Olezarsen in Patients with Hypertriglyceridemia at High Cardiovascular Risk: Rationale and Design of the Essence–TIMI 73b Trial

Abstract

Background

Elevated triglycerides are an important risk factor for atherosclerosis. However, the magnitude of triglyceride lowering with currently available therapies is modest and the impact of triglyceride-lowering on atherosclerosis remains undefined. Olezarsen is an antisense oligonucleotide (ASO) targeting mRNA for apolipoprotein C-III (apoC-III), an inhibitor of triglyceride clearance.

Methods

The Essence–TIMI 73b trial (NCT05610280) is a randomized, double-blind, placebo-controlled phase 3 trial of olezarsen 50 mg or 80 mg every 4 weeks compared with placebo. The trial enrolled adults with either moderate hypertriglyceridemia (200–499 mg/dL) plus increased cardiovascular risk, or severe hypertriglyceridemia (≥500 mg/dL). The primary endpoint is the percent change in triglyceride levels from baseline to 6 months for each olezarsen dose versus pooled placebo. A coronary computed tomography angiography (CTA) substudy will examine changes in non-calcified plaque volume from baseline to 12 months.

Results

A total of 1,478 patients were randomized at 160 sites in North America and Europe. The median age is 63 (IQR 56–69) years, 39% are women, and 71% are non-Hispanic White. Overall, 60% of patients have diabetes, and 42% have atherosclerotic cardiovascular disease. At randomization, 97% were receiving lipid-lowering therapies, including 82% on a statin. The median baseline triglyceride level was 249 (195–339) mg/dL and 9% of patients had triglycerides ≥500 mg/dL at enrollment. Approximately 1000 patients completed a baseline CTA, of whom 555 (55%) have had measurable non-calcified coronary plaque and continued in the substudy.

Discussion

Targeting apoC-III to facilitate clearance of triglyceride-rich lipoproteins is a potential therapeutic strategy for lowering triglyceride levels, regressing atherosclerosis, and reducing cardiovascular risk. The phase 3 Essence–TIMI 73b trial, which has enrolled nearly 1,500 patients, including over 550 in a coronary CTA substudy, should provide key insights into the efficacy and safety of olezarsen in patients with largely moderate hypertriglyceridemia and elevated cardiovascular risk.

Trial registration

Clinicaltrials.gov: NCT05610280

Background

While low-density lipoprotein cholesterol (LDL-C) has been the primary lipid target for atherosclerotic cardiovascular disease (ASCVD) risk reduction, triglyceride-rich lipoproteins (TRL) are at least as atherogenic as LDL per particle.^1–5 As such, elevated levels of triglycerides, which indicate higher concentrations of TRLs, are an important and potentially modifiable ASCVD risk factor. However, therapies intended to lower triglyceride levels have rarely impacted cardiovascular outcomes among statin-treated patients in randomized trials.⁶ This disconnect may be related to whether a therapy reduces apolipoprotein B (apoB) levels, a measure of atherogenic particle count, or only lowers triglycerides without affecting overall concentrations of apoB-containing particles.⁷

In this context, olezaresen, an N-acetylgalactosamine (GalNAc3)-conjugated antisense oligonucleotide (ASO) targeting apolipoprotein C-III (apoC-III), holds potential as a novel agent intended to reduce triglycerides, TRLs, and apoB. ApoC-III increases circulating triglyceride levels by inhibiting lipoprotein lipase (LPL), among other mechanisms,⁸ and loss-of-function mutations in the APOC3 gene are associated with lower cardiovascular risk.^9–12 A phase 2b study of olezarsen, the Bridge–TIMI 73a trial, found 49–53% reductions in plasma triglyceride levels compared with placebo, as well as 18–19% reductions in apoB levels.¹³ The Essence–TIMI 73b trial, which is nearly 10-fold larger than Bridge–TIMI 73a, is a phase 3 study to assess the efficacy and safety of olezarsen in patients with moderate hypertriglyceridemia (≥200 mg/dL) plus elevated cardiovascular risk or with severe hypertriglyceridemia (≥500 mg/dL).

