One Failed Heart-Drug Trial Hits Ionis, Novartis and Amgen: What Happened and Why It Matters

One Failed Heart-Drug Trial Hits Ionis, Novartis and Amgen: What Happened and Why It Matters

Biotechnology stocks are being punished today after a closely watched cardiovascular trial produced a disappointing answer to an important medical question: Does dramatically lowering lipoprotein(a), an inherited form of cholesterol-related risk, actually prevent heart attacks, strokes and cardiovascular deaths?

For Novartis and its partner Ionis Pharmaceuticals, the answer from their large Phase 3 trial was no—or at least not sufficiently to meet the trial’s primary goal. Their experimental drug, pelacarsen, successfully lowered patients’ lipoprotein(a), commonly abbreviated Lp(a), but did not produce a statistically significant reduction in major cardiovascular events compared with a placebo.

The result is directly damaging to Ionis and Novartis, but it is also raising doubts about Amgen’s olpasiran, another experimental medicine intended to reduce cardiovascular events by lowering the same target. That explains why Amgen is falling even more sharply than Ionis today.

As of approximately 12:25 p.m. ET on September 8, Ionis shares were down about 5%, Novartis’s U.S.-listed shares were down approximately 14%, and Amgen had fallen nearly 10%. Other companies developing treatments related to Lp(a) were also under pressure.

What Is Lp(a), and Why Were These Drugs Considered So Promising?

Lipoprotein(a), pronounced “L-P-little-a,” is a cholesterol-carrying particle found in the blood. It resembles LDL—the type commonly called “bad cholesterol”—but has an additional protein attached to it that appears to make the particle especially troublesome.

In plain English, Lp(a) can contribute to fatty plaque in the arteries, inflammation and blood clotting. High levels are associated with an increased risk of heart attack, stroke, peripheral artery disease and narrowing of the heart’s aortic valve.

Unlike ordinary cholesterol, Lp(a) is determined primarily by genetics. Levels are approximately 90% inherited and generally do not respond very much to diet, exercise or the statin drugs commonly prescribed to lower LDL cholesterol. A person can therefore live a healthy lifestyle, have reasonably controlled conventional cholesterol and still carry substantial additional cardiovascular risk from elevated Lp(a).

Elevated Lp(a) is common. Novartis estimates that it affects approximately one in five people worldwide, yet there is currently no approved medicine specifically designed to lower it.

That created what appeared to be a very large medical and commercial opportunity. If a drug could suppress production of Lp(a) and thereby prevent cardiovascular events, it might eventually be prescribed to millions of high-risk patients.

But lowering a laboratory measurement is not enough. Drugmakers ultimately need to prove that changing that measurement produces a meaningful improvement in patients’ health. That was the question the pelacarsen trial was designed to answer.

How Pelacarsen Was Supposed to Work

The liver produces apolipoprotein(a), the distinctive protein used to assemble Lp(a) particles. The body makes that protein by following genetic instructions carried by messenger RNA.

A useful way to picture messenger RNA is as a temporary copy of a recipe. The underlying gene contains the original instructions, and messenger RNA carries a copy of those instructions to the cell’s protein-making machinery.

Pelacarsen is an “antisense oligonucleotide,” or ASO. That is a short, synthetic strand of genetic material designed to recognize and attach to the particular messenger RNA containing the recipe for apolipoprotein(a). Once pelacarsen attaches to that messenger RNA, the cell destroys or disables the message. With fewer usable instructions available, the liver makes less apolipoprotein(a), and the amount of Lp(a) circulating in the blood falls.

Pelacarsen therefore does not rewrite a patient’s DNA. It temporarily intercepts one specific genetic message before the liver can use it to manufacture the targeted protein. Continued dosing is required because the body keeps producing new messenger RNA.

Earlier studies showed that pelacarsen could lower Lp(a) substantially, in some dosing groups by roughly 80%. That established that the drug could hit its biological target. The unresolved question was whether patients would consequently suffer fewer heart attacks, strokes and other serious cardiovascular events.

What the Phase 3 Trial Found

The Lp(a)HORIZON trial enrolled 8,323 patients who had both elevated Lp(a) and established cardiovascular disease. These were not generally healthy people being treated solely because of an abnormal blood test. They were high-risk patients who had already developed cardiovascular disease.

Participants also received guideline-recommended treatment for their other cardiovascular risks, including cholesterol-lowering and blood-pressure medications. Pelacarsen was therefore being asked to demonstrate an additional benefit on top of modern standard care.

The trial’s primary endpoint was a combination of four outcomes:

• cardiovascular death;

• nonfatal heart attack;

• nonfatal stroke; and

• an urgent procedure to restore coronary blood flow that required hospitalization.

Novartis announced that pelacarsen lowered Lp(a), as expected, but did not significantly reduce this combined measure of cardiovascular events in the overall trial population compared with placebo. Novartis’s announcement

That is the central disappointment: the drug changed the biomarker but did not establish that the change improved clinical outcomes.

