Efficacy and safety of alirocumab once-monthly in patients with atherosclerotic cardiovascular disease and without history of an acute atherothrombotic event

Long-term reduction of low-density lipoprotein cholesterol (LDL-C) is the foundation of secondary prevention in atherosclerotic cardiovascular disease (ASCVD) [1]. A substantial proportion of patients with established ASCVD have not yet experienced an acute coronary syndrome (ACS) or stroke, yet remain at very high risk and are candidates for intensive, lifelong lipid-lowering therapy. PCSK9 monoclonal antibodies (mAbs) produce large, durable LDL-C reductions, and their clinical benefit depends on sustained adherence over many years; regimens that lower injection frequency without sacrificing efficacy may therefore be particularly relevant in this group. The recent VESALIUS-CV trial confirmed that PCSK9 mAbs reduce cardiovascular events in patients with ASCVD but no prior myocardial infarction or stroke [2], and a pooled ODYSSEY analysis showed robust LDL-C lowering with alirocumab before the first cardiovascular event [3]. Complementing these trial data, the OPTIMUS–CLASS observational study recently demonstrated that, in a large real-world US population of 19,670 patients with ASCVD but without prior ischemic events, PCSK9i mAb therapy was associated with a 30.9% relative risk reduction and a 7.8% absolute risk reduction in the composite of non-fatal myocardial infarction, non-fatal ischemic stroke, or all-cause mortality over 5 years, with findings concordant with the Cholesterol Treatment Trialists' (CTT) meta-analysis predictions based on the magnitude of LDL-C reduction achieved [4]. However, data specifically on once-monthly (Q4W) dosing in this subgroup remain limited. We evaluated the efficacy and safety of alirocumab 300 mg Q4W versus placebo in participants with established ASCVD without prior ischemic events enrolled in ODYSSEY CHOICE I.

This post hoc analysis of the phase 3 ODYSSEY CHOICE I study (NCT01926782; full design reported previously [5]) included adults with established ASCVD and without prior ACS (myocardial infarction/unstable angina) or stroke. In the parent trial, participants were randomized to alirocumab 300 mg Q4W or placebo (with a 75 mg Q2W calibrator arm not included here); those not achieving pre-specified LDL-C targets at week 8 were switched from 300 mg Q4W to 150 mg Q2W at week 12. Co-primary endpoints were percentage change in calculated LDL-C from baseline to week 24 and the average change over weeks 21 to 24. Secondary endpoints included LDL-C change at weeks 12 and 48; changes in lipoprotein(a) [Lp(a)], total cholesterol, non-HDL-C, triglycerides (TG), and apolipoprotein B (ApoB); and LDL-C goal attainment. Efficacy was analyzed in the intention-to-treat (ITT) population using a mixed-effect model with repeated measures; estimates are least-squares (LS) mean (95% confidence interval [CI]). This analysis was not pre-specified, and all p-values are nominal and unadjusted for multiplicity.

A total of 117 participants with ASCVD without prior ACS or stroke (78 alirocumab, 39 placebo) were identified; the ITT population comprised 116 (78 vs. 38). Groups were well balanced (mean age approximately 64 years, approximately 68% male, baseline LDL-C 107–112 mg/dL). Alirocumab 300 mg Q4W reduced calculated LDL-C by 58.8% (95% CI: −65.9 to −51.8) at week 24 and by 67.6% (95% CI: −75.5 to −59.6) on average over weeks 21 to 24, versus negligible change with placebo (both p < 0.0001; Fig. 1A). Reductions were evident by week 12 (−59.9%) and sustained through week 48 (−56.0%; p < 0.0001). At week 24, most alirocumab-treated participants achieved 2016 and 2019 guideline-recommended LDL-C goals of <70 mg/dL (83.8% vs. 8.6%) and <55 mg/dL (70.3% vs. 2.9%; both p < 0.0001; Fig. 1B), respectively. Alirocumab also produced significant reductions across atherogenic lipids at week 24 (Lp(a) −21.8%, total cholesterol −34.2%, non-HDL-C −48.2%, ApoB −46.3%, and TG −17.2%), all sustained to week 48 (Fig. 1C). Among the 19 participants (24%) switched to 150 mg Q2W per protocol, LS-mean lipid reductions were of similar magnitude to those who continued 300 mg Q4W, with no significant between-stratum differences at any time point. Treatment-emergent adverse events (TEAEs) occurred in 87.2% of alirocumab and 71.8% of placebo participants (p = 0.071) and were predominantly mild; serious TEAEs (17.9% vs. 15.4%), discontinuations for TEAEs (6.4% vs. 7.7%), and deaths (0 vs. 0) were comparable (Fig. 1D).