Methods

Study Design

Essence–TIMI 73b (NCT05610280) is a randomized, multicenter, double-blind, placebo-controlled, phase 3 clinical trial evaluating 2 doses (50 mg and 80 mg) of olezarsen in patients either with moderate hypertriglyceridemia (200–499 mg/dL) plus elevated cardiovascular risk, or with severe hypertriglyceridemia (≥500 mg/dL). The treatment phase lasts 12 months, after which participants are followed for an additional 13 weeks for safety monitoring. The primary objective is to compare the percent change in triglyceride levels from baseline to 6 months for each dose of olezarsen versus placebo.

Study Organization

The Essence–TIMI 73b trial is a collaboration between the Thrombolysis in Myocardial Infarction (TIMI) Study Group, an Academic Research Organization at the Brigham and Women’s Hospital, and Ionis Pharmaceuticals, the trial sponsor. A joint trial leadership team is responsible for the study protocol, scientific content, and trial oversight. Subject data are obtained at the site level. A data and safety monitoring board (DSMB), supported by an independent statistical team, has access to unblinded data and monitors safety events. Independent, blinded, centralized adjudication committees are evaluating all potential cases of acute pancreatitis as well as major adverse cardiovascular events during the study.

The Essence–TIMI 73b trial has been approved by all relevant Institutional Review Boards and requires each patient’s written informed consent. The trial is registered at www.clinicaltrials.gov under identification NCT05610280. The TIMI Study Group will have access to the complete trial data and will draft and submit study results for publication.

Population

Patients aged ≥18 years were eligible if they had either moderate hypertriglyceridemia plus increased cardiovascular risk, or severe hypertriglyceridemia. The initial triglyceride range for moderate hypertriglyceridemia was originally 150–499 mg/dL, however the minimum triglyceride level was changed to 200 mg/dL via protocol amendment on June 27, 2023. For eligibility purposes, increased cardiovascular risk initially included patients with an established diagnosis of ASCVD or an increased risk for ASCVD, defined as either a diagnosis of type 2 diabetes mellitus or the presence of 2 or more cardiovascular risk-enhancing factors. The increased risk for ASCVD criterion was simplified via the protocol amendment on June 27, 2023 to the combination of diabetes mellitus plus age ≥55 years.

Patients were expected to be on stable and optimized lipid-lowering therapy, defined according to local guidelines, for at least 4 weeks prior to screening. All laboratory tests were collected in the fasting state. Key exclusion criteria were newly diagnosed or poorly controlled diabetes mellitus; a recent acute coronary syndrome, cerebrovascular event, major surgery, or pancreatitis; or relevant hepatic or renal laboratory abnormalities. A complete listing of inclusion and exclusion criteria is provided in Table 1.

Table 1.

