Treatment wth olpasiran, a small interfering RNA product targeting lipoprotein (a) synthesis, led to a profound and sustained reduction in Lp(a) concentration when administered every 12 weeks in a new phase 2 study.
The OCEAN(a)-DOSE study showed that doses of 75 mg or more of olpasiran every 12 weeks led to reductions of more than 95% in levels of Lp(a) in individuals with high serum Lp(a) levels at baseline and a history of atherosclerotic cardiovascular disease.
In terms of safety, the overall incidence of adverse events was similar to placebo, with the most common olpasiran-related adverse events being injection site reactions, primarily pain, but these were described as mild in severity and resolved without treatment.
The study findings were presented November 6 at the American Heart Association (AHA) Scientific Sessions 2022 by Michelle O’Donoghue, MD, MPH, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
They were also simultaneously published online in The New England Journal of Medicine.
“These findings set the foundation for phase 3 testing scheduled to commence later this year,” O’Donoghue concluded.
Amgen, the drug’s manufacturer, has not yet announced the dose that will be used in the phase 3 trials.
“Here we have evidence that a small interfering RNA product truly leads to a marked and sustained reduction in Lp(a) levels, with effects that persist over 12 weeks,” O’Donoghue told theheart.org | Medscape Cardiology.
“There is tremendous enthusiasm for Lp(a) as a therapeutic target. A large body of evidence shows that Lp(a) plays a causal role in coronary heart disease, but there is no approved therapy for reducing this lipoprotein,” she said. “For individuals with high levels, there is an urgent need to develop therapeutics that could benefit them. So, it’s a great opportunity to have a therapeutic that only requires dosing once every 12 weeks and leads to sustained reductions in Lp(a) that exceed 95% at the higher doses.”
Another drug targeting Lp(a), pelacarsen, has recently started phase 3 trials. Pelacarsen, an antisense oligonucleoside, is being dosed once every 4 weeks. Phase 2 study data suggested it brought about reductions in Lp(a) of about 70%-80%.
“Our results suggest that olpasiran may produce greater reductions in Lp(a) than pelacarsen and that olpasiran needs a less frequent administration schedule,” O’Donoghue said.
“You may ask whether that much of a reduction is necessary, but some of the genetic data suggests that very large absolute reductions in Lp(a) levels may be needed to translate into meaningful clinical benefit,” she added.
The OCEAN(a)-DOSE study included 281 patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol/L (70 mg/dL).
They were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously.
The primary endpoint was the percentage change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percentage change). Safety was also assessed.
The median concentration of Lp(a) at baseline was 260.3 nmol/L, and the median concentration of LDL cholesterol was 67.5 mg/dL. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a PCSK9-inhibitor.
Results showed that at 36 weeks, the Lp(a) concentration had increased by a mean of 3.6% in the placebo group, whereas it was significantly and substantially reduced in the olpasiran groups in a dose-dependent manner.
The placebo-adjusted mean percentage changes were −70.5% with the 10-mg dose, −97.4% with the 75-mg dose, −101.1% with the 225-mg dose administered every 12 weeks, and −100.5% with the 225-mg dose administered every 24 weeks.
The overall incidence of adverse events and serious adverse events was similar among patients who were treated with olpasiran and those who received placebo. The incidence of adverse events leading to the discontinuation of olpasiran or placebo was similar across the trial groups (2% in each group), and there were no cases of clinically important changes in safety laboratory evaluations.
Higher percentages of patients reported hypersensitivity and injection-site reactions with higher doses (≥75 mg) of olpasiran than with placebo, but the majority were mild in severity and were reported as isolated events that resolved within 48 hours after onset, without treatment.
The most common olpasiran-related adverse event was injection-site pain. Injection-site reactions led to the discontinuation of olpasiran in three patients; none of the events was considered by the investigators to be severe, and all the affected patients had preexisting dermatologic conditions, the researchers report.
O’Donoghue explained that olpasiran is a small interfering RNA (siRNA) molecule directed to the liver where it prevents assembly of the Lp(a) particle by linking to an RNA-induced silencing complex (RISC); the complex then binds to apo(a) mRNA, leading to its degradation and preventing translation of the Lp(a) protein.
“The binding of olpasiran to the RISC complex allows it to repeat its mechanism of action, degrading the mRNA transcripts repeatedly and that is what allows for the 12-weekly dosing,” she said.
O’Donoghue noted that levels of Lp(a) are mainly determined genetically and the level that is considered unhealthy is not understood completely at present.
“The relationship between Lp(a) and cardiovascular events is broadly log linear,” she said. “So, there isn’t a clear threshold effect, but there are consensus guidelines that have declared a threshold somewhere around 50 mg/dL (or 125 nmol/L) as being abnormal. That is essentially based on the top 20% of the distribution in the population.”
It is therefore not known how many people may benefit from therapies that reduce Lp (a).
“The first phase 3 trials are enrolling individuals with the highest levels, but it may be the case that people with lower levels will also benefit. That was the case with LDL and the statins. Those drugs were first tested in patients with the highest LDL levels but now we know they have benefits in patients with much lower levels too,” O’Donoghue said.
Many Questions Remain
Stephen Nicholls, MD, Monash University, Melbourne, Australia, the discussant of the OCEAN(a)-DOSE study at the “Late Breaking Clinical Trials” session, explained that both population and genetic studies show a clear relationship between increasing Lp(a) levels and cardiovascular disease, but that hope is now in sight for patients with elevated Lp(a).
He said the OCEAN(a) trial showed encouraging results and provided an additional option for Lp(a) lowering beyond antisense oligonucleotides and RNA silence approaches, which are also in clinical development and have been demonstrated previously to lower Lp(a) “in a comparable fashion by 80% to 90% or even more.”
However, he pointed out that it is not yet known whether reducing Lp(a) levels will reduce cardiovascular risk, or how much Lp(a) lowering will be required.
“The genetic analyses suggest that a substantial lowering will be needed — maybe in excess of 100mg/dL reduction. Many of us will hope that is not the case as we have many patients with elevated Lp(a) levels between 70 and 100 mg/dL,” he noted.
Other questions include whether it will be more important to lower Lp(a) in patients with established cardiovascular disease or in the primary prevention setting, and whether the presence of other factors such as inflammation influence the potential modifiability of Lp(a) lowering.
“We will need multiple outcome trials to answer these questions,” Nicholls commented.
Another issue will be the long-term consequences of essentially silencing Lp(a) or reducing its levels by more than 90%. “There is concern about possible diabetes risk as observational data show that while high Lp(a) levels are associated with increased cardiovascular risk, they also associate with a lower risk for diabetes. That will obviously be looked at closely in the outcome trials,” he said.
“Finally, we are close to being able to lower Lp(a) in our patients but to do that we have to know what their Lp(a) levels are. In most countries there are considerable barriers to simply being able to order an Lp(a) test. As we move forward it will be important to increase the availability of testing,” Nicholls added.
The OCEAN(a)-DOSE study was supported by Amgen. O’Donoghue reports grant funding from Amgen, Novartis, AstraZeneca, and honoraria from Amgen, Novartis, AstraZeneca, and Janssen. Nicholls reports research support from AstraZeneca, New Amsterdam Pharma, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience; and consulting and honoraria from AstraZeneca, Amarin, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, Boehringer Ingelheim, and Vaxxinity.
American Heart Association (AHA) 2022 Scientific Sessions: Presentation number 18643: Presented November 6, 2022.
N Eng J Med. Published online November 6, 2002. Abstract