Lepodisiran lowers lipoprotein(a) concentrations in early trial

Treatment with lepodisiran yields dose-dependent and durable reductions in serum lipoprotein(a) levels while being well tolerated, according to the results of a phase I trial.

The study included 48 participants (mean age 46.8 years, 35 percent women, 48 percent Asians) with lipoprotein(a) levels (≥75 nmol/L or or ≥30 mg/dL) who were free of cardiovascular disease at baseline. These participants were randomly assigned to receive a single dose of lepodisiran (at 4, 12, 32, 96, 304, or 608 mg) or placebo. Treatment was given subcutaneously.

The primary endpoint was the safety and tolerability of the single ascending doses of lepodisiran. Secondary endpoints included plasma lepodisiran levels for 168 days after dose administration and changes in fasting lipoprotein(a) serum concentrations over a maximum follow-up of 48 weeks.

One participant had a facial injury after a fall from a bicycle, which occurred 141 days after injection. No other participants had a serious adverse event. Plasma lepodisiran concentrations reached peak levels within 10.5 hours and were undetectable by 48 hours.

In terms of efficacy, the median lipoprotein(a) concentrations dropped from baseline by a median of 5 percent (IQR, −16 percent to 11 percent) in the placebo group, 41 percent (IQR, −47 percent to −20 percent) in the 4-mg lepodisiran group, 59 percent (IQR, −66 percent to −53 percent) in the 12-mg dose group, 76 percent (IQR, −76 percent to −75 percent) in the 32-mg dose group, 90 percent (IQR, −94 percent to −85 percent) in the 96-mg dose group, 96 percent (IQR, −98 percent to −95 percent) in the 304-mg dose group, and 97 percent (IQR, −98 percent to −96 percent) in the 608-mg dose group.

At week 48, the median lipoprotein(a) concentration decreased by 94 percent (IQR, −94 percent to −85 percent) in the 608-mg lepodisiran group.