The effect of evolocumab on the risk of adverse clinical outcomes in patients with cardiovascular diseases: results of a double-blind, placebo-controlled, randomized trial

Prerequisites for the study

Elevated concentrations of low-density lipoprotein (LDL) cholesterol (LC) are among the known and modifiable risk factors for the development of complications of cardiovascular diseases (CVD). Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin 9 (PCSK9) are a new class of drugs that effectively reduce blood LDL cholesterol levels [1]. Evolocumab belongs to this class of drugs and is a completely human monoclonal antibody; the use of this drug leads to a decrease in LDL cholesterol levels by approximately 60% [2-6].

The results of genetic studies indicated an association between the presence of a loss-of-function mutation in the PCSK 9

with lower levels of LDL cholesterol and a reduced risk of myocardial infarction (MI) [7, 8]. Moreover, the results of an exploratory analysis of data obtained during long-term follow-up of participants in phase II and III studies assessing the effectiveness of PCSK9 inhibitors indicated a statistically significant reduction in the risk of developing CVD complications [9, 10]. However, overall, only slightly more than 100 adverse outcomes occurred in these studies.

Repata, 1 piece, 1 ml, 140 mg/ml, solution for subcutaneous administration

Mechanism of Action Evolocumab is a fully human monoclonal immunoglobulin G2 (IgG2) that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). Evolocumab binds selectively and with high affinity to PCSK9 and inhibits the binding of circulating PCSK9 to the low-density lipoprotein receptor (LDL-R) on the surface of liver cells, thereby preventing PCSK9-mediated breakdown of LDL-R. As a result, increased expression of LDL-R in the liver leads to a decrease in serum concentrations of low-density lipoprotein cholesterol (LDL-C). Pharmacodynamic properties In patients with primary hyperlipidemia and mixed dyslipidemia, evolocumab has been shown to reduce concentrations of unbound PCSK9, LDL-C, total cholesterol (TC), apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), and very low-density lipoprotein cholesterol (VLDL-C), triglycerides and lipoprotein(a) (Lp[a]), increases the concentrations of high-density lipoprotein cholesterol\0009 (HDL-C) and apolipoprotein A1 (ApoA1), improving the OC/HDL-C, ApoB ratio /apolipoprotein A1 (ApoA1). A single subcutaneous injection of 140 or 420 mg evolocumab resulted in maximal suppression of circulating unbound PCSK9 at 4 hours, accompanied by a reduction in LDL-C reaching a mid-nadir at days 14 and 21, respectively. Changes in unbound PCSK9 and serum lipoprotein concentrations are reversible after discontinuation of evolocumab. There was no compensatory increase in the production of PCSK9 and LDL-C during treatment, nor was there an increase in the concentrations of unbound PCSK9 or LDL-C after withdrawal of evolocumab (no “rebound syndrome”). With a dosing regimen of 140 mg evolocumab every two weeks or 420 mg evolocumab once a month, the maximum reduction in LDL-C reached from -72% to -57% of baseline values compared with placebo. Dosing regimens are equivalent in terms of mean reduction in LDL-C (average at weeks 10 and 12). A similar decrease in LDL-C was observed both when using evolocumab in monotherapy and as part of combination therapy with other lipid-lowering drugs. The LDL-C lowering effect is stable, and the maximum duration of therapy is currently 112 weeks. External and internal factors, such as demographic characteristics, concomitant therapy, variability in laboratory parameters and disease status do not affect the response to evolocumab therapy (see Dosage Regimen). Immunogenicity As with all therapeutic proteins, there is a potential risk of developing immunogenicity. Immunogenicity was determined using immunochemiluminescent binding to detect antibodies to evolocumab. If antibodies to evolocumab were detected in patients during immunological screening, an additional biological analysis was performed to assess whether these antibodies were neutralizing. In clinical studies, binding antibodies were detected in 0.1% of patients (7 of 4846 patients with primary hypercholesterolemia and mixed dyslipidemia and none of 80 patients with