Fig. 1.

Central Illustration — Efficacy and safety of once-monthly alirocumab 300 mg Q4W versus placebo in participants with established ASCVD without prior ischemic events (ODYSSEY CHOICE I; ITT population, n = 78 alirocumab vs. n = 38 placebo). (A) Percentage change from baseline in calculated LDL-C over time (co-primary endpoints: week 24 and average of weeks 21-24). (B) Proportion of participants achieving LDL-C goals of <70 and <55 mg/dL at week 24. (C) Percentage change from baseline at week 24 in Lp(a), total cholesterol, non-HDL-C, ApoB, and triglycerides. (D) Treatment-emergent adverse events over the 48-week double-blind period. Error bars denote 95% CIs. Efficacy estimates (panels A and C) are least-squares mean (95% CI) from a mixed-effect model with repeated measures; goal attainment (panel B) is the proportion of participants achieving each goal (logistic regression), with 95% CIs; safety comparisons (panel D) by Fisher's exact test. All p-values are nominal and unadjusted for multiplicity.

ApoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; CI, confidence interval; D/C, discontinuation; HDL-C, high-density lipoprotein cholesterol; ITT, intention-to-treat; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); Q2W, every 2 weeks; Q4W, every 4 weeks; TEAE, treatment-emergent adverse event; TG, triglycerides.

Discussion

In this very-high-risk ASCVD subgroup without prior ischemic events, once-monthly alirocumab 300 mg produced robust, sustained LDL-C reductions of approximately 60%, with over 70% of treated patients reaching the contemporary <55 mg/dL goal and consistent improvements across all measured atherogenic lipoproteins. The safety profile matched the established alirocumab class effect, with no unexpected signals. These findings extend the evidence for PCSK9 inhibition in ASCVD patients before their first acute event, a group increasingly recognized in trials such as VESALIUS-CV, to the specific setting of a once-monthly regimen. The comparable lipid response between the continued-Q4W and protocol-switched-Q2W strata is consistent with prior analyses showing equivalent efficacy of 150 mg Q2W and 300 mg Q4W [6], reinforcing that the once-monthly dose delivers a genuine treatment signal in this population. Because clinical benefit from PCSK9 mAbs accrues from durable adherence, a lower injection burden is of particular relevance in patients expected to remain on lifelong therapy.

The analysis has important limitations. The sample size (n = 117) is modest, and the analysis was post hoc and not pre-specified, so p-values for secondary endpoints are nominal and descriptive and the findings should be considered hypothesis-generating. Cardiovascular outcomes were not assessed given the short duration; the analysis focused on LDL-C, a validated marker of cardiovascular risk. The Q2W-switched stratum is not a matched comparator, having been transitioned for a sub-optimal week-8 response.

In conclusion, once-monthly alirocumab 300 mg produced clinically meaningful and durable LDL-C and atherogenic-lipid reductions with good tolerability in patients with established ASCVD who had not yet experienced an acute ischemic event. For this very-high-risk population, in whom long-term persistence is critical, the once-monthly regimen represents a feasible option that may favor adherence during lifelong secondary prevention.

Declaration of generative AI and AI-assisted technologies in the manuscript preparation process

Generative AI (Concierge - Sanofi's AI companion) was used for formatting support. All outputs were reviewed and verified by the authors, who assume full responsibility for the final manuscript.

Funding

This work was supported by Sanofi. The sponsor was involved in the design and conduct of the parent ODYSSEY CHOICE I clinical trial and provided medical-writing support for this manuscript. The authors had unrestricted access to the data and final responsibility for the decision to submit for publication.

Data availability

Qualified researchers may request access to patient-level data and related study documents. Patient-level data will be anonymized, and study documents will be redacted to protect participant privacy. Further details on Sanofi's data-sharing criteria, eligible studies, and process for requesting access are available at https://www.vivli.org.

Ethics statement

The ODYSSEY studies were conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidance, the Declaration of Helsinki, and local regulatory requirements. The ODYSSEY CHOICE I protocol (NCT01926782) was approved by the Institutional Review Boards or Ethics Committees at all participating research sites. Written informed consent was obtained from all participants. This sub-analysis does not contain individually identifiable participant data.