Eligibility Criteria

Inclusion Criteria
1. Subject has provided informed consent prior to any study procedures
2. Age ≥ 18 years
3. One of the following categories (a or b) of triglyceride levels and ASCVD:
a. Hypertriglyceridemia with fasting TG ≥ 200* mg/dL (1.69 mmol/L) and < 500 mg/dL (5.65 mmol/L) with either
i. Clinical diagnosis of ASCVD, defined as documented coronary artery disease, cerebrovascular disease, or peripheral artery disease, or
ii. At increased risk for ASCVD, defined as:
• Diabetes mellitus, and
• Age ≥ 55 years
b. Severe hypertriglyceridemia with fasting TG ≥ 500 mg/dL (5.65 mmol/L)
4. Stable and optimized standard-of-care lipid-lowering medications for at least 4 weeks
5. Willing to comply with diet and lifestyle recommendations
6. Satisfy the following requirements:
a. Females: must be non-pregnant, non-lactating, and either surgically sterile, post-menopausal, sexually abstinent, or use a highly effective contraceptive method
b. Males: must be either surgically sterile, abstinent, or, if engaged in sexual relations with a female of childbearing potential, use a highly effective contraceptive method
Exclusion Criteria
Conditions related to hypertriglyceridemia or ASCVD
• Acute coronary syndrome or cerebrovascular event within 6 months
• Major surgery, peripheral revascularization, or non-urgent percutaneous coronary intervention within 3 months, or upcoming planned major surgery or major procedure during the study
• Active pancreatitis within 4 weeks
Other medical conditions
• Diabetes mellitus with any of the following:
○ Newly diagnosed within 12 weeks
○ HbA1c ≥ 9.5%
○ Change in basal insulin regimen > 20% within 3 months
○ For patients with type 1 diabetes: an episode of diabetic ketoacidosis or ≥ 3 episodes of severe hypoglycemia within 6 months
• Laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values that would render a patient unsuitable for inclusion:
○ ALT or AST > 3.0 × ULN
○ Total bilirubin > 1.5 ULN, unless due to Gilbert’s syndrome
○ eGFR < 30 mL/min/1.73 m2
○ UPCR ≥ 500 mg/g (56.5 mg/mmol)
• Uncontrolled arterial hypertension (blood pressure > 180/100 mmHg) despite antihypertensive therapy
• Uncontrolled hypothyroidism or thyroid hormone therapy that has not been stable for ≥ 4 weeks
• Active infection requiring systemic antiviral or antimicrobial therapy
• Active infection with HIV, hepatitis C, or hepatitis B, diagnosed by initial serological testing and confirmed with RNA testing (HIV, hepatitis C) or positive HBsAg (hepatitis B), or treatment for hepatitis C within 6 months
• Malignancy diagnosed or treated within 5 years, except for non-melanoma skin cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma that has been successfully treated
Prior or concomitant therapies or procedures
• Hypersensitivity to the active substance or any of the excipients (olezarsen or placebo)
• Treatment with another investigational drug (non-oligonucleotide), biological agent, or device within 1 month of screening, or 5 half-lives of the investigational agent, whichever is longer
• Previous treatment with an oligonucleotide (including siRNA) within 4 months or 5 half-lives, whichever is longer
• Concomitant medication/procedure restrictions:
○ Systemic corticosteroids or anabolic steroids within 6 weeks
○ Use of bile acid resins within 4 weeks
○ Plasma apheresis within 4 weeks prior to, or during screening or planned during the study
○ Change in titration of therapies known to exacerbate hypertriglyceridemia, such as non-selective beta-blockers, thiazides, isotretinoin, oral antidiabetic medications, tamoxifen, estrogens, or progestins within 4 weeks
○ Change in titration of therapies known to significantly reduce triglycerides, such as GLP-1 agonists, other incretin mimetics, phentermine/topiramate, naltrexone/bupropion, xenical, or bariatric surgery within 3 months
○ Change in atypical antipsychotic medications within 3 months
• Blood or plasma donation of 50–499 mL within 30 days or of > 499 mL within 60 days
Other exclusions
• Unwillingness to cooperate or comply with study procedures
• Have any other conditions which, in the opinion of the investigator, would make the patient unsuitable for inclusion or could interfere with the patient participating in or completing the study

Inclusion criteria were assessed during the screening period. If fasting triglyceride levels at a screening visit were below the eligibility threshold, up to 2 additional tests were allowed, and the average value was used to determine eligibility at that visit.

^*The minimum triglyceride threshold was increased from 150 mg/dL to 200 mg/dL by protocol amendment on June 27, 2023.

ASCVD indicates atherosclerotic cardiovascular disease; eGFR, estimated glomerular filtration rate; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides. Exclusion criteria were assessed during the screening period. If exclusionary medications or procedures were not present at screening but expected during the study, patients were not eligible for participation. ALT, alanine aminotransferase; AST, aspartate aminotransferase; GLP-1, glucagon-like peptide 1; HIV, human immunodeficiency virus; LLN, lower limit of normal; siRNA, small interfering ribonucleic acid; ULN, upper limit of normal; UPCR, urine protein/creatinine ratio.

Intervention and Assessments

Following a screening period of up to 12 weeks, which included a diet and lifestyle stabilization period of at least 2 weeks, patients were randomly allocated in a 1:3 ratio to a 50 mg or an 80 mg cohort (Figure 1). Within each cohort, patients were then randomized 3:1 to receive subcutaneous olezarsen every 4 weeks or volume-matched placebo. Randomization was stratified by fasting triglyceride levels at screening (<500 vs ≥500 mg/dL). With respect to the qualifying triglyceride threshold, a patient was eligible if the triglyceride levels at screening and qualification were both ≥200 mg/dL (or ≥150 mg/dL prior to the first protocol amendment). If the initial triglyceride level at screening or qualification was below this threshold, up to two additional samples were allowed, with the average of all obtained values used to assess eligibility. For analyses, baseline triglyceride level will be defined as the average of all triglyceride levels obtained prior to the first dose of study drug, which includes the screening and qualification periods plus Day 1 prior to drug administration.

