Evinacumab (Evkeeza®): A Comprehensive Monograph on the First-in-Class ANGPTL3 Inhibitor for Homozygous Familial Hypercholesterolemia

1.0 Executive Summary

Evinacumab, marketed under the brand name Evkeeza®, is a first-in-class, fully human recombinant IgG4 monoclonal antibody that represents a significant advancement in the management of lipid disorders.[1] It is specifically designed to inhibit angiopoietin-like protein 3 (ANGPTL3), a key regulator of lipoprotein metabolism.[1] The primary therapeutic indication for evinacumab is as an adjunct to other lipid-lowering therapies for the treatment of homozygous familial hypercholesterolemia (HoFH), a rare and severe genetic disorder characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) from birth.[1]

The novelty of evinacumab lies in its mechanism of action, which is independent of the low-density lipoprotein receptor (LDLR) pathway.[4] By inhibiting ANGPTL3, evinacumab restores the activity of lipoprotein lipase (LPL) and endothelial lipase (EL), thereby enhancing the clearance of VLDL remnants and reducing the production of LDL-C.[4] This unique mechanism addresses a critical unmet medical need for patients with HoFH, particularly those with null/null LDLR mutations who are refractory to conventional LDLR-dependent therapies such as statins and PCSK9 inhibitors.[9]

Clinical development has been anchored by the pivotal Phase 3 ELIPSE HoFH trial, which demonstrated that evinacumab, administered at a dose of 15 mg/kg intravenously every four weeks, achieved a profound reduction in LDL-C levels. When added to maximally tolerated background therapies, evinacumab lowered LDL-C by approximately 49% compared to placebo at 24 weeks.[2] This robust efficacy has been consistently observed across adult, adolescent, and pediatric populations as young as one year old.[15]

The safety profile of evinacumab is generally well-tolerated. The most common adverse reactions include nasopharyngitis and influenza-like illness.[2] The most significant safety concern is the risk of serious hypersensitivity reactions, including anaphylaxis, which necessitates administration in a monitored healthcare setting.[7] Based on animal studies, the drug also carries a warning for potential embryo-fetal toxicity.[7]

Recognizing its potential to address a life-threatening condition with limited treatment options, regulatory agencies granted evinacumab an expedited development and review pathway, including Orphan Drug, Breakthrough Therapy, and Priority Review designations.[2] It received its first approval from the U.S. Food and Drug Administration (FDA) in February 2021.[2] Evinacumab has fundamentally altered the treatment landscape for HoFH, offering a powerful new tool to achieve previously unattainable lipid-lowering goals.

2.0 Introduction to Evinacumab and its Therapeutic Target

2.1 The Clinical Challenge of Homozygous Familial Hypercholesterolemia (HoFH)

2.1.1 Pathophysiology

Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal dominant genetic disorder of lipoprotein metabolism with a global prevalence estimated between 1 in 160,000 and 1 in 300,000 individuals.[10] The condition arises from the inheritance of pathogenic loss-of-function (LOF) mutations in both alleles of genes critical for LDL-C clearance.[19] Approximately 90% of cases are caused by mutations in the low-density lipoprotein receptor (LDLR) gene, with less common mutations occurring in genes encoding apolipoprotein B (APOB), the ligand for the LDLR, or proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that promotes LDLR degradation.[19]

These genetic defects lead to a severe impairment or complete absence of functional LDLRs on the surface of hepatocytes.[4] Consequently, the liver's ability to clear LDL particles from the bloodstream is drastically reduced, resulting in a massive accumulation of LDL-C in the plasma from birth.[9]

2.1.2 Clinical Manifestations

Patients with HoFH exhibit extremely high plasma LDL-C levels, often exceeding 500 mg/dL (>13 mmol/L) if left untreated.[4] This lifelong burden of hypercholesterolemia drives the rapid and premature development of atherosclerotic cardiovascular disease (ASCVD).[19] Clinical manifestations include the early appearance of cutaneous xanthomas (cholesterol deposits in the skin) and coronary artery disease.[4] Without aggressive treatment, major adverse cardiovascular events can occur in childhood or adolescence, and life expectancy is severely curtailed, with mortality often occurring before the age of 20.[9]

