Repatha(evolocumab)—为新一代治疗降胆固醇新药
近日，美国FDA批准Repatha（evolocumab）注射剂用于某些使用目前治疗选择不能使其低密度脂蛋白胆固醇得到控制的患者。
Repatha是新型 PCSK9 抑制剂类药物中第二款获得批准的药物，该药物被批准结合饮食及最大耐受量的他汀药物用于需要额外降低LDL胆固醇的杂合子家族性高胆固醇血症（HeFH）、纯合子家族性高胆固醇血症（HoFH）、或临床上有动脉粥样硬化性心血管病，如心脏病发作或中风的患者。
家族性高胆固醇血症（包括 HeFH 和 HoFH）是一种遗传性疾病，它可以导致高水平的LDL胆固醇。血液中高水平LDL胆固醇与心血管或心脏疾病相关。心脏疾病是美国男女患者死亡的第一杀手。据美国疾病控制与预防中心提供的信息，美国每年大约有61万人死于心脏疾病，这相当于每4例死亡中就有1例是因心脏疾病死亡。
药品评价和研究中心新药室主任说：“Repatha提供在这个新类型另外治疗选择为患者有家族性超胆固醇血症或已知心血管病用他汀类不足以减低其LDL胆固醇，” “心血管病是严重威胁美国人健康，和FDA承诺促进发展和批准有效和安全药物解决这个重要的公共健康问题。”
批准日期：2015年8月27日；公司：Amgen Inc.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use REPATHA ® safely and effectively. See full prescribing information for REPATHA .
REPATHA (evolocumab) injection, for subcutaneous use
Initial U.S. Approval: 2015
RECENT MAJOR CHANGES
Dosage and Administration (2.2) 7/2016
INDICATIONS AND USAGE
REPATHA is a PCSK9 (proprotein convertase subtilisin kexin type9) inhibitor antibody indicated as an adjunct to diet and:
Maximally tolerated statin therapy for treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C). (1.1)
Other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C. (1.2)
Limitations of Use
The effect of REPATHA on cardiovascular morbidity and mortality has not been determined. (1.3)
DOSAGE AND ADMINISTRATION
Administer subcutaneously. (2.1)
Primary hyperlipidemia with established clinical atherosclerotic CVD or HeFH: 140 mg every 2 weeks or 420 mg once monthly in abdomen, thigh, or upper arm. (2.1)
HoFH: 420 mg once monthly. (2.1)
The 420 mg dose of REPATHA can be administered:
○ over 9 minutes by using the single-use on-body infusor with prefilled cartridge, or
○ by giving 3 injections consecutively within 30 minutes using the single-use prefilled autoinjector or single-use prefilled syringe. (2.2)
See Dosage and Administration for important administration instructions. (2.2)
DOSAGE FORMS AND STRENGTHS
Injection: 140 mg/mL solution in a single-use prefilled syringe (3)
Injection: 140 mg/mL solution in a single-use prefilled SureClick® autoinjector (3)
Injection: 420 mg/3.5 mL solution in a single-use PushtronexTM system (on-body infusor with prefilled cartridge) (3)
CONTRAINDICATIONS
Patients with a history of a serious hypersensitivity reaction to REPATHA. (4)
WARNINGS AND PRECAUTIONS
Allergic Reactions: Rash and urticaria have occurred. If signs or symptoms of serious allergic reactions occur, discontinue treatment with REPATHA, treat according to the standard of care, and monitor until signs and symptoms resolve. (5.1)
ADVERSE REACTIONS
Common adverse reactions in clinical trials (> 5% of patients treated with REPATHA and occurring more frequently than placebo): nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 7/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1  INDICATIONS AND USAGE
1.1 Primary Hyperlipidemia 
REPATHA® is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C).
1.2  Homozygous Familial Hypercholesterolemia
REPATHA is indicated as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.
1.3  Limitations of Use
The effect of REPATHA on cardiovascular morbidity and mortality has not been determined.
2 DOSAGE AND ADMINISTRATION
2.1  Recommended Dosage
The recommended subcutaneous dosage of REPATHA in patients with HeFH or patients with primary hyperlipidemia with established clinical atherosclerotic CVD is either 140 mg every 2 weeks OR 420 mg once monthly. When switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen.
The recommended subcutaneous dosage of REPATHA in patients with HoFH is 420 mg once monthly. In patients with HoFH, measure LDL-C levels 4 to 8 weeks after starting REPATHA, since response to therapy will depend on the degree of LDL-receptor function. 
If an every 2 week or once monthly dose is missed, instruct the patient to:
Administer REPATHA as soon as possible if there are more than 7 days until the next scheduled dose, or, 
Omit the missed dose and administer the next dose according to the original schedule.
2.2 Important Administration Instructions
• The 420 mg dose of REPATHA can be administered:
 ○ over 9 minutes by using the single-use on-body infusor with prefilled cartridge, or
 ○ by giving 3 injections consecutively within 30 minutes using the single-use prefilled autoinjector or single-use prefilled syringe.
• Provide proper training to patients and/or caregivers on how to prepare and administer REPATHA prior to use, according to the Instructions for Use, including aseptic technique. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use REPATHA.
• Keep REPATHA in the refrigerator. Prior to use, allow REPATHA to warm to room temperature for at least 30 minutes for the single-use prefilled autoinjector or single-use prefilled syringe and for at least 45 minutes for the single-use on-body infusor with prefilled cartridge. Do not warm in any other way. Alternatively, for patients and caregivers, REPATHA can be kept at room temperature at 68°F to 77°F (20°C to 25°C) in the original carton. However, under these conditions, REPATHA must be used within 30 days [see How Supplied/Storage and Handling (16)].
• Visually inspect REPATHA for particles and discoloration prior to administration. REPATHA is a clear to opalescent, colorless to pale yellow solution. Do not use if the solution is cloudy or discolored or contains particles.
• Administer REPATHA subcutaneously into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated using a single-use prefilled syringe, single-use prefilled autoinjector, or single-use on-body infusor with prefilled cartridge.
• Do not co-administer REPATHA with other injectable drugs at the same administration site.
• Rotate the site of each subcutaneous administration.
3 DOSAGE FORMS AND STRENGTHS
REPATHA is a sterile, clear to opalescent, colorless to pale yellow solution available as follows:
Injection: 140 mg/mL solution in a single-use prefilled syringe
Injection: 140 mg/mL solution in a single-use prefilled SureClick® autoinjector
Injection: 420 mg/3.5 mL solution in a single-use PushtronexTM system (on-body infusor with prefilled cartridge)
4 CONTRAINDICATIONS
REPATHA is contraindicated in patients with a history of a serious hypersensitivity reaction to REPATHA [see Warnings and Precautions (5.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Allergic Reactions
Hypersensitivity reactions (e.g., rash, urticaria) have been reported in patients treated with REPATHA, including some that led to discontinuation of therapy. If signs or symptoms of serious allergic reactions occur, discontinue treatment with REPATHA, treat according to the standard of care, and monitor until signs and symptoms resolve.
6 ADVERSE REACTIONS
The following adverse reactions are also discussed in other sections of the label:
Allergic Reactions [see Warnings and Precautions (5.1)]
6.1  Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Adverse Reactions in Patients with Primary Hyperlipidemia and in Patients with Heterozygous Familial Hypercholesterolemia
REPATHA is not indicated for use in patients without familial hypercholesterolemia or atherosclerotic CVD [see Indications and Usage (1.1)].
The data described below reflect exposure to REPATHA in 8 placebo-controlled trials that included 2651 patients treated with REPATHA, including 557 exposed for 6 months and 515 exposed for 1 year (median treatment duration of 12 weeks). The mean age of the population was 57 years, 49% of the population were women, 85% White, 6% Black, 8% Asians, and 2% other races.
Adverse Reactions in a 52-Week Controlled Trial
In a 52-week, double-blind, randomized, placebo-controlled trial (Study 2), 599 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies (14.1)]. The mean age was 56 years (range: 22 to 75 years), 23% were older than 65 years, 52% women, 80% White, 8% Black, 6% Asian, and 6% Hispanic. Adverse reactions reported in at least 3% of REPATHA-treated patients, and more frequently than in placebo-treated patients in Study 2, are shown in Table 1. Adverse reactions led to discontinuation of treatment in 2.2% of REPATHA-treated patients and 1% of placebo-treated patients. The most common adverse reaction that led to REPATHA treatment discontinuation and occurred at a rate greater than placebo was myalgia (0.3% versus 0% for REPATHA and placebo, respectively).
Table 1. Adverse Reactions Occurring in Greater than or Equal to 3% of REPATHA-treated Patients and More Frequently than with Placebo in Study 2

