With the power to promote plaque build-up, blood clots and inflammation, Lp(a) has been likened to a “triple-headed monster.” \n In the early 1960s, Norwegian physician Kåre Berg, M.D., was trying to identify new blood types when he accidentally discovered a lipoprotein with perplexing properties. Similar to cholesterol, but not quite the same, and also the lookalike of a clot-busting protein, the molecule still vexes researchers many decades later. It also might just revolutionize cardiovascular medicine as we know it.The potential impact of medicines that lower lipoprotein(a)—abbreviated as Lp(a) and often read as “L-P-little A”—is obvious. Elevated Lp(a) is a known risk factor for a range of bad cardiac outcomes, from heart attacks and strokes to heart valve malfunctions. And the scale of the problem is almost too large to fathom: an estimated 20% of the global population has Lp(a) levels that put them at risk. Guidelines from a suite of expert groups, led by the American College of Cardiology and American Heart Association, now recommend that everyone have their Lp(a) levels tested at least once in their life.Unlike cholesterol, Lp(a) is almost entirely genetically controlled, meaning it can’t be lowered with a new diet or an exercise regimen. But Lp(a)’s genetic control, as well as its manufacturing site in the liver, make it a prime candidate for targeting by small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs).Should the Lp(a)-lowering candidates now in the clinic reach their full potential, they could surpass statins—the most prescribed medications in the world—in their use, multiple experts told Fierce Biotech. “In the U.S., it\'s 65 million people with high Lp(a) that would be theoretically eligible,” Sam Tsimikas, M.D., cardiovascular leader at Ionis Pharmaceuticals and a pioneer of Lp(a) drug development, told Fierce. “It\'s going to be huge.”The first pivotal trial set to read out is for Novartis and Ionis’ ASO pelacarsen, with data expected in the next few months; candidates from Amgen and Eli Lilly will follow over the coming years. Should pelacarsen’s phase 3 Horizon trial succeed, it would trigger a tidal wave of interest in the Lp(a) field, experts agreed. But while pelacarsen could be approved as early as next year, there would still be a long way to go before the Lp(a) drug class as a whole ascends to the mega-blockbuster level of statins.“There\'s a couple of things that really need to happen to get to that market opportunity,” Myles Minter, Ph.D., a healthcare analyst with William Blair, told Fierce. Cracking the primary cardiac prevention market could be a challenge, Minter and others said, and much still remains unknown about Lp(a)’s relationship with different kinds of heart risks. In fact, the basic question of what Lp(a) is supposed to do in the body remains unanswered.But even if statin-like success remains unattainable, Minter added, “in my book, these are all blockbuster opportunities regardless.”And Lp(a) innovation isn\'t stopping there. AstraZeneca is pursuing a combination of a PCSK9 inhibitor and an Lp(a) disruptor, as is the recently rebranded cardio outfit Thalia Therapeutics.David Solomon, Ph.D., the former CEO of GLP-1 biotech Zealand Pharma, who now leads Thalia, thinks the Lp(a) market could even top the current obesity frenzy.Just as GLP-1 medicines have come of age in recent years, “I think in the next five to 20 years, this field will come to fruition,” Solomon told Fierce. “This is just a huge market opportunity.” Mystery molecule After Berg’s initial discovery of Lp(a) in 1963, the field went quiet for about a decade. That silence was shattered in 1974, when researchers realized that the molecule wasn’t just present in some people, as Berg had thought, but was in fact found in everyone. From there, its relationship with heart attacks was established, and over the subsequent decades, its ability to potentiate multiple kinds of cardiac events was solidified.The signature “little a” of Lp(a) refers to apolipoprotein(a), the key feature of Lp(a) that makes the molecule so tricky to study. Apo(a) consists of units called kringles—named after a twisty Northern European pastry—some of which repeat. Different genetic variants of the apo(a) gene lead to different numbers of kringle repeats, which in turn produces Lp(a) molecules of different sizes. When people have short Lp(a) molecules, they tend to build up more easily in the blood, leading to elevated levels and increased cardiovascular risk. Marlys Koschinsky, Ph.D., an Lp(a) expert at Western University in Ontario, Canada, has spent decades unraveling Lp(a)’s structure and how it relates to its ability to cause cardiac harm, going back to a postdoctoral position at Genentech that she took in 1988. She calls Lp(a) a “triple-headed monster” because it can clog arteries using its cholesterol component, enable blood clots to build with its apo(a) component by interfering with the clot-destroying protein plasminogen and wriggle into blood vessels to trigger inflammation.Ionis’ Tsimikas agrees with this monstrous characterization. “Lp(a) is, in many ways, a diabolical compound,” he said. Despite being discovered 63 years ago, scientists still aren’t sure how the body breaks it down or if it has any dedicated receptors that it binds to on the surface of cells. Part of the problem for a while was that there was no reliable way to measure Lp(a); all those repeating kringles could attract multiple antibodies used to quantify it, making one Lp(a) molecule look like multiple. That issue, at least, has been solved now, and Roche sells a reliable assay for measuring the molecule in blood.