2.1.3 Treatment Limitations

The management of HoFH is exceptionally challenging due to the underlying pathophysiology. Conventional first-line lipid-lowering therapies, including high-intensity statins and PCSK9 inhibitors, exert their effects primarily by upregulating the expression of LDLRs on hepatocytes.[5] In patients with HoFH who have minimal to no residual LDLR function (often termed "null-null" or "receptor-negative" patients), these therapies are largely ineffective.[9] While other treatments like lomitapide or invasive lipoprotein apheresis can lower LDL-C independently of the LDLR, many patients still fail to achieve guideline-recommended LDL-C targets.[10] This persistent therapeutic gap has highlighted a profound unmet medical need for novel agents with LDLR-independent mechanisms of action.

2.2 Angiopoietin-like Protein 3 (ANGPTL3) as a Validated Therapeutic Target

2.2.1 Physiological Role

Angiopoietin-like protein 3 (ANGPTL3) is a glycoprotein primarily synthesized and secreted by the liver that has emerged as a central regulator of lipid and glucose metabolism.[1] Its principal function in lipid homeostasis is to act as a potent endogenous inhibitor of two key lipolytic enzymes: lipoprotein lipase (LPL) and endothelial lipase (EL).[3] LPL is primarily responsible for the hydrolysis of triglycerides within triglyceride-rich lipoproteins (TRLs) such as very-low-density lipoproteins (VLDL), while EL primarily hydrolyzes phospholipids within high-density lipoproteins (HDL).[3] By suppressing the activity of these enzymes, ANGPTL3 effectively slows the catabolism of lipoproteins, leading to increased plasma levels of triglycerides, LDL-C, and HDL-C.[1]

2.2.2 Genetic Validation

The validation of ANGPTL3 as a therapeutic target was strongly supported by human genetic studies. These studies served as a "natural experiment," revealing the long-term consequences of reduced ANGPTL3 function. It was observed that individuals carrying heterozygous LOF mutations in the ANGPTL3 gene exhibit a distinct and favorable lipid profile, characterized by significantly lower plasma levels of triglycerides, LDL-C, and HDL-C.[1] Crucially, this genetic predisposition was associated with a substantially reduced lifetime risk of coronary artery disease.[1] This human-centric evidence provided a powerful rationale for the development of a pharmacological agent that could mimic this naturally occurring, cardioprotective state by inhibiting ANGPTL3. This approach de-risked the development program by providing a high degree of confidence that therapeutic inhibition would be both effective and well-tolerated over the long term.

2.3 Evinacumab: A Targeted Monoclonal Antibody

2.3.1 Drug Identity

Evinacumab is a recombinant, fully human monoclonal antibody of the immunoglobulin G4 (IgG4) subclass that specifically targets and inhibits ANGPTL3.[1] It was developed by Regeneron Pharmaceuticals utilizing their proprietary Velocimmune® technology, which employs genetically engineered mice with a humanized immune system to produce optimized, fully human antibodies.[12]

The development of evinacumab represents a fundamental paradigm shift in the treatment strategy for HoFH. Rather than attempting to augment the function of a deficient or absent LDLR, evinacumab bypasses this primary genetic defect entirely. It works by activating an alternative, parallel pathway for lipoprotein clearance that is completely independent of the LDLR system, thereby offering a novel and effective therapeutic solution for a previously intractable condition.