homozygous familial hypercholesterolemia [HoFH]) who received at least 1 dose of evolocumab (4 patients had transient antibodies). For these patients, additional testing for neutralizing antibodies was performed. Neutralizing antibodies were not detected in any of the patients. The detected binding antibodies did not lead to changes in the pharmacokinetic parameters of the drug and did not affect the therapeutic response or safety of the drug. Clinical efficacy and safety The results of clinical studies of evolocumab demonstrate that inhibition of PCSK9 activity by evolocumab reduces serum LDL-C concentrations and improves other indicators of lipid metabolism. These results demonstrate the consistent effectiveness of evolocumab in improving lipid metabolism in patients with primary hyperlipidemia (heterozygous familial and non-familial) and mixed dyslipidemia and HoFH in all populations and with any study design. Dosing regimens of 140 mg evolocumab every two weeks (Q2W) and 420 mg (QM) evolocumab once a month are clinically equivalent in patients with primary hypercholesterolemia and mixed dyslipidemia in reducing LDL-C, total cholesterol, ApoB, non-HDL-C, VLDL cholesterol, triglycerides and Lp(a); increasing the concentration of HDL-C and ApoA1 and improving the ratio of total cholesterol/HDL-C, ApoB/ApoA1. As a result of therapy with evolocumab, a decrease in LDL-C concentrations of approximately 55-75% was achieved, which was maintained throughout the entire period of long-term therapy. Maximum response was typically achieved 12 weeks after administration of 140 mg Q2W and 420 mg QM, respectively. 80-85% of patients receiving evolocumab at any dosage experienced a reduction in LDL-C concentrations of more than 50% by an average of 10 to 12 weeks of use. Evolocumab was superior to ezetimibe in lowering LDL-C concentrations. Evolocumab 140 mg Q2W and 420 mg QM were effective in all placebo and ezetimibe subgroups, with no significant differences between subgroups defined by patient characteristics such as age, race affiliation, gender, region of origin, body mass index (BMI), National Cholesterol Education Program (NCEP) risk score, statin dose and intensity, smoking status, baseline risk of coronary heart disease (CHD), family history of early CHD, Glucose intolerance or intolerance (i.e., type 2 diabetes mellitus, metabolic syndrome, or neither), hypertension, baseline unrelated PCSK9, baseline LDL-C concentration, and baseline triglyceride concentration were not observed. Results from the overall efficacy analysis in the HoFH trials indicated that evolocumab was effective in reducing LDL-C, total cholesterol, ApoB, and non-HDL-C concentrations in HoFH patients. With long-term treatment with evolocumab at doses of 420 mg QM and 420 mg Q2W, a prolonged therapeutic effect was observed, as evidenced by a decrease in LDL-C concentrations of approximately 20% - 30% in patients with HoFH who did not receive apheresis treatment, and in approximately 15% - 25% patients with HoFH who received apheresis. Overall, no differences in the safety or efficacy of evolocumab were observed between groups aged 12 years or older and adult HoFH patients. The proportion of patients experiencing adverse events was generally balanced between groups across all 3 comprehensive safety data periods and between subgroups and treatment regimens. There were no safety concerns regarding adverse events reported for other types of lipid-lowering therapy (i.e., episodes of diabetes mellitus and liver and muscle complications) or events that may theoretically be associated with inhibition of PCSK9/increased expression of LDL receptors (i.e. episodes of hepatitis C development). There were no signs indicating a risk of developing neurocognitive complications with evolocumab. Neurocognitive complications were similar in studies with placebo or active controls. The types and numbers of adverse events were comparable across all studies, whether evolocumab was used as monotherapy or as part of combination therapy (with or without statins with or without ezetimibe) or in patients intolerant to statins. No new safety signals were identified when comparing adverse event data from studies of HoFH patients with adverse event data from studies of primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.

