Novartis Cardiovascular Drug Fails in Phase 3 Trial, Suffering Setback in First Test of ‘Devil’s Molecule’ Target

A cardiovascular risk-targeting drug developed by Novartis failed to reduce the risk of cardiovascular disease in a large clinical trial.

According to Fierce Biotech on the 5th (local time), Novartis said pelacarsen, which it is co-developing with Ionis, failed to meet the primary endpoint in the Phase 3 clinical trial “Lp(a)HORIZON.”

The trial enrolled 8,323 patients with elevated Lp(a) levels who had cardiovascular disease or experienced a cardiovascular event. Researchers sought to determine whether lowering Lp(a) with pelacarsen, an antisense oligonucleotide, could reduce the risk of recurrence in high-risk patients.

Shreeram Aradhye, Novartis’ chief medical officer and president of development, said, “Although we observed that pelacarsen treatment lowered Lp(a) levels, this did not translate into a reduction in cardiovascular risk across the overall study population.”

“Although this was not the outcome we had hoped for, it provides important evidence that will advance scientific understanding of the relationship between Lp(a) lowering and cardiovascular outcomes,” he added. Novartis plans to disclose the full results at a future medical meeting.

Lp(a) is short for lipoprotein(a), and an estimated approximately 20% of the global population has levels that increase cardiovascular risk. However, the molecule’s precise role in the body has not yet been determined.

William Blair analysts suggested in a report that pelacarsen may not have lowered Lp(a) sufficiently to show an effect. In previous studies, the drug lowered Lp(a) by an average of 72%.

They noted that follow-on RNA interference therapies, including Amgen’s olpasiran and Eli Lilly’s lepodisiran, lower Lp(a) by more than 90%, and analyzed that “deeper Lp(a) suppression could provide motivation for additional clinical development beyond pelacarsen.”

Citigroup analysts also assessed, “We would not declare the mechanism itself dead,” adding, “If cardiovascular benefit requires exceeding a biological threshold, stronger target suppression may be important.”

Experts expect the setback to slow development in the Lp(a) field but not bring it to a halt. Sam Chimis, head of Ionis’ cardiovascular division, said, “No one is going to stop,” adding that “regardless of the HORIZON results, [Amgen’s and Lilly’s development programs] will continue.”