Novartis announced that its late-stage clinical study evaluating the experimental drug pelacarsen failed to prevent major cardiovascular complications in patients with established heart disease. The Phase 3 HORIZON study, commonly referenced as the pelacarsen trial, showed that sharply lowering circulating levels of the blood particle lipoprotein(a) did not translate into fewer heart attacks, strokes, urgent revascularization procedures, or deaths over nearly five years of patient follow-up. Investigators shared the complete findings at the American Heart Association scientific sessions in Chicago. The data presented a difficult outcome for an approach that guided cardiovascular research for decades [1].
Pelacarsen Trial Findings at AHA Sessions
Novartis developed the experimental therapy with Ionis Pharmaceuticals as an injectable antisense medicine designed to shut down hepatic synthesis of apolipoprotein(a). By binding messenger RNA in liver cells, the molecule stopped the body from assembling new lipoprotein(a) particles [2].
In the pelacarsen trial, investigators tracked cardiovascular outcomes across more than 8,000 individuals with pre-existing heart disease who received either pelacarsen or a placebo alongside their regular therapies. Pelacarsen achieved its biological target by driving down circulating levels of the particle by substantial margins throughout the treatment schedule. Despite this pronounced reduction in circulating lipoprotein(a), rates of cardiovascular death, nonfatal heart attacks, and ischemic strokes were virtually identical between the active drug and placebo arms over nearly five years. The New England Journal of Medicine published the full report, which documented the absence of clinical benefit [5].
Company leaders acknowledged the disappointing clinical outcome while defending the quality of the multiyear trial. “These are not the results we hoped for,” said Shreeram Aradhye, chief medical officer at Novartis. He explained that the trial results will guide subsequent cardiovascular strategies [2].
Biology of Lipoprotein(a)
Discovered in 1963, lipoprotein(a) carries serious cardiovascular consequences. Lipoprotein(a) consists of a low-density lipoprotein core chemically linked to an apolipoprotein(a) glycoprotein, but medical laboratories struggled for decades to quantify its circulating levels in diverse patient populations. Long-term epidemiological investigations eventually proved that individuals inheriting elevated concentrations faced more than twice the risk of experiencing a heart attack, as circulating particles accumulate inside arterial walls to accelerate plaque formation and promote blood clotting [3].
According to the American Heart Association, about 20% of people carry high levels of lipoprotein(a). Circulating amounts are determined almost entirely by genetic variation in the LPA gene and cannot be meaningfully changed through diet, aerobic exercise, or routine lifestyle adjustments [2].
Because diet cannot lower this particle, drugmakers turned to molecular tools to silence its genetic source in liver tissue. An earlier Phase 2 study published by Tsimikas and colleagues in the New England Journal of Medicine evaluated an antisense compound known as APO(a)-L Rx in 286 patients with established cardiovascular illness [6]. The trial showed dose-dependent reductions in lipoprotein(a) concentrations after six to twelve months of treatment. These data created optimism that reducing the particle would prevent heart attacks in larger clinical cohorts [2].
Design of the HORIZON Study
Participants in the pelacarsen trial presented with high baseline arterial risks. The HORIZON study enrolled 8,323 participants who already suffered from coronary heart disease, cerebrovascular disease, or peripheral artery disease. Investigators tracked major adverse cardiovascular events over an average follow-up period of nearly five years to determine whether pelacarsen lowered overall clinical risks [1].
Every trial participant received intensive baseline therapy. Under prevailing clinical guidelines, clinicians administered high-potency statins and ezetimibe to suppress low-density lipoprotein cholesterol to historical lows, evaluating therapies such as statins for healthy people to stabilize vulnerable vascular beds. Because these established background medications reduce cardiovascular events substantially on their own, proving that an experimental add-on medicine provides additional survival benefits has become far more difficult and expensive for sponsors like Novartis [3].