Placebo (N = 302) %	REPATHA (N = 599) %
Nasopharyngitis	9.6	10.5
Upper respiratory tract infection	6.3	9.3
Influenza	6.3	7.5
Back pain	5.6	6.2
Injection site reactions†	5.0	5.7
Cough	3.6	4.5
Urinary tract infection	3.6	4.5
Sinusitis	3.0	4.2
Headache	3.6	4.0
Myalgia	3.0	4.0
Dizziness	2.6	3.7
Musculoskeletal pain	3.0	3.3
Hypertension	2.3	3.2
Diarrhea	2.6	3.0
Gastroenteritis	2.0	3.0

includes erythema, pain, bruising
Adverse Reactions in Seven Pooled 12-Week Controlled Trials
In seven pooled 12-week, double-blind, randomized, placebo-controlled trials, 993 patients received 140 mg of REPATHA subcutaneously every 2 weeks and 1059 patients received 420 mg of REPATHA subcutaneously monthly. The mean age was 57 years (range: 18 to 80 years), 29% were older than 65 years, 49% women, 85% White, 5% Black, 9% Asian, and 5% Hispanic. Adverse reactions reported in at least 1% of REPATHA-treated patients, and more frequently than in placebo-treated patients, are shown in Table 2.
Table 2. Adverse Reactions Occurring in Greater than 1% of REPATHA-treated Patients and More Frequently than with Placebo in Pooled 12-Week Studies