2.3.2 Structural Features

Evinacumab is a whole antibody of the IgG4 kappa isotype.[2] Its heavy chains have been engineered with a stabilizing serine-to-proline substitution at position 234 in the hinge region. This modification is designed to promote the stability of inter-chain disulfide bonds and minimize the formation of "half-antibodies," thereby enhancing the molecule's structural integrity and therapeutic consistency.[12] The chemical formula for evinacumab is , and it has a molecular weight of approximately 146.1 kDa.[2]

2.3.3 First-in-Class Status

Evinacumab is the first ANGPTL3 inhibitor to receive regulatory approval, establishing a new class of lipid-lowering agents.[1] Its unique mechanism of action provides a synergistic therapeutic option that is complementary to existing lipid-lowering therapies, particularly for patients with HoFH.[1]

3.0 Pharmacological Profile

3.1 Detailed Mechanism of Action

The pharmacological activity of evinacumab is centered on its specific and high-affinity binding to circulating ANGPTL3.[1] This interaction effectively sequesters ANGPTL3, preventing it from binding to and inhibiting its physiological targets, LPL and EL.[1]

1. Disinhibition of Lipases: By neutralizing ANGPTL3, evinacumab removes the natural inhibitory constraint on LPL and EL. This "disinhibition" restores the lipolytic activity of these enzymes, allowing them to efficiently metabolize their respective lipoprotein substrates.[1]
2. The LDLR-Independent Pathway for LDL-C Reduction: This is the cornerstone of evinacumab's efficacy in HoFH. The restored activity of LPL and EL accelerates the hydrolysis of triglycerides and phospholipids in TRLs, such as VLDL.[4] This enhanced processing promotes the rapid conversion of VLDL to smaller remnant particles, which are then efficiently cleared from the circulation via hepatic remnant receptors—a process that does not depend on functional LDLRs.[5] By depleting the upstream precursor pool (VLDL and intermediate-density lipoproteins), the subsequent formation of LDL is substantially reduced.[1] This mechanism is supported by kinetic studies in HoFH patients, which demonstrated that evinacumab treatment markedly increases the fractional catabolic rate of both IDL-apoB and LDL-apoB, confirming that it lowers LDL-C predominantly by increasing lipoprotein clearance.[25]
3. Effects on Other Lipids: The mechanism of action also directly explains the observed changes in other lipid parameters. The restoration of LPL activity leads to enhanced catabolism of TRLs, resulting in a significant reduction in plasma triglycerides (TG).[1] Concurrently, the restoration of EL activity increases the catabolism of HDL particles, leading to a decrease in HDL-C levels.[1] The overall effect is a broad reduction in atherogenic lipoproteins, reflected by decreases in total cholesterol and apolipoprotein B (ApoB), the primary structural protein of VLDL and LDL.[1]

The reduction in HDL-C is a direct, on-target pharmacodynamic effect of ANGPTL3 inhibition and should not be misinterpreted as an adverse off-target toxicity. This is a crucial point for clinical interpretation, as the genetic validation studies showed that individuals with lifelong low ANGPTL3 function also have low HDL-C but are paradoxically protected from ASCVD, indicating that the overall impact of ANGPTL3 inhibition on cardiovascular risk is highly favorable despite the reduction in HDL-C.[25]

3.2 Pharmacokinetics (PK)

The pharmacokinetic profile of evinacumab has been characterized through population PK modeling using data from clinical trials in healthy volunteers and patients with dyslipidemia, including HoFH.[20]

3.2.1 Absorption and Distribution

Evinacumab is administered via a 60-minute intravenous infusion.[2] Its disposition in the body is well-described by a two-compartment model.[20] The steady-state volume of distribution () has been estimated to be approximately 4.7 to 4.8 L.[1] This relatively small volume of distribution indicates that the drug is primarily confined to the plasma and interstitial fluid compartments, which is typical for a large monoclonal antibody.

