Repatha

Repatha (evolocumab)

• Injectable drug from Amgen
• Second in a new class of drugs called PCSK9 inhibitors
• Approximate molecular weight (MW) of 144 kDa
• Produced in genetically engineered mammalian (Chinese hamster ovary) cells.
• 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 [2]
• Each single-use Pushtronex® 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 [2]

Mechanismus účinku

• Evolocumab is a human monoclonal immunoglobulin G2 (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
• Permitting LDLR to recycle back to the liver cell surface [2]
• 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 [2]

Indikace

• Approved for patients to reduce low-density lipoprotein cholesterol (LDL-C).
• Heterozygous or homozygous familial hypercholesterolemia
• HeFh or HoFh
• Inherited condition that causes high LDL cholesterol levels
• Approved for patients who have had a heart attack or stroke.
• Patients who aren't responding to currently available medications or who can't take them because they experience side effects

Primary Hyperlipidemia

• Including Heterozygous Familial Hypercholesterolemia [2]

Homozygous Familial Hypercholesterolemia - HoFH

Kombinace

• Diet, alone or in combination with other lipid-lowering therapies
• Statins
• Ezetimibe
• LDL apheresis [2]

Dávkování

• Can be self-administered through a prefilled auto-injector pen or syringe [1]

Adults with established cardiovascular disease or primary hyperlipidemia - incl. heterozygous familial hypercholesterolemia - HeFH

• 140 mg every 2 weeks
• OR 420 mg once monthly
• Based on patient preference for dosing frequency and injection volume [2]

HoFH

• 420 mg once monthly
• Measure LDL-C levels 4 to 8 weeks after starting Repatha
• Response to therapy will depend on the degree of LDL-receptor function.
• LDL-C for patients receiving Repatha 420 mg once monthly, LDL-C can vary considerably during the dosing interval in some patients [2]

If a dose is missed

• Instruct the patient to administer Repatha within 7 days from the missed dose and resume the patient’s original schedule.
• If an every-2-week dose is not administered within 7 days
• Instruct the patient to wait until the next dose on the original schedule.
• If a once-monthly dose is not administered within 7 days
• Instruct the patient to administer the dose and start a new schedule based on this date [2]

Most common side effects

• Inflammation in the nasal or throat passages
• Upper respiratory tract infections
• Flu and black pain
• Injection site reactions including
• Redness, pain and bruising
• Hives have also been reported
• 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 [2]

Imunogenicita

• In a pool of placebo- and active-controlled clinical trials, 0.3% (48 out of 17,992) of patients treated with at least one dose of Repatha tested positive for the development of binding antibodies.
• Patients whose sera tested positive for binding antibodies were further evaluated for neutralizing antibodies;
• None of the patients tested positive for neutralizing antibodies. [2]
• Allergic reactions: Angioedema
• Influenza-like illness

Metabolism and Elimination

• Two elimination phases were observed for Repatha
• At low concentrations
• Elimination is predominately through saturable binding to target (PCSK9)
• Higher concentrations
• 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. [2]

Literatura