Novartis Phase 3 Trial Fails for Lp(a) Drug Pelacarsen
Novartis's pelacarsen, an antisense drug developed with Ionis to lower lipoprotein(a), did not reduce major cardiovascular events in high-risk patients in
Novartis has announced that its partnered drug pelacarsen failed to lower cardiovascular risk in a major Phase 3 trial. The Lp(a)Horizon study of 8,323 high-risk patients did not show that reducing levels of the lipoprotein(a) molecule prevented heart attacks or strokes.
Shreeram Aradhye, Novartis's chief medical officer, stated the results in a company release. "Although lower Lp(a) levels were observed with pelacarsen, the findings did not demonstrate that this translated into reduced cardiovascular risk in the overall study population," he said. Novartis plans to present the full data at a future medical meeting.
The trial enrolled patients who had raise Lp(a) and a prior cardiovascular event or established cardiovascular disease. They received pelacarsen, an antisense oligonucleotide designed to lower Lp(a). The primary goal was to see if this reduction would cut the chance of a subsequent major adverse cardiovascular event.
The Lp(a) Target and Market Potential
Lipoprotein(a), or Lp(a), is a known genetic risk factor for heart disease. An estimated 20% of people globally have levels considered high risk. For years, the biotech industry has viewed drugs that lower Lp(a) as potential blockbuster therapies, despite uncertainty about the molecule's exact biological role.
Analysts from William Blair and Citi provided immediate reactions to the topline failure. They suggested the depth of Lp(a) reduction might be a key factor. In prior studies, pelacarsen lowered Lp(a) by an average of 72%. Competing RNA interference drugs from Amgen and Eli Lilly have shown reductions exceeding 90% in earlier trials.
| Drug (Company) | Drug Class | Reported Lp(a) Reduction |
|---|---|---|
| Pelacarsen (Novartis/Ionis) | Antisense oligonucleotide | ~72% |
| Olpasiran (Amgen) | RNA interference | >90% |
| Lepodisiran (Eli Lilly) | RNA interference | >90% |
The William Blair analysts noted that deeper inhibition or focusing on patients with very high baseline Lp(a) levels might still be viable paths. "We would not declare the mechanism dead," wrote the Citi team, arguing that greater target suppression might be needed to cross a biological threshold for benefit.
Expert Reactions and Field Outlook
Experts cited by Fierce Biotech had anticipated that a failure in this trial would not halt the entire field. Rafael Zubirán, a researcher at the National Heart, Lung and Blood Institute, told the publication in April that a failure would not be the end of Lp(a) research. "It will be a huge win if it does provide a good reduction," he said.
Sam Tsimikas, a cardiovascular leader at Ionis and a pioneer in Lp(a) research, agreed. He stated that other companies were likely to continue their programs regardless of the Horizon outcome. "I don't think anybody's going to stop," Tsimikas said. "Those are going to continue, no matter what happens with Horizon."
Analysis of the Trial Result
The outcome raises immediate questions about the Lp(a) hypothesis itself. The Citi analysts emphasized that the detailed data will be important to interpret the result. They said it would be important to "distinguish a near-neutral result from a directional benefit that missed statistical significance."
Differences in trial design for the competing drugs from Amgen and Lilly may also influence future outcomes. The failure of this first major Phase 3 test provides what Novartis called "important evidence" for the scientific understanding of Lp(a) and cardiovascular risk management. The company's drug pelacarsen successfully lowered the biomarker but did not translate that effect into a clinical benefit for patients in this large study.
