One-Shot RNAi Therapy Lepodisiran Reduces Key Lipid Biomarker by 94% for Nearly a Year

▎Edited by the WuXi AppTec content team

At the 2023 American Heart Association Scientific Sessions, Eli Lilly and Company presented significant results of the RNAi therapy lepodisiran in reducing lipoprotein(a) — Lp(a) levels. The results showed,A single injection of lepodisiran reduced Lp(a) levels to undetectable levels for nearly a year.This important research finding was simultaneously published in the authoritative medical journal, *The Journal of the American Medical Association* (

JAMA).

In this trial, 48 volunteers with an average Lp(a) level of 110 nmol/L received a single subcutaneous injection. Among them, 12 were randomly assigned to receive a placebo, and 36 received different doses of lepodisiran.

Main findings include:

Drug levels rose rapidly and returned to baseline within 48 hours, indicating a swift transfer of the drug from the bloodstream to the liver.

At the highest dose (608 mg) of lepodisiran, Lp(a) levels rapidly decreased, becoming undetectable on day 29, remaining undetectable from day 29 to day 281, then slightly increased, with the median Lp(a) level reduced by 94% at 48 weeks.

At lower doses of lepodisiran, the duration of Lp(a) level reduction was somewhat shortened; however, in patients receiving the 304 mg dose, a 75% reduction was still maintained at 48 weeks.

Lepodisiran is a small interfering RNA that reduces the production of Lp(a) by disrupting the mRNA that produces apolipoprotein (a) in the liver.

Apolipoprotein (a) is a key component of Lp(a) particles. The drug, through specific modifications, enables absorption by hepatocytes.

Some people experienced adverse events at the injection site, such as pain, which resolved during the initial three-day monitoring period. Three participants had a transient elevation in creatine kinase; other adverse reactions were mild and transient, such as nasal congestion or headache.

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