Large, Sustained Reductions in Lp(a) With Lepodisiran in Phase I Study

Lepodisiran, a long-duration, short-interfering RNA (siRNA), dramatically slashed Lp(a) levels in a small, phase I study presented this weekend at the American Heart Association (AHA) 2023 Scientific Sessions.

Presentation AHA 2023

Lepodisiran: An Extended-Duration siRNA Targeting Lipoprotein(a)

Lead investigator Steven Nissen, MD (Cleveland Clinic, OH), presented the new data showing that a single subcutaneous injection reduced Lp(a) levels by 94% at 48 weeks. It’s early days for lepodisiran (Eli Lilly), but the siRNA therapy was well tolerated, with Nissen saying the results of this study justify its further development.

Fully 64 million Americans, and 1.4 billion people around the world, have elevated Lp(a), Nissen said during a press conference announcing the results. “We've never been able to treat elevated lipoprotein(a). We are now having emerging therapies using nucleic acid therapeutics that offer the potential for these patients to be treated,” he noted.

If there are any doubts that the treatment of lipoprotein(a) is the next frontier for the prevention of atherosclerotic cardiovascular disease (ASCVD), the number of emerging therapies should convince skeptics otherwise.

Lepodisiran joins an increasingly crowded field of treatments targeting Lp(a). Like olpasiran (Amgen) and zerlasiran (Silence Therapeutics), lepodisiran is an siRNA that targets LPA, the gene that encodes for apolipoprotein(a), which an essential component needed by the liver to make Lp(a). By degrading the mRNA to make apolipoprotein(a), Lp(a) levels are reduced. Pelacarsen (Novartis/Ionis Pharmaceuticals), which is perhaps the furthest along in its clinical development, is an antisense oligonucleotide (ASO) that inhibits the production of apolipoprotein(a) while an oral small molecule inhibitor is also in early-stage testing, with phase I data published in the summer. 

The reason for the hunt for an effective therapeutic is that elevated Lp(a) has been shown to be associated with a higher risk of ASCVD in observational and in mendelian randomization studies. It’s also gained prominence in multiple guidelines over the years. In the US cholesterol guidelines, elevated Lp(a) is considered a risk-enhancing factor, one that can help physicians and patients make a decision about whether or not to start LDL cholesterol-lowering treatment. In Europe, it’s recommended physicians check Lp(a) at least once during the patient’s lifetime, particularly if there is a family history of premature ASCVD. Canadian dyslipidemia guidelines also recommend measuring Lp(a) once in a person’s lifetime as part of lipid screening.

“This is a genetic risk factor so we recommend that people sometime early in life, maybe in their 20s, have their Lp(a) level checked,” Nissen told TCTMD. “If it's not elevated, it will not be elevated later in life. There's no evidence that it actually increases over time. It's a one-time measurement. If you are elevated, then you know you have this risk factor. You can have your other risk factors treated, which is how we manage these patients now, but in the very near future, we hope that we'll be able to actually reduce Lp(a) levels and prevent the lifelong risk of atherosclerotic disease.”

Almost Completely Gone at 48 Weeks

In this phase 1, dose-escalating study, investigators enrolled 48 patients (mean age 47 years; 35% female) and randomized them to placebo or a single dose of lepodisiran. The median baseline Lp(a) level was 113 nmol/L and the mean LDL cholesterol level was 132 mg/dL.

From baseline to 48 weeks, the mean Lp(a) level declined 5% in the placebo group and 41%, 59%, 76%, 90%, 96%, and 97% across the different dosages of lepodisiran (4, 12, 32, 96, 304, and 608 mg, respectively). The percentage change in Lp(a) lasted longer with the highest doses of lepodisiran. At the highest dose, the median Lp(a) concentration was below the lower limit of quantification for the majority of the study period. Overall, treatment was well tolerated, with the most common adverse events reported being headache and rhinorrhea.

Speaking during the late-breaking clinical session, Michelle O’Donoghue, MD (Brigham and Women’s Hospital, Boston, MA), who led the OCEAN(a)-DOSE trial with olpasiran, said that what’s most interesting about the data is lepodisiran’s durable effect. With other therapies, particularly the ASO pelacarsen, there is a more rapid return to baseline levels. The large treatment effects with the various therapeutics in development—olpasiran and zerlasiran also cut Lp(a) levels by close to 100%-- are important because it’s believed that significant reductions will be needed to reduce ASCVD outcomes, assuming that these agents can impact clinical events.

“There have been a variety of genetic estimates ranging from 66 to 101.5 mg/dL, or 140 to 217 nmol/L,” she said. “That's a very large drop in Lp(a) needed to see comparable effects to approximate what we would see with a 1 mmol/L drop in LDL cholesterol over a median of 4.8 years, or roughly a 22% relative risk reduction.”

Right now, the only therapy that lowers Lp(a) are PCSK9 inhibitors, which can reduce levels by about 25% to 30%, although there is a fair degree of interpatient variability in that response, said O’Donoghue.

Race to the Finish Line

To TCTMD, Nissen said a phase II study with lepodisiran is underway, but they aren’t yet sure if the subcutaneous injection will be once or twice per year.

“I would like to make it once a year because it'd be like a vaccine,” he said. “Come into your physician's office, get your injection, and you're done for the year. It's not permanent, of course, as the VERVE-101 [PCSK9 gene-editing] therapy is, but it's a pretty convenient approach if you can get it once a year. Even if you have to get it twice a year, that's probably not a big burden in terms of the patients being able to be treated.”

Karol Watson, MD, PhD (UCLA Health, Los Angeles, CA), who spoke during the AHA press conference, said that while lepodisiran doesn’t completely turn off the production of Lp(a), treatment is remarkably effective at keeping levels extremely low for close to 1 year. “And the safety profile looked really clean,” she said, noting that the hope with lepodisiran, as well as the other Lp(a)-lowering therapies, is that they will lower risk of ASCVD events. “We don't know yet if that will work, but we are hopeful that it will, and we await more data,” she said.

In terms of Lp(a)-lowering treatments, pelacarsen has the jump on its competition. Lp(a) HORIZON trial, which is assessing cardiovascular outcomes in approximately 8,300 patients treated with pelacarsen, has already completed enrollment and results are expected in 2025. The OCEAN(a) Outcomes study with olpasiran is also underway, a trial that is being led by the TIMI Study Group. Results of that study are expected in 2026.