Recaticimab: The First Fc-Engineered PCSK9 Monoclonal Antibody for More Long-Lasting Effect in Lipid Lowering

Abstract

Atherosclerotic cardiovascular disease (ASCVD) continues to be a leading cause of morbidity and mortality worldwide, with elevated low-density lipoprotein cholesterol (LDL-C) being a major modifiable risk factor. Despite the efficacy of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in LDL-C reduction, suboptimal adherence remains a significant challenge and may limit the cardiovascular benefits achievable with these therapies. Recaticimab, the first Fc-engineered anti-PCSK9 monoclonal antibody incorporating YTE mutation (M252Y/S254T/T256E), was specifically designed to prolong half-life through enhanced neonatal Fc receptor (FcRn) binding, thereby enabling ultra-long dosing intervals of up to 12 weeks. Results from three Phase III clinical trials demonstrated that recaticimab achieves potent and sustained LDL-C reductions, either as monotherapy or in combination with statins, with a favorable safety and tolerability profile. By integrating the YTE mutation-derived structural innovation with robust Phase III clinical evidence, recaticimab may help address some limitations of existing PCSK9 inhibitors, including frequent injections and suboptimal persistence in real-world use. However, whether these pharmacological advantages translate into improved cardiovascular outcomes remains to be established, particularly given that current clinical evidence is largely derived from studies conducted in Chinese populations, and thus requires further validation in broader populations. Future studies should evaluate its impact on real-world adherence, cardiovascular outcomes, and cost effectiveness.

Key Points

Recaticimab is the first Fc-engineered anti-PCSK9 monoclonal antibody incorporating a YTE mutation to extend half-life.

Recaticimab may offer a durable lipid-lowering strategy, although its impact on long-term cardiovascular outcomes remains to be established.

From a clinical and public health perspective, recaticimab may help address clinical unmet needs related to treatment adherence and dosing burden.

Introduction

Atherosclerotic cardiovascular disease (ASCVD) remains a leading global cause of morbidity and mortality, with its burden intensifying due to population aging, lifestyle change and elevated healthcare costs [1–3]. Low-density lipoprotein cholesterol (LDL-C) is a key modifiable risk factor for ASCVD [4]. Large-scale meta-analyses have shown that each 1.0 mmol/L reduction in LDL-C reduces major adverse cardiovascular events by 21% [5]. Statins, the first-line lipid-lowering therapy (LLT), typically reduce LDL-C by 30–50% [6]. However, a considerable proportion of patients are either intolerant to statins, non-adherent, or unable to achieve target LDL-C levels despite high-intensity statin therapy [7], underscoring the need for alternative or adjunctive LLTs.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), negatively regulates LDL receptor (LDLR) recycling, thereby reducing LDL-C clearance [8]. Proprotein convertase subtilisin/kexin type 9 inhibition has emerged as a validated therapeutic approach, leading to the development of monoclonal antibodies (mAbs) that lower LDL-C by 50–60% in patients with inadequate response to statins [9]. However, currently available mAbs generally require biweekly or monthly subcutaneous (SC) injections and are frequently used in combination with statins, which complicates treatment regimens and negatively impacts long-term adherence [10–12]. Real-world studies have reported suboptimal adherence due to factors such as injection-related anxiety and high out-of-pocket costs [13–15].

To overcome these limitations, Fc engineering has been developed to lower the dosing frequency of therapeutic antibodies [16]. Mutations such as YTE (M252Y/S254T/T256E) and LS (M428L/N434S) enhance binding to the neonatal Fc receptor (FcRn), thereby extending antibody persistence and enabling less frequent dosing, which is particularly beneficial for chronic conditions requiring long-term treatment [17, 18]. Recaticimab, the first Fc-engineered anti-PCSK9 mAb, incorporates the YTE mutation to prolong its half-life, making it the longest-acting anti-PCSK9 mAb developed to date [19]. Notably, recaticimab is effective both as monotherapy and in combination with statins, with flexible dosing intervals ranging from every 4 to 12 weeks (requiring only 12 injections per year) [12, 19]. The extended dosing schedule may reduce treatment burden and could potentially improve patient adherence by decreasing injection frequency. Clinical studies have demonstrated its efficacy in adults with primary hypercholesteremia, including heterozygous familial hypercholesterolemia (HeFH) and non-FH and mixed dyslipidemia, either alone or with statins, resulting in its regulatory approval in China [20, 21]. Compared to other PCSK9 inhibitors, the long-acting property and monotherapy option of recaticimab may represent a clinically meaningful advancement in lipid management [12]. This review focuses on the structural innovation of YTE mutation and summarizes the clinical efficacy and potential benefits of recaticimab in long-term lipid management.

PCSK9 Biology and the Evolution of Inhibitor Therapies

Proprotein convertase subtilisin/kexin type 9, a serine protease primarily produced in the liver, has emerged as a crucial therapeutic target in lipid management. Secreted into the circulation, PCSK9 plays a key role in regulating plasma LDL-C levels by modulating LDLR turnover [9, 22].

LDLR-Mediated LDL-C Clearance

Low-density lipoprotein cholesterol clearance is primarily mediated by LDLRs, which are abundantly expressed on hepatocyte plasma membranes [23, 24]. At physiological pH, LDLRs bind circulating LDL-C and undergo clathrin-mediated endocytosis [25–28]. In the acidic endosomal environment, LDL-C dissociates from LDLR, allowing the receptor to recycle back to the cell surface [29], while internalized LDL-C is subsequently degraded in lysosomes (Fig. 1A).

Fig. 1.