“You\'ve got to be rather insane, really, to spend a career trying to work on it,” Koschinsky told Fierce. “All the kringle repeats, the isoform size variability—and people for a long time didn\'t even believe that it was a risk factor in the clinic.”With so many well-documented negative effects, one would be forgiven for wondering why, exactly, the human body makes any Lp(a) at all. Tsimikas thinks the molecule’s ability to promote blood clots may have, at one point, helped stanch bleeding during childbirth.“It\'s not relevant now, because pretty much everybody gives birth in a hospital, but in the old days, women died of childbirth from hemorrhage,” he said. Under these conditions, more Lp(a) meant less bleeding, with surviving mothers then able to pass on their genes for elevated Lp(a) to their offspring, he posited.Tsimikas’ fellow Lp(a) pioneer Koschinsky, though, remains unconvinced that Lp(a) has any use whatsoever. The molecule is found only in humans and certain species of monkeys. In fact, some people have extremely low levels of it with no apparent problems—which makes Koschinsky suspect it doesn’t serve any deep-seated evolutionary purpose. “I guess there\'s people who believe, like there\'s also people who believe in UFOs, that it\'s got to have some kind of a biological function,” she said. “If there is something, we haven\'t found it.” Any day now All the experts Fierce spoke with agreed that Novartis and Ionis’ Horizon trial is a pivotal test for the Lp(a) field, albeit not necessarily a make-or-break one.Horizon is a secondary prevention trial, focused on 8,323 patients with established cardiovascular disease and elevated Lp(a), most of whom have had a heart attack or stroke before. The goal is for pelacarsen treatment to lower Lp(a) levels and demonstrate a concomitant reduction in risk of a second cardiac event.The enrolled patients have an average Lp(a) level of 108 mg/dl, according to a 2025 publication. With pelacarsen expected to lower Lp(a) by around 70% based on past data, William Blair’s Minter said, the vast majority of treated patients should get below 50 mg/dl, the generally accepted level at which Lp(a) is considered too high.“You\'re trying to stop the second event,” Minter said. “We\'re going to find out whether interventional lowering of around about 70%, 80%, [depending] on the exposure of pelacarsen, is enough to do it.”Should Horizon succeed, it will offer proof of the hypothesis that therapeutically lowering Lp(a) can reduce cardiovascular risk, Western University\'s Koschinsky said.“That hypothesis has been out there for years,” Koschinsky said. And while a positive Horizon outcome won’t definitively prove it for all kinds of cardiovascular events, the result will likely spur skeptical providers to finally start testing their patients’ Lp(a) levels.“People are going to really be nervous [that] if they\'re not testing it, then they\'re really not fulfilling their mandate to their patients,” said Koschinsky, who was first author on the National Lipid Association’s 2019 statement advocating for routine Lp(a) measurement.The many mysteries that remain swirling around Lp(a) frustrate clinicians, she added, who are still waiting for definitive proof that lowering levels of the lipoprotein is worth it. “You\'ve got to change hearts and minds on this,” she said. The other experts Fierce spoke with agreed that a Horizon success would undoubtedly spark significant interest in Lp(a) testing and treatment.“You\'re going to see testing skyrocket,” Ionis’ Tsimikas said, “and then there\'ll be a lot of interest to treat high-risk primary prevention,” even though Horizon is addressing secondary prevention. He noted that he sees many patients at his clinic who have elevated Lp(a) and family histories of heart problems.“They all want to have some therapy for their problem,” he said. “We\'re going to have to deal with a lot of demand for access to this drug.” If everything had gone according to plan, Horizon would have already provided an answer to the Lp(a) question. Novartis initially expected data to read out last year, following delays due to the COVID-19 pandemic, but Tsimikas told Fierce that the trial should wrap up in the next few months. That’s because the study won’t stop until a certain number of cardiac events have happened, and the chances of heart attacks and strokes in the patient population have changed over time.