REPATHA (Evolocumab) PCSK9 Inhibitor for Treatment of Familial Hypercholesterolemia

REPATHA (evolocumab) injection, for subcutaneous use 

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. 

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.

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.

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. 

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 the estimated absolute bioavailability was 72%.

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 the 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. 

Initial U.S. Approval: 2015

REPATHA is a PCSK9 (proprotein convertase subtilisin Kexin type 9) inhibitor antibody indicated: 
  • to reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease. 
  • as an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for the treatment of adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia) to reduce low-density lipoprotein cholesterol (LDL-C).
  • as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C. 

Administer subcutaneously
  • Adults with established cardiovascular disease or primary hyperlipidemia (including heterozygous familial hypercholesterolemia): 140 mg every 2 weeks or 420 mg once monthly in the abdomen, thigh, or upper arm. 
  • HoFH: 420 mg once monthly.
  • The 420 mg dose of REPATHA can be administered: o over 9 minutes by using the single-use on-body infusor with prefilled cartridge, or o by giving 3 injections consecutively within 30 minutes using the single-use prefilled autoinjector or single-use prefilled syringe. 

  • 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 Pushtronex® system (on-body infusor with prefilled cartridge)

Patients with a history of a serious hypersensitivity reaction to REPATHA.

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.

Common adverse reactions in clinical trials in primary hyperlipidemia (including HeFH) (> 5% of patients treated with REPATHA and occurring more frequently than placebo):
  • nasopharyngitis,
  • upper respiratory tract infection,
  • influenza,
  • back pain, and 
  • injection site reactions.

Common adverse reactions in the cardiovascular outcomes trial (> 5% of patients treated with REPATHA and occurring more frequently than placebo): 
  • diabetes mellitus,
  • nasopharyngitis and 
  • upper respiratory tract infection.