Figure 1. Trial Schema.

Study schema for the Essence–TIMI 73b trial. A total of 1478 patients with either moderate hypertriglyceridemia plus elevated cardiovascular risk or severe hypertriglyceridemia were randomized 1:3 to a 50 mg or 80 mg cohort, and then 3:1 to olezarsen or volume-matched placebo within each cohort. ALT – alanine transaminase; ApoB – apolipoprotein B; ApoC-III – apolipoprotein C-III; ASCVD – atherosclerotic cardiovascular disease; AST – aspartate transaminase; CTA – computed tomography angiography; HTG – hypertriglyceridemia.

The treatment period is 12 months after randomization, with subcutaneous injections of study drug every 4 weeks through week 48. At each study visit, adverse events and concomitant medications are assessed. Laboratory parameters, including fasting lipids, are obtained at screening, qualification, and weeks 0, 4, 8, 12, 24, 36, and 52 of the treatment period. The 80 mg dose (blinded olezarsen or placebo) may be adjusted to 50 mg in case of tolerability issues or adverse events. Patients are asked to attend in-person visits and procedures irrespective of study drug discontinuation during the treatment period. After the month 12 visit, patients enter a 13-week safety follow-up period without study drug administration.

Study staff, investigators, and patients are not to perform unblinded lipid monitoring during the treatment and follow-up periods. For safety purposes, triglyceride levels are measured centrally every 3 months. If values (a) exceed 880 mg/dL in patients with baseline levels < 500 mg/dL; (b) exceed 2000 mg/dL and increase by ≥ 10% from baseline in patients with baseline levels between 500 mg/dL and < 2000 mg/dL; or (c) increase by ≥ 30% from baseline in patients with baseline levels ≥ 2000 mg/dL, the site team is notified to contact the patient for education and counseling. To maintain blinding and to balance the frequency of alerts, the same notification is provided for a patient in the alternative treatment group. If values remain elevated at the following assessment, a qualified individual ideally not associated with the study is informed to manage the patient’s triglycerides during the trial.

Endpoints

The primary endpoint is percent change in triglyceride level from baseline to 6 months for each olezarsen dose versus pooled placebo. Secondary endpoints include percent change in triglycerides at 12 months, proportion of patients who achieve triglycerides <150 mg/dL at 6 and 12 months, and percent changes in fasting apoC-III, very-low-density lipoprotein cholesterol (VLDL-C), remnant cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), HDL-C, apoB, and low-density lipoprotein cholesterol (LDL-C) at 6 and 12 months compared with pooled placebo patients. Exploratory endpoints include major adverse cardiovascular events (cardiovascular death, myocardial infarction, ischemic stroke, and any arterial revascularization), measures of glycemia, and change in non-calcified coronary plaque volume (coronary computed tomography angiography [CTA] sub-study described below), percent changes in fasting total cholesterol and apolipoprotein A-1, and adjudicated pancreatitis events in patients with prior pancreatitis within 10 years prior to screening as well as in all patients. Additionally, blood samples from consenting patients are stored for biomarker and genetic analyses.

Statistical Analysis

The 2 doses of olezarsen, 50 mg and 80 mg, will be tested against pooled placebo patients for each endpoint. For each dose cohort, the primary efficacy endpoint will be analyzed using an analysis of covariance (ANCOVA) model to assess the efficacy of each olezarsen dose group compared with pooled placebo in participants with baseline triglycerides <500 mg/dL who received at least 1 dose of study drug (modified intention-to-treat population; mITT). The restriction of the mITT population to those with baseline triglycerides <500 mg/dL was implemented in the June 2023 protocol amendment in response to regulatory feedback. This change impacted only the analysis plan, not patient recruitment, treatment, or follow-up. All primary and secondary endpoints will be tested hierarchically in the mITT population to preserve a study-level two-sided alpha of 0.05. The effect of olezarsen on triglyceride levels and other lipid parameters will be analyzed among patients with baseline triglycerides ≥500 mg/dL in an exploratory fashion. All patients receiving at least one dose of study medication will be included in the safety analyses regardless of baseline triglyceride levels.

