Lipoprotein(a)-lowering with zerlasiran succeeds in phase II trial

The small-interfering RNA zerlasiran appears promising in the treatment of patients with atherosclerotic cardiovascular disease (ASCVD), reducing time time-averaged lipoprotein(a) concentration by more than 80 percent over 36 weeks of follow-up, as shown in a phase II trial.

The trial included 178 patients (mean age 63.7 years, 25.8 percent female) with stable ASCVD and serum lipoprotein(a) concentrations of at least 125 nmol/L (median 213 nmol/L). These patients were randomly assigned to receive zerlasiran 450 mg every 24 weeks for two doses (n=45), zerlasiran 300 mg every 16 weeks for three doses (n=42), zerlasiran 300 mg every 24 weeks for two doses (n=44), placebo every 16 weeks for three doses (n=23), or placebo every 24 weeks for two doses (n=24). Treatment was administered subcutaneously.

Researchers measured the time-averaged percent change in lipoprotein(a) concentration from baseline to 36 weeks as the primary endpoint. They said that this endpoint more accurately described the effects of treatment over time, including intervals between doses, as compared with maximal reduction in lipoprotein(a) or lowering at a specific time point.

A total of 172 patients completed the trial. At week 36, the least-squares mean time-averaged percent change in lipoprotein(a) concentration from baseline relative to the combined placebo group was −85.6 percent with zerlasiran 450 mg every 24 weeks, −82.8 percent with 300 mg every 16 weeks, and −81.3 percent with 300 mg every 24 weeks. The corresponding median percent changes in lipoprotein(a) concentration were −94.5 percent, −96.4 percent, and −90.0 percent.

As for safety, injection site reactions were the most common treatment-related adverse effects, with mild pain occurring in 2.3 percent to 7.1 percent of patients on the first day following drug administration. A total of 20 serious adverse events were documented in 17 patients, none of which were considered related to the study drug.