Placebo (N = 1224) %	REPATHA† (N = 2052) %
Nasopharyngitis	3.9	4.0
Back pain	2.2	2.3
Upper respiratory tract infection	2.0	2.1
Arthralgia	1.6	1.8
Nausea	1.2	1.8
Fatigue	1.0	1.6
Muscle spasms	1.2	1.3
Urinary tract infection	1.2	1.3
Cough	0.7	1.2
Influenza	1.1	1.2
Contusion	0.5	1.0

140 mg every 2 weeks and 420 mg once monthly combined
Adverse Reactions in Eight Pooled Controlled Trials (Seven 12-Week Trials and One 52-Week Trial)
Adverse Reactions in Eight Pooled Controlled Trials (Seven 12-Week Trials and One 52-Week Trial)
The adverse reactions described below are from a pool of the 52-week trial (Study 2) and seven 12-week trials. The mean and median exposure durations of REPATHA in this pool of eight trials were 20 weeks and 12 weeks, respectively.
Local Injection Site Reactions
Injection site reactions occurred in 3.2% and 3.0% of REPATHA-treated and placebo-treated patients, respectively. The most common injection site reactions were erythema, pain, and bruising. The proportions of patients who discontinued treatment due to local injection site reactions in REPATHA-treated patients and placebo-treated patients were 0.1% and 0%, respectively.
Allergic Reactions
Allergic reactions occurred in 5.1% and 4.7% of REPATHA-treated and placebo-treated patients, respectively. The most common allergic reactions were rash (1.0% versus 0.5% for REPATHA and placebo, respectively), eczema (0.4% versus 0.2%), erythema (0.4% versus 0.2%), and urticaria (0.4% versus 0.1%).
Neurocognitive Events
In placebo-controlled trials, neurocognitive events were reported in less than or equal to 0.2% in REPATHA-treated and placebo-treated patients.
Low LDL-C Levels
In a pool of placebo- and active-controlled trials, as well as open-label extension studies that followed them, a total of 1988 patients treated with REPATHA had at least one LDL-C value < 25 mg/dL. Changes to background lipid-altering therapy were not made in response to low LDL-C values, and REPATHA dosing was not modified or interrupted on this basis. Although adverse consequences of very low LDL-C were not identified in these trials, the long-term effects of very low levels of LDL-C induced by REPATHA are unknown.
Musculoskeletal Events
Musculoskeletal adverse reactions were reported in 14.3% of REPATHA-treated patients and 12.8% of placebo-treated patients. The most common adverse reactions that occurred at a rate greater than placebo were back pain (3.2% versus 2.9% for REPATHA and placebo, respectively), arthralgia (2.3% versus 2.2%), and myalgia (2.0% versus 1.8%).
Adverse Reactions in Patients with Homozygous Familial Hypercholesterolemia
In a 12-week, double-blind, randomized, placebo-controlled trial of 49 patients with HoFH (Study 4), 33 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies (14.3)]. The mean age was 31 years (range: 13 to 57 years), 49% were women, 90% White, 4% Asian, and 6% other. The adverse reactions that occurred in at least two (6.1%) REPATHA-treated patients, and more frequently than in placebo-treated patients, included:
Upper respiratory tract infection (9.1% versus 6.3%)
Influenza (9.1% versus 0%)
Gastroenteritis (6.1% versus 0%)
Nasopharyngitis (6.1% versus 0%)
6.2 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of REPATHA has been evaluated using an electrochemiluminescent bridging screening immunoassay for the detection of binding anti-drug antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies. 
In a pool of placebo- and active-controlled clinical trials, 0.1% of patients treated with at least one dose of REPATHA tested positive for binding antibody development. Patients whose sera tested positive for binding antibodies were further evaluated for neutralizing antibodies; none of the patients tested positive for neutralizing antibodies.
There was no evidence that the presence of anti-drug binding antibodies impacted the pharmacokinetic profile, clinical response, or safety of REPATHA, but the long-term consequences of continuing REPATHA treatment in the presence of anti-drug binding antibodies are unknown.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to REPATHA with the incidence of antibodies to other products may be misleading.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no data available on use of REPATHA in pregnant women to inform a drug-associated risk. In animal reproduction studies, there were no effects on pregnancy or neonatal/infant development when monkeys were subcutaneously administered evolocumab from organogenesis through parturition at dose exposures up to 12 times the exposure at the maximum recommended human dose of 420 mg every month. In a similar study with another drug in the PCSK9 inhibitor antibody class, humoral immune suppression was observed in infant monkeys exposed to that drug in utero at all doses. The exposures where immune suppression occurred in infant monkeys were greater than those expected clinically. No assessment for immune suppression was conducted with evolocumab in infant monkeys. Measurable evolocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that evolocumab, like other IgG antibodies, crosses the placental barrier. FDA’s experience with monoclonal antibodies in humans indicates that they are unlikely to cross the placenta in the first trimester; however, they are likely to cross the placenta in increasing amounts in the second and third trimester. Consider the benefits and risks of REPATHA and possible risks to the fetus before prescribing REPATHA to pregnant women.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
