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Eli Lilly RNA Drug Lowered Heart Disease Risk Biomarker for Nearly a Year in Phase I Trial

Eli Lilly biotechnology center in San Diego

NEW YORK – A first-in-human study of Eli Lilly's lepodisiran has yielded promising activity in patients at risk for atherosclerotic cardiovascular disease (ASCVD) due to a certain cholesterol biomarker. 

Although lepodisiran is in early development and Lilly has yet to prove that patients can avoid major cardiovascular events by taking it, experts are encouraged by the small interfering RNA drug's ability to lower levels of a biomarker long associated with ASCVD risk. 

Lepodisiran is designed to prevent the assembly and reduce levels of lipoprotein(a), a low-density lipoprotein (LDL) cholesterol. It does this by degrading the messenger RNA that encodes for one of Lp(a)'s core components, apolipoprotein(a). Elevated Lp(a) is considered a prevalent and independent risk factor for ASCVD that is primarily determined by variants in the LPA gene, and this risk can't be mitigated by lifestyle modifications like diet and exercise.

As a common genetic factor thought to affect at least 20 percent of people, Lp(a) "is a very attractive target for reducing cardiovascular disease [risk]," said Steven Nissen, chief academic officer at the Cleveland Clinic's Heart, Vascular & Thoracic Institute and lead author of a paper in the Journal of the American Medical Association last week describing results from a Phase I study of lepodisiran. "We've not been able to treat it until the development of nucleic acid therapeutics in the last several years."

While there are currently no treatments targeting Lp(a), along with Lilly, drugmakers Silence Therapeutics, Novartis, and Amgen are all racing to bring one to market. 

Lilly's Phase I trial, data from which researchers presented at the American Heart Association's Scientific Sessions in Philadelphia last week, was designed to assess the safety, tolerability, and pharmacokinetics of lepodisiran. Investigators enrolled 48 patients in the US and Singapore without cardiovascular disease who had elevated Lp(a) and received one of six lepodisiran doses or a placebo.

At the highest dose of 608 milligrams, lepodisiran reduced Lp(a) by 96 percent two weeks after injection and patients maintained a median Lp(a) reduction of more than 94 percent nearly a year later. Lepodisiran at other doses reduced Lp(a) less dramatically, and patients maintained the reduction for a shorter duration. Across all treatment groups, plasma concentrations of the drug were "undetectable" by 48 hours after injection, according to the paper.

The "intensity" of Lp(a) reduction at the top lepodisiran dose, paired with its durability, is striking, Nissen said, and suggests the drug could be administered to patients infrequently and still be effective. "It means that the drug potentially can be given once or perhaps twice a year, which, from the patient's point of view, is obviously advantageous," he said.

By contrast, standard first-line therapy to reduce the risk of ASCVD involves taking statins to lower LDL cholesterol and other lipids, and patients must typically take these medications daily. A once-a-year injection like lepodisiran could have dosing advantages in this regard, especially if it proves to be efficacious and safe compared to available treatments. 

In terms of safety and tolerability, investigators observed no issues with lepodisiran in the Phase I trial, aside from mild injection site reactions.

Lilly is conducting a Phase II trial to further assess lepodisiran's activity on the heels of this completed Phase I trial. Nissen is also an investigator in the Phase II trial, which is slated to wrap up by October 2024. Based on the readout from this next study, Lilly will decide whether to continue developing lepodisiran, a Lilly spokesperson said in an email.

"We are encouraged by the data we have so far, indicating lepodisiran is safe and effective at lowering Lp(a), with near-total elimination of Lp(a) lasting a significant amount of time," the spokesperson said. "We look forward to continuing to study this therapeutic in further trials, including our larger Phase II trial currently underway."

The bevy of investigational drugs targeting Lp(a) as a way to lower ASCVD risk has also sharpened the biotech industry's focus on the biomarker. The American Heart Association, for example, has launched a research project to develop standard approaches for clinicians to screen and manage patients with elevated Lp(a), and direct-to-consumer genetic testing firm 23andMe is piloting a program through which customers can buy blood-based screening tests for Lp(a) levels.

"What's driving the attention," Nissen said, "is that we actually have treatments on the horizon."

Evidence of Lp(a)'s possible role in increasing the risk of cardiovascular disease has been accumulating for decades. However, a treatment has been "elusive," the study authors wrote in the JAMA paper. Since Lp(a) is primarily genetically determined, lifestyle changes are not a suitable solution, and other common cardiovascular therapies like statins and fibrates have not been found to lower Lp(a) levels.

Last year, Nissen and colleagues published a paper in the journal Open Heart, describing their efforts to assess Lp(a) levels in patients with a history of myocardial infarction, ischemic stroke, or peripheral artery disease across 48 countries globally. They found that only 13.9 percent of the more than 48,000 participants had previously undergone testing for Lp(a) before being enrolled in the study, despite having an established diagnosis of disease.

"People said, 'If we can't treat it, why should we measure it?'" Nissen said. Now, "we're in the midst of changing that."

In addition to Lilly's drug, Silence Therapeutics' siRNA candidate, zerlasiran (SLN360), which, like lepodisiran, aims to inhibit production of apo(a), is under evaluation in a Phase II trial. Amgen's siRNA drug olpasiran (AMG 890) and Novartis Pharmaceuticals' antisense oligonucleotide pelacarsen (TQJ230) are both in Phase III testing for lowering elevated Lp(a), but unlike the one-time injection being considered with lepodisiran, the drugmakers are assessing olpasiran and pelacarsen's efficacy with more frequent dosing.

Lilly, meanwhile, still has more to prove with lepodisiran. The drug, so far, has shown promise in successfully reducing a biomarker associated with ASCVD risk, but Lilly must still show that the treatment can reduce major adverse cardiovascular events or that reductions in Lp(a) can predict such benefits. It's also unclear how much Lp(a) would need to be lowered to effectively reduce cardiovascular risk in patients.

"We're within a couple years of getting the first of these drugs through a full cardiovascular outcome trial in Phase III," Nissen said, referring to the multiple Lp(a)-targeting drugs in clinical trials. "At the end of these trials, we'll have a pretty rigorous answer to the question about whether lowering lipoprotein(a) produces benefit."