“When the trial was designed, the power calculations were based on Fourier,” Tsimikas explained, referring to Amgen’s phase 3 trial for its PCSK9 inhibitor Repatha.To match the Fourier placebo group’s yearly cardiac event rate of 4.6%, the Horizon team calculated that they’d need to follow patients for around 4.25 years and accrue 993 events, he said.However, in the time it took to get the trial off the ground, the cardio risk field changed, and Horizon’s enrolled patients have a baseline level of LDL cholesterol far below that of Fourier, putting them at a lower overall risk of heart attacks and strokes.“It may actually not make a difference in the readout of the trial, even though the event rates are lower, because the event rates are going down because of LDL, not because of Lp(a),” Tsimikas said. LDL and Lp(a) are independent risk factors, as far as we know.It is possible that the relationship between LDL, Lp(a) and cardiac risk could change at very low levels of LDL, he added, but that won’t be clear until the data finally come in.Horizon “will push the field either forward or backwards, depending on the result,” Rafael Zubirán, M.D., a researcher in the lipoprotein metabolism laboratory at the National Heart, Lung and Blood Institute, told Fierce. But with Lp(a)’s link to bad cardiac outcomes so clear, even a fail from pelacarsen likely wouldn’t stop the field in the long run.“It won\'t be the end of [Lp(a)] if it fails; it will be a huge win if it does provide a good reduction,” Zubirán said. Follow the leader While Novartis and Ionis are, for now, focusing pelacarsen on patients who have had cardiac events already, their competitors are hot on their heels, with an eye toward the lucrative primary prevention market.Amgen’s siRNA olpasiran is set to read out a secondary prevention trial in December and a primary prevention trial in 2031, both phase 3, while Lilly’s siRNA lepodisiran has a phase 3 primary prevention trial set to wrap up in 2029.Amgen licensed olpasiran from Arrowhead Pharmaceuticals back in 2016, while Lilly developed lepodisiran through a 2018 research pact with Dicerna Pharmaceuticals (since acquired by Novo Nordisk). Ionis, meanwhile, published the first results of the ASO that became pelacarsen in 2011. Amgen and Lilly’s next-gen molecules are both more potent than pelacarsen, so far reducing Lp(a) levels by more than 90%. Whether this more drastic reduction translates to improved risk reduction relative to pelacarsen is a key open question, as is whether or not dropping Lp(a) to near zero causes any unwanted side effects.Even if the improved standard of care in cardiac risk reduction—thanks to statins, PCSK9 inhibitors and aspirin—dulls pelacarsen’s apparent efficacy in Horizon, the Lp(a) cat is already out of the bag. Ionis’ Tsimikas doesn’t think a negative result for Horizon would matter to Amgen and Lilly’s trials.“I don\'t think anybody\'s going to stop,” he said. “Those are going to continue, no matter what happens with Horizon.”By blazing the Lp(a) trail, Ionis and partner Novartis now enjoy a lead on Amgen of about a year and a half. But even before a positive Horizon result potentially sparks an Lp(a) gold rush, others are already piling onto the bandwagon. In addition to lepodisiran, Lilly is also testing an oral small molecule called muvalaplin, with its own phase 3 trial set to conclude in 2031. It’s the possibility of an Lp(a)-lowering pill that most excites William Blair’s Minter. That would make the \"holy grail\" that AstraZeneca is pursuing, a combo of an oral PCSK9 inhibitor and an oral Lp(a) disruptor, much closer to reality. AstraZeneca has such a PCSK9 inhibitor in phase 3 development, known as AZD0780, and licensed a preclinical Lp(a) asset from CSPC Pharmaceutical Group in 2024.“That\'s your combination therapy moving forward, that basically manages your apolipoproteins for life,” Minter said.The potential of a combo therapy also piqued Thalia\'s interest. The U.K. biotech rebranded from N4 Pharma in February, with a focus on a dual-acting siRNA meant to inhibit both PCSK9 and Lp(a). While still preclinical, Thalia’s new CEO, David Solomon, has high hopes for the approach as a once-yearly cardiovascular risk reducer.“The dual is a really strong approach,” he told Fierce, comparing it to the obesity field that is now awash with assets aiming for GLP-1, amylin and other target combos. And even though Thalia is far behind the competition, Solomon isn’t concerned.“In the world of statins, Mevacor was first, and everyone thought Merck had done it,” he said. “But the most successful statin was the number six statin, which was [AstraZeneca’s] Crestor. There\'s room in cardiovascular medicine for multiple medicines against similar targets that address a lot of unmet need.”With so much competition swirling, Ionis is committed to staying on top of the Lp(a) field, Tsimikas said. After licensing a planned follow-up to pelacarsen to Novartis in 2023, the Big Pharma has since handed the asset back to Ionis. This decision was partly driven by Novartis\' desire to move pelacarsen follow-ons into the clinic quickly, he explained, with the next-gen Ionis asset still being early in development.“We\'re not going to sit on it,” Tsimikas said. “We want to stay the Lp(a) leaders, in many ways. Whether it\'s siRNA, gene editing, whatever.”