Low-density lipoprotein (LDL)-mediated LDL-cholesterol (LDL-C) clearance and mechanism of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition. A LDL recycling and PCSK9-mediated LDL degradation. At physiological pH (7.4), LDL receptors on hepatocyte membranes bind circulating LDL-C via interactions between the ligand-binding domain and apolipoprotein B (ApoB)-100. The LDL receptor–LDL-C complex is internalized through clathrin-coated pits and trafficked to endosomes. In the acidic endosomal environment, LDL-C dissociates from LDL receptor, allowing the it to adopt a closed conformation and recycle back to the cell surface, whereas LDL-C is degraded in lysosomes. B Mechanism of anti-PCSK9 monoclonal antibodies. Anti-PCSK9 antibodies bind circulating PCSK9, blocking its interaction with LDLR. This preserves LDL receptor recycling, increases hepatocyte surface LDL receptor availability, and enhances LDL-C clearance

PCSK9-Mediated LDLR Degradation and Atherogenic Impact

In addition to mediating LDL-C uptake, LDLRs also serve as receptors for circulating PCSK9 [30]. Proprotein convertase subtilisin/kexin type 9 interacts with LDLR via its catalytic domain, leading to internalization of the complex and lysosomal degradation of LDLR, thereby reducing LDL-C clearance [27, 31]. Acidic endosomal pH enhances the affinity of the PCSK9-LDLR interaction by over 150-fold [31], preventing LDLR recycling and redirecting the complex to the lysosomal degradation pathway (Fig. 1A). Elevated plasma PCSK9 levels reduce LDLR availability on the hepatocyte surface, resulting in increased plasma LDL-C and promoting atherosclerosis [32]. Genetic studies have shown that individuals with PCSK9 loss-of-function mutations exhibit substantially lower LDL-C levels and a reduced risk of cardiovascular disease, validating PCSK9 as a compelling therapeutic target [33–36].

Approved and Emerging PCSK9-Targeted Therapies

Advances in the understanding of PCSK9 biology have led to the development of PCSK9-targeted drugs. To date, six anti-PCSK9 mAbs, evolocumab [37], alirocumab [38], tafolecimab [39], recaticimab [19], ebronucimab [40], and ongericimab [41], have been approved for dyslipidemia management by effectively blocking the PCSK9-LDLR interaction (Fig. 1B). The first-generation agents, evolocumab (Amgen) and alirocumab (Sanofi/Regeneron), are fully human mAbs that received regulatory approval in 2015 [37, 38]. Randomized controlled trials demonstrated that these agents reduce LDL-C levels by 50–60% and significantly lower the risk of major adverse cardiovascular events [42, 43]. More recently, several anti-PCSK9 mAbs have shown comparable lipid-lowering efficacy and were approved between 2023 and 2025 for dyslipidemia management [19, 40, 41, 44]. In addition, inclisiran (Novartis), a synthetic small interfering RNA (siRNA) that inhibits hepatic PCSK9 synthesis, was approved in 2021 [45]. Administered twice yearly, inclisiran provides LDL-C reductions similar to those of mAbs [46]; however, cardiovascular outcomes data are currently lacking (Table 1).

Table 1.

Approved PCSK9-targeted therapies: mechanism, dosing, and indications

Drug name	Drug type	IgG subtype	YTE mutation	FcRn binding mechanism	Dosing interval	Indication(s)	Approval time
Recaticimab	Humanized antibody	IgG1	Yes	Enhanced FcRn recycling	150 mg Q4W 300 mg Q8W	Monotherapy: adjunct to diet ± statin, primary hypercholesterolemia, HeFH, mixed dyslipidemia	China, 2025
Evolocumab	Fully human antibody	IgG2	No	Standard FcRn recycling	140 Q2W 420 mg QM	Primary hyperlipidemia, HeFH, HoFH, mixed dyslipidemia, ASCVD risk reduction	Global, 2015
Alirocumab	Fully human antibody	IgG1	No	Standard FcRn recycling	75 mg/150 mg Q2W 300 mg Q4W	Primary hyperlipidemia, HeFH, HoFH, ASCVD risk reduction	Global, 2015
Tafolecimab	Fully human antibody	IgG2	No	Standard FcRn recycling	150 mg Q2W 450 mg Q4W	Primary hypercholesterolemia, HeFH, mixed dyslipidemia	China, 2023
Ongericimab	Fully human antibody	IgG4	No	Standard FcRn recycling	150 mg Q2W 450 mg Q4W	Primary hypercholesterolemia, HeFH, mixed dyslipidemia	China, 2024
Ebronucimab	Fully human antibody	IgG1	No	Standard FcRn recycling	150 mg Q2W 450 mg Q4W	Primary hypercholesterolemia, HeFH, mixed dyslipidemia	China, 2024
Inclisiran	siRNA-based drug	N/A	N/A	Hepatic RISC degradation	Q6M (initial + Month 3)	Adjunct to diet and exercise for hyperlipidemia, including HeFH; and for pediatric HoFH; China: monotherapy approved	Global, 2020

ASCVD atherosclerotic cardiovascular disease, FcRn neonatal Fc receptor, HeFH heterozygous familial hypercholesterolemia, IgG1 immunoglobulin G1, HoFH homozygous familial hypercholesterolemia, N/A not applicable, PCSK9 proprotein convertase subtilisin/kexin type 9, Q every, Q2W every 2 weeks, RISC RNA-induced silencing complex, siRNA Small interfering RNA

Nowadays, oral PCSK9 inhibitors are under active clinical development, with some agents demonstrating significant LDL-C–lowering efficacy comparable to monoclonal antibodies in Phase III trials [47, 48], and may offer improved accessibility compared with injectable therapies. However, their use may require strict dietary control, and their effectiveness in real-world settings remains to be further established. Other emerging approaches, including gene editing strategies, peptide-based PCSK9 vaccines, may represent potentially transformative options for long-term lipid control [49, 50]. These emerging modalities may further expand the therapeutic landscape of PCSK9-targeted interventions. Nevertheless, long-term safety, off-target effects, and cardiovascular outcomes will need to be carefully addressed in future studies.