3.2.2 Metabolism and Elimination

As a protein-based therapeutic, evinacumab is not metabolized by cytochrome P450 enzymes. Instead, it is expected to be degraded into small peptides and amino acids through general catabolic pathways, in the same manner as endogenous immunoglobulins.[1]

A defining feature of evinacumab's pharmacokinetics is its dual elimination pathway, which results in non-linear kinetics.[1]

• Linear Pathway: At higher, clinically relevant concentrations, elimination is primarily driven by a non-saturable, linear proteolytic clearance pathway, which is concentration-independent.[1]
• Saturable Pathway: At lower concentrations, a saturable, target-mediated clearance pathway becomes predominant. This involves the binding of evinacumab to ANGPTL3, followed by the cellular uptake and degradation of the drug-target complex.[1]

This dual pathway means that the effective half-life of evinacumab is concentration-dependent and not a fixed value.[1] The existence of this complex elimination profile is fundamental to the drug's dosing strategy. The recommended 15 mg/kg every-4-weeks regimen is designed to maintain plasma concentrations high enough to continuously saturate the ANGPTL3 target. This ensures that the rapid, target-mediated clearance pathway is saturated, allowing the drug's persistence to be governed by the slower, linear pathway. This strategy provides maximal, sustained target engagement and a consistent pharmacodynamic effect throughout the entire dosing interval.

3.2.3 Steady State and Dosing

Following the recommended intravenous dosage of 15 mg/kg every 4 weeks, steady-state plasma concentrations are achieved after the fourth dose.[1] Population PK analyses have confirmed that this weight-based dosing approach results in consistent drug exposure across a wide range of body weights and across different age groups, including children, adolescents, and adults.[20] This consistency validates the use of a simple, weight-based regimen without the need for more complex dose adjustments.

3.3 Pharmacodynamics (PD)

3.3.1 Exposure-Response Relationship

The relationship between evinacumab exposure and its lipid-lowering effect has been characterized using an indirect exposure-response model.[36] This model assumes that evinacumab concentration inhibits the production rate of LDL-C, which aligns with its known mechanism of reducing the formation of LDL particles from their VLDL precursors.[36]

3.3.2 Sensitivity

The pharmacodynamic modeling revealed a noteworthy finding: patients with higher baseline LDL-C levels exhibited a lower half-maximal inhibitory concentration (), the drug concentration required to achieve 50% of the maximal effect.[37] This suggests that patients with more severe hypercholesterolemia may be more sensitive to the LDL-C-lowering effects of evinacumab. The population PK/PD model proved to be highly predictive, accurately forecasting the proportion of HoFH patients who would achieve predefined LDL-C treatment goals in the pivotal ELIPSE HoFH study, further validating the model and the chosen dosing strategy.[36]

4.0 Clinical Efficacy and Development Program

4.1 The Pivotal ELIPSE HoFH Trial (NCT03399786)

The cornerstone of the evinacumab clinical development program is the ELIPSE HoFH (Evinacumab Lipid Studies in Patients with Homozygous Familial Hypercholesterolemia) trial, a Phase 3 study that established its efficacy and safety in this patient population.[12]

4.1.1 Trial Design

ELIPSE HoFH was a multinational, randomized, double-blind, placebo-controlled, parallel-group trial.[2] The study enrolled 65 patients aged 12 years and older with a genetic or clinical diagnosis of HoFH.[2] Participants were required to be on stable, maximally tolerated background lipid-lowering therapies, which could include statins, ezetimibe, PCSK9 inhibitors, lomitapide, and lipoprotein apheresis.[12] Patients were randomized in a 2:1 ratio to receive either intravenous evinacumab at a dose of 15 mg/kg or a matching placebo every 4 weeks for 24 weeks.[12]

4.1.2 Patient Population

The enrolled population represented a cohort with severe, refractory disease. Despite receiving aggressive multimodal background therapy, the mean baseline LDL-C level was approximately 255 mg/dL.[12] Critically, the trial included a substantial proportion of patients with the most severe form of the disease, characterized by null/null (receptor-negative) variants in the LDLR gene, who are typically unresponsive to LDLR-dependent therapies.[10]

4.1.3 Primary Endpoint and Efficacy

The primary efficacy endpoint of the trial was the percent change in calculated LDL-C from baseline to week 24.[12] The trial met this endpoint with a high degree of statistical significance.

