Has Elevated Lipoprotein(a), the Elusive Cardiovascular Risk Factor, Met Its Match?

Lepodisiran, an RNA interference drug, joined the growing number of promising drugs in development that target lipoprotein(a) today with results from a small study presented today at the American Heart Association (AHA) Scientific Sessions meeting that show that it has minimal side effects and, in a dose-dependent fashion, reduced lipoprotein(a) levels.

A single injection of the highest dose (608 mg) of the RNA inference drug resulted in lipoprotein(a) levels that were below levels where they could be quantified for many months and at 337 days afterward, the median change was 94% lower.

“It wasn’t just LP, little a, lowering,” said Karol E. Watson, M.D., Ph.D., the discussant at the press briefing about the study, using the shorthand for lipoprotein(a) that many physicians use and venturing into enthusiastic overstatement. “You got rid of it altogether.”

Watson is a professor of professor of the David Geffen School of Medicine at University of California, Los Angeles.

Lepodisiran is being developed by Eli Lilly, which sponsored the study and designed its protocol. Steven E. Nissen, M.D., a renowned cardiologist and researcher at the Cleveland Clinic, presented the data at the meeting earlier today and was the first author of the research article describing the results that was simultaneously published in JAMA.

A phase 2 study testing multiple doses is underway, said Nissen. Ideally, he said, the evidence will show that the drug can be given once a year.

“It’d be like a vaccine. You come into your physician’s office to your injection and you would be done for the year,” said Nissen.

At the AHA press briefing Nissen said there were no indications that lepodisiran posed safety issues: “In phase 1 [trials] it is always about safety, and we really didn’t see anything,” adding later that there were some transient injection site reactions. The results reported in JAMA show that more of the 36 patients assigned to active treatment experienced headaches than the 12 assigned to the placebo group (5 vs. 1), and that elevated C-reactive protein levels were common (14 in the active treatment group) but they were also common in the placebo group (7 study volunteers). Watson said the “safety profile [of lepodisiran] looked really clean.”

Reducing elevated lipoprotein(a) has been an elusive target for cardiovascular risk reduction. A person’s levels are determined by inherited genetics and are not influenced by the lifestyle changes (more exercise, healthier eating) or statins. Niacin and PCSK9 inhibitors — Repatha (evolocumab) and Praluent (alirocumab) have a limited effect.

“There are number of patients that you do everything right, you get their blood pressure under control, you get them on a statin, and they still have [cardiovascular] events because we haven’t controlled this risk factor,” said Watson, who said she had elevated lipoprotein(a).

Donald M. Lloyd-Jones, M.D., M.Sc., a professor at Northwestern University’s Feinberg School of Medicine and the moderator of the press briefing on the lepodisiran trial and other trials of other lipid-lowering therapies, said lipoprotein(a) attaches to LDL particles, turning them into “uber particles” that are more likely to get into the walls of arteries and cause inflammation in atheroscelortic plaque

As described by Nissen and in the JAMA article, lepodisiran is short segment of double-stranded RNA that interferes with the functioning of the messenger RNA that transcribes the DNA-genetic code of the LPA gene to produce lipoprotein(a). By interfering with the messenger RNA, lepodisiran blocks the production of lipoprotein(a).

According to Nessen, 64 million Americans have elevated lipoprotein(a), so presumably there would be a large market for any therapy that lowers lipoprotein(a).

The race is on to develop treatments for lipoprotein(a). In the JAMA article, Nissen and his colleagues said that pelacaren and olpasirn are iin phase 3 trials. Zerlasiran, like lepodisiran, is in a phase 2 trial, they wrote.

“We’ve never been able to treat elevated lipoprotein(a),” Nissen said at the press briefing. “We are now having emergingn therapies, using nucleic acid therapeutics that offer the potential for these patients to be treated. We will need to do big phase 3 trials to determine whether lowering levels [of lipoprotein(a)] will actually reduce risk.”