Pharmacokinetics

The pharmacokinetics of evolocumab after subcutaneous administration shows a non-linear pattern. Absorption: Median maximum serum concentrations were achieved within 3 to 4 days with an estimated absolute bioavailability of 72% following a single subcutaneous injection of evolocumab 140 mg or 420 mg in healthy volunteers. The average maximum concentration (Cmax mean (SD)) was 18.6 (7.3) μg/ml after administration of a dose of 140 mg. The final area under the concentration-time curve (AUClast) was 188 (98.6) days µg/ml. Similar Cmax and AUClast values were 59.0 (17.2) μg/ml and 924 (346) μg/ml day, respectively, after administration of a dose of 420 mg. Distribution The mean estimated volume of distribution at steady state was 3.3 (0.5) L after a single dose of 420 mg IV evolocumab, suggesting limited tissue distribution of evolocumab. Metabolism The calculated mean systemic clearance was 12 (2) ml/h after a single 420 mg intravenous dose of evolocumab. Repeated subcutaneous administration of evolocumab over 12 weeks in clinical studies resulted in a dose-proportional increase in exposure for dosing regimens of 140 mg or greater. Approximately two- to three-fold accumulation was observed at minimum serum concentrations (Cmin [SD]) of 7.21 [6.6]) with dosing regimens of 140 mg every 2 weeks or 420 mg once monthly (Cmin [SD] 11.2 [10.8]). Trough serum concentrations reached equilibrium by week 12 of dosing. The estimated effective half-life of evolocumab was 11 to 17 days. There were no time-related changes in evolocumab serum concentrations over 124 weeks. Elimination Because evolocumab is a fully human IgG2 monoclonal antibody, clearance of evolocumab is due to specific binding and complexation with the target ligand, PCSK9, as well as standard IgG clearance pathways in the reticuloendothelial system. Evolocumab is broken down into small peptides and amino acids through these catabolic pathways. An increase in clearance of approximately 20% was observed when combined with statins. This increase is due in part to a statin-induced increase in PCSK9 concentrations and does not adversely affect the lipid pharmacodynamics of evolocumab. Pharmacokinetic analysis in populations did not reveal significant differences in serum concentrations of evolocumab in patients with hypercholesterolemia (familial and non-familial) while taking statins. Selected Patient Groups Based on population pharmacokinetic analysis, no dose adjustment is required based on age, race, or gender. Body weight affects the pharmacokinetics of evolocumab, but does not significantly affect the lipid-lowering effect of evolocumab. Therefore, adjustment of the dosage regimen depending on body weight is not required. Pharmacokinetic analysis in populations based on pooled clinical trial data did not reveal differences in the pharmacokinetics of the drug in patients with mild to moderate renal impairment compared with patients with normal renal function. The drug was administered as a single subcutaneous injection of 140 mg to 8 patients with mild liver dysfunction, 8 patients with moderate impairment, and 8 healthy volunteers. Exposure to evolocumab was reduced by 40% - 50% compared to healthy volunteers. However, baseline PCSK9 concentrations and the extent and timing of PCSK9 neutralization remained similar in all three groups. Thus, a similar effect on lowering LDL-C was observed.

Sick

The study included patients 40–85 years of age with clinical manifestations of CVD caused by atherosclerosis, which was diagnosed by a history of MI, nonhemorrhagic stroke, or clinically manifested peripheral arterial disease, which had additional characteristics indicating a higher risk of developing CVD complications. In addition, to be included in the study, the concentration of LDL cholesterol had to reach 1.8 mmol/L or more, or the concentration of lipoprotein cholesterol of all types except high-density lipoprotein cholesterol (non-HDL-C) 2.6 mmol/L or more, despite the use optimized regimen, which was to include a predominantly intensive statin regimen using at least 20 mg of atorvastatin or an equivalent dose of another statin, with or without ezetimibe. The detailed baseline characteristics of the patients included in the study are presented in the table.

Table. Baseline characteristics of patients included in the study* Note:* - Data are presented as mean ± standard deviation or as median values (interquartile range), unless otherwise specified. ** — formally, there were no statistically significant differences between the groups in terms of baseline characteristics, with the exception of differences in body weight (p=0.01) and frequency of use of aspirin, P2Y12 inhibitor, or their combined use (p=0.03). CVD - cardiovascular disease; MI - myocardial infarction; ACE - angiotensin-converting enzyme; ARB—angiotensin II receptor blocker; CS - cholesterol; LDL - low density lipoproteins; HDL is high density lipoprotein.

Repata, 140 mg/ml, solution for subcutaneous administration, 1 ml, 1 pc.

Pharmacokinetics

Intervention

Patients were assigned in a 1:1 ratio to subcutaneous evolocumab (either 140 mg every 2 weeks or 420 mg once a month, depending on patient preference) or placebo. Randomization was performed using a double-blind method and a centralized computerized system with stratification of patients depending on the results of the last measurement of LDL cholesterol concentration during the preliminary examination (less than 2.2 mmol/L or 2.2 mmol/L or more) and on the region of residence.

Evaluation criteria/Clinical outcomes

The main combined effectiveness indicator: the incidence of such severe CVD complications as:

- death from complications of CVD

- stroke

- hospitalization for unstable angina

— performing myocardial revascularization.

The main additional combined effectiveness indicator of the incidence of such adverse outcomes as:

- death from complications of CVD

- stroke.