Cardiovascular specialists are analyzing whether certain patient sub-groups showed any hint of benefit from the therapy. Jefferies analyst Dennis Ding wrote that his team would examine baseline particle levels, the depth of reduction, and the statistical effect of participants who stopped taking the drug [2].
Novo Nordisk and the ZEUS Trial
The disappointing outcome for pelacarsen was not an isolated event at the American Heart Association meeting in Chicago. Novo Nordisk presented detailed findings from its ZEUS trial, an outcomes study testing the monoclonal antibody ziltivekimab in patients with established cardiovascular disease and chronic kidney disease. Ziltivekimab was engineered to inhibit interleukin-6, an inflammatory cytokine that many cardiologists believe drives plaque rupture and acute coronary events. Out-of-control vascular inflammation has long been viewed as a primary contributor to cardiovascular and metabolic damage, making interleukin-6 an attractive target for clinical trials [4].
Although ziltivekimab lowered circulating inflammatory markers, it failed to decrease heart attacks, strokes, or deaths compared with placebo in the ZEUS study. In September, Novo Nordisk stopped two sister studies known as HERMES and ATHENA when an independent safety panel found little chance of clinical success [4].
Detailed results from both ZEUS and HORIZON appeared in the New England Journal of Medicine. Both publications highlighted the biological gap between modifying blood markers and preventing actual emergencies [4, 8]. In both studies, advanced biotechnology drugs altered their intended molecular targets by wide margins without sparing patients from recurrent heart attacks or cardiovascular death. The parallel failures suggest that when arterial atherosclerosis has progressed for decades, modifying a single circulating risk factor in older patients with established disease may arrive too late to alter clinical outcomes [1, 4].
Why the Pelacarsen Trial Shook Investors
Financial markets responded negatively when top-line results from the pelacarsen trial were announced. Novartis shares fell 3% in extended trading, while Ionis Pharmaceuticals dropped 10%. Amgen shares fell 5%, and NewAmsterdam Pharma fell 12% as investors reassessed the commercial viability of lipoprotein(a) drugs [3].
The clinical failure brought a commercial setback for Novartis as it navigates what chief executive officer Vas Narasimhan described as the steepest patent cliff in the company’s history. Its bestselling heart medication, Entresto, lost key patent exclusivities, leaving the firm in need of new blockbuster therapies to sustain its cardiovascular portfolio. Analysts at William Blair had projected peak annual U.S. sales of $6 billion for pelacarsen if the trial succeeded, while other financial models anticipated $4 billion to $5 billion in global annual revenues [2, 3]. The loss of those anticipated sales leaves a significant gap in Novartis’s growth plans [3].
Wall Street analysts observed that pelacarsen appeared to miss even modest statistical thresholds for clinical efficacy. Barclays analysts said that a 13% reduction in cardiovascular events would have yielded statistical significance in the trial population, but the drug fell short of that benchmark [3]. Myles Minter of William Blair wrote in a client note that the data introduce “meaningful risk” to competing trials targeting the particle [2].
Future of Lipoprotein(a) Therapies
Despite the disappointing HORIZON data, academic researchers and industry analysts maintain that the broader lipoprotein(a) hypothesis remains alive. In an assessment of the trial outcome, Citi analysts wrote that “The Lp(a) hypothesis is weakened, but not disproven”. They explained that later studies must show whether deeper particle lowering can deliver a 15% reduction in major adverse cardiovascular events [3]. The unexpected outcome in the pelacarsen trial has prompted researchers to reassess whether pelacarsen failed because its biological mechanism was insufficient or because lowering the particle cannot reverse advanced cardiovascular disease in high-risk patients [1].
Competing companies are testing alternative RNA technologies designed to achieve greater suppression of the target particle. Silence Therapeutics and Eli Lilly are advancing RNA drugs that block particle synthesis, while Amgen is studying olpasiran, a small interfering RNA that reduced lipoprotein(a) levels by more than 95% in mid-stage clinical testing [2, 7]. A trial published by O’Donoghue and colleagues in the New England Journal of Medicine confirmed those substantial reductions [7].
