随机、对照试验：成纤维细胞生长因子 21 类似物 Pegozafermin 在 NASH 中的应用。
Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH.
机构信息
From the NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, La Jolla (R.L.), Velocity Clinical Research, Los Angeles (J.P.F.), and 89bio, San Francisco (M.D.G., S.F., G.D.A., C.L.H., H.M.); the Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond (A.J.S.); Liver Institute Northwest, Seattle (K.V.K.); Mount Sinai Heart, Icahn School of Medicine at Mount Sinai Health System, New York (D.L.B.); Arizona Liver Health, Chandler (N.A.); Liverpat, Paris (P.B.); Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom (S.A.H.); Pinnacle Clinical Research, San Antonio, TX (S.A.H.); ObjectiveHealth-Digestive Health Research, Nashville (D.L.); Ocala GI Research, Ocala, FL (R.B.); 89bio, Rehovot, Israel (M.M.); and the Division of Hepatobiliary Disease, Mayo Clinic, Rochester, MN (M.F.A.).
出版信息
N Engl J Med. 2023 Sep 14;389(11):998-1008. doi: 10.1056/NEJMoa2304286. Epub 2023 Jun 24.
BACKGROUND
Pegozafermin is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) fibroblast growth factor 21 (FGF21) analogue in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. The efficacy and safety of pegozafermin in patients with biopsy-proven noncirrhotic NASH are not well established.
METHODS
In this phase 2b, multicenter, double-blind, 24-week, randomized, placebo-controlled trial, we randomly assigned patients with biopsy-confirmed NASH and stage F2 or F3 (moderate or severe) fibrosis to receive subcutaneous pegozafermin at a dose of 15 mg or 30 mg weekly or 44 mg once every 2 weeks or placebo weekly or every 2 weeks. The two primary end points were an improvement in fibrosis (defined as reduction by ≥1 stage, on a scale from 0 to 4, with higher stages indicating greater severity), with no worsening of NASH, at 24 weeks and NASH resolution without worsening of fibrosis at 24 weeks. Safety was also assessed.
RESULTS
Among the 222 patients who underwent randomization, 219 received pegozafermin or placebo. The percentage of patients who met the criteria for fibrosis improvement was 7% in the pooled placebo group, 22% in the 15-mg pegozafermin group (difference vs. placebo, 14 percentage points; 95% confidence interval [CI], -9 to 38), 26% in the 30-mg pegozafermin group (difference, 19 percentage points; 95% CI, 5 to 32; P = 0.009), and 27% in the 44-mg pegozafermin group (difference, 20 percentage points; 95% CI, 5 to 35; P = 0.008). The percentage of patients who met the criteria for NASH resolution was 2% in the placebo group, 37% in the 15-mg pegozafermin group (difference vs. placebo, 35 percentage points; 95% CI, 10 to 59), 23% in the 30-mg pegozafermin group (difference, 21 percentage points; 95% CI, 9 to 33), and 26% in the 44-mg pegozafermin group (difference, 24 percentage points; 95% CI, 10 to 37). The most common adverse events associated with pegozafermin therapy were nausea and diarrhea.
CONCLUSIONS
In this phase 2b trial, treatment with pegozafermin led to improvements in fibrosis. These results support the advancement of pegozafermin into phase 3 development. (Funded by 89bio; ENLIVEN ClinicalTrials.gov number, NCT04929483.).
背景
Pegozafermin 是一种长效糖基化（使用特定的糖基转移酶进行糖基化）成纤维细胞生长因子 21（FGF21）类似物，正在开发用于治疗非酒精性脂肪性肝炎（NASH）和严重高甘油三酯血症。在未经活检证实的非肝硬化 NASH 患者中，pegofamerin 的疗效和安全性尚未得到充分证实。
方法
在这项 2b 期、多中心、双盲、24 周、随机、安慰剂对照试验中，我们将经活检证实患有 NASH 和 F2 或 F3（中或重度）纤维化的患者随机分为皮下注射 15mg 或 30mg 每周一次、44mg 每两周一次或安慰剂每周一次或每两周一次。两个主要终点是在 24 周时纤维化改善（定义为降低≥1 期，评分范围为 0 至 4，分数越高表示严重程度越高），同时 NASH 无恶化，以及在 24 周时 NASH 缓解且纤维化无恶化。还评估了安全性。
结果
在 222 名接受随机分组的患者中，219 名患者接受了 pegozafermin 或安慰剂治疗。在安慰剂组中，有 7%的患者符合纤维化改善标准，在 15mg pegofamerin 组中为 22%（与安慰剂相比，差异为 14 个百分点；95%置信区间[CI]，-9 至 38），在 30mg pegofamerin 组中为 26%（差异为 19 个百分点；95%CI，5 至 32；P=0.009），在 44mg pegofamerin 组中为 27%（差异为 20 个百分点；95%CI，5 至 35；P=0.008）。在安慰剂组中，有 2%的患者符合 NASH 缓解标准，在 15mg pegofamerin 组中为 37%（与安慰剂相比，差异为 35 个百分点；95%CI，10 至 59），在 30mg pegofamerin 组中为 23%（差异为 21 个百分点；95%CI，9 至 33），在 44mg pegofamerin 组中为 26%（差异为 24 个百分点；95%CI，10 至 37）。与 pegofamerin 治疗相关的最常见不良事件是恶心和腹泻。
结论
在这项 2b 期试验中，pegofamerin 治疗可改善纤维化。这些结果支持将 pegofamerin 推进到 3 期开发。（由 89bio 资助；ENLIVEN 临床试验.gov 编号，NCT04929483。）
Zotero 插件