The safety of study therapy was assessed by obtaining data on the development of adverse events (AEs) and the results of tests performed in a central laboratory.

Members of the central adverse outcomes validation committee, led by the TIMI study group, considered all possible adverse outcomes included in the efficacy measures, as well as incident diabetes mellitus (DM) in the absence of information on the results of patient allocation to a particular strategy and lipid concentrations in the group. blood.

Statistical analysis methods

The primary outcome analysis was based on the length of time between randomization and the first adverse outcome included in the primary composite outcome measure. In the case of a statistically significant decrease in the main combined indicator in the evolocumab group compared to the placebo group (p<0.05), using a hierarchical approach, we proceeded to test the effect of evolocumab use on the main additional indicator, and then on mortality from CVD complications at a statistical significance level of 0 .05.

All statistical analyzes of effectiveness were performed on the assumption that all patients received the assigned treatment. No imputation was performed for missing data on the development of adverse clinical outcomes. The safety analysis included data from all patients who were randomized and given at least one dose of study drug if post-dose data were available for them.

Sample size calculations were based on the incidence of adverse clinical outcomes included in the primary secondary outcome; Moreover, it was found that 1630 of these outcomes were required to achieve 90% power to detect a 15% difference between the evolocumab group and the placebo group. Hazard ratios and 95% CIs were calculated using the Cox proportional hazards model using stratification factors as covariates, and the p value was calculated by performing a log-rank analysis of time to adverse clinical outcome.

results

From January 2013 to June 2015, a total of 27,564 patients were included in the study: 13,784 and 13,780 patients in the evolocumab group and placebo group, respectively. There were no significant differences between the groups in the main baseline characteristics of the patients (see table). The average age of the patients was 63 years; 24.6% women; 81.1% of patients had a previous MI, 19.4% had a nonhemorrhagic stroke, and 13.2% had clinical manifestations of peripheral arterial disease. At study entry, intensive and moderate-intensive statin therapy (according to the combined recommendations of the American College of Cardiology and the American Heart Association [11]) was used in 69.3 and 30.4% of patients, respectively; in addition, 5.2% of patients were also taking ezetimibe. During the study, only 9.8% of patients changed their basic lipid-lowering therapy. Rates of use of therapies aimed at secondary prevention of CVD complications were generally high: at study entry, antiplatelet agents, β-blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers, aldosterone antagonists, or a combination of these were used 92,3,75. 6 and 78.2% of patients, respectively.

A total of 27,525, or 99.9%, of patients received at least 1 dose of study drug. 12.5% of patients (5.7% per year) persistently stopped using the study drug, and 0.7% of patients (0.3% per year) refused to continue participation in the study and less than 0.1% of patients (0. 03% per year) contact was lost. Moreover, this frequency was similar in both groups. The median follow-up duration was 26 months (interquartile range, 22 to 30 months), corresponding to a total follow-up of 59,865 person-years. Assessment of clinical outcomes included in the primary outcome was completed for 99.5% of possible person-years of follow-up.

The median LDL cholesterol concentration at enrollment in the study overall was 2.4 mmol/L (IQR 2.1 to 2.8 mmol/L). At 48 weeks after randomization, the percentage reduction in LDL cholesterol concentration, calculated using the least squares method, in the evolocumab group compared with the placebo group reached 59% (95% CI 58 to 60%; p < 0.001) with a mean absolute reduction the level of LDL cholesterol in the blood by 1.45 mmol/l (with 95% CI from 1.43 to 1.47) to the concentration of LDL cholesterol, the median of which was 0.78 mmol/l (IQR from 0.49 to 1.2 ). The degree of reduction in LDL cholesterol concentrations was maintained throughout the study. After 48 weeks, LDL cholesterol levels in the evolocumab group had decreased to 1.8 mmol/L or less, 1 mmol/L or less, and 0.65 mmol/L or less in 87%, 67%, and 42% of patients, respectively, while As in the placebo group, a decrease in LDL cholesterol concentrations to this level was observed in 18, 0.5 and less than 0.1% of patients, respectively (p < 0.001 for all comparisons between the evolocumab group and the placebo group). Similarly, evolocumab compared with placebo resulted in corresponding reductions in other atherogenic lipids: at 48 weeks, non-HDL-C and apolipoprotein B levels were reduced by 52% and 49% in the evolocumab group compared with placebo, respectively (p < 0.001 for both). indicators).