Real-World Challenges: Adherence and Long-Term Persistence

Adherence is a critical determinant of effective dyslipidemia management, given the chronic nature of the disease [14] and the well-established link between sustained LDL-C reduction and decreased cardiovascular risk [5, 15]. However, real-world data reveal suboptimal adherence across different classes of LLTs [11]. Statins and ezetimibe are associated with poor long-term persistence [51–53], with reported 36-month persistence rate of 20.6% and 22.3%, respectively [54, 55]. Despite their potent lipid-lowering efficacy, adherence to PCSK9 inhibitors in a real-world setting also remains suboptimal (Table 2). Report proportion of days covered (PDC) averages approximately 0.64 [56], and patients achieving PDC ≥ 80% ranged from 49 to 64% [56, 57]. Similarly, over 30% of patients fail to reach medication possession ratio (MPR) ≥ 80% [57]. In clinical practice, discontinuation rates for anti-PCSK9 mAbs exceed 30% within the first year of therapy [58, 59], and long-term persistence continues to decline thereafter. At 36 months post-initiation, only 50.9% of patients remained on anti-PCSK9 mAbs therapy [54].

Table 2.

Global real-world evidence on adherence and persistence with PCSK9 monoclonal antibodies

Study (Year)	Country/population	Drug(s)	Adherence assessment	Key findings
Elis et al, J Clin Med 2023 [57]	Israel, Maccabi HMO, ASCVD or very high-risk	Alirocumab	PDC, MPR (≥ 80% = high adherence)	PDC ≥ 80%: 64.4%; MPR ≥80%: 69.1%
Hines et al, Vasc Health Risk Manag 2018 [56]	US commercial and Medicare early users	Evolocumab, alirocumab	PDC (≥ 0.8 = high adherence)	Mean PDC = 0.64; 48.9% achieved PDC ≥ 0.8; 42.6% discontinued within 1 year
Svensson et al, Ups J Med Sci 2024 [59]	Sweden, nationwide retrospective, ASCVD (n≈1858)	Evolocumab	Persistence (refill gap), PDC	12-month persistence: 76%; PDC adherence: 86%; mean LDL-C reduction ≈ 53%
Takahashi et al, J Atheroscler Thromb 2025 [58]	Japan, claims database, high-risk ASCVD (n=276)	Evolocumab/alirocumab	Persistence (1-year)	1-year persistence: 67.0%
Muntner et al, Adv Ther 2024 [55]	US, commercial claims, PCSK9i initiators (n≈16,600)	Evolocumab, alirocumab	Persistence (60-day gap), PDC ≥ 80%	6-month persistence: 76%; 12-month persistence: 82%; adherence 74%; slightly higher than ezetimibe

ASCVD atherosclerotic cardiovascular disease, HeFH heterozygous familial hypercholesterolemia, HMO health maintenance organization, LDL-C low-density lipoprotein cholesterol, PCSK9i proprotein convertase stubtilisin/kexin type 9 inhibitor, PDC proportion of days covered, MPR medication possession ratio

Nonadherence is a multifactorial issue influenced by patient-related factors and socioeconomic barriers, with key contributors including drug cost, accessibility, and healthcare system infrastructure [60, 61]. In the context of PCSK9 inhibitors, common obstacles include injection-related anxiety, out-of-pocket costs, and the lack of immediate perceptible benefits [14, 56]. Most currently available anti-PCSK9 mAbs require frequent SC administration (typically every 2 or 4 weeks), resulting in 24 to 36 injections per year [57, 62]. Inclisiran provides a twice-yearly dosing alternative; however, its relatively delayed onset of action may be less suitable for patients requiring rapid LDL-C reduction [10, 46]. Moreover, both frequent mAb dosing and RNA-based therapy may be associated with economic burdens, which could negatively influence long-term adherence.

Long-acting agents and simplified dosing regimens have been associated with improved treatment adherence [13, 14], although adherence to biologic therapies remains influenced by multiple factors. For anti-PCSK9 mAbs, extending dosing intervals may help reduce injection-related burden, including injection fatigue or anxiety, and could potentially improve treatment persistence [12, 63]. Given their well-established efficacy in lowering LDL-C, the development of long-acting mAbs that maintain efficacy with fewer administrations represents a potentially useful strategy to address treatment adherence challenges.

Recaticimab, an Fc-engineered, long-acting anti-PCSK9 mAb, was approved in China on January 8, 2025, for the treatment of primary hypercholesteremia and mixed dyslipidemia. To date, the available clinical evidence and regulatory approval are largely derived from studies in Chinese populations, and the generalizability of these findings to other populations requires further investigation. Recaticimab offers flexible dosing intervals ranging from every 4 to 12 weeks, with equivalent annual dosing exposure across regimens (12 injections/year). Recaticimab has been included in the Chinese National Reimbursement Drug List, which may improve its accessibility for patients in China. Based on current pricing and dosing regimens, its annual treatment cost (6576 CNY Chinese yuan) appears broadly comparable to other anti-PCSK9 mAbs and lower than that of siRNA-targeted therapies (Table 3). However, the actual out-of-pocket burden to patients will depend on regional reimbursement policies and co-payment structures.

Table 3.

Estimated monthly and annual treatment costs of PCSK9-targeted therapies in China

Generic name	Unit price, CNY	Cost calculation basis	Monthly cost, CNY	First-year cost, CNY	Economic note
Recaticimab	548/injection	150 mg (1 injection) Q4W/300 mg (2 injections) Q8W	548	6576	Equivalent monthly cost across Q4W and Q8W regimens
Evolocumab	283.8/injection	140 mg (1 injection) Q2W	567.6	6811.2	Alternative: 420 mg monthly
Alirocumab	286/injection	75 mg (1 injection) Q2W	572	6864	Based on Q2W regimen
Tafolecimab	279/injection	150 mg (1 injection) Q2W	558	6696	Based on Q2W regimen
Ongericimab	272/injection	150 mg (1 injection) Q2W	544	6528	Based on Q2W regimen
Ebronucimab	276.55/injection	150 mg (1 injection) Q2W	553.1	6637.2	Based on Q2W regimen
Inclisiran	2790/injection	3 injections in first year	697.5	8370	First-year cost based on 3 injections; long-term monthly average ≈465

Costs were estimated based on publicly available prices and simplified standard dosing schedules. For Q2W regimens, monthly cost was estimated using 2 injections per month; for inclisiran, first-year cost was based on 3 injections in Year 1

CNY Chinese yuan, Q2W every 2 weeks, PCSK9 proprotein convertase subtilisin/kexin type 9

Recaticimab: The First Fc-Engineered and Longest-Acting PCSK9 Antibody

Fc engineering has emerged as a promising strategy to lower dosing frequency of mAbs [16, 64]. Modifying the Fc region to enhance its affinity for FcRn improves the recycling and serum persistence of antibodies, resulting in a prolonged serum half-life and reduced dosing frequency [18]. Among these modifications, the YTE (M252Y/S254T/T256E) and LS (M428L/N434S) mutations are the most widely studied [17]. These advances have paved the way for the development of long-acting biologics. Recaticimab, the first Fc-engineered, humanized immunoglobulin G1 (IgG1) anti-PCSK9 mAb, was specifically designed with a YTE mutation in its Fc region, making it the longest-acting anti-PCSK9 mAb globally (Fig. 2).

