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Lepodisiran

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What are the phase 3 clinical trials for lepodisiran?

Two phase 3 lepodisiran trials in adults with elevated Lp(a) are in progress. ACCLAIM-Lp(a) evaluates reduction of major adverse cardiovascular events, and ACCLAIM-CTA evaluates change in coronary plaque volume.

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Content Overview

What is lipoprotein(a) (Lp(a))?
What is the design of the ACCLAIM-Lp(a) trial?
What is the design of the ACCLAIM-CTA trial?
References

What is lipoprotein(a) (Lp(a))?

Lipoprotein(a), or Lp(a), is a low-density lipoprotein–like particle in which a large glycoprotein, apolipoprotein(a), is covalently bound to apolipoprotein B by a disulfide bridge.^1,2 Circulating Lp(a) levels are largely determined by the LPA gene locus, with minimal dietary or environmental influence.²

Elevated Lp(a) is an independent, causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis.^1,3 Mechanistically, Lp(a) contributes to cardiovascular disease through proatherogenic, proinflammatory, and prothrombotic effects.²

Lepodisiran (LY3819469) is an investigational small interfering RNA (siRNA) that targets hepatic LPA messenger RNA to reduce production of apolipoprotein(a) and, consequently, circulating Lp(a) levels.⁴

In the phase 2 ALPACA trial, a single dose of lepodisiran produced sustained placebo-adjusted reductions in Lp(a) exceeding 90% through 180 days after administration.⁴ Two phase 3 trials of lepodisiran, ACCLAIM-Lp(a) and ACCLAIM-CTA, are now in progress.^5,6

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What is the design of the ACCLAIM-Lp(a) trial?

ACCLAIM-Lp(a) Study Design

ACCLAIM-Lp(a) (NCT06292013) is a phase 3, randomized, double-blind, placebo-controlled, parallel-group study evaluating whether lepodisiran, administered subcutaneously, reduces the incidence of major adverse cardiovascular events (MACE) in adults with elevated Lp(a) who

have established atherosclerotic cardiovascular disease (ASCVD), or
are at risk for a first cardiovascular (CV) event.⁵

The trial is event-driven and has an estimated enrollment of 17,300 participants across multiple geographies, with follow-up for up to approximately 4.5 years.⁵ The design and outcome measures for ACCLAIM-Lp(a) are shown in Figure 1.

ACCLAIM-Lp(a) trial design schematic showing objective, study design, outcome measures, and treatment period

Figure 1. ACCLAIM-Lp(a) Trial Design⁷

Figure 1 description: The schematic summarizes the ACCLAIM-Lp(a) phase 3, randomized, double-blind, placebo-controlled study. The objective, outcome measures, estimated enrollment of 15,000 patients with an additional 1,700 participants (total 16,700), primary endpoint (time to first component of MACE-4), key secondary endpoints, and the treatment period showing subcutaneous lepodisiran or placebo with follow-up of up to approximately 4.5 years are shown.
Notes: Enrollment values shown in the figure reflect the original planned enrollment (16,700); the current estimated enrollment on ClinicalTrials.gov is 17,300 participants, which includes an additional 1,700 participants enrolled in an addendum exploring Lp(a) lowering with an alternative dosing scheme.
Abbreviations: ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; Lp(a) = lipoprotein(a); MACE = major adverse cardiovascular event; MACE-4 = 4-component major adverse cardiovascular event composite (cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or urgent coronary revascularization); MI = myocardial infarction.

ACCLAIM-Lp(a) Inclusion and Exclusion Criteria

The key inclusion and exclusion criteria for ACCLAIM-Lp(a) are shown in Table 1.

**Table 1. Key Inclusion and Exclusion Criteria for ACCLAIM-**Lp(a)⁵
Key inclusion criteria	Key exclusion criteria
Adults with an Lp(a) level ≥175 nmol/L who meet one of the following: adults 18 years of age or older with established ASCVD with an event or revascularization, or adults 55 years of age or older who are at risk for a first CV event with documented coronary artery disease, carotid stenosis, or peripheral artery disease without a history of event or revascularization; known familial hypercholesterolemia; or a combination of high-risk factors.	Major cardiovascular event or surgery (e.g., MI, stroke, or coronary or peripheral revascularization) less than 60 days before screening; uncontrolled hypertension; New York Heart Association class IV heart failure; lipoprotein apheresis within 90 days of screening or planned during the study; severe renal failure (estimated glomerular filtration rate <15 mL/min/1.73 m² or ongoing dialysis); active nephrotic syndrome or urine albumin-creatinine ratio ≥5000 mg/g at screening; and acute or chronic hepatitis, cirrhosis, or other liver disease other than metabolic-associated steatotic liver disease.