• Relative Reduction: Patients in the evinacumab group experienced a mean reduction in LDL-C of 47.1% from baseline, whereas patients in the placebo group had a mean increase of 1.9%. This resulted in a least-squares mean difference between the groups of -49.0 percentage points (95% CI, -65.0 to -33.1; ).[2]
• Absolute Reduction: The absolute mean reduction in LDL-C from baseline was 135 mg/dL in the evinacumab group compared to a 3 mg/dL reduction in the placebo group, for a between-group difference of -132.1 mg/dL ().[13] The lipid-lowering effect was rapid, with significant reductions observed as early as week 2 and sustained throughout the 24-week treatment period.[13]

4.1.4 Efficacy in LDLR-Null Patients

A landmark finding of the ELIPSE HoFH trial was the profound efficacy of evinacumab in patients with little to no functional LDLR activity. In the subgroup of patients with null/null LDLR variants, evinacumab treatment resulted in a mean LDL-C reduction of 43.4%, in stark contrast to a 16.2% increase observed in the placebo group.[27] This result provided definitive clinical confirmation of evinacumab's LDLR-independent mechanism of action and established its utility in the most difficult-to-treat segment of the HoFH population.[10]

4.1.5 Secondary Endpoints

Evinacumab also demonstrated significant improvements in key secondary lipid parameters compared to placebo. At week 24, there were substantial reductions in apolipoprotein B (ApoB), non-HDL-C, and total cholesterol, further underscoring its broad impact on atherogenic lipoproteins.[13]

4.2 Efficacy in Pediatric Populations

Given that HoFH manifests from birth, establishing efficacy and safety in younger patients is critical for early intervention to mitigate long-term cardiovascular risk.

4.2.1 Trial in Children (Ages 5-11; NCT04233918)

The efficacy of evinacumab in younger children was evaluated in a Phase 3, open-label, single-arm trial that enrolled 14 patients with HoFH aged 5 to 11 years.[15] The baseline characteristics of this cohort were severe, with a mean LDL-C of 264 mg/dL despite optimized background therapies, including lipoprotein apheresis in 50% of patients.[15]

The study successfully met its primary endpoint, demonstrating a mean LDL-C reduction from baseline of 48.3% at week 24.[15] This magnitude of reduction was remarkably consistent with that observed in the adult and adolescent population. Furthermore, 79% of the children achieved at least a 50% reduction in their LDL-C levels.[17] Significant reductions were also seen in ApoB (-41.3%), non-HDL-C (-48.9%), and total cholesterol (-49.1%).[15]

The remarkable consistency of the approximate 50% LDL-C reduction across diverse patient populations—spanning adults, adolescents, and children, and crucially, across both null/null and non-null LDLR genotypes—provides the strongest possible clinical validation of the drug's fundamental mechanism. It indicates that evinacumab targets a central, upstream regulatory node in lipid metabolism that is common to all these patients, functioning as a "master switch" for an alternative clearance pathway that is independent of the specific genetic defect or age-related metabolic state.

4.2.2 Data in Young Children (Ages 1-5)

Regulatory approval for children under 5 years of age was granted based on safety and efficacy data from compassionate use and expanded access programs involving a small number of patients.[45] These data demonstrated similarly robust LDL-C reductions and did not identify any new safety concerns, supporting the extension of the indication to this very young and vulnerable population and allowing for earlier therapeutic intervention.[45]

4.3 Long-Term Efficacy and Open-Label Extension (OLE) Studies

The durability of evinacumab's effect is crucial for a lifelong condition like HoFH. Data from open-label extension studies, such as NCT03409744 and the OLE phase of the ELIPSE trial, have shown that the significant reductions in LDL-C are well-maintained over long-term treatment periods of 48 weeks and beyond.[10] Real-world evidence from a French cohort study further supports these findings, reporting a sustained mean LDL-C reduction of 56% over a median follow-up of 3.5 years.[49] This long-term, durable efficacy is a critical attribute for chronic management.