Fig. 2.

Structural model of recaticimab Fc region highlighting YTE mutation. Ribbon and surface representation of recaticimab Fc fragment highlighting the YTE triple mutation (M252Y/S254T/T256E, shown in magenta). The YTE substitution enhances binding affinity to the neonatal Fc receptor (FcRn) at acidic pH, thereby prolonging antibody recycling, and serum half-life. This Fc engineering underpins the ultra-long dosing interval of recaticimab, distinguishing it as the longest-acting anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody globally

FcRn-Mediated Recycling of IgG

Immunoglobulin G (IgG), which constitutes approximately 85% of circulating antibodies, is widely used in therapeutic applications due to its long serum half-life [65]. The long half-life is primarily mediated by FcRn, which protects IgG from intracellular degradation through a recycling pathway [66].

Neonatal Fc receptor (FcRn) is expressed in various tissue and plays a key role in maintaining IgG homeostasis by binding and recycling IgG within cells [67, 68]. Following nonspecific endocytosis, IgG enters acidified endosomes, where FcRn binds to IgG [69, 70]. The IgG-FcRn complex is subsequently recycled back to the cell surface and released into the circulation at neutral pH, thereby avoiding lysosomal degradation [71].

This interaction is pH-dependent: IgG binds FcRn with high affinity under acidic conditions but dissociates at neutral pH, a mechanism largely driven by protonation of histidine residues in the Fc region [72–75]. This pH-dependent interaction is essential for preventing IgG from lysosomal degradation, ensuring its prolonged serum persistence (Fig. 3A).

Fig. 3.

FcRn-mediated IgG recycling enhanced by YTE engineering. A Physiological FcRn–IgG recycling. Circulating IgG is taken up by endothelial cells or monocytes via fluid-phase endocytosis into acidified endosomes. At acidic pH (≈ 6.0), protonation of Fc histidine residues enables pH-dependent binding of IgG to the neonatal Fc receptor (FcRn) in a 2:1 stoichiometry (two FcRn heterodimers per IgG molecule). This interaction protects IgG from lysosomal degradation and sorts IgG–FcRn complexes into recycling vesicles. Upon reaching the cell surface, neutral pH triggers dissociation and IgG is released back into the circulation, thereby extending its serum half-life. B YTE-enhanced FcRn recycling. The YTE triple mutation (M252Y/S254T/T256E) in the Fc region significantly increases FcRn binding affinity under acidic conditions while maintaining low binding at neutral pH. This results in more efficient FcRn-mediated recycling and reduces lysosomal degradation, prolonging antibody serum persistence. Recaticimab leverages this modification with extended dosing intervals (Q4W, Q8W, Q12W)

YTE Mutation Significantly Enhances FcRn Binding

To further prolong the half-life of therapeutic antibodies, Fc engineering strategies have been employed to enhance FcRn binding [16]. One of the most well-characterized modifications is the YTE mutation (M252Y/S254T/T256E), which increases IgG-FcRn affinity at acidic pH while maintaining minimal binding at neutral pH [76]. Preclinical studies in cynomolgus monkeys have shown that the YTE mutation can extend antibody serum half-life by up to 4-fold [76], and it has been successfully applied to therapeutic antibodies, such as nirsevimab [77]. Recaticimab similarly incorporates the YTE mutation, resulting in an approximately 10-fold increase in FcRn binding affinity compared with wild-type IgG1 or other PCSK9 antibodies (patent data). The enhanced affinity facilitates more efficient FcRn-mediated recycling and contributes to its prolonged serum half-life (Fig. 3B). Consequently, recaticimab supports extended dosing intervals of up to 12 weeks through proportional dose adjustments [i.e., 150 mg every 4 weeks (Q4W), 300 mg every 8 weeks (Q8W), 450 mg every 12 weeks (Q12W)], while maintaining efficacy. The Fc engineering approach illustrates the potential of FcRn-targeted modifications to optimize antibody pharmacokinetics and enable less frequent dosing.

PK/PD Profile of YTE-Modified Recaticimab

The YTE mutation substantially prolongs recaticimab’s systemic persistence through enhanced FcRn binding, resulting in a median half-life close to four weeks—considerably longer than that of conventional PCSK9 mAbs. Following SC administration, serum concentrations rise gradually (T_max ≈ 6–9 days) and remain well above the efficacy threshold of ~ 1.2 μg/mL across Q4W, Q8W, and Q12W regimens, ensuring consistent LDL-C suppression without the need for dose escalation [78, 79].

Population pharmacokinetic/pharmacodynamic (PK/PD) modeling based on seven clinical studies demonstrated highly predictable exposure–response relationships and confirmed that baseline characteristics (e.g., weight, body mass index [BMI], sex), clinical factors (statin co-therapy, renal function, injection site), and immunogenicity do not meaningfully influence drug exposure [79, 80]. These findings support a fixed-dose strategy and allow for simplified, flexible administration without individualized adjustment.

Pharmacodynamically, recaticimab achieves rapid and sustained PCSK9 inhibition, with free PCSK9 levels suppressed within 48 h post-dose and LDL-C reductions approaching 50% by day 7 [78]. Nadir LDL-C levels are typically observed by weeks 3–4, with placebo-adjusted reductions of − 56 to − 66% across dosing regimens, followed by stable maintenance throughout the dosing interval. In addition to LDL-C, durable reductions were observed in TC, non-HDL-C, ApoB, and Lp(a). Besides, no clinically meaningful accumulation was observed with repeated dosing.