The use of evolocumab compared with placebo led to a statistically significant reduction in the main composite indicator of mortality from complications of CVD, the incidence of myocardial infarction, stroke, hospitalization for unstable angina, or myocardial revascularization. Adverse outcomes included in the primary outcome occurred in 9.8% and 11.3% of patients in the evolocumab group and placebo group, respectively (hazard ratio 0.85, 95% CI 0.79 to 0.92; p<0.001). In addition, the evolocumab group had similar reductions in the main additional composite endpoint of CVD mortality, myocardial infarction or stroke, compared with the placebo group. Adverse clinical outcomes included in this indicator occurred in 5.9% and 7.4% of patients in the evolocumab group and placebo group, respectively (hazard ratio 0.80, 95% CI 0.73 to 0.88; p<0.001) . There was a trend towards an increase in the severity of the decrease in the main indicator over time from 12% (with 95% CI from 3 to 20%) during the first year of observation to 19% (with 95% CI from 11 to 27%) subsequently. In addition, there was a similar increase over time in the magnitude of the reduction in the risk of adverse outcomes included in the main secondary outcome, from 16% (95% CI 4 to 26%) in the first year to 25% (95% CI 15 to 26%). 34%) subsequently.

The results of the analysis of individual components of the assessed indicators indicated that there was no effect of evolocumab use on mortality from CVD complications, and therefore, for other outcomes, when assessing the p value, the exploratory nature of the analysis of individual components of combined indicators should be taken into account. The risk of MI, stroke, and revascularization was reduced by 21% to 27% with no effect on hospitalization for unstable angina, CVD mortality, or hospitalization for worsening HF, or overall mortality.

The benefits of evolocumab over placebo on the primary and major secondary endpoints were generally similar across subgroups of patients based on certain characteristics, including age, sex, and type of vascular disease due to atherosclerosis. Benefits were also comparable among patients with baseline LDL-C levels in different quartiles, including patients with baseline LDL-C levels in the top quartile (3.3 mmol/L; IQR 3 to 3.7 mmol/L) and patients , whose initial LDL cholesterol level corresponded to the lower quartile (1.9 mmol/l; IQR from 1.8 to 2 mmol/l). The benefits of evolocumab were also consistent across different intensities of statin therapy, regardless of ezetimibe use, and across both evolocumab dosing regimens (140 mg every 2 weeks or 420 mg once a month).

There were no statistically significant differences between the groups in the overall incidence of AEs, including severe AEs or AEs that could be considered attributable to study drug use and led to discontinuation of study drug use. Similarly, the incidence of complications due to muscle toxicity, as well as the development of cataracts, neurocognitive AEs and hemorrhagic stroke did not differ significantly between groups. Reactions at the injection site of the study drug were observed rarely, but more often in the evolocumab group than in the placebo group (in 2.1 and 1.6% of patients, respectively). The majority of these reactions (approximately 90% in each group) were considered mild, and only 0.1% of patients in each group discontinued the study drug due to injection site reactions. The incidence of confirmed cases of diabetes did not differ significantly between groups (risk ratio 1.05, 95% CI 0.94 to 1.17). The incidence of allergic reactions also did not differ statistically significantly between the groups (such reactions in the evolocumab group and the placebo group were observed in 3.1 and 2.9% of patients, respectively). In the evolocumab group, antibodies to evolocumab were detected in 0.3% of patients and neutralizing antibodies were not detected in any case.

Repatha

Mechanism of action

Evolocumab selectively binds to proprotein convertase subtilisin/kexin type 9 (PCSK9) and prevents circulating PCSK9 from binding to low-density lipoprotein receptors (LDL-R) on the surface of hepatocytes, thereby preventing PCSK9-mediated degradation of LDL-R. An increase in hepatic LDL-R levels leads to a corresponding decrease in the concentration of low-density lipoprotein cholesterol (LDL-C) in the blood serum.

Pharmacodynamic effects

In patients with primary hypercholesterolemia and mixed dyslipidemia, Repatha reduces the concentrations of unbound PCSK9, LDL-C, total cholesterol (TC), apolipoprotein B (ApoB), cholesterol not associated with high-density lipoproteins (non-HDL-C), lipoprotein cholesterol very low density lipoprotein cholesterol (VLDL-C), triglycerides (TG) and lipoprotein(a) (Lp[a]), and also increases the concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (AnoAl), improving the total cholesterol/cholesterol ratio HDL, ApoB/ApoA1.