The profound lipid-lowering achieved with evinacumab also has significant implications for patient quality of life. Many patients with severe HoFH rely on lipoprotein apheresis, an invasive, time-consuming, and not universally available procedure.[9] The substantial LDL-C reduction provided by evinacumab, even when added to a regimen including apheresis, has the potential to reduce the frequency of or even eliminate the need for this burdensome procedure in many patients, representing a major clinical and lifestyle benefit.[22]

4.4 Impact on Other Dyslipidemias

While HoFH is the primary approved indication, the mechanism of ANGPTL3 inhibition suggests broader therapeutic potential. Post-hoc analyses of clinical trial data and separate Phase 2 studies have demonstrated that evinacumab is also highly effective in reducing levels of triglyceride-rich lipoproteins (TRLs).[50] It has shown significant efficacy in patients with severe hypertriglyceridemia and in those with refractory hypercholesterolemia (both familial and non-familial forms), suggesting that ANGPTL3 inhibition could become a valuable strategy for a wider range of severe dyslipidemias in the future.[5]

5.0 Safety and Tolerability

5.1 Comprehensive Adverse Event Profile

Across the clinical development program, evinacumab has been shown to be generally well-tolerated.[2] The safety profile is consistent with that expected for a monoclonal antibody therapeutic administered via intravenous infusion.[18]

5.1.1 Common Adverse Reactions

The most frequently reported adverse reactions are typically mild to moderate in severity. Based on pooled data from placebo-controlled trials in adults and adolescents, the common adverse reactions (occurring in 5% of patients) are nasopharyngitis (symptoms of the common cold), influenza-like illness, dizziness, rhinorrhea (runny nose), and nausea.[2] In the pediatric trial involving children aged 5 to 11, the safety profile was similar, with the additional adverse reaction of fatigue being reported in 15% of patients.[7]

The following table summarizes the incidence of common adverse reactions from pooled placebo-controlled trials.

Table 1: Adverse Reactions Occurring in >3% of Patients in Pooled, Placebo-Controlled Trials

Adverse Reaction	Evinacumab 15 mg/kg Q4W (%)	Placebo (%)
Nasopharyngitis	16	11
Influenza-like illness	7	4
Dizziness	6	0
Rhinorrhea	5	0
Nausea	5	2
Pain in extremity	4	0
Asthenia	4	2
	7

5.2 Serious Adverse Events and Reactions of Special Interest

5.2.1 Hypersensitivity Reactions

The most clinically significant risk associated with evinacumab is serious hypersensitivity reactions.[18]

• Anaphylaxis: A case of anaphylaxis was reported in one patient (1.2%) in the clinical trial program, compared to none in the placebo group.[18]
• Infusion-Related Reactions: Less severe infusion-related reactions were reported in approximately 7% of patients treated with evinacumab compared to 4% in the placebo group.[11] These reactions can manifest as pruritus, pyrexia, or other symptoms during or shortly after the infusion.[6] Management involves slowing, interrupting, or discontinuing the infusion and providing standard-of-care treatment.[7]

5.2.2 Hepatotoxicity and Myopathy

Importantly, evinacumab has not been associated with adverse reactions commonly seen with some other classes of lipid-lowering therapies. Clinical trials showed no signal of hepatotoxicity, with no clinically significant elevations in liver transaminases (ALT/AST), nor was there any signal of myopathy or rhabdomyolysis, as indicated by stable creatine kinase levels.[3]

5.2.3 Immunogenicity

The potential for monoclonal antibodies to elicit an immune response is a standard safety consideration. However, throughout the clinical trials, no patients treated with evinacumab developed treatment-emergent anti-drug antibodies (ADAs), suggesting a low risk of immunogenicity.[5]

