Novartis reported that its experimental cholesterol drug pelacarsen, developed jointly with Ionis Pharmaceuticals, failed to significantly improve cardiovascular outcomes in a late-stage trial despite reducing levels of lipoprotein(a), a harmful form of cholesterol. The company announced the results after market close Friday; Novartis shares fell 3% on Monday.
The trial marks the first major clinical setback in the pharmaceutical industry's pursuit of treatments targeting Lp(a), a genetically determined risk factor estimated to affect roughly one in five people worldwide. No approved targeted therapy currently exists for the condition, which contributes to arterial plaque buildup and blood clotting and was linked nearly 50 years after its 1963 discovery to more than double the risk of heart attack in carriers with elevated levels.
Analysts at Citigroup said the trial weakens but does not disprove the Lp(a) hypothesis, noting that insufficient detail has been provided on how substantially pelacarsen lowered Lp(a) levels or the magnitude of any cardiovascular benefit observed. The question remains whether the miss reflects the drug's mechanism, the trial's design, or a broader challenge to the idea that lowering Lp(a) meaningfully reduces heart attacks and strokes, Citigroup added. Novartis plans to present full results at an upcoming medical congress.
The trial enrolled more than 8,000 patients who were already receiving optimized cardiovascular care, a factor that may have complicated the study's ability to demonstrate incremental benefit from an experimental therapy. Jefferies analysts wrote that improving standards of care are themselves reducing cardiovascular events, raising the bar for new drugs seeking to prove added value.
Novartis had modeled peak annual sales of roughly $4 billion to $5 billion for pelacarsen, a figure that would have provided meaningful offset as the company navigates what CEO Vas Narasimhan has termed the steepest patent cliff in its history. Bestselling heart drug Entresto has already lost key patent exclusivities, and additional blockbusters face generic competition in coming years.
The announcement reverberated across the sector. Amgen shares fell about 5% in extended Friday trading, Ionis Pharmaceuticals dropped 10%, and U.S.-listed Netherlands-based NewAmsterdam Pharma — which is also developing an Lp(a) therapy — declined 12% in extended trading.
Amgen's competing drug, olpasiran, faces the most direct read-through from the Novartis result, while Eli Lilly's lepodisiran is being tested in a broader patient population that includes individuals without established cardiovascular disease, potentially limiting the spill-over effect, Citigroup analysts said. Lepodisiran is also less material to Lilly's overall valuation, they added.
Some investors had already viewed the trial as risky and expected only a moderate benefit, which may explain the relatively contained reaction in Novartis shares, falling just 3% in extended trading on Friday. Barclays noted that Novartis had indicated even a 13% benefit would have been statistically significant in the overall population, and the results appeared to fall materially short of that threshold.
William Blair analysts said other experimental drugs using different mechanisms could still achieve deeper Lp(a) reductions, giving developers reason to continue pursuing the space, particularly for patients with very high baseline levels. However, they acknowledged there is "meaningful risk to a potential future" for Lp(a)-driven cardiovascular trials in light of Novartis' results.
