Efficacy and safety of zalfermin co-administered with semaglutide in participants with fibrosis and cirrhosis due to metabolic dysfunction-associated steatohepatitis: a phase 2, dose-ranging, double-blind, randomised controlled trial.

Methods

This proof-of-concept, phase 2, dose-ranging, double-blind, randomised controlled trialwas done in 187 clinical trial sites in Australia, Belgium, Bulgaria, Canada, Czech Republic, Denmark, France, Germany, Greece, India, Italy, Japan, Malaysia, Poland, Portugal, Russia, Singapore, South Korea, Spain, Taiwan, Türkiye, and the USA.

这项概念验证的II期剂量范围试验，是一项双盲随机对照试验，在澳大利亚、比利时、保加利亚、加拿大、捷克共和国、丹麦、法国、德国、希腊、印度、意大利、日本、马来西亚、波兰、葡萄牙、俄罗斯、新加坡、韩国、西班牙、台湾、土耳其和美国的187个临床试验地点进行。

Eligible participants were aged 18 years or older with histological confirmation of steatohepatitis on liver biopsy (baseline or historical within 180 days).

符合条件的参与者年龄在18岁或以上，并且在肝活检（基线或180天内的历史记录）上对脂肪性肝炎有组织学确认。

Eligible participants had clinically significant fibrosis (stage F2-F4c) in the absence of decompensation.

符合条件的参与者在没有失代偿的情况下，有临床显著的纤维化（F2-F4c期）。

Eligible participants were randomly assigned to receive subcutaneous zalfermin 7·5 mg plus subcutaneous semaglutide 2·4 mg, zalfermin 15 mg plus semaglutide 2·4 mg, zalfermin 30 mg plus semaglutide 2·4 mg, zalfermin 30 mg, semaglutide 2·4 mg, cagrilintide 2·4 mg plus semaglutide 2·4 mg, or placebo only once a week for 52 weeks.

符合条件的参与者被随机分配每周一次接受皮下注射 zalfermin 7.5 mg 加上皮下注射 semaglutide 2.4 mg、zalfermin 15 mg 加上 semaglutide 2.4 mg、zalfermin 30 mg 加上 semaglutide 2.4 mg、单独的 zalfermin 30 mg、单独的 semaglutide 2.4 mg、cagrilintide 2.4 mg 加上 semaglutide 2.4 mg 或仅安慰剂，持续 52 周。

The primary endpoint was improvement in liver fibrosis on the NASH CRN fibrosis scale of at least one stage and no worsening of metabolic dysfunction-associated steatohepatitis at week 52.

主要终点是至少改善一个阶段的肝纤维化，根据 NASH CRN 纤维化评分，并且在第 52 周时没有代谢功能障碍相关脂肪性肝炎的恶化。

Efficacy was assessed in the full analysis set (all randomly assigned participants) and safety was analysed in all participants who were randomly assigned and received at least one dose of trial product or placebo.

疗效评估是在全分析集（所有随机分配的参与者）中进行的，安全性分析是在所有随机分配并至少接受一次试验产品或安慰剂的参与者中进行的。

The trial is registered with ClinicalTrials.gov, NCT05016882, and is completed.

该试验已在ClinicalTrials.gov上注册，注册号为NCT05016882，并已完成。

Results

Between Aug 31, 2021, and March 14, 2025, 2420 people were screened for inclusion. 178 withdrew before random assignment and 1544 were disqualified. 698 participants were enrolled and randomly assigned to zalfermin 7·5 mg plus semaglutide 2·4 mg (n=99), zalfermin 15 mg plus semaglutide 2·4 mg (n=100), zalfermin 30 mg plus semaglutide 2·4 mg (n=99), zalfermin 30 mg (n=101), semaglutide 2·4 mg (n=100), cagrilintide 2·4 mg plus semaglutide 2·4 mg (n=99), or placebo (n=100). 441 (63%) of 698 participants were female and 257 (37%) were male. 484 (69%) of 698 participants were White and 172 (25%) were Asian.

在2021年8月31日至2025年3月14日期间，共有2420人被纳入筛查。在随机分组前，有178人退出，1544人不符合纳入标准。698名参与者被随机分配到zalfermin 7.5 mg加semaglutide 2.4 mg组（n=99），zalfermin 15 mg加semaglutide 2.4 mg组（n=100），zalfermin 30 mg加semaglutide 2.4 mg组（n=99），zalfermin 30 mg组（n=101），semaglutide 2.4 mg组（n=100），cagrilintide 2.4 mg加semaglutide 2.4 mg组（n=99）或安慰剂组（n=100）。698名参与者中，441名（63%）为女性，257名（37%）为男性。698名参与者中，484名（69%）为白人，172名（25%）为亚洲人。

At week 52, the proportion of participants who had an improvement in liver fibrosis and no worsening of metabolic dysfunction-associated steatohepatitis with zalfermin 30 mg plus semaglutide 2·4 mg was not significantly greater than with placebo (24 [24%] of 99 participants in the combination group vs 16 [16%] of 100 participants in the placebo group; estimated difference in responder proportions [EDP] 7·98, 95% CI -3·82 to 19·79; p=0·19).