5.3 Warnings, Precautions, and Contraindications

5.3.1 Contraindication

Evinacumab is contraindicated in patients with a known history of a serious hypersensitivity reaction, such as anaphylaxis, to evinacumab-dgnb or to any of the excipients in the formulation.[6]

5.3.2 Embryo-Fetal Toxicity

A significant warning pertains to potential embryo-fetal toxicity. This warning is based on findings from animal reproduction studies conducted in pregnant rabbits, where administration of evinacumab during organogenesis resulted in an increased incidence of fetal malformations at exposures below the human therapeutic dose.[6] Consequently, evinacumab may cause fetal harm when administered to a pregnant woman. It is strongly recommended that a pregnancy test be performed in females of reproductive potential prior to initiating therapy. Patients who may become pregnant must be advised to use effective contraception during the entire course of treatment and for at least 5 months following the final dose of evinacumab.[1]

5.3.3 Lactation

There are no available data on the presence of evinacumab in human or animal milk, or its effects on the breastfed infant or on milk production.[7] Because evinacumab is a large protein molecule (molecular weight ~146 kDa), the amount transferred into breast milk is likely to be very low, and any ingested antibody would likely be degraded in the infant's gastrointestinal tract.[5] However, until more data are available, caution is advised when considering its use in breastfeeding mothers.[58]

5.4 Drug Interaction Profile

To date, no clinically significant drug-drug interactions have been identified for evinacumab.[5] Specific drug interaction studies have not been conducted. However, a clinical trial analysis showed that the plasma concentrations of co-administered statins (atorvastatin, rosuvastatin, and simvastatin) were not meaningfully altered by evinacumab.[5] As a standard precaution for intravenous infusions, the prescribing information advises not to mix evinacumab with other medications or administer other drugs concomitantly through the same infusion line.[6]

6.0 Regulatory Status and Prescribing Information

6.1 Global Regulatory Approvals

Evinacumab's development and approval were expedited by regulatory agencies in recognition of the high unmet medical need in HoFH. It received multiple special designations, including Orphan Drug, Breakthrough Therapy, and Priority Review status from the U.S. FDA, which facilitated a rapid path to market.[2]

Table 2: Summary of Global Regulatory Milestones for Evinacumab (Evkeeza®)

Regulatory Agency/Body	Milestone	Date	Indication/Population
U.S. FDA	Orphan Drug Designation	February 8, 2016	Treatment of HoFH
U.S. FDA	Breakthrough Therapy Designation	2017	Treatment of HoFH
U.S. FDA	Initial Approval	February 11, 2021	HoFH, Ages 12 years
EMA (CHMP)	Positive Opinion	April 2021	HoFH, Ages 12 years
EMA (EC)	Initial Approval	June 2021	HoFH, Ages 12 years
U.S. FDA	Pediatric Expansion Approval	March 22, 2023	HoFH, Ages 5 to 11 years
EMA (EC)	Pediatric Expansion Approval	December 18, 2023	HoFH, Ages 5 to 11 years
U.S. FDA	Pediatric Expansion Approval	September 26, 2025*	HoFH, Ages 1 to <5 years
EMA (EC)	Pediatric Expansion Approval	(Post-Dec 2023)	HoFH, Ages 6 months
*.2 Note: The source 64 lists a future approval date of September 2025; this is presented as cited but is likely a typographical error for a past date.

The drug was developed by Regeneron Pharmaceuticals, Inc..[9] In some regions, including Europe, it is marketed in collaboration with Ultragenyx Pharmaceutical, Inc..[1]

6.2 Approved Indications and Limitations of Use

The approved indications for evinacumab are specific and consistent across major regulatory bodies, with minor differences in the lower age limit.