A single subcutaneous administration of Repat at a dose of 140 mg or 420 mg after 4 hours provides maximum suppression of circulating unbound PCSK9 with a subsequent decrease in LDL-C, the concentration of which reaches a minimum on average at 14 and 21 days, respectively. Changes in the concentrations of unbound PCSK9 and serum lipoproteins are reversible after discontinuation of Repat therapy. There was no increase in unbound PCSK9 or LDL-C concentrations above baseline concentrations during the washout period of evolocumab. This suggests that during treatment, compensatory mechanisms to increase the production of PCSK9 and LDL-C are not activated.

Repat therapy regimens with subcutaneous administration of 140 mg once every 2 weeks and 420 mg once a month were equivalent in terms of the average reduction in LDL-C (average value after 10-12 weeks), the concentration of which decreased by 57-72% of the initial value according to compared to placebo. Treatment with Repat resulted in a similar decrease in LDL-C when used as monotherapy or in combination with other lipid-lowering agents.

Clinical efficacy and safety

Clinical effectiveness in primary hypercholesterolemia and mixed dyslipidemia

As a result of evolocumab therapy, a reduction in LDL-C concentrations of approximately 55-75% was achieved in week 1 and was maintained throughout the entire period of long-term therapy. The maximum response is usually achieved after 1-2 weeks using a regimen of 140 mg once every 2 weeks and 420 mg once a month.

Repatha was effective in all subgroups compared with placebo and ezetimibe, with no significant differences between individual subgroups based on age, race, sex, geographic region, body mass index, National Cholesterol Education Program risk category, current smoking status, baseline risk factors for coronary artery disease (CAD), family history of early-onset CAD, glucose tolerance status (i.e., type 2 diabetes mellitus, metabolic syndrome, or absence of both), hypertension, hypertension, dose and intensity of statin therapy, baseline concentrations of unbound PCSK9, LDL-C and triglycerides.

80-85% of all patients with primary hyperlipidemia who received evolocumab at any dosage experienced a decrease in LDL-C concentrations of ≥ 50% after an average of 10-12 weeks of therapy. Up to 99% of patients who received Repatha at any dose achieved LDL-C concentrations <2.6 mmol/L, and up to 95% achieved LDL-C concentrations <1.8 mmol/L after an average of 10-12 weeks of therapy.

Use in combination with a statin or with a statin and other lipid-lowering drugs

The LAPLACE-2 study was a 12-week study that included 1896 patients with primary hypercholesterolemia or mixed dyslipidemia.

Repata provided a significant reduction in LDL-C concentrations to average values after 10-12 weeks relative to baseline compared with placebo in the rosuvastatin and simvastatin groups and compared with placebo and ezetimibe in the atorvastatin group (p < 0.001). Repatha provided a significant decrease in TC, ApoB, non-HDL cholesterol, TC/HDL cholesterol, ApoB/ApoA1, VLDL cholesterol, TG and Lp(a), as well as an increase in the concentration of HDL cholesterol (average value after 10-12 weeks relative to baseline) compared with placebo in the rosuvastatin and simvastatin groups (p < 0.05) and significantly reduced the concentrations of TC, ApoB, non-HDL cholesterol, TC/HDL cholesterol, ApoB/ApoA1 and Lp(a) compared with placebo and ezetimibe in the atorvastatin group (p < 0.001).

The RUTHERFORD-2 study was a 12-week study that included 329 patients with heterozygous familial hypercholesterolemia receiving lipid-lowering therapy.

The drug Repata significantly reduced the concentration of LDL-C to average values after 10-12 weeks relative to the initial level compared with placebo (p < 0.001). Repatha significantly reduced TC, ApoB, non-HDL cholesterol, TC/HDL cholesterol, ApoB/ApoA1, VLDL cholesterol, TG and Lp(a), and also increased the concentrations of HDL cholesterol and AnoAl to average values by 10-12 week relative to baseline compared with placebo (p < 0.05).

Patients intolerant to statins

The GAUSS-2 study was a 12-week study that included 307 patients with complete statin intolerance or intolerance to an effective statin dose. Repatha significantly reduced LDL-C compared with ezetimibe (p < 0.001). Repatha significantly reduced TC, ApoB, non-HDL cholesterol, TC/HDL cholesterol, ApoB/ApoA1 and Lp(a) to average values at 10-12 weeks relative to baseline compared with ezetimibe (p < 0.001).

