Novartis' pelacarsen fail raises questions for other drugs
Lp(a)HORIZON lead author Steven Nissen of the Cleveland Clinic.
The data from Novartis' disappointing cardiovascular outcomes trial with Lp(a)-targeting pelacarsen have been revealed, leaving cardiologists scratching their heads.
At the AHA cardiology congress in Chicago, delegates got a first look at the 8,300-subject Cleveland Clinic. study, which showed that pelacarsen given as a once-monthly subcutaneous injection worked as expected, reducing Lp(a) by 78% in patients with elevated levels of the biomarker and cardiovascular disease (CVD).
Despite that, the drug was unable to reduce the risk of cardiovascular events – cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularisation requiring hospitalisation – compared to placebo over almost five years of follow-up. A string of secondary measures, zeroing in on different cardiovascular outcomes, all followed the same pattern.
"I cannot avoid the disappointing conclusion – it didn't work," said Steven Nissen of the Cleveland Clinic, who is the senior author for the trial, which has also been published in the New England Journal of Medicine.
"There was basically no effect on outcomes, not even a trend, even in subpopulations," he added, whilst insisting that does not mean Lp(a) is irrelevant.
"It means we need more in-depth research to help us fully understand the underlying mechanisms of Lp(a), its interactions with other CVD risk factors and how it does or does not impact cardiovascular outcomes," said Nissen. "So for anyone currently enrolled in an Lp(a) trial, don't drop out because of these findings. Lp(a) is still an important piece of the overall cardiovascular disease puzzle, an important cause of morbidity and mortality worldwide."
Like LDL-cholesterol, elevated Lp(a) is recognised as an independent genetic risk factor for coronary artery disease, heart attack, stroke, peripheral arterial disease, and aortic stenosis. Roughly 20% of people globally have elevated Lp(a), and there is no approved therapies to reduce it.
The comprehensive failure of Lp(a)HORIZON has cast a pall over the prospects for other Lp(a)-targeting drugs, including Amgen's olpasiran and Eli Lilly's lepodisiran, two similarly-acting injectables that are respectively in the OCEAN(a)-Outcomes and ACCLAIM-Lp(a) trials due to read out in the next couple of years.
Meanwhile, Lilly is also developing an oral, small-molecule Lp(a) inhibitor called muvalaplin in the phase 3 MOVE-Lp(a) trial in adults with elevated Lp(a) and cardiovascular risk.
"I am eager to see the results of those trials in the next few years," said Nissen. "Together with the results of Lp(a) HORIZON, we will hopefully have a more robust picture about lowering Lp(a) and its relationship to CVD outcomes."
Novartis licensed pelacarsen from Ionis in 2019 for $150 million upfront, with another $650 million in potential development, regulatory, and sales milestone payments.