Simulation analyses further support flexible initiation and maintenance strategies: therapy can begin with 150 mg Q4W or 300 mg Q8W for rapid LDL-C lowering, followed by maintenance with 300 mg Q8W or 450 mg Q12W once steady-state is reached [79]. These data collectively provide a strong mechanistic and clinical basis for extended-interval dosing, balancing potent LDL-C control with enhanced convenience.

Immunogenicity of YTE-Modified Recaticimab

In addition to its pharmacokinetic (PK)advantages, the immunogenicity of YTE-modified recaticimab represents an important consideration for long-term clinical use. Available data from Phase I–III trials indicate that anti-drug antibodies (ADAs) were detected in approximately 14.1% of patients, with neutralizing antibodies (Nabs) observed in 3.2%. In these studies, the presence of ADAs was not associated with a clear impact on lipid-lowering efficacy or safety outcomes. The LDL-C reductions were generally comparable between ADA-positive and ADA-negative patients (47–60% vs 46–54%, respectively). The incidence of treatment related adverse events (TRAEs) was 29.5% in ADA-positive and 22.5% ADA-negative patients [81]. These findings contrast with those observed for bococizumab, a humanized anti-PCSK9 mAb that was discontinued due to high rates of immunogenicity, leading to attenuated LDL-C reduction and increased variability in treatment response [82].

Although current data for recaticimab are encouraging, the clinical relevance of immunogenicity, particularly with YTE mutation and prolonged exposure, remains to be fully established. Continued monitoring in long-term and real-world studies will be essential to better characterize its immunogenic profile. A Phase IV trial is currently ongoing in Chinese patients with ASCVD or at high risk for ASCVD who have not achieved lipid targets (ChiCTR2500099939).

YTE Mutation Enables Potent LDL-C Reduction with Extended Dosing Intervals

The YTE mutation enables recaticimab to maintain potent LDL-C reduction while supporting extended dosing intervals (Q4W–Q12W), which have been consistently evaluated across clinical trials [20, 21, 78]. Confirmatory trials subsequently demonstrated that these less frequent dosing schedules maintained robust efficacy in lowering LDL-C and other lipid parameters (Table 4).

Table 4.

Efficacy and safety of recaticimab with YTE mutation in Chinese patients across Phase Ib/II and Phase III trials