• U.S. FDA Indication: "EVKEEZA is an angiopoietin-like 3 (ANGPTL3) inhibitor indicated as an adjunct to other low-density lipoprotein-cholesterol (LDL-C) lowering therapies for the treatment of adult and pediatric patients, aged 1 year and older, with homozygous familial hypercholesterolemia (HoFH).".[6]
• EMA Indication: "Evkeeza is indicated as an adjunct to diet and other low-density lipoprotein-cholesterol (LDL-C) lowering therapies for the treatment of adult and paediatric patients aged 6 months and older with homozygous familial hypercholesterolaemia (HoFH).".[35]

Both agencies specify the following Limitations of Use:

• The safety and effectiveness of Evkeeza have not been established in patients with other causes of hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH).[5]
• The effects of Evkeeza on cardiovascular morbidity and mortality have not been determined.[5]

6.3 Dosing and Administration

6.3.1 Dosage

The recommended dosage of evinacumab for all approved age groups is 15 mg/kg of body weight.[3]

6.3.2 Administration

Evinacumab is administered as a 60-minute intravenous infusion once monthly (every 4 weeks).[3] It can be administered without regard to the timing of lipoprotein apheresis sessions.[6]

6.3.3 Preparation

Evinacumab is supplied as a sterile, preservative-free solution in single-dose vials at a concentration of 150 mg/mL.[3] Aseptic technique must be used for preparation.

1. The required volume is calculated based on the patient's weight and withdrawn from the vial(s).
2. The withdrawn volume is transferred into an IV infusion bag containing either 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. The maximum volume of the diluent depends on patient weight, up to a maximum of 250 mL.[6]
3. The final concentration of the diluted solution should be between 0.5 mg/mL and 20 mg/mL.[6]
4. The diluted solution should be administered through an intravenous line containing a sterile, in-line or add-on 0.2-micron to 5-micron filter.[6]
5. If not used immediately, the prepared infusion can be stored under refrigeration (2°C to 8°C) for up to 24 hours or at room temperature (up to 25°C) for up to 6 hours from preparation to the end of infusion.[6]

7.0 Conclusion and Future Perspectives

Evinacumab (Evkeeza®) represents a landmark therapeutic innovation for the management of homozygous familial hypercholesterolemia. As the first-in-class ANGPTL3 inhibitor, it introduces a novel, LDLR-independent mechanism that directly addresses the profound unmet need of a patient population largely refractory to conventional lipid-lowering therapies. The robust and consistent efficacy demonstrated across clinical trials—achieving approximately 50% additional LDL-C reduction on top of maximally tolerated background treatments—has fundamentally altered the therapeutic landscape for HoFH. Its effectiveness in patients with null/null LDLR mutations is particularly transformative, offering a powerful option for the most severely affected individuals.

The clinical impact of evinacumab extends beyond its potent lipid-lowering effects. By enabling patients to achieve previously unattainable LDL-C goals, it holds the potential to significantly alter the natural history of this devastating disease. Furthermore, its ability to substantially lower LDL-C may reduce or eliminate the need for burdensome and invasive procedures like lipoprotein apheresis, offering a significant improvement in quality of life. The drug's generally well-tolerated safety profile, with manageable risks primarily related to hypersensitivity reactions, supports its use as a foundational adjunct therapy in this high-risk population.

Looking forward, several key questions remain. The most critical is to determine the long-term impact of evinacumab-mediated lipid lowering on hard cardiovascular outcomes. While the profound reduction in atherogenic lipoproteins is strongly expected to translate into clinical benefit, prospective cardiovascular outcome trials will be necessary to formally quantify this effect. Continued long-term surveillance will also be important to monitor the consequences of sustained, mechanism-based HDL-C reduction, although existing genetic data are highly reassuring. Finally, the demonstrated efficacy of evinacumab in reducing triglycerides and cholesterol in other severe dyslipidemias opens promising avenues for future research and potential indication expansion, which could extend the benefits of ANGPTL3 inhibition to a broader population of patients at high cardiovascular risk. In conclusion, evinacumab stands as a testament to the power of translating genetic insights into targeted, life-altering therapies.

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