Pinnacle Clinical Research, San Antonio, TX, USA.
Ruane Clinical Research, Los Angeles, CA, USA.
Nat Med. 2021 Jul;27(7):1262-1271. doi: 10.1038/s41591-021-01425-3. Epub 2021 Jul 8.
Preclinical and clinical data suggest that fibroblast growth factor 21 (FGF21) is anti-fibrotic, improves metabolic status and has potential to treat non-alcoholic steatohepatitis (NASH). We assessed the safety and efficacy of efruxifermin, a long-acting Fc-FGF21 fusion protein, for the treatment of NASH. BALANCED was a randomized, placebo-controlled study in patients with NASH conducted at 27 centers in the United States (ClinicalTrials.gov NCT03976401 ). Eighty patients, stratified by hepatic fat fraction (HFF) and fibrosis stage, were randomized using a centrally administered minimization algorithm 1:1:1:1 to receive placebo (n = 21) or efruxifermin 28 mg (n = 19), efruxifermin 50 mg (n = 20) or efruxifermin 70 mg (n = 20) via weekly subcutaneous injection for 16 weeks. The primary endpoint-absolute change from baseline in HFF measured as magnetic resonance imaging-proton density fat fraction at week 12-was met. For the full analysis set, the least squares mean absolute changes (one-sided 97.5% confidence interval) from baseline in HFF were -12.3% (-infinity (-inf), -10.3), -13.4% (-inf, -11.4) and -14.1% (-inf, -12.1) in the 28-, 50- and 70-mg groups, respectively, versus 0.3% (-inf, 1.6) in the placebo group, with statistically significant differences between efruxifermin groups and placebo (P < 0.0001 each). Overall, 70 of 79 patients who received the study drug (89%) experienced at least one treatment-emergent adverse event (TEAE), with the majority grade 1-2 (64 (81%)), five (6%) grade 3 and one grade 4. The most commonly reported drug-related TEAEs were grade 1-2 gastrointestinal (36 (46%)). Treatment with efruxifermin significantly reduced HFF in patients with F1-F3 stage NASH, with an acceptable safety profile.
临床前和临床数据表明，成纤维细胞生长因子 21（FGF21）具有抗纤维化、改善代谢状态的作用，并有可能治疗非酒精性脂肪性肝炎（NASH）。我们评估了长效 Fc-FGF21 融合蛋白 efruxifermin 治疗 NASH 的安全性和疗效。BALANCED 是一项在美国 27 个中心进行的随机、安慰剂对照的 NASH 患者研究（ClinicalTrials.gov NCT03976401）。根据肝脂肪分数（HFF）和纤维化分期，80 名患者采用中央管理的最小化算法按 1:1:1:1 比例随机分为安慰剂组（n=21）或 efruxifermin 28mg 组（n=19）、efruxifermin 50mg 组（n=20）和 efruxifermin 70mg 组（n=20），每周皮下注射 16 周。主要终点-第 12 周时磁共振成像质子密度脂肪分数（HFF）的绝对变化-达到了。在全分析集（FAS）中，HFF 的最小二乘均数绝对变化（单侧 97.5%置信区间）分别为-12.3%（-无限大（inf），-10.3%）、-13.4%（-inf，-11.4%）和-14.1%（-inf，-12.1%），安慰剂组为 0.3%（-inf，1.6%），efruxifermin 组与安慰剂组相比，差异有统计学意义（P<0.0001）。总的来说，79 名接受研究药物的患者中有 70 名（89%）发生了至少一次治疗后出现的不良事件（TEAE），大多数为 1-2 级（64[81%]），5 例（6%）为 3 级，1 例为 4 级。最常见的药物相关 TEAEs 为 1-2 级胃肠道不良事件（36[46%]）。在 F1-F3 期 NASH 患者中，efruxifermin 治疗可显著降低 HFF，安全性可接受。