Study (year)	Population	Primary endpoint	Secondary endpoint	Dosing regimen	Efficacy	Safety summary
Phase Ib/II (Xu et al, 2022) [78] Randomized, double-blind, placebo-controlled, Phase Ib/II study	Adults aged 18 to 65 years, non-HoFH, LDL-C ≥2.6 mmol/L before randomization (either for those receiving statin therapy and/or other LLTs and LDL-C ≥ 2.6 mmol/L, or without any LLT and LDL-C ≥ 3.4 mmol/L), fasting TG ≤ 4.5 mmol/L, BMI of 18 to 35 kg/m2.	The primary endpoint was percentage change in LDL-C from baseline to EoT: at Week 16 for patients receiving treatment Q4W and Q8W and at Week 24 for patients receiving treatment Q12W	Secondary efficacy endpoints included absolute change in LDL-C from baseline to EoT, percentage changes from baseline to EoT in other lipids (including total cholesterol [TC], high-density lipoprotein-cholesterol [HDL-C], non-HDL-C, and TG), apolipoproteins (including ApoB, ApoA1, and Lp[a]), and free PCSK9	75 mg Q4W, 150 mg Q4W/8W, 300 mg Q8W/12W, 450 mg Q12W + atorvastatin; At each allocated dose and schedule, patients were randomized, in a 5:1 ratio, to receive recaticimab or matching placebo	Recaticimab significantly reduced LDL-C vs placebo at all doses (all  p < 0.0001). LDL-C (− 43.9 to − 55.1%) vs placebo (+4.4%), with placebo-adjusted reductions of − 48.4 to − 59.5% and absolute reductions of − 1.59 to − 1.92 mmol/L. Maximum LDL-C reductions occurred at week 4 for 150 mg Q8W (− 73.5%) and 300 mg Q8W (− 59.3%), and week 3 for 300 mg Q12W (− 65.7%) and 450 mg Q12W (− 65.5%), followed by slight rebound before the next dose Recaticimab also reduced TC (− 31.3 to − 37.8%), non-HDL-C (− 39.9 to − 52.3%), ApoB (− 35.6 to − 47.7%), and Lp(a) (− 21.6 to − 47.5%) vs minimal changes with placebo	The incidence of TEAEs was similar between recaticimab (74.7% [68/91]) and placebo (73.7% [14/19]), with most events being mild. Moderate TEAEs occurred in 5.5% of recaticimab-treated patients, and one (1.1%) had a severe event (elevated gamma-glutamyl transferase). All moderate and severe treatment-related TEAEs were alleviated or resolved by symptomatic treatments or interruption of study treatment, except the outcome of a ventricular extrasystole was unknown due to end of study No serious TEAEs, discontinuations, or deaths occurred; injection-site reactions were reported in 5.5% of recaticimab patients
REMAIN-1 (Xu et al, 2024) [21] Multicenter, randomized, double-blind, placebo-controlled, Phase III study	Eligible patients were men and women aged ≥ 18 to ≤ 80 years, fasting LDL-C level of ≥ 2.6 to < 4.9 mmol/L, a fasting TG level of ≤ 5.6 mmol/L, non-FH, and a 10-year ASCVD risk score of < 10%	The primary endpoint was percentage change in LDL-C from baseline to Week 12 for 150 mg Q4W and 450 mg Q12W dosing groups and to Week 16 for the 300 mg Q8W dosing group	Absolute change in LDL-C from baseline to the end of core treatment; % changes in non–HDL-C, ApoB, TC/HDL-C, ApoB/ApoA1, Lp(a), and TG from baseline to the end of core treatment; proportion of patients achieving LDL-C lowering target of < 2.6 mmol/L (< 100 mg/dL) at the end of core treatment; percentage change in LDL-C from baseline to Week 24; proportion of patients achieving LDL-C lowering target of < 2.6 mmol/L at week 24; safety; immunogenicity	Eligible patients were randomly assigned (2:2:2:1:1:1) to receive SC injections of recaticimab at 150 mg Q4W, 300 mg Q8W, or 450 mg Q12W or matching placebo under the same dosing strategy	Recaticimab significantly reduced LDL-C vs placebo across all dosing regimens (all p < 0.0001), with LS mean reductions of − 45.6 to − 50.5% vs − 0.6 to +2.3% for placebo, and placebo-adjusted reductions of − 45.0 to − 52.8% (absolute change in LDL-C relative to placebo were − 1.6 to − 1.9 mmol/L); 86.9 to 91.0% of patients achieved LDL-C < 2.6 mmol/L vs 3.9 to 8.2% with placebo; recaticimab also reduced non-HDL-C (− 43.4 to − 47.3%), ApoB (− 40.3 to − 46.0%), and Lp(a) (− 18.3 to − 32.4%) vs placebo (all p < 0.0001); after 24 weeks, LDL-C reductions were sustained (− 47.3 to − 53.1%), with 84.5 to 92.8% of patients maintaining LDL-C < 2.6 mmol/L	TRAEs occurred in 14.1% [66/468] of recaticimab-treated and 11.1% [26/235] of placebo patients, mostly mild; 0.2% experienced serious TRAEs, and 0.2% discontinued treatment. The majority of TRAEs were mild in severity (114 [24.4%] patients). The most common TRAEs were injection site reactions (4.9%), hyperuricemia (4.1%), elevated CPK (3.6%), and upper respiratory infections (3.4%). Serious TRAE was reported in 1 (0.2%) patient (acute myeloid leukemia, with causality in relation to recaticimab being unassessable). ADA and NAb positivity were observed in 18.6% [85/456] and 5.9%[27/456] of patients, respectively, with no impact on LDL-C lowering or TRAE rates No dose-dependent safety signals or fatal AEs were reported
REMAIN-2 (Sun et al, 2024) [20] Multicenter, randomized, double-blind, placebo-controlled, Phase III study	Eligible patients aged 18 to 80 years, with an LDL-C level of ≥1.8 or ≥2.6 mmol/L and a fasting TG level of ≤5.6 mmol/L, non-FH, with background LLT, including moderate- or high-intensity statin, with or without other LLT (cholesterol absorption inhibitors [ezetimibe] or fenofibrate)	The primary endpoint was the percentage change in LDL-C level from baseline to Week 24	Secondary endpoints included absolute change from baseline to Week 24 in LDL-C, absolute change and percentage change from baseline to Week 48 in LDL-C, proportion of patients achieving LDL-C targets (define as < 1.8 mmol/L for patients with ASCVD and < 2.6 mmol/L for those without) at Weeks 24 and 48, percentage changes from baseline to Weeks 24 and 48 in non-HDL-C, ApoB, the ratio of TC to HDL-C, the ratio of ApoB to ApoA1, Lp(a), and TG	Patients were assigned randomly in a 2:2:2:1:1:1 ratio to receive SC injections of recaticimab 150 mg Q4W, 300 mg Q8W, or 450 mg Q12W, or matching placebo (Q4W, Q8W, or Q12W) for 48 weeks	Recaticimab significantly reduced LDL-C levels at Week 24 across all dosing regimens (150 mg Q4W − 62.2%, 300 mg Q8W − 59.7%, and 450 mg Q12W − 53.4%), with consistent superiority over placebo (P < 0.0001). LDL-C target achievement rates reached 85.8 to 94.5% with recaticimab, versus only 13.9 to 15.9% with placebo. The decreases in LDL-C with recaticimab were maintained through Week 48 across all dosing regimens The absolute LDL-C reduction 1.5 to 1.7 mmol/L across all dosing regimens, regardless of age, BMI, ASCVD, T2DM, baseline LDL-C, or background LLT. Recaticimab also improved other lipid parameters, including non-HDL-C, TC/HDL-C, ApoB, ApoB/ApoA1, and Lp(a)	At Week 48, TRAEs occurred in 28.5% [130/456] of recaticimab-treated and 26.6% [62/233] of placebo patients, with overall AEs in 84.4%[385/456] and 82.8% [193/233], respectively. Most TRAEs were mild and similar across dosing groups; 1.1% of recaticimab patients discontinued due to TRAEs. Serious TRAEs were rare (0.4%) and no treatment-related deaths occurred. The most common TRAEs were elevated ALT (4.6%), AST (3.3%), CPK (4.4%) , hyperuricemia (3.7%), and injection site reactions (3.9%) ADA and NAb positivity were observed in 21.2% [96/452] and 4.4% [20/452] of patients, respectively, without impact on LDL-C lowering or TRAE rates
REMAIN-3 (Chen et al, 2024) [83] Multicenter, randomized, double-blind, placebo-controlled Phase III study	Adults with HeFH on stable LLT for ≥28 days, LDL-C of ≥2.6 mmol/L (≥1.8 mmol/L if with a history of ASCVD), and fasting TG of ≤5.6 mmol/L	The primary endpoint was the percentage change in LDL-C from baseline to Week 12.	Secondary endpoints included absolute change in LDL-C from baseline to Week 12; percentage changes in non-HDL-C, ApoB, TC/HDL-C, ApoB/ApoA1, Lp(a), and TG from baseline to Week 12; proportion of patients achieving LDL-C lowering target (< 1.8 mmol/L for patients with a history of ASCVD and < 2.6 mmol/L for those without a history of ASCVD) at Week 12; safety; and immunogenicity	Pts were randomly allocated (2:1) to receive recaticimab or placebo (SC, 150 mg, Q4W) for 12 weeks, stratified by concomitant use of ezetimibe (yes vs no) and LDL-C (≥ vs < 4.1 mmol/L)	At Week 12, the mean percentage change in LDL-C was − 54.4% (95% CI, − 57.9 to − 50.8%) in the recaticimab group and − 4.5% (95% CI, − 9.4 to 0.3%) in the placebo group, with a treatment difference of − 49.8% (95% CI, − 55.8 to − 43.9%; p < 0.0001). Recaticimab was superior to placebo in improving other lipids, including non-HDL-C, ApoB, TC/HDL-C, ApoB/ApoA1, and Lp(a)	TRAEs occurred in 26 (27.4%) recaticimab patients vs 12 (25.0%) placebo. The only TRAEs ≥5% with ≥2% difference were injection-site reaction [8 (8.4%) vs none] and increased blood CPK [5 (5.3%) vs 1 (2.1%)] After 12 weeks, 8 (8.4%)/95 recaticimab patients developed ADAs, 7 (7.4%) were NAb-positive; none in placebo were positive. Median ADA onset: 89 days (range 83–156). ADA positivity had no effect on LDL-C lowering (Week 12: − 63.6% vs − 52.5%) or safety

