Novartis's closely watched cardiovascular trial has failed, raising significant questions about one of the pharmaceutical industry's most prominent drug development races and casting uncertainty over rival therapies from U.S. giants Amgen and Eli Lilly.

After the market closed on Friday, Novartis announced that pelacarsen, developed in partnership with Ionis Pharmaceuticals, effectively lowered lipid(a) or Lp(a) levels in late-stage trials but failed to produce a meaningful improvement in cardiovascular outcomes. The news sent Novartis shares down 3% on Monday.

This marks the first significant clinical failure in the Lp(a)-targeting drug development arena. About one in five people worldwide has elevated Lp(a) levels, increasing their risk of cardiovascular disease, yet no approved treatment specifically targets this factor. While Amgen and Eli Lilly are testing different technological approaches that have demonstrated more substantial Lp(a) reductions, analysts note the pelacarsen failure heightens risk across this market segment, which has projected sales in the tens of billions of dollars.

Citi analysts wrote in a research note: "The Lp(a) hypothesis has been weakened but not disproven." They highlighted that beyond the missed primary endpoint, publicly available information remains thin, including the specific degree of Lp(a) reduction achieved by pelacarsen. Further data is needed, they added, to determine whether this trial failure stems from pelacarsen's mechanism of action, the trial's design, or fundamentally undermines the core hypothesis that lowering Lp(a) reduces heart attacks and strokes.

Novartis stated that complete trial results will be presented at a future medical congress. The company's Chief Medical Officer, Shreeram Aradhye, commented: "These results provide important evidence that deepens the scientific community's understanding of the link between reducing Lp(a) levels and cardiovascular outcomes, and may inform future cardiovascular risk management approaches."

Lp(a), discovered in 1963, promotes arterial plaque formation and can trigger blood clots. Nearly fifty years after its discovery, researchers established that people with high Lp(a) levels face more than double the risk of heart attacks. Lp(a) levels are almost entirely genetically determined, and unlike LDL cholesterol, lifestyle factors like diet and exercise have little impact.

Novartis emphasized that all 8,000-plus trial participants received optimal standard care. Jefferies analysts noted in a Sunday report that as standard treatments improve and cardiovascular event rates decline, the bar for new drugs to demonstrate additional clinical benefit is rising, increasing both the difficulty and cost of trials.

Analysts had previously estimated that if pelacarsen succeeded, its peak annual sales could reach $4-5 billion. For Novartis, confronting the most severe patent cliff in its history, this drug represented a potential growth driver. The core patent on its blockbuster heart medication Entresto has expired, and several other major drugs face generic competition soon.

The clinical trial's impact extends well beyond Novartis. After Friday's close, shares of Amgen fell roughly 5%, while Ionis Pharmaceuticals dropped 10%. Citi analysts wrote: "The first trial specifically measuring cardiovascular outcomes has failed, which undermines confidence in the entire drug class. Subsequent trials must now demonstrate that greater Lp(a) reductions can achieve a clinically significant reduction of approximately 15% in major adverse cardiovascular events, placing considerable pressure on future research."

Analysts indicate that Amgen's competing drug olpasiran faces the most direct impact from this failure. Eli Lilly's lepodisiran trial includes a broader patient population, with some participants not yet diagnosed with cardiovascular disease, which limits the direct spillover effect. Additionally, lepodisiran represents a smaller portion of Eli Lilly's overall valuation.

Many investors had anticipated high risk for this trial, expecting only modest benefits, which helps explain Novartis's relatively limited share decline of just 3%. Barclays remarked: "The market never expected a stunning result, at best anticipating moderate gains. Novartis previously indicated that achieving just a 13% benefit across all participants would reach statistical significance. Reading between the lines of the announcement, pelacarsen clearly fell far short of that threshold."

Novartis has not yet responded to inquiries, nor has it disclosed specific figures for Lp(a) reduction or cardiovascular risk decrease from the trial. Shares of Dutch company NAMS, which also develops Lp(a)-lowering drugs, fell 12% in U.S. after-hours trading on Friday.

William Blair analysts suggest other candidate drugs employ different technology platforms, with some achieving more substantial Lp(a) reductions than pelacarsen. This provides rationale for companies to continue Lp(a) research, particularly among patients with extremely high baseline levels. However, they cautioned that based on Novartis's results, the entire Lp(a) cardiovascular drug development landscape now faces significantly elevated risk.