Experts Say It’s Too Early to Ditch the Lp(a) Hypothesis

A major phase 3 clinical trial was widely expected to confirm the lipoprotein(a) [Lp(a)] hypothesis — that lowering it yields cardiovascular benefit.Harpreet Bhatia, MDWhen the disappointing results of the Lp(a)HORIZON trial came out last month, the hypothesis was suddenly on very shaky ground.However, with more detailed trial results yet to be released, some experts say it’s too early to give up on pipeline therapies aimed at reducing Lp(a) levels in patients at risk for heart attack and stroke.“There are trial differences and drug differences, so there is still hope that Lp(a)-targeted therapy might pan out,” said Harpreet Bhatia, MD, cardiologist at UC San Diego Health. What Went WrongThe Lp(a)HORIZON trial found pelacarsen did not reduce the risk for major adverse cardiovascular events (MACE) despite achieving reduced Lp(a) levels. The full significance of the trial miss will not be clear until Novartis presents detailed results at the American Heart Association’s Scientific Sessions in November.In the trial, Novartis compared a monthly injection of pelacarsen with a placebo in over 8000 patients with a history of myocardial infarction (MI) or stroke and Lp(a) levels over 70 mg/dL or 90 mg/dL. The patients were followed for 4 years.As the primary outcome measure, researchers tracked a composite endpoint made up of cardiovascular death, nonfatal MI, nonfatal stroke, and urgent coronary revascularization requiring hospitalization.Secondary outcome measures included time to coronary heart disease, urgent coronary revascularization, all-cause death, and other events. Novartis did not include findings for secondary endpoints in its September release.Pelacarsen is an antisense oligonucleotide drug developed by Novartis partner Ionis Pharmaceuticals (previously Isis Pharmaceuticals). It lowers plasma Lp(a) levels by targeting apolipoprotein(a) messenger RNA for degradation in the liver. Lp(a) is formed when apolipoprotein(a) binds covalently to apolipoprotein B.George Thanassoulis, MDGeorge Thanassoulis, MD, associate professor of medicine at McGill University in Montreal, Quebec, Canada, and the national principal investigator for HORIZON in Canada, said the results mean pelacarsen is “very unlikely to be approved for use.”The typical reference range for plasma Lp(a) is between 2.1 and 75.0 mg/dL. Patients with Lp(a) levels above 30 mg/dL are considered to have moderately increased risk, while those whose levels are 50 mg/dL or greater have significantly increased risk. An individual’s Lp(a) level is almost entirely determined by variations in the LPA gene. There are currently no FDA-approved Lp(a)-lowering therapies.It’s Not Time to Give Up YetYears of studies on Lp(a) provide “very strong evidence for causality, but they don’t prove it,” said Michael Boffa, PhD, professor in the Department of Biochemistry at the University of Western Ontario in London, Ontario, Canada. He added that the final piece of evidence required would be a positive result in a major Lp(a)-lowering cardiovascular outcomes trial. That’s why so many physicians and researchers were looking to the HORIZON results as the last piece of the Lp(a) puzzle.Michael Boffa, PhD“We really need to know more about how Lp(a) works,” said Boffa, who conducts basic research on Lp(a). “Now, more than ever, it’s imperative that we understand how this stuff actually works to cause disease, because only then can we hope to mitigate its effects.”For example, Boffa noted that the development of atherosclerosis with exposure to Lp(a) is a lifelong process, but little is known about whether Lp(a) becomes important at the early or later stages. If the effects of Lp(a) occur in the early stages, then intervention later, once the plaques have formed, probably would not help. “But it might play a role at the later stages, and lowering it then could potentially reverse the progress of the disease. In theory, anyway,” Boffa said.The HORIZON trial itself may also be to blame for the failure. “In this study, patients actually had very well-controlled risk factors, including their LDL [low-density lipoprotein] cholesterol,” Thanassoulis said. “If you control all of the risk factors and you reduce risk in every other way, is there enough residual risk from Lp(a) to make a difference?”Bhatia agreed it might have been too difficult to show a benefit in the aggressively treated trial population. “On the other hand, if that’s the reason the trial was negative, then that at least would tell us in an analogous population, they don’t necessarily need an Lp(a)-targeted drug,” he said.Bhatia, who was involved with an open-label extension trial of pelacarsen but not the HORIZON trial, also wondered whether there might have been more of a signal in the patient group with higher Lp(a) levels, at over 90 mg/dL, or whether one of the individual endpoints, such as MI, might have shown a stronger relationship with reduced Lp(a) levels.Therapies in the PipelineThe development pipeline includes two small interfering RNA therapies, Amgen’s olpasiran and Eli Lilly’s lepodisiran, both of which are in phase 3 trials. In the OCEAN(a) trial, Amgen is comparing olpaseran to placebo in over 7000 patients with atherosclerotic cardiovascular disease and elevated Lp(a). And in the ACCLAIM-Lp(a) trial, Eli Lilly is hoping to show a benefit for lepodisiran in patients