Assuming a standard deviation of 73% for the primary endpoint and a 20% drop-out rate, 30 patients in each olezarsen dose group and 40 in the pooled placebo group would provide at least 90% power to detect a treatment difference of 60% in the percent change of triglycerides between each olezarsen arm and placebo. In addition to achieving adequate power for testing the effect of olezarsen on triglyceride levels, the trial size also needed to satisfy regulatory requirements for total patient-years of exposure to olezarsen. A target sample size of approximately 1475 patients was expected to achieve these objectives.

Coronary Computed Tomography Angiography Substudy

A coronary CTA substudy is being performed at selected sites with coronary CTA capabilities to explore the effect of olezarsen on coronary plaque. Coronary CTA allows for the noninvasive quantification of changes in coronary plaque volume and composition, with good correlation to intracoronary imaging such as intravascular ultrasound.^14–16 Patients enrolled in the substudy undergo the baseline CTA before the first dose of study drug and, if non-calcified plaque is present, again at month 12. The primary endpoint of the CTA substudy is percent change in non-calcified plaque volume from baseline to month 12.¹⁷ Additional exploratory endpoints include other measures of coronary plaque volume, such as changes in subcomponents of noncalcified plaque (low-attenuation plaque , fibro-fatty plaque, and fibrous plaque), calcified plaque, and total plaque volume, as well as extra-coronary findings such as pericoronary adipose tissue. Exclusion criteria for the substudy are a baseline estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m², contrast allergy or contrast-induced nephropathy, prior coronary artery bypass graft surgery, poorly controlled heart rate, contraindication to nitroglycerin, or inability to hold breath for more than 6 seconds. All CTA images will be evaluated by an independent central core laboratory at the Massachusetts General Hospital blinded to treatment allocation.

The CTA substudy has targeted at least 400 patients with paired CTAs to achieve >80% power to detect a 10% difference in the percent change of non-calcified plaque volume between olezarsen and placebo, assuming a standard deviation of 30% and a two-sided alpha of 0.05. With an anticipated approximately 40% of patients without detectable non-calcified plaque at baseline and an additional 20% drop-out rate during the study, approximately 900 patients were needed to undergo a baseline CTA for 500 to be included in the substudy and 400 to provide CTA images both at baseline and month 12.

Current Status and Baseline Characteristics

The first patient was enrolled in the Essence–TIMI 73b trial in November 2022, and 1478 patients were ultimately randomized at 160 sites in North America and Europe through February 2024. Baseline characteristics for the overall trial cohort and the primary analysis population are shown in Table 2. The median age is 63 (IQR 56–69) years, 39% are women, and 71% are non-Hispanic White. Overall, 60% of patients have diabetes, and 42% have atherosclerotic cardiovascular disease. At randomization, 97% were receiving lipid-lowering therapies, including 82% on a statin. The median baseline triglyceride level was 249 (195–339) mg/dL and 9% of patients had triglycerides ≥500 mg/dL at enrollment. Approximately 1000 patients have completed a baseline CTA, of whom 555 (55%) have had quantifiable non-calcified coronary plaque and continued in the substudy.

Table 2.

Patient Characteristics

	Total Trial Cohort N=1,478	Modified Intention-to-Treat Cohort1 N=1,349
Age (yrs)	63 (56–69)	64 (56–70)
Female sex	39	40
Race/Ethnicity
White	91	92
Hispanic/Latino	22	23
Black	5	5
Hispanic/Latino	28	22
Asian	1	1
Other/multiple	2	2
Prior pancreatitis	4	3
ASCVD	42	42
Diabetes mellitus	60	60
Triglycerides (mg/dL)	249 (195–339)	239 (191–308)
Triglycerides ≥500 mg/dL	9	0
Non-HDL-C (mg/dL)	130 (103–165)	127 (101–159)
ApoB (mg/dL)	92 (75–112)	91 (75–111)
LDL-C (mg/dL)	81 (59–109)	83 (61–110)
Lipid-lowering therapy	97	97
Statin	82	82
Fibrate	25	23
Omega-3 fatty acid	23	23
Niacin	1	1
PCSK9 inhibitor	5	5
≥2 therapies	44	43

¹Defined as patients with baseline triglyceride level <500 mg/dL and receiving at least one dose of study drug.