In cynomolgus monkeys, no effects on embryo-fetal or postnatal development (up to 6 months of age) were observed when evolocumab was dosed during organogenesis to parturition at 50 mg/kg once every 2 weeks by the subcutaneous route at exposures 30- and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. No test of humoral immunity in infant monkeys was conducted with evolocumab.
8.2  Lactation
Risk Summary
There is no information regarding the presence of evolocumab in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for REPATHA and any potential adverse effects on the breastfed infant from REPATHA or from the underlying maternal condition. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts.
8.4  Pediatric Use
The safety and effectiveness of REPATHA in combination with diet and other LDL-C-lowering therapies in adolescents with HoFH who require additional lowering of LDL-C were established based on data from a 12-week, placebo-controlled trial that included 10 adolescents (ages 13 to 17 years old) with HoFH [see Clinical Studies (14.3)]. In this trial, 7 adolescents received REPATHA 420 mg subcutaneously once monthly and 3 adolescents received placebo. The effect of REPATHA on LDL-C was generally similar to that observed among adult patients with HoFH. Including experience from open-label, uncontrolled studies, a total of 14 adolescents with HoFH have been treated with REPATHA, with a median exposure duration of 9 months. The safety profile of REPATHA in these adolescents was similar to that described for adult patients with HoFH.
The safety and effectiveness of REPATHA have not been established in pediatric patients with HoFH who are younger than 13 years old.
The safety and effectiveness of REPATHA have not been established in pediatric patients with primary hyperlipidemia or HeFH.
8.5  Geriatric Use
In controlled studies, 1420 patients treated with REPATHA were ≥ 65 years old and 171 were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
8.6 Renal Impairment
No dose adjustment is needed in patients with mild to moderate renal impairment. No data are available in patients with severe renal impairment [see Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
No dose adjustment is needed in patients with mild to moderate hepatic impairment (Child-Pugh A or B). No data are available in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].
11 DESCRIPTION
Evolocumab is a human monoclonal immunoglobulin G2 (IgG2) directed against human proprotein convertase subtilisin kexin 9 (PCSK9). Evolocumab has an approximate molecular weight (MW) of 144 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.
REPATHA is a sterile, preservative-free, clear to opalescent, colorless to pale yellow solution for subcutaneous administration. Each 1 mL single-use prefilled syringe and single-use prefilled SureClick® autoinjector contains 140 mg evolocumab, acetate (1.2 mg), polysorbate 80 (0.1 mg), proline (25 mg) in Water for Injection, USP. Sodium hydroxide may be used to adjust to a pH of 5.0. Each single-use PushtronexTM system (on-body infusor with prefilled cartridge) delivers a 3.5 mL solution containing 420 mg evolocumab, acetate (4.2 mg), polysorbate 80 (0.35 mg), proline (89 mg) in Water for Injection, USP. Sodium hydroxide may be used to adjust to a pH of 5.0.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Evolocumab is a human monoclonal IgG2 directed against human proprotein convertase subtilisin kexin 9 (PCSK9). Evolocumab binds to PCSK9 and inhibits circulating PCSK9 from binding to the low density lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLR, evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.
12.2 Pharmacodynamics
Following single subcutaneous administration of 140 mg or 420 mg of evolocumab, maximum suppression of circulating unbound PCSK9 occurred by 4 hours. Unbound PCSK9 concentrations returned toward baseline when evolocumab concentrations decreased below the limit of quantitation.
12.3  Pharmacokinetics
Evolocumab exhibits non-linear kinetics as a result of binding to PCSK9. Administration of the 140 mg dose in healthy volunteers resulted in a Cmax mean (standard deviation [SD]) of 18.6 (7.3) μg/mL and AUClast mean (SD) of 188 (98.6) day•μg/mL. Administration of the 420 mg dose in healthy volunteers resulted in a Cmax mean (SD) of 59.0 (17.2) μg/mL and AUClast mean (SD) of 924 (346) day•μg/mL. Following a single 420 mg intravenous dose, the mean (SD) systemic clearance was estimated to be 12 (2) mL/hr. An approximate 2- to 3-fold accumulation was observed in trough serum concentrations (Cmin [SD] 7.21 [6.6]) following 140 mg doses administered subcutaneously every 2 weeks or following 420 mg doses administered subcutaneously monthly (Cmin [SD] 11.2 [10.8]), and serum trough concentrations approached steady state by 12 weeks of dosing.
Absorption
Following a single subcutaneous dose of 140 mg or 420 mg evolocumab administered to healthy adults, median peak serum concentrations were attained in 3 to 4 days, and estimated absolute bioavailability was 72%.