The announcement provided only top-line results. Novartis has not yet disclosed the actual difference in event rates, the statistical confidence interval or the results for individual components such as heart attacks and strokes. It also has not disclosed whether patients with the highest starting Lp(a) levels appeared to benefit more than the overall population.

Those details are expected to be presented at a future medical meeting, and they will be essential to understanding just how decisively the trial failed.

A study can miss its primary endpoint in very different ways. The drug might have provided essentially no benefit, or it might have produced a potentially useful reduction that fell short of statistical significance. There could also be differences involving the dose, the amount of Lp(a) reduction achieved, the duration of treatment or the types of patients enrolled.

For now, however, the only responsible conclusion is that pelacarsen did not prove that it reduces cardiovascular events in the population studied.

Where Ionis Fits Into the Story

Ionis discovered pelacarsen and conducted its early development. Novartis exercised an option in 2019 and obtained worldwide rights to develop, manufacture and commercialize the drug.

Under that arrangement, Novartis assumed responsibility for the enormous and expensive Phase 3 program, while Ionis retained the right to receive development and regulatory milestones plus royalties if pelacarsen eventually reached the market.

Ionis was eligible for as much as $650 million in additional development, regulatory and commercial milestone payments from Novartis. It was also entitled to tiered royalties ranging from the mid-teens to the low-20% range on net pelacarsen sales.

In 2023, Ionis sold Royalty Pharma 25% of those future pelacarsen royalty payments while retaining the remaining 75% and all its rights to the Novartis milestones. Ionis–Royalty Pharma agreement

Royalty Pharma said following the trial announcement that it no longer expects to make any pelacarsen-related milestone payments to Ionis. That is a strong indication that the parties currently view the program as a clinical failure rather than a temporary delay. Royalty Pharma’s update

The direct financial damage to Ionis is therefore the probable loss of a potentially valuable future royalty stream and remaining milestone payments. Ionis does not bear the same loss Novartis does from funding the Phase 3 program, because development responsibility had already passed to Novartis.

Pelacarsen was meaningful to Ionis, but it was not the company’s entire investment story. Ionis has other commercial products, partnered medicines and wholly owned pipeline programs. That helps explain why IONS is down considerably less than Amgen or Novartis.

There is nevertheless a second concern for Ionis investors. Pelacarsen uses the antisense technology upon which Ionis has built its business. The drug clearly succeeded at lowering its intended target, so this is not necessarily a failure of Ionis’s underlying platform. Still, a highly visible late-stage disappointment can weigh on investor confidence, particularly when a program once appeared capable of generating substantial royalties.

Why Amgen Is Falling Even More Than Ionis

Amgen had no direct role in the pelacarsen trial. Its stock is falling because it is developing olpasiran, a different RNA-targeting drug designed to accomplish essentially the same medical objective: reduce Lp(a) production in the liver and determine whether that prevents major cardiovascular events.

Olpasiran uses small interfering RNA, or siRNA, rather than Ionis’s antisense technology. The molecular machinery is different, but the plain-English objective is similar.

Pelacarsen attaches to the messenger RNA carrying the apolipoprotein(a) instructions and causes that message to be disabled. Olpasiran recruits the cell’s natural RNA-silencing machinery to repeatedly find and destroy those same messages. Both approaches leave the underlying DNA unchanged and reduce the amount of apolipoprotein(a) the liver produces.

Earlier studies suggested that olpasiran could lower Lp(a) by more than 90% at selected doses, potentially producing a deeper and longer-lasting reduction than pelacarsen. Amgen is now conducting the large Phase 3 OCEAN(a)-Outcomes trial to determine whether that laboratory effect translates into fewer coronary heart-disease deaths, heart attacks and urgent procedures to restore coronary blood flow.

Results from Amgen’s outcomes trial are not expected until approximately mid-2028.

Pelacarsen’s failure does not prove that olpasiran will fail. There are meaningful differences between the drugs:

Olpasiran’s greater potency leaves Amgen with a plausible path to success. It is possible that Lp(a) must be reduced more deeply, for longer or earlier in the disease process before a clear cardiovascular benefit becomes measurable.

However, the pelacarsen result introduces a more troubling possibility: Lp(a) may be associated with cardiovascular disease—and may even contribute causally to it—without being a sufficiently powerful treatment target to produce a large additional benefit in patients whose other risks are already being aggressively managed.

In other words, there are now two competing interpretations:

1. Pelacarsen was not potent enough, was not given in the optimal way, or was tested in circumstances that made its benefit difficult to demonstrate. Under this interpretation, olpasiran could still succeed.

2. Lowering Lp(a) simply does not prevent enough cardiovascular events to justify the enormous expectations placed on this drug class. Under this interpretation, olpasiran and other Lp(a)-lowering programs may also disappoint.

Until the detailed pelacarsen data become available, investors cannot know which explanation is closer to the truth.

Why the Market Reaction Is So Severe

Wall Street had already assigned olpasiran a substantial probability of success. Cantor Fitzgerald analyst Carter Gould estimated that the market was pricing in a success probability of at least 65%. When pelacarsen failed, investors did not reduce the value of an existing Amgen product; they reduced the probability-weighted value of a potentially important future product.