Values are presented as % or median (interquartile range) and are based on an interim data snapshot taken October 2024. ApoB – apolipoprotein B; ASCVD – atherosclerotic cardiovascular disease (coronary artery disease, cerebrovascular disease, or peripheral artery disease); LDL-C – low-density lipoprotein cholesterol; non-HDL-C – non-high-density lipoprotein cholesterol; TG – triglycerides.

Discussion

Reducing risk for atherosclerosis by lowering LDL-C is one of the great successes of modern medicine. However, residual risk remains, and TRL’s are hypothesized to be an important contributor.¹⁸ Moderate to severe hypertriglyceridemia is common, yet whether or how these patients should be treated is uncertain.¹ The complex metabolism of TRL’s provides multiple potential therapeutic targets, such as apoC-III, angiopoietin-like protein 3 (ANGPTL3), ANGPTL4, and LPL, as well as several mechanisms of inhibition, including ASO’s, small interfering ribonucleic acids (siRNA), and monoclonal antibodies.^{19, 20} Lowering levels of apoC-III appears to be a particularly compelling strategy.

Genetic and epidemiologic observations indicate that lower apoC-III levels are associated with lower triglyceride levels as well as lower risk for ASCVD.^{9–11, 21} Further, early studies of apoC-III inhibition have been promising. The unconjugated parent compound for olezarsen, volanesorsen, showed significant reductions in triglycerides in patients with familial chylomicronemia syndrome (FCS) as well as those with elevated triglycerides without FCS, though with a potential increase in thrombocytopenia.^22–25 Olezarsen is a GalNAc3–conjugated ASO selectively taken up by hepatocytes, which is intended to reduce the likelihood of off-target effects.^{13, 26, 27} Olezarsen has been studied in two phase 2 trials in patients with largely moderate hypertriglyceridemia, both showing approximately 65–75% lowering of apoC-III levels and approximately 50–60% reductions in triglyceride levels compared with placebo at 6 and 12 months for 50 – 80 mg total monthly doses, with no major safety concerns.^{13, 27} By comparison, the degree of triglyceride-lowering achieved by currently available therapies, including statins, ezetimibe, fibrates, omega−3 fatty acids, and niacin, only typically ranges from less than 10% to approximately 30–40%.²⁸ Olezarsen has also been studied in patients with FCS, with the phase 3 Balance trial showing an 88% numerical reduction in acute pancreatitis events in addition to significant triglyceride-lowering.²⁹

In parallel, plozasiran, an siRNA targeting apoC-III, has been studied in patients with varying degrees of hypertriglyceridemia.^30–32 Reductions in triglyceride levels of approximately 50% relative to placebo have been observed with every 3-month to every 6-month dosing, though worsened glycemia has been observed as a potential safety concern.^30–32

Importantly, the reductions in triglyceride levels with olezarsen and plozasiran have been accompanied by significant reductions in apoB levels,^{13, 26, 27, 30–32} indicating that these agents are leading to a net clearance of atherogenic particles. Prior trials of triglyceride-lowering therapies in statin-treated patients have not shown a reduction in cardiovascular risk, potentially due to a combination of modest triglyceride-lowering plus no major effect on apoB levels.^{6, 33} In the case of olezarsen, placebo-adjusted reductions in apoB of 18.2% and 18.5% were seen in the Bridge-TIMI 73a trial with the 50 mg and 80 mg monthly doses, respectively, with 8–10% placebo-adjusted reductions seen in LDL-C not meeting statistical significance.¹³

These changes in the lipid profile are encouraging, but the question remains whether triglyceride-lowering can reduce the risk of cardiovascular events. We designed the coronary CTA substudy to determine whether olezarsen will slow or reverse coronary plaque progression, a surrogate indicator of risk for coronary events.^34–36 With over 550 patients with a baseline CTA with quantifiable plaque, this trial will provide one of the largest cohorts to-date of patients with paired coronary CTA’s over one year and has the opportunity to provide compelling evidence that sustained treatment with olezarsen has the potential to alter the course of coronary atherosclerosis and impact clinical outcomes. In addition to plaque volume, the CTA’s will provide data on plaque characteristics, such as the presence of low-attenuation plaque, which may offer insight into plaque stabilization with apoC-III inhibition.^{37, 38}

