Efimosfermin alfa (BOS-580), a long-acting FGF21 analogue, in participants with phenotypic metabolic dysfunction-associated steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2a trial.

Efimosfermin alfa (efimosfermin, formerly BOS-580) is a long-acting, engineered variant of FGF21 designed to have a prolonged half-life.

Efimosfermin alfa（efimosfermin，原名BOS-580）是FGF21的一种长效工程变体，设计具有延长的半衰期。

We aimed to assess the safety and tolerability of multiple efimosfermin doses and dosing regimens compared with placebo and to evaluate exploratory biomarkers of efficacy in participants with phenotypic MASH.

我们旨在评估多种efimosfermin剂量及其给药方案的安全性和耐受性，与安慰剂进行比较，并评估具有表型MASH的参与者的疗效探索性生物标志物。

Methods

This multicentre, randomised, double-blind, placebo-controlled, phase 2a trial was conducted at 12 centres in the USA.

这项多中心、随机、双盲、安慰剂对照的2a期试验在美国的12个中心进行。

Individuals with phenotypic MASH, aged 18-75 years and with a BMI of 30-45 kg/m2, were eligible for the study.

具有表型MASH，年龄在18-75岁之间，BMI在30-45 kg/m^2之间的个体符合本研究的资格。

Participants were randomly assigned, using a centralised interactive randomisation system with no stratification factors, to one of five dosing cohorts: efimosfermin 75 mg once every 4 weeks, 75 mg once every 2 weeks, 150 mg once every 4 weeks, 150 mg once every 2 weeks, or 300 mg once every 4 weeks, for a 12-week treatment period.

参与者使用一个没有分层因素的集中式互动随机化系统随机分配到五个剂量队列之一：每4周一次75 mg的efimosfermin，每2周一次75 mg，每4周一次150 mg，每2周一次150 mg，或每4周一次300 mg，为期12周的治疗期。

Participants were assigned 1:1:1:1 to all cohorts except efimosfermin 150 mg once every 4 weeks, which was initiated after assignment to the other cohorts was complete.

参与者被按1:1:1:1的比例分配到所有队列中，除了efimosfermin 150 mg每4周一次的队列，该队列是在其他队列分配完成后才开始的。

Within each cohort, participants were randomly assigned 4:1 to receive efimosfermin or placebo, via subcutaneous injection, in fixed blocks of size five.

在每个队列中，参与者通过固定大小为五的块随机分配为4:1比例，接受efimosfermin或安慰剂的皮下注射。

Investigators and participants were masked to group assignment and treatment allocation.

研究人员和参与者对分组分配和治疗分配进行了盲法处理。

The primary endpoint was safety and tolerability and was assessed throughout the 12-week treatment period and at the follow-up visit 4 weeks after the final dose in the full analysis set, defined as enrolled participants who received at least one dose of study medication.

主要终点是安全性和耐受性，该评估贯穿整个12周的治疗期，并在最终剂量后4周的随访访问中进行，全分析集定义为至少接受一次研究药物剂量的入组参与者。

Part A (reported here) of this phase 2 study is complete, while other parts of the phase 2 study are ongoing.

本项2期研究的A部分（此处报告）已完成，而2期研究的其他部分仍在进行中。

This trial is registered with ClinicalTrials.gov (NCT04880031).

该试验已在ClinicalTrials.gov注册（NCT04880031）。

Results

Between Aug 27, 2021, and July 22, 2022, 360 individuals were screened, of whom 102 were eligible and were randomly assigned to receive placebo (n=37) or efimosfermin 75 mg every 4 weeks (n=8), 75 mg every 2 weeks (n=14), 150 mg every 4 weeks (n=15), 150 mg every 2 weeks (n=15), or 300 mg every 4 weeks (n=13), for a total of 12 weeks. 45 (44%) of the 102 participants were female and 57 (56%) were male, with a mean age of 53 years (SD 11) and mean BMI of 36·5 kg/m2 (SD 4·1).

