Shiffman Mitchell, Da Ben, Goel Aparna, Kwong Allison, Stein Lance, Moreno Christophe, Nicoll Amanda, Mehta Ashwini, Louvet Alexandre, Flamm Steven, Pyrsopoulos Nikolaos, Satapathy Sanjaya, Kuo Alexander, Ganger Daniel, Aloman Costica, Strasser Simone I, Tse Edmund, Russo Mark W, Rockey Don, Gray Meagan, Mitchell Mack, Thursz Mark, Krebs William, Scott Deborah, Blevins Christina, Ellis Dave, Brown James, Sussman Norman, Lin WeiQi
Bon Secours Liver Institute, Richmond, VA.
Northwell Health, Manhasset, NY.
NEJM Evid. 2025 Feb;4(2):EVIDoa2400243. doi: 10.1056/EVIDoa2400243. Epub 2025 Jan 28.
Larsucosterol is a DNA methyltransferase inhibitor in development for alcohol-associated hepatitis (AH), a disease for which there is no approved therapy.
In this phase 2b trial, patients with severe AH were randomly assigned 1:1:1 to receive 30 mg or 90 mg of larsucosterol or placebo; a second dose was administered after 72 hours if the patient remained hospitalized. All patients received supportive care as determined by investigators. Patients in the placebo group, if prescribed, received 32 mg of methylprednisolone, while patients in the larsucosterol groups received matching placebo capsules. The primary end point was 90-day mortality or liver transplant (LT) rate. The key secondary end point was 90-day mortality. We prespecified the reporting of U.S. results separately.
Among 307 enrolled patients, 301 received at least one treatment dose. The difference in 90-day mortality or LT between the 30-mg or 90-mg larsucosterol and placebo groups did not reach statistical significance. Ninety-day mortality in the placebo and the 30-mg and 90-mg groups was 25 out of 103, 15 out of 102, and 17 out of 102, respectively. Among U.S. patients (76% of all enrolled patients), there were 21 deaths and 4 LTs among 77 patients in the placebo group, 8 deaths and 5 LTs among 73 patients in the 30-mg larsucosterol group, and 10 deaths and 8 LTs among 77 patients in the 90-mg larsucosterol group. In patients who were treated within less than 10 days of hospitalization (75%), mortality in the placebo group was 20 out of 79 (U.S. patients 17/57), mortality in the 30-mg larsucosterol group was 7 out of 74 (U.S. patients 4/57), and mortality in the 90-mg larsucosterol group was 13 out of 77 (U.S. patients 9/66). Most adverse events arising during treatment were attributable to hepatic disease, and there was no imbalance in adverse events that could not be ascribed to liver disease.
The trial did not meet the primary end point of showing a beneficial effect of larsucosterol on 90-day mortality or LT in patients with severe AH. Equipoise has been established for a further trial of larsucosterol on AH survival. (The trial was funded by the DURECT Corporation; its ClinicalTrials.gov number is NCT04563026.).
拉苏可司特醇是一种正在研发用于治疗酒精性肝炎（AH）的DNA甲基转移酶抑制剂，目前该疾病尚无获批的治疗方法。
在这项2b期试验中，重度AH患者被随机按1:1:1分配，分别接受30毫克或90毫克的拉苏可司特醇或安慰剂；如果患者仍住院，72小时后给予第二剂药物。所有患者均接受研究者确定的支持性治疗。安慰剂组患者（如处方）接受32毫克甲泼尼龙，而拉苏可司特醇组患者接受匹配的安慰剂胶囊。主要终点是90天死亡率或肝移植（LT）率。关键次要终点是90天死亡率。我们预先指定分别报告美国的结果。
在307名入组患者中，301名接受了至少一剂治疗。30毫克或90毫克拉苏可司特醇组与安慰剂组之间的90天死亡率或LT差异未达到统计学意义。安慰剂组、30毫克组和90毫克组的90天死亡率分别为103例中的25例、102例中的15例和102例中的17例。在美国患者中（占所有入组患者的76%），安慰剂组77名患者中有21例死亡和4例肝移植，30毫克拉苏可司特醇组73名患者中有8例死亡和5例肝移植，90毫克拉苏可司特醇组77名患者中有10例死亡和8例肝移植。在住院不到10天内接受治疗的患者中（75%），安慰剂组死亡率为79例中的20例（美国患者17/57），30毫克拉苏可司特醇组死亡率为74例中的7例（美国患者4/57），90毫克拉苏可司特醇组死亡率为77例中的13例（美国患者9/66）。治疗期间出现的大多数不良事件归因于肝脏疾病，且不良事件中不存在无法归因于肝脏疾病的不平衡情况。
该试验未达到主要终点，即未显示拉苏可司特醇对重度AH患者的90天死亡率或肝移植有有益效果。已确定在AH生存方面对拉苏可司特醇进行进一步试验的平衡状态。（该试验由杜雷克特公司资助；其在ClinicalTrials.gov上的编号为NCT04563026。）
