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Extended-Duration Short Interfering RNA Targets Hepatic Production of Apolipoprotein(a)

In a phase 1 study of 48 participants, lepodisiran reduced serum lipoprotein(a) concentrations through its actions on the production of apolipoprotein(a) in the liver. The drug, a short interfering RNA, produced long-duration reductions, the authors report, supporting its further study for patients with elevated lipoprotein(a) levels.

In the U.S. and Singapore, single doses of lepodisiran 4 mg, 12 mg, 32 mg, 96 mg, 304 mg, or 608 mg were administered subcutaneously to adults without cardiovascular disease and with lipoprotein(a) serum concentrations of 75 nmol/L or greater (≥30 mg/dL). The primary outcome was the safety and tolerability of the single ascending doses of lepodisiran. 

“Of the 48 participants enrolled (mean age, 46.8 [SD, 11.6] years; 35% were women), 1 serious adverse event occurred,” the authors write. “The plasma concentrations of lepodisiran reached peak levels within 10.5 hours and were undetectable by 48 hours.… The maximal median change in lipoprotein(a) concentration was −5% (IQR, −16% to 11%) in the placebo group, −41% (IQR, −47% to −20%) in the 4 mg of lepodisiran group, −59% (IQR, −66% to −53%) in the 12-mg dose group, −76% (IQR, −76% to −75%) in the 32-mg dose group, −90% (IQR, −94% to −85%) in the 96-mg dose group, −96% (IQR, −98% to −95%) in the 304-mg dose group, and −97% (IQR, −98% to −96%) in the 608-mg dose group. At day 337, the median change in lipoprotein(a) concentration was −94% (IQR, −94% to −85%) in the 608 mg of lepodisiran group.”

Source: JAMA