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Single Dose of Lepodisiran Shows Promise in Lowering Lp(a) Over an Extended Period

A single subcutaneous injection of lepodisiran, an siRNA targeting mRNA for the LPA gene, substantially lowered lipoprotein(a), or Lp(a), below baseline levels for 48 weeks, according to new late-breaking science presented Nov. 12 at AHA 2023 and simultaneously published in JAMA.

The first-in-human study enrolled 48 participants with abnormal levels of Lp(a), averaging 110 nmol/L, all of whom were given a single subcutaneous injection. Twelve participants were randomly assigned to receive a placebo and 36 participants received lepodisiran in doses of either 4 mg, 12 mg, 32 mg, 96 mg, 304 mg or 608 mg (n=6 for each dosing group). Participants were discharged three days after receiving the injection, and follow-up blood tests were done for 48 weeks.

Among the key findings, patients who received the 608 mg dose of lepodisiran saw the greatest results, with blood levels of Lp(a) declining rapidly and becoming undetectable by day 29. From there, Lp(a) levels remained unmeasurable from days 29 to 281 and then rose slightly, with a median reduction of Lp(a) levels at 94% below baseline at 48 weeks, according to lead study author Steve Nissen, MD, MACC. Overall, the maximal median change from baseline in serum Lp(a) concentrations was -5% in the placebo group and -41%, -59%, -76%, -90%, -96% and -97% in the 4 mg, 12 mg, 32 mg, 96 mg, 304 mg and 608 mg lepodisiran groups, respectively. According to Nissen, no major safety issues were observed, although low-grade, transient, injection site reactions occurred.

“Elevation of Lp(a) is a common risk factor responsible for considerable cardiovascular morbidity and mortality with no pharmacological therapies approved by regulatory authorities,” said Nissen. “Nucleic acid therapeutics offer a highly promising approach to treat this previously untreatable disorder. Cardiovascular outcomes trials will determine whether these therapies can reduce the incidence of MACE. Stay tuned.”

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia

Keywords: American Heart Association, AHA23, Dyslipidemias

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