Evolocumab

Evolocumab is a high-affinity, fully human monoclonal antibody that neutralises circulating PCSK9, a serine protease secreted primarily by the liver that targets the LDL receptor for lysosomal degradation. By preventing PCSK9–LDLR binding, evolocumab restores hepatic LDL receptor recycling to the cell surface and accelerates clearance of LDL-C from plasma.

Mechanism of Action

• PCSK9 biology: under normal physiology, hepatic LDL receptors bind circulating LDL-C, internalise the particles, deliver them to the lysosome for degradation, and recycle back to the cell surface. PCSK9 binds LDLR in the bloodstream; the complex is internalised together, and PCSK9 redirects LDLR to lysosomal destruction rather than recycling, reducing the surface pool of LDLR and elevating circulating LDL-C.
• Familial hypercholesterolaemia: many cases involve gain-of-function PCSK9 mutations (e.g., D374Y) that supercharge LDLR degradation. Loss-of-function PCSK9 variants conversely confer very low lifetime LDL-C and reduced cardiovascular risk — the natural-experiment finding that validated PCSK9 as a therapeutic target.
• Evolocumab binding: evolocumab binds the catalytic domain of PCSK9 immediately adjacent to the LDLR binding site, sterically blocking the PCSK9–LDLR interaction. Both wild-type PCSK9 and the D374Y gain-of-function mutant are neutralised.
• Magnitude of effect: LDL-C reductions of approximately 55–75% on top of maximally tolerated statin therapy, with proportional reductions in apolipoprotein B and lipoprotein(a) (~25% reduction in Lp(a), unique among LDL-lowering classes).
• Cardiovascular outcomes: in the FOURIER trial (27,564 patients with atherosclerotic CVD on statin therapy), evolocumab reduced major cardiovascular events by approximately 15% over 2.2 years; longer-term open-label follow-up suggested progressive benefit accrual.

Pharmacokinetics

• Absorption: subcutaneous bioavailability estimated at ~72% in humans (~82% in cynomolgus monkeys); peak plasma concentration approximately 3–4 days post-injection.
• Distribution: limited tissue distribution typical of a 142 kDa IgG monoclonal antibody.
• Elimination: dual-route — target-mediated clearance via binding to soluble PCSK9 (saturable at therapeutic doses) and non-specific catabolism by the reticuloendothelial system; non-linear, dose-dependent clearance.
• Effective half-life: approximately 11–17 days, supporting biweekly or monthly dosing.
• No renal/hepatic metabolism of clinical relevance — proteins are catabolised to amino acids.

• Established atherosclerotic cardiovascular disease in adults: reduction in the risk of myocardial infarction, stroke, and coronary revascularisation.
• Primary hyperlipidaemia (including heterozygous familial hypercholesterolaemia) in adults and paediatric patients ≥10 years: as an adjunct to diet and other lipid-lowering therapies to reduce LDL-C.
• Homozygous familial hypercholesterolaemia (HoFH) in adults and paediatric patients ≥10 years: as an adjunct to other lipid-lowering therapies. Note that response in HoFH depends on residual LDLR function — patients with null/null receptor mutations may show minimal response.

• Hypersensitivity to evolocumab or any of the excipients.

Common (≥1/100 to <1/10): nasopharyngitis, upper respiratory tract infection, influenza, headache, nausea, back pain, arthralgia, myalgia, injection site reactions (most frequently bruising, erythema, haemorrhage, pain, swelling), rash, urticaria, influenza-like illness.

Uncommon (≥1/1,000 to <1/100): hypersensitivity reactions, angioedema.

Long-term outcome data: in FOURIER and its open-label extension, no signal of cognitive decline, new-onset diabetes, cataract, or muscle adverse events attributable to very low achieved LDL-C (some patients reached LDL-C below 25 mg/dL).

Evolocumab is a fully human monoclonal antibody and is not metabolised by CYP enzymes. Pharmacokinetic interactions with small molecules are not anticipated. Pharmacodynamic interactions are limited to other LDL-lowering agents — additive, not multiplicative.

• Statins (atorvastatin, rosuvastatin, simvastatin): statins induce PCSK9, raising circulating substrate; this slightly accelerates evolocumab clearance (~20%) but the clinical effect is preserved and the combination is the standard of care.
• Ezetimibe: additive LDL-C lowering.
• Bempedoic acid, inclisiran: limited combination data — assess for cumulative effect and cost.

No food or alcohol interaction.

Evolocumab is administered subcutaneously into the abdomen, thigh, or upper arm. Rotate injection sites with each dose. Allow the pre-filled device to reach room temperature (~30 minutes out of the fridge) before injection.

Hyperlipidaemia and Cardiovascular Event Reduction (Adults and Paediatric ≥10 y)

• 140 mg once every 2 weeks OR 420 mg once monthly — clinically equivalent regimens; choose based on patient preference and adherence considerations.

Homozygous Familial Hypercholesterolaemia (Adults and Paediatric ≥10 y)

• 420 mg once monthly; if clinically meaningful response is not achieved after 12 weeks, may be increased to 420 mg every 2 weeks (limited to HoFH).

Renal Impairment

No dose adjustment in mild-to-moderate impairment. Limited data in severe renal impairment and end-stage renal disease — protein-based therapeutics generally do not require renal dose adjustment.

Hepatic Impairment

No dose adjustment in mild-to-moderate hepatic impairment. Limited data in severe impairment.

Missed Dose

If a dose is missed and there are more than 7 days until the next scheduled dose, administer as soon as possible and resume the regular schedule. If within 7 days of the next scheduled dose, skip the missed dose and resume the regular schedule.

Injection Technique

Patients and caregivers should be trained in subcutaneous self-injection — auto-injector pen, pre-filled syringe, and on-body infusor each have specific instructions. Do not inject into areas where skin is tender, bruised, red, or hard, or into scars or stretch marks.

Cold-Chain Handling

Maintain 2–8 °C storage. The product can spend up to 30 days at room temperature (≤25 °C) in the original carton if required by the patient’s lifestyle. Once exposed to room temperature for >30 days or to >25 °C at any point, discard. Do not freeze; do not shake.

Hypersensitivity

Discontinue and treat as clinically indicated for any hypersensitivity reaction. Patients with prior hypersensitivity to evolocumab should not be re-challenged.

Pregnancy and Lactation

• Pregnancy: no adequate human data. IgG2 antibodies are known to cross the placenta in the second and third trimesters. Use only if clearly needed; discontinuation may be reasonable.
• Breastfeeding: limited data; benefit-risk assessment required.

Paediatric

Approved from age 10 for HeFH and HoFH. No paediatric indication outside FH.

Elderly

No specific dose adjustment.

Effect on Driving

No influence on the ability to drive or operate machinery.

Store in a refrigerator (2–8°C) in the original carton to protect from light. Do not freeze. Do not shake. If removed from the refrigerator, Repatha may be stored at room temperature (up to 25°C) in the original carton and must be used within 1 month.

Typically 36 months from manufacture; refer to the product expiry date. Within shelf life, the 30-day room-temperature window applies once removed from refrigeration.

Prescription required (Rx). Cold-chain logistics required for distribution to the patient.