In ORION-10 (N=1561) on top of a maximally tolerated statin 

Difference from placebo at month 17 (95% CI: -56%, -49%; P<0.0001)¹ (LEQVIO n=781 or placebo n=780)¹

LDL-C reduction on top of a maximally tolerated statin, LEQVIO vs placebo¹

Study Design: ORION-10 (N=1561) and ORION-11 (N=1617) were multicenter, double-blind, randomized, placebo-controlled, 18-month, Phase III trials in patients with established ASCVD (ORION-10 and ORION-11) or increased risk for CVD^† (ORION-11). Patients were taking a maximally tolerated statin with or without other lipid-modifying therapy and required additional LDL-C reduction. The primary efficacy measure was the percent change in LDL-C from baseline to day 510.^1,3

^†Factors that increase risk of CVD include HeFH, T2DM, or 10-year risk of ≥20%.²

LEQVIO DEMONSTRATED CONSISTENT REDUCTION ACROSS PREDEFINED SUBGROUPS^4,5

Study Design: ORION-1 was a Phase II, multicenter, double-blinded, randomized, placebo-controlled clinical trial of 345 subjects with established ASCVD who were taking a maximally tolerated statin and required additional LDL-C reduction. Of those, 91 patients received the 284-mg dose of LEQVIO. The primary efficacy end point was the percent reduction in LDL-C from baseline to day 180 and was calculated for multiple time points at days 14, 30, 60, 90, 120, 150, 180, 210, and 240.^1,6

In ORION-8 (N=3274), an open-label extension study

Study Design: ORION-8, an open-label extension trial that included 3274 patients from ORION-9, ORION-10, ORION-11, and ORION-3, was designed to assess the long-term safety, efficacy, and tolerability of LEQVIO in patients with ASCVD or at increased risk for CVD^† and elevated LDL-C, despite ongoing treatment with lipid-lowering therapy.⁸

Limitations: Study was not blinded nor controlled and includes inherent self-selection bias for continuing onto the extension trial. The open-label design and absence of a control group may present difficulties in the interpretation of results, allowing comparisons only to baseline values.^{11 ||||}

^†Factors that increase risk of CVD include HeFH, T2DM, or 10-year risk of ≥20%.^2
§209 (6.4%) patients had exposure to LEQVIO for 6+ years, 213 (6.5%) patients had exposure to LEQVIO for 5+ years, 1553 (47.4%) patients had exposure for 4+ years, and 2095 (64%) patients had exposure for 3+ years.^9
||LDL-C target was <70 mg/dL for patients with ASCVD and <100 mg/dL for patients at increased risk for CVD§ and aligns with AHA/ACC guidelines.^7,8
¶End of study was defined as day 1080 or ≥90 days after the last LEQVIO dose.⁸

V-INITIATE compared immediate LEQVIO use after failure to reach LDL-C target^# with maximally tolerated statin vs usual care, which was physician-determined based on the 2018 AHA/ACC guidelines.¹⁰

In the usual care arm, most patients (73%) remained on statins only, with a minority of patients receiving any additional nonstatin lipid-lowering therapy, including 10 patients who received at least 1 dose of LEQVIO.¹⁰

^#Guideline-recommended LDL-C target was <70 mg/dL for patients with ASCVD.^2,8

Early LEQVIO use after failure to reach LDL-C target on statin¹⁰

Study design for V-INITIATE: A 12-month, randomized, open-label, Phase IIIb study in patients with ASCVD (N=450) evaluated the efficacy and safety of early initiation with LEQVIO immediately upon failure to reach LDL-C <70 mg/dL on maximally tolerated statin vs usual care in a real-world setting.¹⁰

The co-primary end points were percentage change in LDL-C from baseline and statin discontinuation rate.¹⁰

Patients with ASCVD achieving LDL-C target^10#

Limitations: Usual care did not reflect “best practice” with little use of guideline-recommended nonstatin therapy; therefore, a comparison of efficacy or safety of LEQVIO vs other nonstatin therapies cannot be made. LEQVIO use (n=10) was permitted in the usual care arm which may impact the effectiveness of comparisons. Although the study was designed to mimic clinical practice, statin discontinuation rates may not reflect the real world due to participants’ potential behavior change as a result of being part of a study. The open-label design has the potential for bias and may present difficulties in the interpretation of results.

Adherence matters: 12-month real-world adherence and persistence study for LEQVIO^11‡‡§§

LEQVIO is HCP administered. Therefore, claims ensure patients received the injection.¹

Evolocumab and alirocumab claims do not confirm self-administration, so PDC for PCSK9 mAbs may be overestimated.^11-13||||

^‡‡The comparison pertains only to differences in adherence or persistence as defined by this analysis and should not be considered a comparison of efficacy or safety.
^§§The allowable dosing window for all treatments was added as per prescribing information. For LEQVIO +90 days and for evolocumab and alirocumab +7 days.^11
||||PDC calculates the proportion of days a patient has access to their prescribed medication over a defined period of interest, which was 12 months for this study.¹¹

Study Design: A retrospective, observational real-world study evaluating 12-month adherence and persistence for newly-initiated patients on LEQVIO (N=852), evolocumab (N=27,171), and alirocumab (N=8,878) using administrative claims databases.^¶¶  Adherence was defined as the proportion of days covered (PDC)^||||; fully adherent patients were defined as having a PDC of ≥0.8. Persistence was defined as patients on therapy for 12 months after index date with ≤90 days gap for LEQVIO and ≤60 days gap for evolocumab and alirocumab between last day of days’ supply and start of the next prescription.¹¹

^¶¶Komodo Health, a nationally representative longitudinal database that captures 330 million patients in the US from open and closed administrative databases was utilized from January 2021 to October 2023.^11 
||||PDC calculates the proportion of days a patient has access to their prescribed medication over a defined period of interest, which was 12 months for this study.¹¹ 

Limitations: The study was conducted using administrative claims data (collected for non-research purposes), with limited details on clinical variables and susceptibility to missing data and coding-related errors. Clinical characteristics and medications were captured during the 12 months prior to the initiation period; anything beyond the 12-month period was not observable. LEQVIO is HCP-administered; therefore, claims ensure patients received the injection, whereas evolocumab and alirocumab claims do not confirm self-administration, thus PDC for PCSK9 mAbs may be over-estimated.^{11 ||||}

^||||PDC calculates the proportion of days a patient has access to their prescribed medication over a defined period of interest, which was 12 months for this study.¹¹