C from baseline to Day 510 and time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 were observed across all subgroups, irrespective of baseline demographics, baseline disease characteristics (including gender, age, body mass index, race and baseline statin use), comorbidities, and geographic regions.
Pharmacokinetics: Absorption: Following a single subcutaneous administration, systemic exposure to inclisiran increased in a linear and dose-proportional manner over a range from 24 mg to 756 mg. At the recommended dosing regimen of 284 mg of inclisiran, plasma concentrations reached peak in approximately 4 hours post-dose with a mean Cmax 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 7980 ng*h/mL. Minimal to no accumulation of inclisiran in plasma was observed after repeat dosing.
Distribution: Inclisiran is 87% protein bound in vitro at the relevant clinical plasma concentrations. Following a single subcutaneous 284 mg dose of inclisiran to healthy adults, the apparent volume of distribution is approximately 500 L. Inclisiran has been shown to have high uptake into, and selectivity for the liver, the target organ for cholesterol-lowering.
Biotransformation/metabolism: Inclisiran is primarily metabolized by nucleases to shorter inactive nucleotides of varying length. Inclisiran is not a substrate for CYP450 or transporters.
Elimination: The terminal elimination half-life of inclisiran is approximately 9 hours, and no accumulation occurs with multiple dosing. Sixteen percent (16%) of inclisiran is cleared through the kidney.
Linearity/non-linearity: In the Phase I clinical study, an approximately dose-proportional increase in inclisiran exposure was observed after administration of subcutaneous doses of inclisiran ranging from 24 mg to 756 mg. No accumulation and no time-dependent changes were observed after multiple subcutaneous doses of inclisiran.
In the Phase I clinical study, a dissociation was observed between inclisiran pharmacokinetic parameters and LDL-C pharmacodynamic effects. Selective delivery of inclisiran to hepatocytes, where it is incorporated into the RNA-induced silencing complex (RISC), results in a long duration of action, beyond that anticipated based on the plasma elimination half-life of 9 hours. The maximal effects of reducing LDL-C were observed with a 284 mg dose, with higher doses not producing greater effects.
In Vitro evaluation of drug interaction potential: No formal clinical drug interaction studies have been performed. Inclisiran is not a substrate, inhibitor or inducer of CYP450 enzymes or transporters and is not expected to cause drug-drug interactions or to be affected by inhibitors or inducers of CYP450 enzymes or transporters. In a population pharmacokinetic analysis, concomitant use of inclisiran had no meaningful impact on atorvastatin or rosuvastatin concentrations.
Special populations: A population pharmacodynamic analysis was conducted on data from 4,328 patients. Age, body weight and gender did not significantly influence inclisiran pharmacodynamics. No dose adjustments are recommended for these demographics.
Renal impairment: Pharmacokinetic analysis of data from a dedicated renal impairment study reported an increase in inclisiran Cmax of approximately 2.3-, 2.0- and 3.3-fold, and an increase in inclisiran AUC of approximately 1.6-, 1.8- and 2.3-fold, in patients with mild, moderate and severe renal impairment relative to patients with normal renal function. Despite the higher transient plasma exposures over 24-48 hours, the reduction in LDL-C was similar across all groups of renal function. Based on population pharmacodynamic modeling, no dose adjustment is necessary in patients with end-stage renal disease. Based on PK, PD and safety assessments, no dose adjustment is recommended in patients with renal impairment (mild, moderate, or severe). The effect of hemodialysis on inclisiran pharmacokinetics has not been studied. Considering that inclisiran is eliminated renally, hemodialysis should not be performed for at least 72 hours after inclisiran dosing.
Hepatic impairment: Pharmacokinetic analysis of data from a dedicated hepatic impairment study reported an increase in inclisiran Cmax of approximately 1.1- and 2.1-fold, and an increase in inclisiran AUC of approximately 1.3- and 2.0-fold, in patients with mild and moderate hepatic impairment relative to patients with normal hepatic function. Despite the higher transient inclisiran plasma exposures, the reduction in LDL-C was 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 markedly lower and the reduction in LDL-C was less than that observed in patients with normal hepatic function. No dose adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A and B). Inclisiran has not been studied in patients with severe hepatic impairment (Child-Pugh class C).
Toxicology: Non-Clinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and carcinogenic potential.
Repeat dose toxicity: In repeat dose toxicology studies conducted in rats and monkeys, the no observed adverse effect levels (NOAEL) were identified as the highest doses of inclisiran administered subcutaneously (250 mg/kg and 300 mg/kg, respectively) and were associated with safety margins of 54.9-fold in rats and 112-fold in monkeys, based on AUC, compared to exposures observed at the MRHD.
Carcinogenicity and mutagenicity: The carcinogenic potential of inclisiran was evaluated in a 6-month study in TgRasH2 mice and a 2-year study in Sprague-Dawley rats. Male and female TgRasH2 mice were administered inclisiran by subcutaneous injection once every 28 days at 300, 600 and 1500 mg/kg. Male and female Sprague-Dawley rats were administered inclisiran by subcutaneous injection once every 28 days at 40, 95 and 250 mg/kg. Inclisiran was not carcinogenic up to the highest doses tested, corresponding to safety margins of 256-fold in mice and 60.7-fold in rats, based on AUC, compared to exposures observed at the MRHD.
No mutagenic or clastogenic potential of inclisiran was found in a battery of tests, including a bacterial mutagenicity assay, in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and an in vivo rat bone marrow micronucleus assay.
Reproductive toxicity: In a male fertility study, inclisiran was administered to male Sprague-Dawley rats by subcutaneous injection at 10, 50 and 250 mg/kg once every two weeks prior to and through mating. Inclisiran was not associated with paternal toxicity or effects on spermatogenesis, fertility or early embryonic development. The highest dose tested was associated with a safety margin of 44.1-fold based on AUC, compared to exposures observed at the MRHD.
In a female fertility study, inclisiran was administered to female Sprague-Dawley rats by subcutaneous injection at 10, 50 and 250 mg/kg once every four days prior to and through mating, and then once daily during the gestation period up to Day 7 post coitum. The high dose administered prior to gestation, 250 mg/kg, was reduced to 150 mg/kg for daily administration during gestation. Inclisiran did not produce maternal toxicity or have adverse effects on female fertility or early embryonic development. The highest dose tested was associated with a safety margin of 20.4-fold based on AUC, compared to exposures observed at the MRHD.
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