Lepodisiran substantially lowers Lp(a) in early trial
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Key takeaways:
- Lipoprotein(a) is a genetic risk factor for CVD, for which there are no treatments currently available.
- A single dose of lepodisiran was well-tolerated, safe and reduced Lp(a) more than 94% for nearly 1 year.
PHILADELPHIA — In a phase 1 study, lepodisiran was well-tolerated and produced dose-dependent reductions in lipoprotein(a) concentrations in adults without CVD who had elevated lipoprotein(a) levels.
“Subcutaneous injection of lepodisiran, a single-interfering RNA targeting mRNA for the LPA gene, substantially lowered lipoprotein(a),” Healio | Cardiology Today Editorial Board Member Steven E. Nissen, MD, MACC, chief academic officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic, said during a press conference at the American Heart Association Scientific Sessions. “These findings support further development of this therapy.”
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Safety, tolerability, Lp(a) reduction
The phase 1 trial enrolled 48 adults with elevated Lp(a) levels of 75 nmol/L or greater. The participants’ mean age was 46 years, 35% were women, 48% were Asian, 33% white and 15% Black.
At baseline, median Lp(a) concentration among all treatment groups was 113 nmol/L.
Participants were randomly assigned to receive placebo or a single dose of subcutaneous lepodisiran (Eli Lilly) 4 mg, 12 mg, 32 mg, 96 mg, 304 mg or 608 mg.
The primary outcome of this study was safety and tolerability and secondary outcomes included changes in Lp(a) concentrations over a maximum follow-up of 48 weeks.
“Now, in phase 1, it’s always about safety. We didn’t really see anything. There were no major lab abnormalities that differed between placebo and the treatment groups. It was a very well-tolerated therapy,” Nissen said.
One serious adverse event was reported.
“There were no major safety issues, although low-grade, transient injection-site reactions occurred,” Nissen said.
According to results presented at AHA 2023, simultaneously published in JAMA, the maximal median change in Lp(a) concentration was as follows:
- –5% in the placebo group
- –41% in the 4 mg group
- –59% in the 12 mg group
- –76% in the 32 mg group
- –90% in the 96 mg group
- –96% in the 304 mg group
- –97% in the 608 mg group
“After the 608 mg dose, serum concentrations of lipoprotein(a) fell below the lower limit of quantitation from days 29 to 281 and remained more than 94% below baseline for 337 days, 48 weeks,” Nissen said.
The researchers noted limitations of this trial, including its first-in-human phase 1 design and small number of patients enrolled. Safety cannot be comprehensively assessed in a trial of this size and duration, Nissen said.
Emerging therapies
Lp(a) is a genetically determined risk factor for CVD. An estimated 64 million Americans and 1.4 billion people worldwide have elevated Lp(a), according to the presentation.
No pharmacological treatments for Lp(a) are currently approved, Nissen said.
“We’ve never been able to treat elevated Lp(a). We are now having emerging 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 will actually reduce risk. Such trials are underway with a variety of therapeutics and I’m very hopeful that this previously untreatable abnormality will become treatable in the very near future,” Nissen said.
While the current study evaluated single doses of lepodisiran, a phase 2 multi-dose trial is underway, Nissen said. “We will be asking the question: [should administration be] twice a year or is it once a year? We don’t know the complete answer yet,” he said. If once a year, “it would be like a vaccine.”
During a discussion of Lp(a) measurement, Nissen said “we recommend that people sometime early in life have their Lp(a) level checked. If it’s not elevated, it will not be elevated later in life. There’s no evidence that it actually increases over time,” he said.
“This is a one-and-done situation right now,” AHA 2023 press conference moderator Donald M. Lloyd-Jones, MD, MSc, FAHA, past president of the AHA and chair of the department of medicine at Northwestern University’s Feinberg School of Medicine, said.
Lp(a) “is not affected by your diet; it’s not affected by your exercise. The current discussion is about only measuring Lp(a) once,” he said. “What your level is, is what your level is going to be for the rest of your life.”
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Karol E. Watson, MD, PhD, FNLA, FACC, FAHA
We have been thinking and hearing about Lp(a) for years. There is an association between elevated Lp(a) levels and CV risk, so we wanted to think about ways to lower that Lp(a) level and hopefully lower risk. Lepodisiran may be one strategy. We saw durable Lp(a) lowering. It wasn’t just Lp(a) lowering; [it] got rid of it altogether. ... The safety profile looked really clean. What the crux of every one of these drugs is: We want to lower CV events. We don’t know yet if that will work [with lepodisiran] but we are hopeful that it will. We await more data.
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Nissen SE, et al. LBS.06. Future of lipid lowering therapy – Novel mechanisms and approaches. Presented at: American Heart Association Scientific Sessions; Nov. 11-13, 2023; Philadelphia.
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