That can cause a large stock move even though Amgen’s own trial has not reported any results.

The selloff is also being intensified by valuation and timing. Amgen shares had risen approximately 34% during 2026 before today’s decline, leaving the stock vulnerable to a reassessment of its pipeline. Investors now face nearly two years of uncertainty before the expected olpasiran results.

BMO Capital also downgraded Amgen from Outperform to Market Perform today while maintaining a $450 price target. The firm cited valuation concerns and Amgen’s slower growth relative to some other large pharmaceutical companies. That downgrade is not solely a response to pelacarsen, but it adds to today’s pressure. Barron’s coverage of Amgen’s decline

Amgen’s high share price also makes its decline unusually influential in the Dow Jones Industrial Average. The Dow is weighted according to each component’s nominal share price rather than its total market value. A large dollar decline in AMGN therefore subtracts far more Dow points than an equivalent percentage move in a lower-priced component.

Why Novartis Is Being Hit Especially Hard

Pelacarsen is only part of the problem for Novartis today.

The company also announced that del-desiran, an experimental treatment for myotonic dystrophy type 1, failed to meet the primary endpoint of its HARBOR study. That drug was a central asset in Novartis’s $12 billion acquisition of Avidity Biosciences and had been expected to become an important future growth product.

The back-to-back failures are raising broader questions about Novartis’s pipeline and its ability to replace revenue threatened by future patent expirations. Novartis has reiterated its financial guidance, but investors are understandably reducing the value they assign to its late-stage pipeline.

The approximately 14% decline in the company’s U.S.-listed shares therefore should not be attributed solely to pelacarsen. It reflects two important clinical disappointments arriving within a matter of days, along with heightened concern about the company’s longer-term growth strategy. Reuters coverage of Novartis’s pipeline setbacks

The Wider Read-Through to Other Biotechs

The negative reaction has extended beyond these three companies. Eli Lilly, NewAmsterdam Pharma and other companies with exposure to cardiovascular drug development or Lp(a)-lowering approaches have also come under pressure.

Several experimental medicines use different methods to lower Lp(a), including Lilly’s injectable siRNA drug lepodisiran and its oral drug muvalaplin. The important question for all of them is no longer whether they can lower Lp(a). Several candidates have already demonstrated very large reductions.

The question is whether lowering Lp(a) produces enough real-world cardiovascular benefit to support regulatory approval, widespread prescribing and the multibillion-dollar sales projections previously attached to the field.

Pelacarsen was the first major Phase 3 outcomes trial positioned to answer that question. Its failure does not end development of the entire class, but it substantially raises the burden of proof for every drug following it.

What Investors Should Watch Next

The complete Lp(a)HORIZON results will be far more informative than the brief top-line announcement. Investors should watch for:

• the actual difference in cardiovascular-event rates between pelacarsen and placebo;

• the size of the estimated risk reduction and its statistical confidence interval;

• whether any individual endpoint, such as heart attacks or strokes, showed a favorable trend;

• whether patients with the highest Lp(a) levels benefited;

• the amount of Lp(a) reduction actually achieved during the trial;

• treatment adherence and discontinuation rates;

• whether the trial lasted long enough for the biological effect to become clinically visible; and

• what Novartis says about continuing or discontinuing the program.

A narrowly missed endpoint accompanied by encouraging subgroup results would have different implications for Amgen than a completely flat result across the study. Conversely, evidence that cardiovascular events were unchanged despite sustained and substantial Lp(a) lowering would be considerably more damaging to the entire field.

Subgroup findings must also be treated cautiously. Once a trial misses its primary endpoint, apparently favorable results from smaller subsets of patients can generate useful hypotheses, but they do not necessarily provide reliable proof that the drug works.

The Bottom Line

For Ionis, this is a genuine financial setback. The company discovered pelacarsen and was positioned to receive substantial milestones and royalties, most of which should now be removed from reasonable valuation estimates unless the complete data reveal a viable path forward. It is not, however, a failure of the entire Ionis business, and pelacarsen did successfully engage its intended biological target.

For Novartis, pelacarsen’s failure eliminates or sharply reduces the prospects for a potential major cardiovascular product. Combined with the separate del-desiran disappointment, it raises more serious questions about the company’s late-stage pipeline and post-2030 growth.

For Amgen, today’s decline is a sympathy reaction, but it is not an irrational one. Amgen’s olpasiran attacks the same target and is pursuing the same ultimate clinical objective. Pelacarsen’s result forces investors to lower the assumed probability that olpasiran will succeed, particularly because considerable optimism was already reflected in Amgen’s valuation.

At the same time, the market does not yet have enough information to conclude that olpasiran is doomed. It may lower Lp(a) more deeply and durably than pelacarsen, and those differences could matter.

The best concise interpretation is that pelacarsen’s failure has not disproved the entire Lp(a) strategy, but it has changed olpasiran and the rest of this drug class from seemingly well-supported opportunities into materially riskier scientific bets. The detailed trial results will determine whether today’s broad selloff ultimately proves to be an overreaction or an appropriate resetting of expectations.