在第52周时，接受zalfermin 30 mg加semaglutide 2.4 mg治疗的参与者中，有改善肝纤维化且代谢功能障碍相关脂肪性肝炎未恶化的人数比例，并没有显著高于安慰剂组（联合治疗组99名参与者中有24名[24%]，安慰剂组100名参与者中有16名[16%]；反应者比例估计差异[EDP]为7.98，95%置信区间为-3.82至19.79；p=0.19）。

A nominally significantly greater proportion of participants in the semaglutide 2·4 mg group achieved this endpoint than in the placebo group (30 [30%] of 100 participants in the semaglutide group; EDP 14·05, 95% CI 1·88 to 26·23; p=0·024), but not in the zalfermin 30 mg group versus placebo (22 [22%] of 101 participants in the zalfermin group; 4·99, -6·51 to 16·49; p=0·39).

在使用2·4 mg的semaglutide组中，达到这一终点的参与者比例显著高于安慰剂组（semaglutide组100名参与者中有30名[30%]；EDP 14·05，95%置信区间1·88至26·23；p=0·024），而在使用30 mg的zalfermin组与安慰剂组之间则没有显著差异（zalfermin组101名参与者中有22名[22%]；4·99，-6·51至16·49；p=0·39）。

Similarly, the proportions of participants achieving this endpoint in the two groups that combined lower doses of zalfermin with semaglutide 2·4 mg and in the exploratory group combining cagrilintide 2·4 mg with semaglutide 2·4 mg were not substantially different than with placebo.

同样地，将较低剂量的zalfermin与2·4 mg的semaglutide结合使用的两组，以及将cagrilintide 2·4 mg与2·4 mg的semaglutide结合使用的探索性组，达到这一终点的参与者比例与安慰剂组相比并没有显著差异。

Adverse events were mostly non-serious and mild to moderate in severity.

不良事件大多为非严重性，轻度至中度严重。

The most frequent adverse events were gastrointestinal, reported in 79 (80%) of 99 participants in the zalfermin 30 mg plus semaglutide 2·4 mg group, 61 (60%) of 101 participants in the zalfermin 30 mg group, 73 (73%) of 100 participants in the semaglutide 2·4 mg group, and 51 (51%) of 100 participants in the placebo group.

最常见的不良事件是胃肠道事件，报告在 zalfermin 30 mg 加 semaglutide 2·4 mg 组的 99 名参与者中有 79 名（80%），zalfermin 30 mg 组的 101 名参与者中有 61 名（60%），semaglutide 2·4 mg 组的 100 名参与者中有 73 名（73%），以及安慰剂组的 100 名参与者中有 51 名（51%）。

Serious adverse events were reported in seven (7%) participants in the zalfermin 30 mg plus semaglutide 2·4 mg group, 13 (13%) participants in the zalfermin 30 mg group, ten (10%) participants in the semaglutide 2·4 mg group, and five (5%) participants in the placebo group.

在 zalfermin 30 mg 加 semaglutide 2·4 mg 组中有7名（7%）参与者报告了严重不良事件，在 zalfermin 30 mg 组中有13名（13%）参与者，在 semaglutide 2·4 mg 组中有10名（10%）参与者，在安慰剂组中有5名（5%）参与者。

Five deaths were reported in the trial, one of which was assessed as possibly related to study drug (heart failure, zalfermin 30 mg group).

试验中报告了五例死亡，其中一例被评估为可能与研究药物有关（心力衰竭，zalfermin 30 mg 组）。

interpretation

In participants with metabolic dysfunction-associated steatohepatitis and clinically significant fibrosis, the combination of zalfermin 30 mg plus semaglutide 2·4 mg did not significantly increase the proportion of participants who had an improvement in liver fibrosis and no worsening of metabolic dysfunction-associated steatohepatitis compared with placebo by week 52.

在患有代谢功能障碍相关脂肪性肝炎和临床显著纤维化的参与者中，30毫克的zalfermin加上2·4毫克的semaglutide的联合治疗，并没有显著增加在第52周时与安慰剂相比，参与者肝纤维化改善且代谢功能障碍相关脂肪性肝炎未加重的比例。

However, a nominally significant treatment effect was observed for semaglutide 2·4 mg versus placebo.

然而，与安慰剂相比，2·4毫克的semaglutide显示出名义上的显著治疗效果。

Semaglutide might be considered for further clinical assessment as a potential disease-modifying therapy in the F4c population.

Semaglutide 可能会被考虑进一步进行临床评估，作为 F4c 人群中的潜在疾病修饰性治疗。

funding

Novo Nordisk.

诺和诺德。