Distribution
Following a single 420 mg intravenous dose, the mean (SD) steady-state volume of distribution was estimated to be 3.3 (0.5) L.
Metabolism and Elimination
Two elimination phases were observed for REPATHA. At low concentrations, the elimination is predominately through saturable binding to target (PCSK9), while at higher concentrations the elimination of REPATHA is largely through a non-saturable proteolytic pathway. REPATHA was estimated to have an effective half-life of 11 to 17 days.
Specific Populations
The pharmacokinetics of evolocumab were not affected by age, gender, race, or creatinine clearance, across all approved populations [see Use in Specific Populations (8.5)].
The exposure of evolocumab decreased with increasing body weight. These differences are not clinically meaningful.
Renal Impairment
Since monoclonal antibodies are not known to be eliminated via renal pathways, renal function is not expected to impact the pharmacokinetics of evolocumab. Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) have not been studied.
Hepatic Impairment
Following a single 140 mg subcutaneous dose of evolocumab in patients with mild or moderate hepatic impairment, a 20-30% lower mean Cmax and 40-50% lower mean AUC were observed as compared to healthy patients; however, no dose adjustment is necessary in these patients.
Pregnancy
The effect of pregnancy on evolocumab pharmacokinetics has not been studied [see Use in Specific Populations (8.1)].
Drug Interaction Studies
An approximately 20% decrease in the Cmax and AUC of evolocumab was observed in patients co-administered with a high-intensity statin regimen. This difference is not clinically meaningful and does not impact dosing recommendations.
13 NONCLINICAL TOXICOLOGY
13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of evolocumab was evaluated in a lifetime study conducted in the hamster at dose levels of 10, 30, and 100 mg/kg administered every 2 weeks. There were no evolocumab-related tumors at the highest dose at systemic exposures up to 38- and 15-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. The mutagenic potential of evolocumab has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.
There were no adverse effects on fertility (including estrous cycling, sperm analysis, mating performance, and embryonic development) at the highest dose in a fertility and early embryonic developmental toxicology study in hamsters when evolocumab was subcutaneously administered at 10, 30, and 100 mg/kg every 2 weeks. The highest dose tested corresponds to systemic exposures up to 30- and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. In addition, there were no adverse evolocumab-related effects on surrogate markers of fertility (reproductive organ histopathology, menstrual cycling, or sperm parameters) in a 6-month chronic toxicology study in sexually mature monkeys subcutaneously administered evolocumab at 3, 30, and 300 mg/kg once weekly. The highest dose tested corresponds to 744- and 300-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.
13.2  Animal Toxicology and/or Pharmacology
During a 3-month toxicology study of 10 and 100 mg/kg once every 2 weeks evolocumab in combination with 5 mg/kg once daily rosuvastatin in adult monkeys, there were no effects of evolocumab on the humoral immune response to keyhole limpet hemocyanin (KLH) after 1 to 2 months exposure. The highest dose tested corresponds to exposures 54- and 21-fold higher than the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. Similarly, there were no effects of evolocumab on the humoral immune response to KLH (after 3 to 4 months exposure) in a 6-month study in cynomolgus monkeys at dose levels up to 300 mg/kg once weekly evolocumab corresponding to exposures 744- and 300-fold greater than the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.
14 CLINICAL STUDIES
14.1  Primary Hyperlipidemia in Patients with Clinical Atherosclerotic Cardiovascular Disease
Study 1 was a multicenter, double-blind, randomized controlled trial in which patients were initially randomized to an open-label specific statin regimen for a 4-week lipid stabilization period followed by random assignment to subcutaneous injections of REPATHA 140 mg every 2 weeks, REPATHA 420 mg once monthly, or placebo for 12 weeks. The trial included 296 patients with atherosclerotic CVD who received REPATHA or placebo as add-on therapy to daily doses of atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg. Among these patients, the mean age at baseline was 63 years (range: 32 to 80 years), 45% were ≥ 65 years old, 33% women, 98% White, 2% were Black, < 1% Asian and 5% Hispanic or Latino. After 4 weeks of statin therapy, the mean baseline LDL-C was 108 mg/dL.
In these patients with atherosclerotic CVD who were on maximum-dose statin therapy, the difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was -71% (95% CI: -81%, -61%; p < 0.0001) and -63% (95% CI: -76%, -50%; p ˂ 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. For additional results see Table 3 and Figure 1.
Table 3. Effect of REPATHA on Lipid Parameters in Patients with Atherosclerotic CVD on Atorvastatin 80 mg, Rosuvastatin 40 mg, or Simvastatin 40 mg (Mean % Change from Baseline to Week 12 in Study 1)

