Nissen Steven E, Wang Qiuqing, Nicholls Stephen J, Navar Ann Marie, Ray Kausik K, Schwartz Gregory G, Szarek Michael, Stroes Erik S G, Troquay Roland, Dorresteijn Jannick A N, Fok Henry, Rider David A, Romano Steven, Wolski Kathy, Rambaran Curtis
Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio.
Victorian Heart Institute, Monash University, Melbourne, Australia.
JAMA. 2024 Dec 17;332(23):1992-2002. doi: 10.1001/jama.2024.21957.
Elevated lipoprotein(a) increases the risk of atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis.
To evaluate the effects of zerlasiran, a small-interfering RNA targeting hepatic synthesis of apolipoprotein(a), on lipoprotein(a) serum concentration.
DESIGN, SETTING, AND PARTICIPANTS: A multicenter trial in patients with stable ASCVD with serum lipoprotein(a) concentrations greater than or equal to 125 nmol/L at 26 sites in Europe and South Africa between January 3, 2023, and April 27, 2023, with last follow-up on July 1, 2024.
Participants randomized to receive a subcutaneous dose of placebo every 16 weeks for 3 doses (n = 23) or every 24 weeks for 2 doses (n = 24) or zerlasiran 450 mg every 24 weeks for 2 doses (n = 45), 300 mg every 16 weeks for 3 doses (n = 42), or 300 mg every 24 weeks for 2 doses (n = 44).
The primary outcome was the time-averaged percent change in lipoprotein(a) concentration from baseline to 36 weeks, with follow-up to 60 weeks.
Among 178 patients, mean (SD) age was 63.7 (9.4) years, 46 (25.8%) were female, with a median (IQR) baseline lipoprotein(a) concentration of 213 (177-282) nmol/L; 172 patients completed the trial. Compared with the pooled placebo group, the least-squares mean time-averaged percent change in lipoprotein(a) concentration from baseline to week 36 was -85.6% (95% CI, -90.9% to -80.3%), -82.8% (95% CI, -88.2% to -77.4%), and -81.3% (95% CI, -86.7% to -76.0%) for the 450 mg every 24 weeks, 300 mg every 16 weeks, and 300 mg every 24 weeks groups, respectively. Median (IQR) percent change in lipoprotein(a) concentration at week 36 was -94.5% (-97.3% to -84.2%) for the 450 mg every 24 weeks group, -96.4% (-97.7% to -92.3%) for the 300 mg every 16 weeks group, and -90.0% (-93.7% to -81.3%) for the 300 mg every 24 weeks group. The most common treatment-related adverse effects were injection site reactions, with mild pain occurring in 2.3% to 7.1% of participants in the first day following drug administration. There were 20 serious adverse events in 17 patients, none considered related to the study drug.
Zerlasiran was well-tolerated and reduced time-averaged lipoprotein(a) concentration by more than 80% during 36 weeks of treatment in patients with ASCVD.
ClinicalTrials.gov Identifier: NCT05537571.
脂蛋白(a)升高会增加动脉粥样硬化性心血管疾病(ASCVD)和主动脉瓣狭窄的风险。
评估靶向肝脏载脂蛋白(a)合成的小干扰RNA泽拉斯兰对脂蛋白(a)血清浓度的影响。
设计、设置和参与者：一项多中心试验，于2023年1月3日至2023年4月27日在欧洲和南非的26个地点对血清脂蛋白(a)浓度大于或等于125 nmol/L的稳定ASCVD患者进行，最后随访时间为2024年7月1日。
参与者被随机分配，每16周皮下注射一次安慰剂，共注射3次(n = 23)，或每24周注射一次，共注射2次(n = 24)，或每24周皮下注射450 mg泽拉斯兰，共注射2次(n = 45)，每16周注射300 mg，共注射3次(n = 42)，或每24周注射300 mg，共注射2次(n = 44)。
主要结局是从基线到36周脂蛋白(a)浓度的时间平均百分比变化，随访至60周。
在178例患者中，平均(标准差)年龄为63.7(9.4)岁，46例(25.8%)为女性，基线脂蛋白(a)浓度中位数(四分位间距)为213(177 - 282)nmol/L；172例患者完成了试验。与合并安慰剂组相比，每24周450 mg组、每16周300 mg组和每24周300 mg组从基线到第36周脂蛋白(a)浓度的最小二乘平均时间平均百分比变化分别为-85.6%(95%CI，-90.9%至-80.3%)、-82.8%(95%CI，-88.2%至-77.4%)和-81.3%(95%CI，-86.7%至-76.0%)。每24周450 mg组在第36周脂蛋白(a)浓度的中位数(四分位间距)百分比变化为-94.5%(-97.3%至-84.2%)，每16周300 mg组为-96.4%(-97.7%至-92.3%)，每24周300 mg组为-90.0%(-93.7%至-81.3%)。最常见的与治疗相关的不良反应是注射部位反应，给药后第一天2.3%至7.1%的参与者出现轻度疼痛。17例患者发生20起严重不良事件，均认为与研究药物无关。
在ASCVD患者的36周治疗期间，泽拉斯兰耐受性良好，可使脂蛋白(a)的时间平均浓度降低80%以上。
ClinicalTrials.gov标识符：NCT05537571。