ADA anti-drug antibodies, ApoB apolipoprotein B, ASCVD atherosclerotic cardiovascular disease, BMI body mass index, CI confidence interval, CPK creatine phosphokinase, EoT end of treatment, FH familial hypercholesterolemia, HeFH heterozygous familial hypercholesterolemia, LDL-C low-density lipoprotein cholesterol, LLT lipid-lowering therapy, Lp(a) lipoprotein(a), NAb neutralizing antibodies, non-HDL-C non–high-density lipoprotein cholesterol, Q4W every 4 weeks, Q8W every 8 weeks, Q12W every 12 weeks, SC subcutaneous, TC/HDL-C total cholesterol to high-density lipoprotein ratio, T2DM type 2 diabetes mellitus, TEAE treatment-emergent adverse event, TG triglycerides, TRAE treatment-related adverse event

Monotherapy: Potent LDL-C Reduction Even with Extended Intervals

For dyslipidemia patients at low risk of ASCVD who are statinnaïve, recaticimab offers an effective monotherapy option with the convenience of infrequent dosing. In the Phase III REMAIN-1 trial, adults with non-familial hypercholesterolemia (FH) and mixed hyperlipidemia, fasting LDL-C ≥ 2.6 to < 4.9 mmol/L, triglyceride ≤  5.6 mmol/L and a 10-year ASCVD risk < 10% were randomized to receive recaticimab 150 mg Q4W, 300 mg Q8W, or 450 mg Q12W or matching placebo [21].

Despite extended dosing intervals, all recaticimab regimens achieved significant LDL-C reductions versus placebo at week 12/16, with mean percent changes of − 49.6% for Q4W, − 52.8% for Q8W, and − 45.0% for Q12W (primary endpoint; all p < 0.0001). In addition to LDL-C, recaticimab significantly reduced secondary lipid parameters, including non-HDL-C, ApoB, Lp(a) across all dose regimens. Recaticimab was well tolerated across all dose regimens, with a safety profile comparable to placebo. The incidence of TRAEs was similar between the recaticimab and placebo groups. Most TRAEs were mild in severity and serious TRAEs were rare (0.2% vs 0%). The most common TRAEs were injection-site reaction, occurring in 4.9% of patients. The REMAIN-1 trial demonstrated that recaticimab monotherapy, even at extended dosing intervals (every 8 or 12 weeks), achieves robust LDL-C reduction with a favorable safety profile. Its long-acting nature and simplified monotherapy regimen may help improve adherence and facilitate the translation of clinical efficacy into real-world effectiveness, although this requires further validation.

Add-On to Statins: Long-Term Goal Achievement with Q8W/Q12W Regimens

Recaticimab has further validated the efficacy of extended dosing intervals in patients with non-FH and mixed hyperlipidemia inadequately controlled on statin therapy. In combination with moderate- or high-intensity statins, it achieves potent and sustained LDL-C reduction with dosing intervals extended to every 8 or 12 weeks. In the Phase III REMAIN-2 trial, adults with LDL-C ≥ 1.8 mmol/L (with ASCVD) or ≥ 2.6 mmol/L (without ASCVD), fasting triglyceride ≤ 5.6 mmol/L and a stable moderate- or high- statin therapy (with or without ezetimibe or fenofibrate) for ≥ 4 weeks were randomized to receive recaticimab 150 mg Q4W, 300 mg Q8W, or 450 mg Q12W or matching placebo for 48 weeks [20].

Recaticimab produced substantial placebo-adjusted reductions in LDL-C at week 24: − 62.2% for Q4W, − 59.7% for Q8W, and − 53.4% for Q12W (primary endpoint, all p < 0.0001). The reductions from baseline in LDL-C were sustained through week 48—supporting the long-term use of recaticimab. Among all dosing strategies, the majority of patients achieved their LDL-C goals at week 24, with 90.2% for 150 mg Q4W, 94.5% for 300 mg Q8W, and 85.8% for 450 mg Q12W. For patients with ASCVD, the proportion achieving an LDL-C  < 1.8 mmol/L was 91.2% (93/102), 94.3% (100/106), and 84.4% (81/96) for the three dose regimens, respectively. Moreover, the proportion of patients achieving their LDL-C goal was sustained until Week 48. In addition to LDL-C, significant improvements were observed in other lipid parameters, including non-HDL-C, apoB, and Lp(a).

Notably, patients at high cardiovascular risk, such as those with type 2 diabetes (T2DM) or a history of ASCVD, are of significant clinical interest, given their elevated risk of recurrent events and greater need for effective lipid control. Subgroup analysis showed that recaticimab maintained robust LDL-C–lowering efficacy even with extended dosing intervals in these high-risk populations. For patients with a history of ASCVD, the placebo-adjusted reductions in LDL-C at Week 24 were − 62.0% (150 mg Q4W), 58.0% (300 mg Q8W), and 53.8% (450 mg Q12W). For patients with T2DM, the corresponding reductions were − 63.4%, 63.2%, and 54.3%, respectively. These findings further demonstrate that even among high-risk populations, recaticimab maintains potent efficacy with extended dosing intervals.

