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TY  - JOUR
AU  - Nissen, Steven E.
AU  - Wolski, Kathy
AU  - Watts, Gerald F.
AU  - Koren, Michael J.
AU  - Fok, Henry
AU  - Nicholls, Stephen J.
AU  - Rider, David A.
AU  - Cho, Leslie
AU  - Romano, Steven
AU  - Melgaard, Carrie
AU  - Rambaran, Curtis
T1  - Single Ascending and Multiple-Dose Trial of Zerlasiran, a Short Interfering RNA Targeting Lipoprotein(a): A Randomized Clinical Trial
PY  - 2024
Y1  - 2024/05/14
DO  - 10.1001/jama.2024.4504
JO  - JAMA
JA  - JAMA
VL  - 331
IS  - 18
SP  - 1534
EP  - 1543
SN  - 0098-7484
AB  - Lipoprotein(a) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis, with no pharmacological treatments approved by regulatory authorities.To assess the safety and tolerability of zerlasiran, a short interfering RNA targeting hepatic synthesis of apolipoprotein(a), and effects on serum concentrations of lipoprotein(a).Single- and multiple-dose study in healthy participants and patients with stable ASCVD, respectively, with lipoprotein(a) serum concentrations greater than 150 nmol/L, conducted at 7 research sites in the US, the Netherlands, UK, and Australia between November 18, 2020, and February 8, 2023, with last follow-up on August 23, 2023.Participants were randomized to receive (1) a single subcutaneous dose of placebo (n = 8), zerlasiran 300 mg (n = 6) or 600 mg (n = 6); or (2) 2 doses of placebo (n = 9), zerlasiran 200 mg (n = 9) at a 4-week interval or 300 mg (n = 9) or 450 mg (n = 9) at an 8-week interval.The primary outcome was safety and tolerability. Secondary outcomes included serum levels of zerlasiran and effects on lipoprotein(a) serum concentrations.Among 37 patients in the multiple-dose group (mean age, 56 [SD, 10.4] years; 15 [42%] women), 36 completed the trial. Among 14 participants with extended follow-up after single doses, 13 completed the trial. There were no serious adverse events. Median baseline lipoprotein(a) concentrations in the multiple-dose group were 288 (IQR, 199-352) nmol/L. Median changes in lipoprotein(a) concentration at 365 days after single doses were 14% (IQR, 13% to 15%) for the placebo group, −30% (IQR, −51% to −18%) for the 300 mg of zerlasiran group, and −29% (IQR, −39% to −7%) for the 600-mg dose group. After 2 doses, maximal median changes in lipoprotein(a) concentration were 19 (IQR, −17 to 28) nmol/L for the placebo group, −258 (IQR, −289 to −188) nmol/L for the 200 mg of zerlasiran group, −310 (IQR, −368 to −274) nmol/L for the 300-mg dose group, and −242 (IQR, −343 to −182) nmol/L for the 450-mg dose group, with maximal median percent change of 7% (IQR, −4% to 21%), −97% (IQR, −98% to −95%), −98% (IQR, −99% to −97%), and −99% (IQR, −99% to −98%), respectively, attenuating to 0.3% (IQR, −2% to 21%), −60% (IQR, −71% to −40%), −90% (IQR, −91% to −74%), and −89% (IQR, −91% to −76%) 201 days after administration.Zerlasiran was well tolerated and reduced lipoprotein(a) concentrations with infrequent administration.ClinicalTrials.gov Identifier: NCT04606602
Y2  - 5/20/2024
UR  - https://doi.org/10.1001/jama.2024.4504
ER  -