Abbreviations: ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; Lp(a) = lipoprotein(a); MI = myocardial infarction.

ACCLAIM-Lp(a) Primary and Key Secondary Endpoints

The primary endpoint of ACCLAIM-Lp(a) is time to first occurrence of any component of the MACE-4 composite endpoint (CV death, non-fatal MI, non-fatal ischemic stroke, or urgent coronary revascularization) from baseline through the end of the study (approximately 4.5 years).⁵

The key secondary endpoints of ACCLAIM-Lp(a) are

change from baseline in Lp(a) level at week 4
time to first occurrence of any component of the MACE-4 composite endpoint in the population at risk for a first CV event, and
time to first occurrence of any component of the MACE-4 composite endpoint in the population with established ASCVD.⁵

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What is the design of the ACCLAIM-CTA trial?

ACCLAIM-CTA Study Design

ACCLAIM-CTA (NCT07613294) is a phase 3, randomized, double-blind, placebo-controlled, parallel-group study evaluating the effect of lepodisiran, administered subcutaneously, on coronary plaque burden in adults with elevated Lp(a) who have established ASCVD or are at risk for a first CV event and have angiographic evidence of coronary artery disease on screening coronary computed tomography angiography (CCTA).⁶ The trial has an estimated enrollment of 252 participants, with the primary endpoint assessed at week 104.⁶

ACCLAIM-CTA Inclusion and Exclusion Criteria

The key inclusion and exclusion criteria for ACCLAIM-CTA are shown in Table 2.

**Table 2. Key Inclusion and Exclusion Criteria for ACCLAIM-CTA**⁶
Key inclusion criteria	Key exclusion criteria
Adults 45 to 80 years of age with an Lp(a) level ≥175 nmol/L; established CV disease or at risk for a first CV event; angiographic evidence of coronary artery disease on screening CCTA; and if taking lipid-lowering medications (statins, prescription-strength niacin, or PCSK9 inhibitors), on a stable regimen for at least 8 weeks.	Major CV event less than 60 days before Lp(a) measurement for eligibility or uncontrolled hypertension at screening; moderate to severe renal dysfunction; severe heart failure; history of coronary artery bypass graft (CABG) surgery; planned coronary angiography, percutaneous coronary intervention (PCI), CABG, or valvular intervention; prior lipoprotein apheresis or therapy specifically targeting Lp(a); and inability to safely undergo CCTA due to medication intolerance, contrast allergies, or anatomical or technical factors.

Abbreviations: CABG = coronary artery bypass graft; CCTA = coronary computed tomography angiography; CV = cardiovascular; Lp(a) = lipoprotein(a); PCI = percutaneous coronary intervention; PCSK9 = proprotein convertase subtilisin/kexin type 9.

ACCLAIM-CTA Primary and Key Secondary Endpoints

The primary endpoint of ACCLAIM-CTA is percent change from baseline in noncalcified plaque volume, measured by CCTA at week 104.⁶

The key secondary endpoints of ACCLAIM-CTA are percent change from baseline in

mean fat attenuation index score at week 104, and
Lp(a) level through week 104.⁶

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References

The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).

Nordestgaard BG, Langsted A. Lipoprotein(a) and cardiovascular disease. Lancet. 2024;404(10459):1255-1264. doi:10.1016/S0140-6736(24)01308-4
Tsimikas S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol. 2017;69(6):692-711. doi:10.1016/j.jacc.2016.11.042
Arsenault BJ, Kamstrup PR. Lipoprotein(a) and cardiovascular and valvular diseases: a genetic epidemiological perspective. Atherosclerosis. 2022;349:7-16. doi:10.1016/j.atherosclerosis.2022.04.015
Nissen SE, Ni W, Shen X, et al. Lepodisiran — a long-duration small interfering RNA targeting lipoprotein(a). N Engl J Med. 2025;392(17):1673-1683. doi:10.1056/NEJMoa2415818
Eli Lilly and Company. A study to investigate the effect of lepodisiran on the reduction of major adverse cardiovascular events in adults with elevated lipoprotein(a) — ACCLAIM-Lp(a). ClinicalTrials.gov identifier: NCT06292013. Updated June 18, 2026. Accessed July 13, 2026. https://clinicaltrials.gov/study/NCT06292013
Eli Lilly and Company. A study to see if lepodisiran can reduce plaque in coronary arteries of adults with elevated Lp(a) who have had heart events or are at high risk — ACCLAIM-CTA. ClinicalTrials.gov identifier: NCT07613294. Updated June 29, 2026. Accessed July 13, 2026. https://clinicaltrials.gov/study/NCT07613294
Data on file, Eli Lilly and Company and/or one of its subsidiaries.

Date of Last Review: July 13, 2026

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