Treatment Group	LDL-C	Non-HDL-C	Apo B	Total Cholesterol
Placebo every 2 weeks (n = 42)	7	2	5	4
REPATHA 140 mg every 2 weeks† (n = 105)	-64	-56	-49	-38
Mean difference from placebo (95% CI)	-71 (-81, -61)	-58 (-67, -49)	-55 (-62, -47)	-42 (-48, -36)
Placebo once monthly (n = 44)	5	5	3	3
REPATHA 420 mg once monthly† (n = 105)	-58	-47	-46	-32
Mean difference from placebo (95% CI)	-63 (-76, -50)	-52 (-63, -41)	-49 (-58, -39)	-36 (-43, -28)

Estimates based on a multiple imputation model that accounts for treatment adherence
140 mg every 2 weeks or 420 mg once monthly yield similar reductions in LDL-C
Figure 1. Effect of REPATHA on LDL-C in Patients with Atherosclerotic CVD when Combined with Statins (Mean % Change from Baseline to Week 12 in Study 1)

Estimates based on a multiple imputation model that accounts for treatment adherence
Error bars indicate 95% confidence intervals
Study 2 was a multicenter, double-blind, randomized, placebo-controlled, 52-week trial that included 139 patients with atherosclerotic CVD who received protocol-determined background lipid-lowering therapy of atorvastatin 80 mg daily with or without ezetimibe 10 mg daily. After stabilization on background therapy, patients were randomly assigned to the addition of placebo or REPATHA 420 mg administered subcutaneously once monthly. Among these patients, the mean age at baseline was 59 years (range: 35 to 75 years), 25% were ≥ 65 years, 40% women, 80% White, 3% Black, 5% Asian, and < 1% Hispanic or Latino. After stabilization on the assigned background therapy, the mean baseline LDL-C was 105 mg/dL.
In these patients with atherosclerotic CVD on maximum-dose atorvastatin therapy with or without ezetimibe, the difference between REPATHA 420 mg once monthly and placebo in mean percent change in LDL-C from baseline to Week 52 was -54 % (95% CI: -65%, -42%; p ˂ 0.0001) (Table 4 and Figure 2). For additional results see Table 4.
Table 4. Effect of REPATHA on Lipid Parameters in Patients with Atherosclerotic CVD on Atorvastatin 80 mg with or without Ezetimibe 10 mg daily (Mean % Change from Baseline to Week 52 in Study 2)

Treatment Group	LDL-C	Non-HDL-C	Apo B	Total Cholesterol
Placebo once monthly (n = 44)	2	3	0	3
REPATHA 420 mg once monthly (n = 95)	-52	-41	-40	-28
Mean difference from placebo (95% CI)	-54 (-65, -42)	-44 (-56, -32)	-40 (-50, -30)	-31 (-39, -24)

Estimates based on a multiple imputation model that accounts for treatment adherence
Figure 2. Effect of REPATHA 420 mg Once Monthly on LDL-C in Patients with Atherosclerotic CVD on Atorvastatin 80 mg with or without Ezetimibe 10 mg Daily

Estimates based on a multiple imputation model that accounts for treatment adherence
Error bars indicate 95% confidence intervals
14.2  Heterozygous Familial Hypercholesterolemia (HeFH) 
Study 3 was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 329 patients with heterozygous familial hypercholesterolemia (HeFH) on statins with or without other lipid-lowering therapies. Patients were randomized to receive subcutaneous injections of REPATHA 140 mg every two weeks, 420 mg once monthly, or placebo. HeFH was diagnosed by the Simon Broome criteria (1991). In Study 3, 38% of patients had clinical atherosclerotic cardiovascular disease. The mean age at baseline was 51 years (range: 19 to 79 years), 15% of the patients were ≥ 65 years old, 42% were women, 90% were White, 5% were Asian, and 1% were Black. The average LDL-C at baseline was 156 mg/dL with 76% of the patients on high-intensity statin therapy.
In these patients with HeFH on statins with or without other lipid lowering therapies, the differences between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was -61% (95% CI: -67%, -55%; p < 0.0001) and -60% (95% CI: -68%, -52%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. For additional results see Table 5.
Table 5. Effect of REPATHA on Lipid Parameters in Patients with HeFH (Mean % Change from Baseline to Week 12 in Study 3)

Treatment Group	LDL-C	Non-HDL-C	Apo B	Total Cholesterol
Placebo every 2 weeks (n = 54)	-1	-1	-1	-2
REPATHA 140 mg every 2 weeks† (n = 110)	-62	-56	-49	-42
Mean difference from placebo (95% CI)	-61 (-67, -55)	-54 (-60, -49)	-49 (-54, -43)	-40 (-45, -36)
Placebo once monthly (n = 55)	4	4	4	2
REPATHA 420 mg once monthly† (n = 110)	-56	-49	-44	-37
Mean difference from placebo (95% CI)	-60 (-68, -52)	-53 (-60, -46)	-48 (-55, -41)	-39 (-45, -33)

Estimates based on a multiple imputation model that accounts for treatment adherence
140 mg every 2 weeks or 420 mg once monthly yield similar reductions in LDL-C
14.3 Homozygous Familial Hypercholesterolemia (HoFH)
Study 4 was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 49 patients (not on lipid-apheresis therapy) with homozygous familial hypercholesterolemia (HoFH). In this trial, 33 patients received subcutaneous injections of 420 mg of REPATHA once monthly and 16 patients received placebo as an adjunct to other lipid-lowering therapies (e.g., statins, ezetimibe). The mean age at baseline was 31 years, 49% were women, 90% White, 4% were Asian, and 6% other. The trial included 10 adolescents (ages 13 to 17 years), 7 of whom received REPATHA. The mean LDL-C at baseline was 349 mg/dL with all patients on statins (atorvastatin or rosuvastatin) and 92% on ezetimibe. The diagnosis of HoFH was made by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration > 500 mg/dL together with either xanthoma before 10 years of age or evidence of HeFH in both parents.
In these patients with HoFH, the difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was -31% (95% CI: -44%, -18%; p < 0.0001). For additional results see Table 6.
Patients known to have two LDL-receptor negative alleles (little to no residual function) did not respond to REPATHA.
Table 6. Effect of REPATHA on Lipid Parameters in Patients with HoFH (Mean % Change from Baseline to Week 12 in Study 4)

