NEW YORK – Amgen is making additional R&D investments to push ahead a "key asset": an investigational RNA treatment targeting a biomarker associated with cardiovascular disease.
High levels of the low-density lipoprotein cholesterol lipoprotein(a) are considered a causal risk factor for atherosclerotic cardiovascular disease (ASCVD), a leading cause of death worldwide. Lp(a) levels are predominantly determined by variation in the LPA gene, and according to previous studies, 20 percent to 30 percent of people could have elevated levels of Lp(a). "Unlike LDL cholesterol, Lp(a) levels are genetically determined and cannot be modified by diet or exercise," E. Magnus Ohman, Amgen's VP of global development, wrote in an email.
This is the setting in which the Thousand Oaks, California-based biopharmaceutical firm is hoping to make a difference with its small interfering RNA (siRNA) therapy, olpasiran. The drug, formerly known as AMG 890, is designed to prevent assembly of Lp(a) by blocking apolipoprotein(a) in the liver, which Amgen is betting will reduce the risk of future cardiovascular events in patients.
Amgen's olpasiran is one of a handful of Lp(a)-targeting drugs that are currently in clinical trials to treat or prevent heart disease. But while Lp(a) is considered an independent and causal risk factor for ASCVD, experts say it's still unclear the extent to which lowering it actually reduces future cardiovascular disease events. Given that uncertainty, cardiologists are closely watching results from studies like the Phase III trial olpasiran is being tested in.
Originally licensed from Arrowhead Pharmaceuticals in 2016, olpasiran is now a point of focus for Amgen. CFO Peter Griffith during a call to discuss Q3 financials last week said that the company plans to increase R&D spending into several "key assets," including olpasiran. Due to this increased investment, Griffith said Amgen is now expecting Q4 non-GAAP earnings per share to be lower than $4.96, its EPS in Q3.
The Phase III trial for olpasiran opened late last year and is actively recruiting adult participants who have a history of ASCVD and Lp(a) levels of more than 200 nanomoles/liter. Early readouts of the trial have been encouraging and build on findings from an earlier Phase II trial that showed the drug led to a prolonged reduction in Lp(a) levels in patients.
Ohman declined to share details on Amgen's regulatory strategy for olpasiran, such as when it is aiming to apply for approval and if the firm would pursue an accelerated or traditional approval pathway with the US Food and Drug Administration.
"For now, we are focused on enrollment for the Phase III study," he said. "We'll have more to say about our regulatory strategy and timing once the Phase III trial is completed."
This is the first study in which Amgen is measuring olpasiran's effect on cardiovascular outcomes themselves, rather than on biomarkers. Investigators aim to enroll 6,000 patients and randomize them to receive either a subcutaneous injection of olpasiran every 12 weeks or a subcutaneous injection of a placebo every 12 weeks. Researchers will then compare the rate of coronary heart disease deaths, myocardial infarctions, and urgent coronary revascularizations in each arm and track patients for four years.
This and other trials reflect drugmakers' growing interest in studying Lp(a) as an independent risk factor for ASCVD. In addition to Amgen's olpasiran, Eli Lilly and Silence Therapeutics both have their own siRNA candidates that aim to inhibit production of apo(a) and the subsequent assembly of Lp(a) in patients with high Lp(a) levels, which are in Phase II trials: lepodisiran (LY3819469) and zerlasiran (SLN360), respectively. Novartis Pharmaceuticals is testing pelacarsen (TQJ230), an antisense oligonucleotide targeting Lp(a), in a Phase III trial of patients with elevated Lp(a). Separately, 23andMe recently launched a pilot program in partnership with Novartis in which customers can buy blood-based screening tests for Lp(a) levels.
In an effort to better address healthcare disparities, Amgen is also collaborating with the Association of Black Cardiologists and Morehouse School of Medicine in Atlanta to study the link between Lp(a) and ASCVD in Black patients and better understand "the disproportionate higher incidence of Lp(a) and cardiovascular disease progression in African Americans," Ohman said, citing a statistic that, in the US, African Americans are 30 percent more likely to die from heart disease than non-Hispanic whites.
But as interest in drug development accelerates, a gap still remains in care management guidelines based on Lp(a) levels. The American Heart Association (AHA) in 2021 released a scientific statement calling Lp(a) a causal and prevalent risk factor for ASCVD but didn't provide guidance on what it considers high Lp(a) or how to manage it. Looking to address that problem, this spring the AHA launched a research project funded by Novartis to develop standard approaches for clinicians to screen and manage patients.
Lp(a) may be a risk factor, "but it's one that we don't have any medications available to readily modify," noted Michelle O'Donoghue, an associate professor in cardiovascular medicine at Harvard Medical School and lead investigator of the now completed Phase II OCEAN(a)-DOSE study of Amgen's drug.
That dose-finding study, which ended in November of last year, enrolled 281 patients with ASCVD and elevated Lp(a) levels who were randomized to receive one of four active subcutaneous doses of olpasiran or a placebo. Patients who received doses of at least 75 milligrams of olpasiran, the third-highest dose the firm tested, had a 95 percent or more reduction in Lp(a) levels 36 weeks after starting treatment, compared to the placebo group, according to data from a final analysis the company shared at the European Society of Cardiology's 2023 Congress in Amsterdam this summer. The most common treatment-related adverse events were injection site reactions, according to data published in the New England Journal of Medicine.
And nearly a year after their final dose, patients in the Phase II trial sustained a 40 percent to 50 percent reduction in Lp(a) levels compared to the placebo group, which is encouraging, O'Donoghue said. "Even when patients transition to being off treatment, they still are able to enjoy continued suppression of Lp(a) that slowly wanes over time," she added. "Of course, we still need a Phase III trial to definitively evaluate the efficacy and safety."