Lipoprotein(a): The next frontier in CV risk reduction
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This installment of Pipeline Pulse focuses on a single cardiovascular risk factor, lipoprotein(a), and examines two CV outcomes trials aimed at reducing CV events through Lp(a) reduction.
Lipoprotein(a), or Lp(a), is produced in the liver and contains two units connected by a covalent disulfide bond, a small LDL-like component and a single apolipoprotein(a) molecule. The apo(a) part of Lp(a) is almost entirely genetically determined, and its highly variable length is generally inversely proportional to Lp(a) concentration. Lp(a) increases CV risk through three pathways — atherogenic, inflammatory and thrombotic — making it a CV triple threat. Copious oxidized phospholipids augment inflammation, thrombosis and atherogenicity; apolipoprotein(a)’s homology to plasminogen increases thrombosis; and the cholesterol content of Lp(a) causes atherosclerosis.
Emerging focus on Lp(a)
We know from many lines of evidence that elevated Lp(a) levels increase risk for CV events. Epidemiologic, genome-wide association and Mendelian randomization studies consistently demonstrate this, and evidence from PCSK9 inhibitor studies lends further support.
Being more than 90% dependent on genetics, Lp(a) levels are typically highly stable throughout one’s life. Though some conditions, such as liver disease, hypothyroidism, nephrotic syndrome and hormonal changes during menopause can impact levels, therapeutic lifestyle changes cannot. And although some medications, such as the PCSK9 inhibitors and niacin, can reduce Lp(a) levels up to 30%, none has been given an FDA indication to do so. In fact, the only currently approved FDA treatment for Lp(a) is lipoprotein apheresis, specifically in the setting of Lp(a) > 60 mg/dL and LDL >100 mg/dL and with either documented CAD or peripheral artery disease. Additionally, although Lp(a) varies significantly by race/ethnicity, high levels are decidedly prevalent across all populations, with significantly elevated levels in 20% of white individuals, 15% of Latin American individuals, 10% of East Asian individuals, 25% of South Asian individuals and 30% of Black individuals.
In view of Lp(a)’s high prevalence, genetically disparate risk and apparent causal role in atherosclerotic CVD, there has been enhanced focus worldwide on better identifying this risk factor in clinical practice. In the U.S., Lp(a) has been highlighted in guidelines as a valuable “risk enhancer,” while in Europe and Canada, guidelines now mandate universal screening. Along with the recent shift to more broadly identifying Lp(a) levels, there is now a recognized urgency to better understand its pathologic attributes and more rapidly identify effective risk-reducing therapies.
CV outcome trials
Consequently, multiple therapeutics are in early development, including an oral small molecule and potential gene editing approaches, but two later-stage drugs are already being studied in large phase 3 CV outcome trials.
Pelacarsen (Novartis/Ionis), a second-generation antisense oligonucleotide, is being studied in the HORIZON trial, and olpasiran (Amgen), a small interfering (or silencing) RNA, is being evaluated in OCEAN(a)-Outcomes. The studies have some key differences.
HORIZON has two co-primary endpoints, the time to first occurrence of expanded major adverse CV events (CV death, nonfatal MI, nonfatal stroke and urgent coronary revascularization requiring hospitalization) in two populations of patients, those with Lp(a) 70 mg/dL and those with Lp(a) > 90 mg/dL. The trial first enrolled participants in December 2019 with the key inclusion criteria for the 8,324 participants being an Lp(a) > 70 mg/dL (approximately 175 nmol/L), and history of spontaneous MI or ischemic stroke within 10 years of screening or symptomatic PAD. The agent is given monthly via subcutaneous injection. Prior studies using the same dose of pelacarsen produced an approximately 80% reduction in Lp(a).
OCEAN(a)-Outcomes has as its primary composite endpoint the time to CHD death, MI, or urgent coronary revascularization, whichever occurs first. It began enrollment in December 2022 with an ultimate goal of 6,000 participants and the key inclusion criteria being a screening Lp(a) > 200 nmol/L, a history of ASCVD, defined as either a prior type 1 MI or prior revascularization with PCI plus at least one specified risk-enhancing feature. The study drug is administered once every 12 weeks via subcutaneous injection. Prior studies with the same dose of olpasiran produced > 95% reduction in Lp(a).
There are a few key distinctions between the studies. HORIZON included ischemic stroke and PAD as qualifying events, while OCEAN(a)-Outcomes did not. Stroke is less consistently associated with elevated Lp(a) than is MI. Still, it is important to understand the relationship of Lp(a) and stroke and whether reducing Lp(a) effectively diminishes risk for stroke, and HORIZON will provide these insights. Similarly, HORIZON will enhance our understanding of Lp(a)’s relationship to PAD, a high-risk and vastly undertreated condition. OCEAN(a)-Outcomes, however, did include PCI as a qualifying event. Evaluating the response to Lp(a) reduction in patients with prior PCI will potentially greatly broaden the utility of Lp(a) reducing therapies if the study is positive. On balance, HORZION enrolled higher-risk patients than did OCEAN(a), but interestingly, HORIZON’s cutpoint for Lp(a) was lower than OCEAN(a)-Outcome’s, 175 nmol/L vs. 200 nmol/L. So, from an Lp(a) standpoint, the OCEAN(a)-Outcomes participants are at somewhat higher risk than HORIZON’s. Regarding endpoints, both studies included urgent coronary revascularization, CHD death and nonfatal MI, but HORIZON included nonfatal stroke and OCEAN(a)-Outcomes did not. Including stroke as an endpoint will not only be informative, but it may also provide a new therapy to mitigate the risk of this highly prevalent and often devastating CV event.
Editor’s Note: Information in this article was up to date at the time of publication. The next installment of Pipeline Pulse will focus on the Inflation Reduction Act (IRA). In this column, Baum will examine the potential impact of this legislation on the CVD drug pipeline.
- References:
- Clinicaltrials.gov. clinicaltrials.gov/ct2/show/NCT04023552. Published July 17, 2019. Accessed April 26, 2023.
- Clinicaltrials.gov. clinicaltrials.gov/ct2/show/NCT05581303. Published Oct. 14, 2022. Accessed April 26, 2023.
- Grundy SM, et al. Circulation. 2019;doi:10.1161/CIR.0000000000000625.
- Tsimikas S, et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2017.11.014.
- For more information:
- Seth J. Baum, MD, is chief scientific officer at Flourish Research and clinical affiliate professor of cardiology at the Florida Atlantic University Charles E. Schmidt College of Medicine. He is also a member of the Cardiology Today Editorial Board. Baum can be reached at sjbaum@fpim.org; Twitter: @sethjbaummd.
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