Looking forward

The Essence–TIMI 73b trial will be the largest trial of an RNA therapy targeting triglyceride metabolism to-date, and will provide important insight into the efficacy and safety of olezarsen in a broad population of patients with hypertriglyceridemia and heightened cardiovascular risk. Additionally, the coronary CTA substudy will inform the likelihood of cardiovascular clinical benefit. Outside of this population, olezarsen is also being evaluated specifically among patients with severe hypertriglyceridemia in the CORE-TIMI 72a (NCT05079919) and CORE2-TIMI72b (NCT05552326) phase 3 trials, which both contribute to an open-label extension (OLE) program (NCT05681351). Both trials also have a hepatic magnetic resonance imaging (MRI) substudy, in which liver MRI is obtained at baseline and month 12 for assessment of hepatic fat fraction. In aggregate, this program will provide a robust evidence base for the efficacy and safety of olezarsen across a range of hypertriglyceridemia syndromes, including with longer-term exposure in the OLE study, and with imaging substudies to assess coronary plaque and hepatic steatosis.

Conclusion

Targeting apoC-III to facilitate clearance of TRLs may be a promising therapeutic strategy for lowering triglyceride levels and reducing cardiovascular risk. The phase 3 Essence–TIMI 73b trial, which has enrolled nearly 1,500 patients, including over 550 in a coronary CTA substudy, should provide key insights into the efficacy and safety of olezarsen in patients with largely moderate hypertriglyceridemia and elevated cardiovascular risk.

Appendix

TIMI Study Group, Brigham and Women’s Hospital, Boston, MA:

Marc S. Sabatine (Study Chairman), Brian A. Bergmark (Principal Investigator), Nicholas A. Marston (Co-Principal Investigator), Robert P. Giugliano (Co-Investigator), Andre Zimerman (Fellow), Filipe Moura (Fellow), Yu Mi Kang (Fellow), Sabina A. Murphy (Director of Statistics), Shuanglu Zhang (Biostatistician/Programmer), Polly Fish (Director of Operations), Alexandra Jevne (Senior Project Director), Devon Kelley (Assistant Project Manager), Nicole LaGanke (Assistant Project Manager)

Ionis Pharmaceuticals Inc.:

Sotirios Tsimikas, MD (SVP, Global Cardiovascular Development), Ewa Karwatowska-Prokopczuk, MD, PhD (VP, Cardiovascular Medicine), Veronica Alexander, PhD (Executive Director, Clinical Development), Thomas Prohaska, MD, PhD (Medical Director, Clinical Development)

Clinical Research Organization:

Medpace

Coronary Computed Tomography Core Laboratory:

Massachusetts General Hospital (Michael Lu, MD, MPH)

Biomarker Core Laboratory:

TIMI Core Lab

Steering Committee:

Assen Goudev (Bulgaria), Daniel Gaudet (Canada), Michal Vrablik (Czech Republic), Henrik Kjaerulf Jensen (Denmark), Philippe Moulin (France), Robert Kiss (Hungary), Alberico Catapano (Italy), Erik Stroes (Netherlands), Jeroen Bax (Netherlands), Maciej Banach (Poland), Jorge Ferreira (Portugal), Daniel Pella (Slovakia), Andrej Džupina (Slovakia). Lina Badimon (Spain), Matthew Budoff (United States)

Major Adverse Cardiovascular Event (MACE) Committee:

Nicolas Danchin (Chair), Basil Lewis, Geros Filippatos, Peter Koudstaal

Pancreatitis Event Committee:

Marco Bruno (Chair), Philippe Ruszniewski, George Webster

Independent Data Monitoring Committee:

Richard C. Becker (Chairman), Jamie P. Dwyer, Willis C. Maddrey, Francois Mach, Charles S. Davis, John L. Reid (retired)

Essence–TIMI 73b:

NCT05610280