Sustained Reductions in Lp(a) Achieved With Novel siRNA Drug

In an early phase multicenter clinical study, large reductions in lipoprotein(a), or Lp(a), were achieved with a well-tolerated small interfering RNA (siRNA) therapeutic, lepodisiran.

The reductions in serum Lp(a) in patients receiving lepodisiran were dose dependent but adverse events were not, said Steven E. Nissen, MD, professor of medicine at the Lerner College of Medicine at Cleveland Clinic, Cleveland, Ohio.

Rather, drug-related adverse events “were uncommon and generally similar across all lepodisiran doses and the placebo group,” reported Nissen, who pointed out that safety and tolerability were the primary endpoints and purpose of this phase 1 study.

Lp(a) Strongly Associated With CV Risk

Similar to low-density lipoprotein cholesterol (LDL-C), elevated levels of serum Lp(a) have been associated with major adverse cardiac events (MACE). In a 2022 review article that summarized pathophysiological, observational, and genetic studies, Lp(a) was found to be implicated in vascular inflammation, atherogenesis, calcification, and thrombosis.

Furthermore, Lp(a) has been associated with residual risk of cardiovascular (CV) events even after tight control of other risk factors, including elevated LDL-C, Nissen said.

So far, no well-tolerated therapy has been found to be effective for reducing Lp(a), but siRNA is a novel and attractive approach, according to Nissen, who presented these results November 12 at the American Heart Association Scientific Sessions 2023. They were also published online in the Journal of the American Medical Association.

By silencing target genes, siRNA therapies can inhibit a basic step in a given pathological process. In this case, lepodisiran silences the LPA gene to halt encoding of apolipoprotein(a), which plays a key role in Lp(a) production.

Lepodisiran is not the only treatment in development for Lp(a), noted the AHA-invited discussant Michelle L. O’Donoghue, MD, chair in cardiology, Brigham and Women’s Hospital, Boston, Massachusetts. She mentioned several other siRNA therapies, including olpasiran that was effective in a phase 2 trial she led and published in the New England Journal of Medicine about a year ago.

Drugs with different mechanisms, such as the antisense oligonucleotide pelacarsen, showed activity when tested earlier this year in a phase 1 study. No study has yet been conducted to link reductions in Lp(a) with CV event risk reduction.

The current study with lepodisiran was conducted with the participation of five clinical research sites in the US and Singapore. Participants between the ages of 18 and 65 years were enrolled if they had a serum Lp(a) of at least 75 nmol/L (30 mg/dL), which is considered moderately elevated.

They were excluded if they had CV disease or significant risk factors, including a blood pressure > 160/40 mm Hg, impaired renal function (eGFR < 60 mL/min/1.73 m2), or tobacco use (> 10 cigarettes/day).

Of 340 candidates screened, 48 were randomly assigned to one placebo or six lepodisiran groups. There were 12 participants in the placebo group and six in each of the lepodisiran dosing groups (4 mg, 12 mg, 32 mg, 96 mg, 304 mg, and 608 mg). All doses and placebo were administered subcutaneously one time with a planned follow-up of up to 48 weeks.

Safety Profile Is Placebo-like

The single most common adverse event, shared by those randomly assigned to placebo, was injection-site reaction. There were no adverse events, including laboratory abnormalities, that were persistent and clearly different for those assigned to any dose of lepodisiran relative to placebo.

The maximum median percentage change in serum Lp(a) out to day 337 of follow-up was 5% reduction in the placebo group. In the active treatment groups, the reductions were 41% on 4 mg, 59% on 12 mg, 76% on 32 mg, 96% on 304 mg, and 97% on 608 mg.

These reductions were generally sustained for as long as therapy was maintained. Maximal reductions were reached at day 85 in the 4-mg group but were achieved by day 29 in the 605-mg group, Nissen reported. In fact, serum Lp(a) was undetectable in the 605-mg group at day 29 and remained so until day 281.

Currently, there is no practical treatment for Lp(a). The only potential exception, apheresis, is “cumbersome” to perform and must be repeated for sustained reductions. Niacin and PCSK9 inhibitors are known to provide modest reductions in Lp(a), but Nissen said they are too modest to expect a meaningful clinical benefit.

Lp(a) Not Responsive to Lifestyle Changes

Statins as well as all lifestyle modifications, including diet, have been shown to have “little or no effect,” Nissen said.

The safety and the evidence so far of sustained Lp(a) lowering has already led to a phase 2 trial, according to Nissen, but the more important test for the future of lepodisiran will be studies powered to confirm reductions in MACE. Lepodisiran may finally allow that hypothesis to be tested.

“I think a lot of us have been waiting a long time for evidence that we can reliably reduce Lp(a),” said Karol Watson, MD, PhD, who has a research interest in lipids and is a professor of medicine at the UCLA Geffen School of Medicine, Los Angeles.

Although she conceded that the overwhelming evidence that Lp(a) is a risk factor does not ensure that any specific Lp(a)-lowering therapy will be clinically viable, she suggested this drug is a promising candidate to move this field forward.

“At the highest doses, lepodisiran is not just lowering L(pa), it appears to be getting rid of it,” she said.

O’Donoghue said that the phase 1 results suggest lepodisiran might have a somewhat longer duration of action than other siRNA therapies studied for Lp(a) so far, but said larger trials are needed to determine whether the growing number of drugs in this class differ in ways that are clinically meaningful.

Overall, the excitement in this field is probably mostly driven by the fact that there are so many promising therapies for Lp(a) that address the target in so many unique ways. O’Donoghue cited, as an example, a gene editing therapy called CTX320 that showed impressive effects in an animal study presented at the AHA meeting as a poster. She called the pipeline for treating Lp(a) “rich.”

Elevated Lp(a) is genetically determined, so levels do not generally change over time, said Donald Lloyd-Jones, MD, chair, Department of Preventive Medicine, Northwestern Medicine, Chicago, Illinois.

“It is not affected by your diet. It is not affected by your exercise. What your level is will be the level you will have for the rest of your life,” he said. Generally, it is recommended to have Lp(a) measured just once to more accurately calculate cardiovascular risk, but Lloyd-Jones predicts that this lipid subfraction might be measured more frequently to verify control if a therapeutic becomes available.

Nissen agreed. Estimating that 64 million people in the United States have significantly elevated Lp(a), he expects this risk to be addressed as a specific and independent target in CV risk management when and if it becomes treatable.

Nissen reported financial relationships with Novartis, Silence Therapeutics, and Eli Lilly, which provided funding for this trial. Watson reported financial relationships with Amgen, Boehringer-Ingelheim, Lilly, and Novartis. Lloyd-Jones has disclosed no relevant financial relationships.

American Heart Association (AHA) Scientific Sessions 2023. Presented November 11, 2023.

J Am Med Assoc. Published online November 12, 2023. Abstract


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