2021年8月27日至2022年7月22日期间，共筛查了360人，其中102人符合入选标准并被随机分配接受安慰剂（n=37）或efimosfermin 75 mg每4周一次（n=8），75 mg每2周一次（n=14），150 mg每4周一次（n=15），150 mg每2周一次（n=15），或300 mg每4周一次（n=13），总共12周。102名参与者中有45名（44%）为女性，57名（56%）为男性，平均年龄为53岁（标准差11），平均体重指数（BMI）为36.5 kg/m2（标准差4.1）。

Of 65 participants treated with efimosfermin, 43 (66%) had treatment-emergent adverse events (TEAEs): four (50%) of eight participants receiving 75 mg every 4 weeks, ten (71%) of 14 participants receiving 75 mg every 2 weeks, six (40%) of 15 participants receiving 150 mg every 4 weeks; 12 (80%) of 15 participants receiving 150 mg every 2 weeks, and 11 (85%) of 13 participants receiving 300 mg every 4 weeks; TEAEs were recorded in 18 (49%) of 37 participants receiving placebo.

在接受efimosfermin治疗的65名参与者中，有43名（66%）出现了治疗后不良事件（TEAEs）：接受75 mg每4周一次的8名参与者中有4名（50%），接受75 mg每2周一次的14名参与者中有10名（71%），接受150 mg每4周一次的15名参与者中有6名（40%），接受150 mg每2周一次的15名参与者中有12名（80%），接受300 mg每4周一次的13名参与者中有11名（85%）；接受安慰剂的37名参与者中有18名（49%）记录了TEAEs。

TEAEs were typically mild-to-moderate in severity and resolved spontaneously.

治疗相关不良事件（TEAEs）通常为轻度至中度，并且通常自行缓解。

The most frequent TEAEs were gastrointestinal in nature, reported by nine (24%) of 37 participants in the placebo group and 26 (40%) of 65 participants who received efimosfermin: two (25%) of eight participants receiving 75 mg every 4 weeks, eight (57%) of 14 participants receiving 75 mg every 2 weeks, two (13%) of 15 participants receiving 150 mg every 4 weeks, eight (53%) of 15 participants receiving 150 mg every 2 weeks, and six (46%) of 13 participants receiving 300 mg every 4 weeks.

最常见的TEAEs是胃肠道性质的，报告如下：安慰剂组37名参与者中有9名（24%），接受efimosfermin治疗的65名参与者中有26名（40%）出现此症状：每4周接受75毫克治疗的8名参与者中有2名（25%），每2周接受75毫克治疗的14名参与者中有8名（57%），每4周接受150毫克治疗的15名参与者中有2名（13%），每2周接受150毫克治疗的15名参与者中有8名（53%），以及每4周接受300毫克治疗的13名参与者中有6名（46%）。

The most common gastrointestinal events were nausea, vomiting, and diarrhoea.

最常见的胃肠道事件是恶心、呕吐和腹泻。

There were no treatment-related deaths.

没有治疗相关的死亡事件。

At week 12, 47 (89%) of 53 participants receiving efimosfermin for whom data were available had at least a 30% reduction in hepatic fat fraction: five (63%) of eight participants receiving 75 mg every 4 weeks, 11 (92%) of 12 participants receiving 75 mg every 2 weeks, nine (90%) of ten participants receiving 150 mg every 4 weeks, 11 (92%) of 12 participants receiving 150 mg every 2 weeks, and all 11 (100%) participants receiving 300 mg every 4 weeks, compared with two (7%) of 30 participants receiving placebo.

在第12周时，53名接受efimosfermin治疗且有可用数据的参与者中，有47名（89%）的肝脂肪分数至少减少了30%：每4周接受75毫克治疗的8名参与者中有5名（63%），每2周接受75毫克治疗的12名参与者中有11名（92%），每4周接受150毫克治疗的10名参与者中有9名（90%），每2周接受150毫克治疗的12名参与者中有11名（92%），以及每4周接受300毫克治疗的11名参与者全部（100%），相比之下，接受安慰剂的30名参与者中有2名（7%）出现了相同程度的减少。

interpretation

In participants with phenotypic MASH, efimosfermin had a favourable safety profile and showed improvements in indicators of hepatic steatosis.

在具有表型MASH的参与者中，efimosfermin具有良好的安全性，并显示出肝脂肪变性的指标改善。

These results help to inform future studies of efimosfermin in this important disease state.

这些结果有助于为未来在这一重要疾病状态中研究efimosfermin提供信息。

funding

Boston Pharmaceuticals.

波士顿制药公司。