诺华与 Ionis 的 pelacarsen 三期 Lp(a)HORIZON 未能降低心血管事件风险

Novartis’ Ionis-partnered drug designed to lower levels of Lp(a), a known cardiovascular risk factor, failed to reduce patients’ risk of a heart attack, stroke, or other major cardiovascular events in the first late-stage test for a drug meant to tackle the mysterious molecule.
The phase 3 Lp(a)Horizon trial enrolled 8,323 patients with elevated Lp(a) who had previously experienced a cardiovascular event or have established cardiovascular disease (CVD). The goal of the trial was to see if lowering Lp(a) with pelacarsen, an antisense oligonucleotide, could reduce the chance that these high-risk patients would experience a second event.
“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,” Shreeram Aradhye, M.D., Novartis’ chief medical officer and president of development, said in a release. “These are not the results we hoped for, but they provide important evidence that advances scientific understanding of the relationship between Lp(a) lowering and cardiovascular outcomes and may help inform future approaches to cardiovascular risk management.”
Novartis plans to share the full results from the trial at an upcoming medical meeting.
An estimated 20% of the global population has levels of Lp(a), short for lipoprotein(a) and read as “L-P-little A,” that put them at risk. Given this large population of potential patients, numerous experts have told Fierce that drugs lowering the “diabolical” molecule could become blockbusters. But what exactly the molecule does in the body remains unknown, and studying it was long difficult due to its repeating structure.
Reflecting on the topline results, analysts from William Blair wrote Friday that it may be that pelacarsen didn’t reduce Lp(a) enough to see an effect; in past studies, the drug has lowered its levels by an average of 72%, and the analysts reported that Ionis said levels were similar in this trial. Other RNA interference candidates coming down the pike behind pelacarsen, including Amgen’s olpasiran and Eli Lilly’s lepodisiran, reduce Lp(a) levels by more than 90%.
“There may be opportunity to consider deeper Lp(a) inhibition than pelacarsen from a given asset as motivation to pursue further clinical development, particularly in a subpopulation of patients with higher baseline Lp(a) levels,” the analysts wrote. “Still, we do see meaningful risk to a potential future in Lp(a)-driven CVD trials in light of results from Lp(a) Horizon.”
Citi analysts expressed a similar view in their Friday note to clients.
“We would not declare the mechanism dead,” the Citi team said, adding that “[g]reater target suppression could matter if cardiovascular benefit requires crossing a biological threshold.” Besides, Amgen and Lilly have different trial designs for their RNA interference therapies.
The Citi analysts argued that detailed data would be important to “distinguish a near-neutral result from a directional benefit that missed statistical significance.”
Experts previously told Fierce that a fail for Horizon might slow down the Lp(a) field, but would be unlikely to bring it to a standstill.
“It won’t be the end of [Lp(a)] if it fails; it will be a huge win if it does provide a good reduction,” Rafael Zubirán, M.D., a researcher in the lipoprotein metabolism laboratory at the National Heart, Lung and Blood Institute, told Fierce in April.
Sam Tsimikas, M.D., cardiovascular leader at Ionis and a pioneer of the Lp(a) field, agreed at the time that Amgen and Lilly are unlikely to stop their own pursuit of potential Lp(a) blockbusters even if Horizon didn’t succeed.
“I don’t think anybody’s going to stop,” he said. “Those are going to continue, no matter what happens with Horizon.”