Treatment without statins

The MENDEL-2 study was a 12-week study of Repatha in 614 patients with primary hypercholesterolemia and mixed dyslipidemia. Repatha significantly reduced LDL-C to mean values after 10-12 weeks from baseline compared to placebo and ezetimibe (p < 0.001). Repatha significantly reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1 and Lp(a) to mean values after 10-12 weeks relative to baseline compared with placebo and ezetimibe (p < 0.001).

Efficacy of long-term therapy for primary hypercholesterolemia and mixed dyslipidemia

The DESCARTES study was a 52-week study that enrolled 901 hyperlipidemic patients treated with diet alone, atorvastatin, or a combination of atorvastatin and ezetimibe. The use of Repata at a dose of 420 mg once a month provided a significant decrease in LDL-C concentration after 52 weeks relative to the baseline compared to placebo (p < 0.001). The effects of treatment persisted for 1 year, as evidenced by a decrease in LDL-C concentrations from 12 to 52 weeks. Lipid-lowering therapy optimized for LDL-C concentrations and cardiovascular risk resulted in a sustained reduction in LDL-C concentrations over 52 weeks from baseline compared to placebo.

Repatha significantly reduced TC, ApoB, non-HDL-C, TC/HDL-C, ApoB/ApoA1, VLDL-C, TG and Lp(a), and also increased HDL-C and AnoAl concentrations at week 52 compared with placebo (p < 0.001). OSLER and OSLER-2 are two studies evaluating the long-term safety and effectiveness of Repata in patients who completed treatment in the main study. A total of 1324 patients were included in the OSLER study. Repatha at a dose of 420 mg once a month significantly reduced LDL-C at 12 weeks and 52 weeks from baseline compared to control (nominal p < 0.001). Treatment effects were maintained for 272 weeks, as evidenced by a decrease in LDL-C concentrations from week 12 in the main study to week 260 in the open-label extension study. A total of 3681 patients were included in the OSLER-2 study. The use of the drug Repata provided a significant decrease in LDL-C concentrations after 12 weeks and after 48 weeks relative to the initial level compared to the control (nominal p < 0.001). Treatment effects were maintained, as evidenced by a decrease in LDL-C concentrations from week 12 to week 104 in an open-label extension study.

The use of the drug Repata provided a significant decrease in the concentrations of TC, ApoB, non-HDL cholesterol, TC/HDL cholesterol, ApoB/ApoA1, VLDL cholesterol, TG and Lp(a), and also increased HDL cholesterol and AnoAl relative to the initial level by 52 weeks in the OSLER study and 48 weeks in the OSLER-2 study compared with control (nominal p < 0.001). LDL-C and other lipid parameters returned to baseline values within 12 weeks after discontinuation of Repat at the start of the OSLER or OSLER-2 study, without signs of rebound.

TAUSSIG is a study to evaluate the long-term safety and efficacy of Repatha used as an adjunct to other lipid-lowering therapy in patients with severe familial hypercholesterolemia (FH), including homozygous familial hypercholesterolemia.

TAUSSIG is a 5-year extension study to evaluate the long-term safety and efficacy of Repatha as an adjunct to other lipid-lowering therapy in patients with severe familial hypercholesterolemia (FH), including homozygous familial hypercholesterolemia. A total of 194 patients with severe familial hypercholesterolemia (non-HoFH) and 106 patients with homozygous familial hypercholesterolemia were included in the TAUSSIG study. All patients in the study initially received Repatha at a dose of 420 mg once a month, with the exception of those who were receiving lipid apheresis at the time of enrollment; these patients began receiving Repatha at a dose of 420 mg once every 2 weeks. Dosing frequency in patients not receiving apheresis could be increased to 420 mg every 2 weeks depending on the response of LDL-C and PCSK9 concentrations. Long-term use of the drug Repata provided a lasting therapeutic effect, as evidenced by a decrease in LDL-C concentrations in patients with severe familial hypercholesterolemia (non-HoFH). Changes in other parameters of lipid metabolism (TC, ApoB, non-HDL cholesterol, TC/HDL cholesterol and ApoB/ApoA1) also indicated a persistent effect of long-term use of Repat in patients with severe familial hypercholesterolemia (non-HoFH).