CRediT authorship contribution statement

Lale Tokgözöğlu: Conceptualization, Writing – review & editing. Yaron Arbel: Writing – review & editing. Clara Bonanad Lozano: Writing – review & editing. Fabrice Martens: Writing – review & editing. Ksenija Stach: Writing – review & editing. Mattea Orsini: Methodology, Data curation, Formal analysis, Writing – review & editing. Hagai Tavori: Conceptualization, Writing – original draft, Writing – review & editing, Resources. Miguel Cainzos-Achirica: Writing – review & editing. Tienush Rassaf: Writing – review & editing. Pasquale Perrone-Filardi: Writing – review & editing. Michal Vrablík: Conceptualization, Writing – review & editing.

Declaration of competing interest

Lale Tokgözöğlu received consulting fees from Abbott, Amgen, Bayer, MSD, Novartis, Sanofi, Novo Nordisk, and Daiichi Sankyo; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbott, Amgen, Amarin, Daiichi Sankyo, MSD, Menarini, Novartis, Novo Nordisk, Sanofi, Servier, Pfizer, Viatris, and Zentiva; support for attending meetings and/or travel from Servier; participated on advisory boards or Data Safety Monitoring Boards for Abbott, Novartis, MSD, Sanofi, Daiichi-Sankyo, Pfizer, Menarini, and Novo Nordisk; and held leadership roles as Past President of the European Atherosclerosis Society and Past President of the Turkish Society of Cardiology.

Yaron Arbel, Clara Bonanad Lozano, and Fabrice Martens declare they have no financial or non-financial interests relevant to this publication.

Ksenija Stach received consulting fees from Amgen, AstraZeneca, BerlinChemie, Daiichi Sankyo, Novartis, MSD, Ultragenyx, and Sanofi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, BerlinChemie, Daiichi Sankyo, Novartis, MSD, Novo Nordisk, Ultragenyx, and Sanofi; support for attending meetings and/or travel from Amgen, AstraZeneca, BerlinChemie, Daiichi Sankyo, Novartis, MSD, Novo Nordisk, and Sanofi; participated on advisory boards or Data Safety Monitoring Boards for Amgen, BerlinChemie, Boehringer Ingelheim, Daiichi Sankyo, Novartis, MSD, Ultragenyx, and Sanofi; and held unpaid leadership or fiduciary roles in DGK, DGIM, DGFL, and DACH.

Mattea Orsini is a consultant from Aixial working for Sanofi.

Hagai Tavori is an employee of Sanofi and holds company shares and stock options.

Miguel Cainzos-Achirica received research support from the National Institutes of Health, the Societat Catalana de Cardiologia, the Instituto de Salud Carlos III, Novo Nordisk, andBoehringer Ingelheim; served as local principal investigator for industry-sponsored clinical trials for Novartis, Novo Nordisk, Eli Lilly, Daiichi Sankyo, and AstraZeneca; participated in ad hoc advisory boards for Novo Nordisk and Sanofi; received speaker honoraria from Sanofi, Novo Nordisk,Daiichi Sankyo, Ferrer, andAmgen; received travel support from Daiichi Sankyo, Organon, Novartis, Sanofi, Ferrer, Boehringer Ingelheim, Novo Nordisk, and Amgen; received institutional support from Sanofi, Almirall, and AstraZeneca; and received other sponsorships from the Sociedad Española de Cardiología, Organon, and Ferrer.

Tienush Rassaf received grants or contracts from the German Research Foundation (RTG 2989; RTG 2762/1, project T3; research grant “Nitritvermittelte Protektion der Mitochondrien im myokardialen Ischämie/Reperfusionsschaden”) and from the Brost Foundation (“Care improvement of elderly cancer patients”); received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Bayer, Novartis, BMS, BerlinChemie, Daiichi Sankyo, Boehringer Ingelheim, Novo Nordisk, Cardiac Dimensions, and Pfizer; received support for attending meetings and/or travel from the German Cardiac Society; holds patents including BNIP3 peptides for treatment of reperfusion injury (EP3966230A1), a system for transportation and delivery of nitric oxide (EP4362913A1), and a method for reducing blood pressure (EP3646861A1); participated on a Data Safety Monitoring Board or advisory board for Cytokinetics; and held leadership or fiduciary roles with the German Research Foundation and the German Cardiac Society.

Pasquale Perrone-Filardi received consulting fees from Bayer, Sanofi, Novartis, Menarini, Amgen, Recordati, Dompè, Servier, AstraZeneca, and Boehringer Ingelheim; received honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, Sanofi, Novartis, Menarini, Amgen, Recordati, Dompè, Servier, AstraZeneca, and Boehringer Ingelheim.

Michal Vrablík received grants or contracts from Pfizer and Krka, and received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Zentiva, MSD, Viatris, Krka, Angelini, Bayer, Novo Nordisk, Sanofi, Boehringer Ingelheim, Servier, andNovartis.