with high Lp(a) who have cardiovascular disease or are at risk for heart attack or stroke vs placebo.There are some key differences between these trials and HORIZON. In a prior study, pelacarsen, an antisense oligonucleotide, reduced Lp(a) by 80% in patients with established cardiovascular disease and Lp(a) over 60 mg/dL.However, Lp(a)-lowering effects for olpasiran and lepodisiran have been greater. In the OCEAN(a)-DOSE trial, patients with established atherosclerotic cardiovascular disease and high Lp(a) experienced placebo-adjusted Lp(a) reductions over 100% at the highest dose levels. And in the phase 2 ALPACA trial, lepodisiran reduced Lp(a) by an average of 93.9% in patients.Erfan Tasdighi, MD“If the absolute reduction of Lp(a) is what counts, the difference between 80% and 95% is a huge difference,” said Erfan Tasdighi, MD, internal medicine resident at Rutgers New Jersey Medical School in Newark, New Jersey, and first author of a 2024 review article on Lp(a). He also noted that the OCEAN(a) trial excludes stroke in its primary outcome measure — instead tracking time to coronary heart disease death, MI, or urgent coronary revascularization — and that the ACCLAIM-Lp(a) trial is being conducted in a high-risk primary prevention population. All of these differences leave room for a potentially different outcome for the other trials.“One point of caution is that all of these drugs lower the same particles,” Tasdighi said. “If HORIZON turns out to truly fall flat rather than being a near miss, higher potency alone may not rescue the hypothesis.”The Evidence So FarThe link between Lp(a) and coronary artery disease was first described in 1981 by researchers from the Institute of Medical Biochemistry at the University of Graz in Austria and the Center of Atherosclerosis Research at Ospedale Regionale in Venice, Italy. A 2009 meta-analysis encompassing 36 studies, 126,634 patients, and over 22,000 recorded events concluded Lp(a) was inversely correlated with coronary artery disease and MI. Another study published in 2009 found a robust causal association between genetically determined Lp(a) levels and the risk for heart attack among over 40,000 participants. Randomized controlled trials of lipid-lowering therapies directed at other targets have linked Lp(a) reduction to a clinical benefit. For example, in results from the ODYSSEY Outcomes trial involving nearly 19,000 patients treated with the PCSK9 inhibitor alirocumab or placebo, alirocumab-induced reductions of Lp(a) predicted lower risk for cardiovascular events independently of LDL cholesterol.The HORIZON result raises questions about whether Lp(a) is an effective treatment target or merely a marker of cardiovascular risk. Although the prior studies are considered strong evidence of causality for Lp(a) in heart attack and stroke risk, it’s still possible that lowering Lp(a) does not alter that risk.This brings with it a sense of deja vu for the pharma industry, which has seen similar disappointments with other cardiovascular biomarkers. Low levels of high-density lipoprotein (HDL) cholesterol, for example, are known to correlate with the development of atherosclerosis. However, clinical trials of drugs that raise HDL and lower LDL have thus far not shown a benefit clearly attributable to HDL increases. Similarly, in August, Novo Nordisk’s interleukin-6-targeted monoclonal antibody ziltivekimab stunned the industry when, like pelacarsen, it failed to reduce MACE risk, despite reductions in free interleukin-6 and high-sensitivity C-reactive protein.Lp(a) Remains Relevant“The last thing I’d like to see is people no longer measuring Lp(a) because of this one negative trial,” Thanassoulis said. “It is an important marker of risk, and we can still try to reduce that risk by targeting factors that we can manage today, including lifestyle and medical therapy.”The American Heart Association recommends all adults receive an Lp(a) test at least once in a lifetime to assess cardiovascular risk, with particular attention to patients with a family history of high Lp(a), a personal or family history of premature heart disease, or familial hypercholesterolemia.For patients with Lp(a) of 50 mg/dL or 125 nmol/L or more, overall atherosclerotic cardiovascular disease risk should be managed through the use of intensive lifestyle modifications, statins, and other lipid-lowering agents targeting LDL cholesterol. “The Lp(a) story has hit a bump in the road,” Boffa said. “But it’s far from over, and even if no drug is ever approved for Lp(a) lowering, measuring Lp(a) will remain an important part of cardiovascular prevention.”Thanassoulis reported consulting or speakers bureau activity for Amgen, Sanofi, Novartis, HLS Therapeutics, Merck, NewAmsterdam Pharma, and Novo Nordisk. Bhatia reported serving as a consultant and advisor for Amgen, Arrowhead, Bayer, Kaneka, Merck, NewAmsterdam Pharma, and Novartis. Boffa reported having research contracts with Amgen and Eli Lilly, receiving consulting and speaking fees from Eli Lilly, and not being involved in the Lp(a)HORIZON trial. Tasdighi reported no relevant financial relationships and no involvement in the Lp(a)HORIZON trial.Catherine Shaffer is a freelance science and medical writer with a background in molecular biology and pharmaceutical research. Her work has appeared extensively in scientific trade and mainstream publications and on public radio.