Can deeper genetic silencing or earlier treatment overcome the disappointment of the HORIZON study? Some cardiologists argue that therapies targeting lipoprotein(a) should be evaluated in younger populations before arterial plaques become permanent and refractory to medical intervention. Eli Lilly is pursuing this concept by enrolling broader patient cohorts for lepodisiran, including individuals who have not yet developed established arterial disease. In the meantime, physicians continue to recommend proven therapies such as statins for healthy people and high-risk patients while awaiting definitive results from competing trials over the next three years [3].
- ONLINE NEWS Cooney, E., & Herper, M. (2026, November 7). Failure of Novartis Lp(a) drug raises questions about cardiovascular strategy. STAT. [Article Link]
- ONLINE NEWS Fidler, B. (2026, September 5). Novartis, Ionis drug failure spurs questions about an emerging class of heart medicines. BioPharma Dive. [Article Link]
- ONLINE NEWS Ohlen, E. (2026, September 8). Cholesterol drug setback casts doubt over multibillion-dollar race. CNBC. [Article Link]
- ONLINE NEWS Cooney, E. (2026, November 7). Despite Novo drug’s failure, cardiologists say they will still pursue anti-inflammatories. STAT. [Article Link]
- ACADEMIC JOURNAL Cho, L., Nicholls, S. J., Frndak, S., Wolski, K., Nordestgaard, B. G., Manning, B., Leitersdorf, E., Landmesser, U., Menon, V., McCluskey, J., Blaha, M. J., Morishita, R., Lincoff, A. M., Zhao, Z., Wang, J., Santos, R. D., Gouni-Berthold, I., Tsimikas, S., Lesogor, A.,. Nissen, S. E. (2026). Pelacarsen and Cardiovascular Outcomes in Patients with High Lipoprotein(a). New England Journal of Medicine. [Article Link]
- ACADEMIC JOURNAL Tsimikas, S., Karwatowska-Prokopczuk, E., Gouni-Berthold, I., Tardif, J., Baum, S. J., Steinhagen-Thiessen, E., Shapiro, M. D., Stroes, E. S., Moriarty, P. M., Nordestgaard, B. G., Xia, S., Guerriero, J., Viney, N. J., O’Dea, L., & Witztum, J. L. (2020). Lipoprotein(a) Reduction in Persons with Cardiovascular Disease. New England Journal of Medicine, 382(3), 244-255. [Article Link]
- ACADEMIC JOURNAL O’Donoghue, M. L., Rosenson, R. S., Gencer, B., López, J. A. G., Lepor, N. E., Baum, S. J., Stout, E., Gaudet, D., Knusel, B., Kuder, J. F., Ran, X., Murphy, S. A., Wang, H., Wu, Y., Kassahun, H., & Sabatine, M. S. (2022). Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease. New England Journal of Medicine, 387(20), 1855-1864. [Article Link]
- ACADEMIC JOURNAL Ridker, P. M., Lincoff, A. M., Marx, N., Navar, A. M., Sattar, N., Tuttle, K. R., Budoff, M., Böttcher, M., Cavender, M. A., Choudhury, R. P., Cornel, J. H., Gajos, G., Komuro, I., Reddy Parvathareddy, K., Pontremoli, R., Saraiva, J. F. K., Simova, I. I., Sloan, L. A., López-Suárez, A.,. Vrolix, M. (2026). Interleukin-6 Inhibition with Ziltivekimab for Atherosclerotic Disease. New England Journal of Medicine. [Article Link]
APA 7: PerEXP Teamworks. (2026, November 8). Novartis Pelacarsen Trial Fails to Lower Heart Event Risk. PerEXP Teamworks. https://perexpteamworks.com/en/pelacarsen-trial-fails-cardiovascular-outcomes/
