Efimosfermin alfa (BOS-580) once per month in people with metabolic dysfunction-associated steatohepatitis with F2 or F3 fibrosis: results from a 24-week, randomised, double-blind, placebo-controlled, phase 2 trial.

The aim of this study was to evaluate the efficacy and safety of efimosfermin alfa (henceforth referred to as efimosfermin, formerly BOS-580), an FGF21 analogue taken once per month, in patients with MASH and moderate or advanced fibrosis.

本研究旨在评估每月一次的FGF21类似物efimosfermin alfa（以下简称efimosfermin，原名BOS-580）在患有MASH和中度或高级纤维化的患者中的疗效和安全性。

Methods

This 24-week, randomised, double-blind, placebo-controlled, phase 2 trial evaluated the safety and efficacy of efimosfermin in participants aged 18-75 years with a BMI of at least 27 kg/m2 and MASH and F2 or F3 fibrosis present on a diagnostic liver biopsy done either during screening or within 6 months before the first day of dosing, and total activity Nonalcoholic Fatty Liver Disease Activity Score (NAS) of at least 4 with a minimum score of 1 point for all three NAS components (steatosis, hepatocyte ballooning, and lobular inflammation).

这项为期24周的随机、双盲、安慰剂对照的2期临床试验评估了efimosfermin在18-75岁、BMI至少为27 kg/m2、存在MASH和F2或F3级纤维化的参与者中的安全性和有效性。这些参与者在筛选期间或在首次给药的第一天前6个月内进行了诊断性肝活检，并且非酒精性脂肪性肝病活动评分（NAS）总分至少为4分，且所有三个NAS组成部分（脂肪变性、肝细胞气球样变和小叶炎症）的最低分数为1分。

The trial was conducted at 34 clinical research study sites in the USA.

该试验在美国的34个临床研究地点进行。

Participants were randomly assigned 1:1 to efimosfermin 300 mg or placebo administered by subcutaneous injection every 4 weeks (Q4W) over 24 weeks, stratified by MASH fibrosis stage (F2 vs F3 stage).

参与者按1:1的比例随机分配接受efimosfermin 300 mg或安慰剂，通过皮下注射每4周（Q4W）给药，持续24周，按MASH纤维化阶段（F2与F3阶段）进行分层。

Participants, investigators, and those assessing outcomes were masked to group assignment.

参与者、研究者以及评估结果的人员对分组分配情况均不知情。

The primary endpoint was safety and tolerability (ie, treatment-emergent adverse events, changes from baseline to week 24 in blood pressure and heart rate, and the incidenceof grade 3 and grade 4 laboratory abnormalities at week 24), analysed in all participants who received at least one dose.

主要终点是安全性和耐受性（即治疗后出现的不良事件、从基线到第24周血压和心率的变化，以及第24周3级和4级实验室异常的发生率），在所有至少接受一次剂量的参与者中进行分析。

This trial is registered with ClinicalTrials.gov (NCT04880031) and was completed on Sept 18, 2024.

该试验已在ClinicalTrials.gov注册（NCT04880031），并于2024年9月18日完成。

Results

Between May 4, 2023, and March 22, 2024, of 1171 participants screened, 84 participants were randomly assigned to efimosfermin 300 mg Q4W (n=43) or placebo (n=41); 44 (52%) were female and 40 (48%) were male. 48 (57%) had F2 fibrosis and 36 (43%) had F3 fibrosis; 65 had evaluable week-24 biopsy results.

在2023年5月4日至2024年3月22日期间，从1171名筛选的参与者中，有84名参与者被随机分配到efimosfermin 300 mg Q4W组（n=43）或安慰剂组（n=41）；其中44名（52%）为女性，40名（48%）为男性。48名（57%）患有F2级纤维化，36名（43%）患有F3级纤维化；65名参与者有可评估的第24周活检结果。

All 43 in the efimosfermin group and 40 of 41 participants in the placebo group received at least one dose.

efimosfermin组的43名参与者和安慰剂组的41名参与者中，有40名接受了至少一次剂量。

Adverse events were reported in 29 (67%) of 43 participants receiving efimosfermin and 22 (55%) of 40 receiving placebo.

在接受efimosfermin治疗的43名参与者中，有29名（67%）报告了不良事件，而在接受安慰剂治疗的40名参与者中，有22名（55%）报告了不良事件。

The majority of treatment-emergent adverse events were mild (24 [56%] of 43 in the efimosfermin group vs 15 [38%] of 40 in the placebo group) or moderate (18 [42%] vs 14 [35%]) in severity.

大多数治疗相关的不良事件为轻度（efimosfermin组43人中有24人[56%]，安慰剂组40人中有15人[38%]）或中度（efimosfermin组43人中有18人[42%]，安慰剂组40人中有14人[35%]）的严重程度。

Most frequent adverse events were gastrointestinal events, which were transient and occurred within the first few weeks of treatment.

最常见的不良事件是胃肠道事件，这些事件是短暂的，并且在治疗的前几周内发生。

There were no clinically meaningful changes in vital signs between treatment and placebo groups, and no clinically significant grade 3 or higher laboratory abnormalities observed for either group.

治疗组和安慰剂组之间的重要生命体征没有临床意义上的变化，且两组均未观察到临床上显著的3级或更高级别的实验室异常。

No deaths or adverse events greater than grade 3 were observed during the study.

在研究期间未观察到死亡或大于3级的不良事件。

interpretation

In this phase 2 trial, treatment with efimosfermin once per month was generally well tolerated in participants with biopsy-confirmed MASH and F2 or F3 fibrosis.

在这项2期试验中，对于经活检证实为MASH以及F2或F3纤维化的参与者，每月一次使用efimosfermin治疗通常耐受性良好。

These results support the further development of efimosfermin for treatment of MASH-related fibrosis.

这些结果支持进一步开发efimosfermin用于治疗与MASH相关的纤维化。

funding

Boston Pharmaceuticals and GSK.

波士顿制药公司和GSK。