Loomba Rohit, Kowdley Kris V, Rodriguez Jose, Kim Nomita J, Alvarez Alina Maria, Morrow Linda, Jeglinski Brenda, Clawson Alicia, Chowdhury Swapan, Bain Gerard, Odrljin Tatjana
MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, California, USA.
Liver Institute Northwest, Velocity Clinical Research, Seattle, WA, USA; Elson S Floyd College of Medicine, Washington State University, Spokane, WA, USA.
Lancet Gastroenterol Hepatol. 2025 Aug;10(8):734-745. doi: 10.1016/S2468-1253(25)00067-6. Epub 2025 Jun 6.
Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive disease characterised by steatosis, inflammation, and liver fibrosis. Efimosfermin alfa (efimosfermin, formerly BOS-580) is a long-acting, engineered variant of FGF21 designed to have a prolonged half-life. 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.
This multicentre, randomised, double-blind, placebo-controlled, phase 2a trial was conducted at 12 centres in the USA. Individuals with phenotypic MASH, aged 18-75 years and with a BMI of 30-45 kg/m, were eligible for the study. 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. 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. Within each cohort, participants were randomly assigned 4:1 to receive efimosfermin or placebo, via subcutaneous injection, in fixed blocks of size five. Investigators and participants were masked to group assignment and treatment allocation. 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. Part A (reported here) of this phase 2 study is complete, while other parts of the phase 2 study are ongoing. This trial is registered with ClinicalTrials.gov (NCT04880031).
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/m (SD 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. TEAEs were typically mild-to-moderate in severity and resolved spontaneously. 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. The most common gastrointestinal events were nausea, vomiting, and diarrhoea. There were no treatment-related deaths. 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.
In participants with phenotypic MASH, efimosfermin had a favourable safety profile and showed improvements in indicators of hepatic steatosis. These results help to inform future studies of efimosfermin in this important disease state.
Boston Pharmaceuticals.
代谢功能障碍相关脂肪性肝炎（MASH）是一种以脂肪变性、炎症和肝纤维化为特征的进行性疾病。阿法依莫司费明（依莫司费明，原称BOS - 580）是一种长效的、经过改造的成纤维细胞生长因子21（FGF21）变体，旨在具有延长的半衰期。我们旨在评估与安慰剂相比，多种依莫司费明剂量和给药方案的安全性和耐受性，并评估表型MASH参与者的探索性疗效生物标志物。
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。年龄在18 - 75岁、BMI为30 - 45 kg/m²的表型MASH个体符合研究条件。参与者使用无分层因素的集中交互式随机系统，被随机分配到五个给药队列之一：依莫司费明75 mg每4周一次、75 mg每2周一次、150 mg每4周一次、150 mg每2周一次或300 mg每4周一次，为期12周的治疗期。除依莫司费明150 mg每4周一次外，其他队列的参与者按1:1:1:1分配，依莫司费明150 mg每4周一次在其他队列分配完成后开始。在每个队列中，参与者以4:1的比例随机分配接受依莫司费明或安慰剂，通过皮下注射，以固定的每组5个的区组进行。研究者和参与者对分组和治疗分配均不知情。主要终点是安全性和耐受性，在整个12周治疗期以及全分析集中最后一剂后4周的随访访视时进行评估，全分析集定义为接受至少一剂研究药物的入组参与者。本2期研究的A部分（在此报告）已完成，而2期研究的其他部分正在进行。该试验已在ClinicalTrials.gov注册（NCT04880031）。
在2021年8月27日至2022年7月22日期间，筛查了360人，其中102人符合条件并被随机分配接受安慰剂（n = 37）或依莫司费明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），共12周。102名参与者中45名（44%）为女性，57名（56%）为男性，平均年龄53岁（标准差11），平均BMI为36.5 kg/m²（标准差4.1）。在接受依莫司费明治疗的65名参与者中，43名（66%）出现治疗中出现的不良事件（TEAE）：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TEAE。TEAE的严重程度通常为轻度至中度，并自发缓解。最常见的TEAE是胃肠道方面的，安慰剂组37名参与者中有9名（24%）报告，接受依莫司费明的65名参与者中有26名（40%）报告：接受75 mg每4周一次的8名参与者中有2名（25%），接受75 mg每2周一次的14名参与者中有8名（57%），接受150 mg每4周一次的15名参与者中有2名（13%），接受150 mg每2周一次的15名参与者中有8名（53%），接受300 mg每4周一次的13名参与者中有6名（46%）。最常见的胃肠道事件是恶心、呕吐和腹泻。没有与治疗相关的死亡。在第12周时，53名接受依莫司费明且有可用数据的参与者中有47名（89%）肝脂肪分数至少降低了30%：接受75 mg每4周一次的8名参与者中有5名（63%），接受75 mg每2周一次的12名参与者中有11名（92%），接受150 mg每4周一次的10名参与者中有9名（90%），接受150 mg每2周一次的12名参与者中有11名（92%），接受300 mg每4周一次的11名参与者全部（100%），而接受安慰剂的30名参与者中有2名（7%）。
在表型MASH参与者中，依莫司费明具有良好的安全性，并显示出肝脂肪变性指标有所改善。这些结果有助于为未来依莫司费明在这种重要疾病状态下的研究提供信息。
波士顿制药公司。