The long-term safety of maintaining LDL-C at very low levels (ie, <0.65 mmol/L [<25 mg/dL]) has not yet been established. Available data show that there are no clinically significant differences in the safety profile of patients with LDL-C concentrations <0.65 mmol/L and patients with higher LDL-C concentrations (see section "Side effects").

Treatment of homozygous familial hypercholesterolemia

The TESLA study was a 12-week study of 49 patients with homozygous familial hypercholesterolemia aged 12 to 65 years.

The use of Repata at a dose of 420 mg once a month as an addition to other types of lipid-lowering therapy (for example, statins, bile acid sequestrants) significantly reduced LDL-C and ApoB after 12 weeks compared with placebo (p < 0.001). Changes in other parameters of lipid metabolism (TC, non-HDL cholesterol, TC/HDL cholesterol and ApoB/ApoA1) also indicated a therapeutic effect of using the drug Repata in patients with homozygous familial hypercholesterolemia.

Efficacy of long-term therapy for homozygous familial hypercholesterolemia

In the TAUSSIG study, long-term use of Repatha provided a durable therapeutic effect, as evidenced by a reduction in LDL-C concentrations of approximately 20-30% in patients with homozygous familial hypercholesterolemia who did not undergo apheresis, and by approximately 10-30% in patients with homozygous familial hypercholesterolemia. hypercholesterolemia due to apheresis. Changes in other parameters of lipid metabolism (TC, ApoB, non-HDL cholesterol, TC/HDL cholesterol and ApoB/ApoA1) also indicated a persistent effect of long-term use of Repat in patients with homozygous familial hypercholesterolemia. The decrease in LDL-C concentration and changes in other parameters of lipid metabolism in 14 adolescents (aged ≥ 12 to < 18 years) with homozygous familial hypercholesterolemia are comparable to those in the general population of patients with this pathology.

Efficacy in atherosclerotic diseases

The effects of Repatha (420 mg once monthly) in patients with atherosclerotic disease, as measured by intravascular ultrasound (IVUS), were assessed in a 78-week study of 968 patients with coronary artery disease on stable optimal statin therapy. . Repatha reduced both relative atheroma volume (PAV; 1.01% [95% CI 0.64-1.38], p < 0.0001) and total atheroma volume (TAV; 4.89 mm3 [95% CI 2.53-7.25], p < 0.0001) compared with placebo. Regression of atherosclerotic lesions according to PAV data was observed in 64.3% (95% CI 59.6-68.7) and 47.3% (95% CI 42.6-52.0) of patients receiving Repata or placebo, respectively. When measured by TAV, regression of atherosclerotic lesions was observed in 61.5% (95% CI 56.7-66.0) and 48.9% (95% CI 44.2-53.7) of patients receiving Repatha or placebo, respectively. The study did not examine the correlation between regression of atherosclerotic disease and the incidence of cardiovascular events.

Reducing the risk of cardiovascular events in adults with diagnosed cardiovascular disease due to atherosclerosis

The Repatha Drug Outcomes Study (FOURIER) was a randomized, double-blind, event-driven trial that enrolled 27,564 patients aged 40 to 86 years (mean age 62.5 years) with established atherosclerotic cardiovascular disease. ; 81% had a previous myocardial infarction (MI), 19% a stroke, and 13% a history of peripheral arterial disease. More than 99% of patients were receiving moderate- to high-intensity statin therapy and at least one other cardiovascular drug, such as antiplatelet agents, beta-blockers, ACE inhibitors, or angiotensin receptor blockers; median (Ql, Q3) baseline LDL-C concentration was 2.4 mmol/L (2.1, 2.8). Absolute cardiovascular risk was balanced between treatment groups: in addition to the index event, all patients had at least 1 major or 2 minor cardiovascular risk factors; 80% had hypertension, 36% diabetes mellitus and 28% were daily smokers. Patients were randomized 1:1 to receive either Repatha (140 mg once every 2 weeks or 420 mg once a month) or matching placebo; The average duration of patient follow-up was 26 months.

There was a significant decrease in LDL-C concentrations throughout the study, with the median LDL-C range reaching 0.8–0.9 mmol/L at each assessment; 25% of patients achieved LDL-C concentrations less than 0.5 mmol/L. Despite achieving very low LDL-C levels, no new safety concerns were observed (see section "Side effects"); The incidence of new cases of diabetes mellitus and cognitive impairment was comparable in patients with LDL-C <0.65 mmol/L and with higher LDL-C concentrations.