Treatment Group	LDL-C	Non-HDL-C	Apo B	Total Cholesterol
Placebo once monthly (n = 16)	9	8	4	8
REPATHA 420 mg once monthly (n = 33)	-22	-20	-17	-17
Mean difference from placebo (95% CI)	-31 (-44, -18)	-28 (-41, -16)	-21 (-33, -9)	-25 (-36, -14)

Estimates based on a multiple imputation model that accounts for treatment adherence
16  HOW SUPPLIED/STORAGE AND HANDLING
REPATHA is a sterile, clear to opalescent, colorless to pale yellow solution for subcutaneous administration supplied in a single-use prefilled syringe, a single-use prefilled SureClick® autoinjector, or a single-use PushtronexTM system (on-body infusor with prefilled cartridge). Each single-use prefilled syringe or single-use prefilled SureClick® autoinjector of REPATHA is designed to deliver 1 mL of 140 mg/mL solution. Each single-use PushtronexTM system (on-body infusor with prefilled cartridge) is designed to deliver 420 mg evolocumab in 3.5 mL solution.

140 mg/mL single-use prefilled syringe	1 pack	NDC 55513-750-01
140 mg/mL single-use prefilled SureClick® autoinjector	1 pack	NDC 55513-760-01
140 mg/mL single-use prefilled SureClick® autoinjector	2 pack	NDC 55513-760-02
140 mg/mL single-use prefilled SureClick® autoinjector	3 pack	NDC 55513-760-03
420 mg/3.5 mL single-use PushtronexTM system (on-body infusor with prefilled cartridge)	1 pack	NDC 55513-770-01

Pharmacy
Store refrigerated at 2°C to 8°C (36° to 46°F) in the original carton to protect from light. Do not freeze. Do not shake.
For Patients/Caregivers
Store refrigerated at 2°C to 8°C (36° to 46°F) in the original carton. Alternatively, REPATHA can be kept at room temperature at 68°F to 77°F (20°C to 25°C) in the original carton; however, under these conditions, REPATHA must be used within 30 days. If not used within the 30 days, discard REPATHA.
Protect REPATHA from direct light and do not expose to temperatures above 25°C (77°F).

