Amgen is betting an experimental medicine it’s developing could become a new way to lower the risk of heart attack and stroke, beyond the lipid-lowering medicines like statins that have been the foundation of cardiovascular care for decades.
Called olpasiran, the drug is aimed at a protein particle known as lipoprotein(a), or Lp(a), that, when elevated in the blood, is associated with greater likelihood of heart disease. Changes in diet and exercise don’t appear to readily remedy high Lp(a) levels and, unlike with low-density lipoprotein, or “bad,” cholesterol, no treatment is approved to lower them.
Clinical trial results show that olpasiran can, and Amgen is launching a large outcomes study to prove that lowering Lp(a) can prevent heart attacks and strokes in people with existing cardiovascular disease. The company will begin enrolling patients in the study in December and aims to recruit 6,000 participants — an expensive endeavor likely to take several years.
Amgen’s confidence comes from trial results that were presented at the American Heart Association’s annual conference in Chicago Sunday evening and simultaneously published in The New England Journal of Medicine. The company had said in May that the study succeeded, but didn’t share details then.
The new data show that, in a mid-stage study of nearly 300 adults with heart disease, treatment with olpasiran sharply reduced or eliminated Lp(a) after six months. By comparison, patients given a placebo saw, on average, their Lp(a) levels rise slightly over the same period.
“This study is eye opening in that when given at higher doses, olpasiran was able to safely achieve just about 100% reduction of Lp(a) in the bloodstream,” said Kiran Musunuru, professor of cardiovascular medicine and genetics at the University of Pennsylvania. “In other words, injections taken every few months were able to entirely clear Lp(a) from the body.”
Participants all had elevated Lp(a) at the study’s start and were randomized to receive one of four doses of olpasiran or placebo. Those on the lowest dose had an average reduction in Lp(a) levels of 70.5% after adjusting for the placebo group’s average increase of 3.6%. Placebo-adjusted changes in the next three dose groups were 97.4%, 101.1% and 100.5%, results showed. (Because the placebo group’s average Lp(a) levels increased, adjusted percentages for the treatment groups could exceed 100%.)
“What's notable is that olpasiran achieved its effects in patients who were already on good lipid-lowering therapies — statins, ezetimibe, and even PCSK9 inhibitors,” Musunuru added. “Since olpasiran works in an entirely different way from the other therapies, it has a shot at becoming an important tool for addressing residual cardiovascular risk.”
Nearly 90% of trial participants were taking a statin, half were on ezetimibe and about a quarter were on PCSK9 inhibitors — newer injectable medicines that can powerfully lower LDL cholesterol.
Treatment was generally safe, with no signs of liver enzyme elevations that can warn of drug-related toxicity. Rates of high blood sugar, new-onset diabetes or muscle aches were similar between drug and placebo groups. Olpasiran did result in more frequent injection site pain and hypersensitivity.
While there are no Lp(a)-lowering treatments available now, olpasiran’s success in the study isn’t the first time a drug has shown a potent impact on protein levels. A 2020 trial showed a Lp(a)-targeting drug being developed by Novartis also was effective in reducing levels, leading the Swiss pharmaceutical company to embark on an outcomes study like the one Amgen is now planning. Results from that trial are expected in 2025.
Comparing across trials can be misleading, but the dramatic reductions in Lp(a) levels observed in both trials validates the drugmaking approach Amgen and Novartis have taken. Although their drugs work slightly differently, both are what’s known as “antisense” drugs, targeting the genetic instructions cells use to turn DNA code into proteins.
In olpasiran’s case, the drug disrupts expression of the gene encoding for Lp(a) production by degrading the related messenger RNA, thereby preventing assembly of Lp(a) particles in liver cells.
Silence Therapeutics, a London-based biotechnology company, is also developing an antisense therapy aimed at Lp(a), and on Sunday presented updated results from a Phase 1 study. (Amgen licensed olpasiran from Arrowhead Pharmaceuticals in 2016, and Novartis bought rights to its treatment from Ionis Pharmaceuticals under a deal signed in 2017.)
While evidence implicating Lp(a) as a genetic risk factor for heart disease is strong, and antisense drugs have now proven effective in lowering Lp(a), it’s not yet clear how well such reductions will translate into a heart benefit. And, unlike with LDL-C, measurement of Lp(a) is not a routine clinical practice, nor are their clear thresholds for assessing a person’s risk.
“Until the clinical trials are done, our estimates [on heart benefits] come from back-of-the-envelope calculations based on epidemiology and genetics,” said Musunuru. “Another complication is that risk reduction might not be linear. There might be a much bigger change in risk if Lp(a) is reduced from very high to high, then from high to medium.”
Both Amgen’s and Novartis’ trials were relatively short, leaving unanswered questions regarding the long-term effects of treatment and whether eliminating Lp(a) from the body results in other, unintended consequences over time. They also enrolled few Black, Hispanic or Latino participants, even though people in these racial and ethnic groups can have higher Lp(a) levels.
Despite the many questions, Amgen’s study builds on Novartis’ in showing dramatic Lp(a)-lowering is possible and, with antisense therapies, generally safe.
“These findings provide the foundation for a large-scale evaluation that will be necessary to confirm a causal role for lipoprotein(a) in atherosclerotic cardiovascular disease,” the study authors wrote in the NEJM publication.
Ben Fidler contributed reporting