A Phase 1 Study Evaluating the Pharmacokinetics, Pharmacodynamics, and Safety of Zerlasiran in Japanese Participants

Abstract

Aim: Zerlasiran is an N-acetylgalactosamine-conjugated small interfering RNA that targets lipoprotein(a), a risk factor for atherosclerosis and calcific aortic stenosis. Zerlasiran has not been studied in Japanese participants previously.

Method: This was an open-label, single-dose trial that enrolled 18 adult participants with lipoprotein(a) levels ≥ 70 nmol/L at a single site in Japan to evaluate subcutaneous doses of zerlasiran (30 mg, 100 mg, and 300 mg) in three ascending-dose cohorts. The participants were monitored for 150 days post-dose to assess the systemic pharmacokinetics, pharmacodynamics (lipoprotein (a) and lipid biomarkers), and safety.

Results: Following dosing, median T_max was reached at 5 hours with plasma concentrations gradually declining to undetectable levels by 36 hours, with t_1/2 approximately 4 hours. Both C_max and AUC_0-inf increased in a dose-dependent manner. The maximum median (interquartile range [IQR]) percent reduction in lipoprotein (a) in the 30 mg, 100 mg, and 300 mg cohorts were -72.8% (-79.7%, -67.1%), 88.8% (-89.5%, -84.7%), and -97.8% (-98.6, -96.9%), respectively, between days 30 and 60, with a sustained effect observed at 150 days at all dose levels. All adverse events were mild and self-limiting.

Conclusion: Zerlasiran was well tolerated with no significant safety findings observed at any dose level. A typical pharmacokinetic profile expected of an N-acetylgalactosamine-conjugated small interfering RNA, coupled with a potent and sustained reduction in lipoprotein(a), was observed in Japanese participants. No adverse effects on either the liver or kidney function were observed.