The safety profile remained favorable, with TRAEs occurring at similar rates in both recaticimab and placebo groups. The TRAEs were mostly of mild severity and showed similar incidence across different dosing regimens. Injection-site reactions occurred in 18 patients (3.9%) receiving recaticimab and 3 patients (1.3%) receiving placebo, with mild-to-moderate severity and self-resolving.

Taken together, the REMAIN-2 trial confirms the potent and sustained LDL-C–lowering efficacy of recaticimab when used in combination with statin therapy. Both bimonthly and quarterly regimens effectively maintained lipid goal attainment over the long term, while preserving a favorable safety and tolerability profile. These findings support recaticimab as a convenient and effective adjunct to statins, offering a simplified treatment approach for high-risk patients requiring intensive lipid management.

However, cardiovascular outcomes data for recaticimab are not yet available. While LDL-C reduction is strongly associated with cardiovascular risk reduction, it should not be considered a substitute for hard clinical endpoints when evaluating a novel therapy. Ongoing studies are expected to address this gap, including the PICASSO trial (NCT07119918), which is assessing recurrent cerebrovascular events in patients with acute ischemic stroke or high-risk transient ischemic attack, and the INCLINE-AMI trial (NCT07290699), which is evaluating early initiation in patients with acute myocardial infarction undergoing percutaneous coronary intervention and its impact on major adverse cardiovascular events.

Clinical Advantages of Fc-Engineered PCSK9 Antibodies

Recaticimab, the first Fc-engineered anti-PCSK9 mAb, represents a notable advancement in LLT by offering reduced dosing frequency without compromising efficacy. When administered once every 8 or 12 weeks, recaticimab achieves LDL-C–lowering efficacy comparable to conventional anti-PCSK9 mAbs, which typically require more frequent dosing every 2–4 weeks. This extended dosing interval is achieved through proportional dose adjustments, eliminating the need for dose escalation while maintaining consistent efficacy. In contrast, agents such as evolocumab require a higher dose to sustain efficacy at longer intervals, for example, 140 mg Q2W (1 injection) or 420 mg Q4W (3 injection) [37] (Fig. 4).

Fig. 4.

Comparison of dosing intervals and injection burden among proprotein convertase subtilisin/kexin type 9 (PCSK9)-targeted therapies. Comparison of dosing schedules among approved anti-PCSK9 monoclonal antibodies over a 24-week treatment period. Recaticimab enables extended dosing intervals of every 8 or 12 weeks while maintaining potent low-density lipoprotein cholesterol (LDL-C)–lowering efficacy comparable to conventional agents that require dosing every 2–4 weeks. The figure illustrates injection frequency and cumulative injection counts for each regimen

Another key advantage of recaticimab is its flexible dosing regimen. Patients can transition between dosing schedules based on physician recommendations and individual preferences regarding injection frequency and volume [79]. The new regimen is administered on the date of the next scheduled injection from the prior regimen. This flexibility may contribute to improved treatment adherence by accommodating patients’ lifestyle and convenience. While extended dosing intervals may improve treatment convenience, they may introduce a clinically relevant “forgiveness gap,” particularly if doses are missed. In such cases, the prolonged interval between administrations could result in periods of suboptimal LDL-C control. Although recaticimab has a relatively long half-life, which may provide some degree of PK buffering, the extent to which this mitigates the clinical impact of missed doses remains to be established.

Recaticimab produces a rapid onset of action, with LDL-C levels beginning to decline within days after administration [78]. This is in stark contrast to siRNA-based therapies, which may take several weeks or even months to reach maximal effect due to their gene-silencing mechanisms. The rapid action of recaticimab is particularly beneficial in patients with established ASCVD who require prompt lipid-lowering intervention [12, 78]. By combining potent efficacy, extended dosing intervals, flexible administration, and rapid onset, recaticimab may address some of the current challenges in ASCVD management, particularly those related to treatment adherence. Infrequent dosing schedules may reduce the burden of ongoing therapy and could potentially lower the risk of discontinuation, thereby supporting sustained LDL-C control [14]. Additionally, the convenience and flexibility of bimonthly or quarterly dosing may improve patient satisfaction and facilitate wider adoption by physicians, although real-world data are needed to confirm these potential benefits.

Conclusions and Future Perspectives

Recaticimab represents a mechanism-driven innovation in lipid management, combining YTE-engineered FcRn binding enhancement with potent PCSK9 neutralization to achieve durable LDL-C lowering at previously unattainable extended dosing intervals (Q4W–Q12W). By leveraging increased FcRn recycling and prolonged systemic exposure, recaticimab maintains serum concentrations well above the PCSK9-saturating threshold throughout the dosing cycle, enabling simplified fixed-dose regimens without the need for individual titration. Phase III REMAIN trials consistently demonstrated ~50%–60% LDL-C reductions, high goal-attainment rates, and a favorable safety and immunogenicity profile across key patient subgroups, including ASCVD, diabetes, and chronic kidney disease (CKD), with no dose-dependent safety signals observed.

From a clinical and public health perspective, recaticimab may address two challenges in lipid-lowering therapy: (1) improving adherence by decreasing injection frequency, and (2) reducing treatment burden in patients requiring lifelong therapy. However, whether these pharmacological and adherence-related advantages translate into improved cardiovascular outcomes remains to be established. In addition, current clinical evidence is largely derived from studies conducted in Chinese populations, and the generalizability of these findings to broader populations requires further validation.

Future priorities include well-designed head-to-head trials against inclisiran and first-generation PCSK9 mAbs to compare efficacy kinetics, durability of LDL-C control, and cost effectiveness, as well as large-scale real-world studies across diverse health-care systems. Such evidence will define recaticimab’s role in global lipid-lowering strategies and may position it as a cornerstone of guideline-directed therapy for ASCVD risk reduction.

Funding

This article was supported by CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-C&T-B-030).

Declarations

Conflict of interest

All authors declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript.

Authors' contributions

Jian-Jun Li conceived, designed, and programmed the paper, Sha Li and Ying Gao wrote the manuscript and Cheng-Gang Zhu reviewed, revised, and finalized the manuscript. All authors have read and approved the final version.

Data availability statement

Data sharing not applicable to this article as no datasets were generated for this review article.

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