Lepodisiran, a Small Interfering RNA, Could Lower Lp(a) by More than 95%

Steve Nissen, MD
Credit: Cleveland Clinic

Results from a phase 1 trial of lepodisiran, a short interfering RNA directed at hepatic synthesis of apolipoprotein(a), indicates use of the 608 mg formulation of the agent was associated with a 97% in lipoprotein(a) [Lp(a)].

Presented at the American Heart Association Scientific Sessions 2023 by Steve Nissen, MD, chief academic officer of the Heart Vascular & Thoracic Institute at Cleveland Clinic, results of the trial provide insight into the safety and efficacy of 6 dosages of lepodisiran relative to placebo therapy for lowering Lp(a) in adults without cardiovascular disease and with Lp(a) serum concentrations of 75 nmol/L or greater.

“It's like nothing the world has ever seen,” said Nissen, in an interview with HCPLive Cardiology. “At the 608 milligram dose levels of lipoprotein(a) dropped to below the lower limit of quantitation for their standard Roche assay, and remained unmeasurable for the next 281 days.”

Sponsored by Eli Lilly and Company, the phase 1 trial was launched in 2020 and conducted in 5 clinical sites in the US and Singapore. For inclusion, patients needed to be between 18 and 65 years in the US and between the ages 21 of 65 years in Singapore, without any known cardiovascular disease except dyslipidemia or well-controlled hypertension, have a body mass index between 18.5 and 40 kg/m2, and have an Lp(a) either 75 nmol/L or more or 30 mg/dL or more.

The trial’s primary outcome was the safety and tolerability of the single ascending doses of lepodisiran. The trial also included multiple secondary outcomes of interest included plasma levels of lepodisiran for 168 days after dose administration and changes in fasting Lp(a) serum concentrations through a maximum follow-up of 48 weeks.

A total of 48 adult patients were enrolled in the trial. This cohort had a mean age of 46.8 (Standard Deviation [SD], 11.6) years and 35% were women. Investigators noted. Initial analysis indicated 1 serious adverse event occurred during the trial, with this event occurring among a patient receiving lepodisiran 4 mg. This event was described as a facial injury secondary to mechanical fall while riding a bicycle.

Results suggested plasma concentrations of lepodisiran reached peak levels within 10.5 hours and were undetectable by 48 hours. Investigators pointed out the median baseline Lp(a) concentration was 111 nmol/L (Interquartile Range [IQR], 78 to 134 nmol/L) in the placebo group, 78 nmol/L (IQR, 50 to 152 nmol/L) in the 4 mg of lepodisiran group, 97 nmol/L (IQR, 86 to 107 nmol/L) in the 12-mg dose group, 120 nmol/L (IQR, 110 to 188 nmol/L) in the 32-mg dose group, 167 nmol/L (IQR, 124 to 189 nmol/L) in the 96-mg dose group, 96 nmol/L (IQR, 72 to 132 nmol/L) in the 304-mg dose group, and 130 nmol/L (IQR, 87 to 151 nmol/L) in the 608-mg dose group.

Results of the investigators’ analysis revealed the maximal median change in lipoprotein(a) concentration were as follows:

• Placebo group: −5% (IQR, −16% to 11%)
• Lepodisiran 4 mg: −41% (IQR, −47% to −20%)
• Lepodisiran 12 mg:−59% (IQR, −66% to −53%)
• Lepodisiran 32 mg: −76% (IQR, −76% to −75%)
• Lepodisiran 96 mg: −90% (IQR, −94% to −85%)
• Lepodisiran 304 mg: −96% (IQR, −98% to −95%)
• Lepodisiran 608 mg: —97% (IQR, −98% to −96%)

For the 608 mg dose of lepodisiran, investigators highlighted a median change in Lp(a) concentration of —94% (95% CI, —94% to —85%) at day 337.

References:

1. Nissen SE, Linnebjerg H, Shen X, et al. Lepodisiran, an Extended-Duration Short Interfering RNA Targeting Lipoprotein(a): A Randomized Dose-Ascending Clinical Trial. JAMA. Published online November 12, 2023. doi:10.1001/jama.2023.21835