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=709338ae-ab8f-44a9-b7d5-abaabec3493a
全球首个PCSK9抑制剂--安进新型降胆固醇REPATHA用于高胆固醇治疗
——针对胆固醇控制不良而需要额外强化降低LDL-C的患者的重要里程碑
2015年7月24日，安进 (NASDAQ：AMGN) 近日宣布，欧盟委员会（EC）批准了全球首个待批准的前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）抑制剂RepathaTM (evolocumab)的上市许可，批准该药用于胆固醇控制不良而需要额外强化降低低密度脂蛋白胆固醇（LDL-C）的患者。Repatha是一种可抑制PCSK9的全人源化单克隆抗体，PCSK9是一种能够降低肝脏从血液中清除LDL-C或“坏”胆固醇的能力的蛋白。LDL-C升高是血液中胆固醇和/或脂肪发生异常，被视为心血管疾病 (CVD) 的重要风险因素。
EC已批准Repatha用于：
•作为饮食的一种辅助疗法，用于治疗原发性高胆固醇血症（杂合子家族性和非家族性[HeFH]）或混合性血脂异常成年患者：
•联合他汀类药物、或者联合他汀类及其他降脂疗法，用于接受最大耐受剂量的他汀类药物治疗仍无法达到LDL-C目标的患者，或者
•单独或联合其他降脂疗法，用于不能耐受他汀或者他汀类药物禁忌的患者。
•联合其他降脂疗法，用于成人或12岁及以上年龄的纯合子家族性（HoFH）患者。
Repatha对心血管发病率和死亡率的影响尚未确定。
欧洲超过60%的高危患者在使用他汀或其他当前获批的降脂药物时仍无法充分降低其LDL-C水平。在极高危患者中，这一比例增至80%以上。欧盟每年CVD方面的医疗保健成本大约为1060亿欧元。
“我们的降胆固醇药物Repatha是全球监管当局批准的首个PCSK9抑制剂，我们为此感到自豪”。安进研发执行副总裁、医学博士Sean E. Harper表示，“LDL胆固醇升高是一项重大的全球健康负担，很多患者在使用最大耐受剂量他汀时仍不能适当控制其LDL胆固醇水平，或因不耐受或禁忌而不能使用他汀类药物。能让欧洲患者获得这种新型降胆固醇药物，这令我们很激动。”
家族性高胆固醇血症 (FH) 患者是一类高危患者群体。FH是一种因基因突变造成的、可在幼年时导致高水平LDL-C的遗传性疾病。估计在大部分国家中，只有低于1%的FH患者（杂合子和纯合子）被确诊。
很多接受降胆固醇治疗的患者，包括家族性高胆固醇血症患者，仍在努力控制他们的LDL胆固醇水平”，阿姆斯特丹大学学术医疗中心(AMC) 血管医学科主任J.P.Kastelein医学教授表示，“作为欧盟此类新型药物的首位成员，对于胆固醇控制不良而需要额外降低LDL胆固醇的患者，evolocumab将为医师提供一个重要的、创新的治疗选择。”
EC的批准授予了欧盟28个成员国使用统一标签的集中上市许可。作为欧洲经济区 (EEA) 成员，挪威、冰岛和列支敦斯登将基于EC的决定作出相应决策。
数据显示，Repatha已在大约6000例原发性高脂血症和混合性血脂异常患者（包括10项3期研究中超过4500例高胆固醇患者在内）中证实了显著且一致的降低LDL-C水平的作用以及其他脂质参数支持性的获益变化。在这些研究中，Repatha较安慰剂显著降低LDL-C水平大约达55-75%；Repatha较依折麦布显著降低LDL-C水平大约达35-45%。在纯合子FH患者中，Repatha较安慰剂显著降低LDL-C的水平大约达15-30%。通过长期治疗可维持LDL-C的下降。
Repatha的不良事件属性总体上与对照组相似。Repatha组发生率≥2%、且频率高于对照组的最常见的不良事件包括鼻咽炎、上呼吸道感染、背痛、关节痛、流感和恶心。完整安全性信息请参见产品特性总结 (SmPC)。
Repatha可在腹部、大腿和上臂区域皮下注射使用。注射部位应轮流交替，不应在娇嫩、擦伤、红肿或硬结皮肤区域注射药物。
禁止静脉或肌肉注射给予Repatha。在启动Repatha 治疗前，应排除导致血液中胆固醇过高和脂肪水平异常的继发性因素（非遗传性）。
本品仅可通过处方获得。
原发性高胆固醇血症患者成人推荐剂量为140mg每两周一次或420mg（3支预充注射器）每月一次；两种剂量具有临床等效性。对于成人纯合子FH患者或大于12岁的儿童纯合子FH患者，起始推荐剂量为420mg每月一次。如经过12周治疗后仍未能实现缓解，剂量可增至420mg每两周一次。
更多信息请参见包装说明书。
关于RepathaTM (evolocumab)
RepathaTM (evolocumab) 是一种可抑制前蛋白转化酶枯草溶菌素/kexin9型 (PCSK9) 的全人源化单克隆抗体1。PCSK9是一种能够降解LDL受体，从而降低肝脏从血液中清除LDL-C或“坏”胆固醇的能力的蛋白18。Repatha由安进的科学家研发获得，用于结合PCSK9，从而抑制PCSK9与肝脏表面LDL受体的结合。在PCSK9缺失的条件下，肝脏表面的LDL受体水平更高，从而能够更有效地清除血液中的LDL-C1。
重要欧盟产品信息
高胆固醇血症和混合性血脂异常
Repatha适用于作为饮食的辅助疗法，治疗原发性高胆固醇血症（杂合子家族性和非家族性[HeFH]）或混合性血脂异常成年患者：
•联合他汀类药物、或者联合他汀类及其他降脂疗法，用于接受最大耐受剂量的他汀类药物治疗仍无法达到LDL-C目标的患者，或者
•单独或联合其他降脂疗法，用于不能耐受或者他汀类药物禁忌的患者。
纯合子家族性高胆固醇血症
Repatha适用于联合其他降脂疗法，用于成人或12岁及以上年龄的纯合子家族性（HoFH）患者。
Repatha对心血管发病率和死亡率的影响尚未确定。
重要安全性信息
对本品可进行额外监测。这样做可迅速鉴定出新的安全性信息。要求医疗专业人士报告所有可疑的不良反应。
禁忌症：
对活性物质或任何辅料过敏。
特殊警告和注意事项：
肾功能损害：尚未对重度肾功能受损（定义为eGFR<30 mL/min/1.73 m2）患者进行研究。在重度肾功能受损患者中应谨慎使用Repatha。肝功能损害：在中度肝功能受损患者中观察到evolocumab总暴露量下降，可能导致降LDL-C作用减弱。因此需对此类患者进行密切监测。尚未对重度肝功能受损(Child-Pugh C) 患者进行研究。在重度肝功能受损患者中应谨慎使用Repatha。干天然橡胶：玻璃预充注射器和预充笔的针帽材质为干天然橡胶（或乳胶衍生物），可能导致过敏反应。钠含量：Repatha每剂含钠量低于1mmol(23 mg)，即基本不含钠。
相互作用：
尚未对Repatha进行药物相互作用研究。未对Repatha与他汀类药物和依泽麦布以外降脂药物之间的药代动力学和药效学相互作用进行研究。
生育能力、妊娠及哺乳：
在妊娠妇女中使用Repatha的数据有限。不应在妊娠妇女中使用Repatha，除非此类患者临床上需要使用evolocumab治疗。尚不清楚evolocumab能否经人乳分泌。尚不能排除对母乳喂养新生儿/婴儿的风险。尚无evolocumab对人生育能力影响的数据。
不良影响：
在关键性对照临床研究中报告了下列常见不良反应（≥ 1/100-< 1/10）：流感、鼻咽炎、上呼吸道感染、皮疹、恶心、背痛、关节痛、注射部位反应。不良反应的完整描述请参见SmPC。
药品注意事项：
冰箱内保存（2– 8摄氏度），不得冷冻。应将预充注射器和预充笔置于原包装纸箱内以避光。如从冰箱内取出，Repatha可在室温下（最高25摄氏度）置于原包装纸箱内保存，但必须在1周内使用。