Radcliffe Department of MedicineUniversity of OxfordOxfordUnited Kingdom.
Department of MedicinePinnacle Clinical ResearchSan AntonioTXUSA.
Hepatol Commun. 2021 Jan 4;5(4):573-588. doi: 10.1002/hep4.1657. eCollection 2021 Apr.
Resmetirom (MGL-3196), a selective thyroid hormone receptor-β agonist, was evaluated in a 36-week paired liver biopsy study (NCT02912260) in adults with biopsy-confirmed nonalcoholic steatohepatitis (NASH). The primary endpoint was relative liver fat reduction as assessed by MRI-proton density fat fraction (MRI-PDFF), and secondary endpoints included histopathology. Subsequently, a 36-week active treatment open-label extension (OLE) study was conducted in 31 consenting patients (including 14 former placebo patients) with persistently mild to markedly elevated liver enzymes at the end of the main study. In patients treated with resmetirom (80 or 100 mg orally per day), MRI-PDFF reduction at OLE week 36 was -11.1% (1.5%) mean reduction (standard error [SE]; < 0.0001) and -52.3% (4.4%) mean relative reduction, < 0.0001. Low-density lipoprotein (LDL) cholesterol (-26.1% [4.5%], < 0.0001), apolipoprotein B (-23.8% [3.0%], < 0.0001), and triglycerides (-19.6% [5.4%], = 0.0012; -46.1 [14.5] mg/dL, = 0.0031) were reduced from baseline. Markers of fibrosis were reduced, including liver stiffness assessed by transient elastography (-2.1 [0.8] mean kilopascals [SE], = 0.015) and N-terminal type III collagen pro-peptide (PRO-C3) (-9.8 [2.3] ng/mL, = 0.0004 (baseline ≥ 10 ng/mL). In the main and OLE studies, PRO-C3/C3M (matrix metalloproteinase-degraded C3), a marker of net fibrosis formation, was reduced in resmetirom-treated patients (-0.76 [-1.27, -0.24], = 0.0044 and -0.68, < 0.0001, respectively). Resmetirom was well tolerated, with few, nonserious adverse events. The results of this 36-week OLE study support the efficacy and safety of resmetirom at daily doses of 80 mg and 100 mg, used in the ongoing phase 3 NASH study, MAESTRO-NASH (NCT03900429). The OLE study demonstrates a potential for noninvasive assessments to monitor the response to resmetirom from an individual patient with NASH.
在一项 36 周的配对肝活检研究（NCT02912260）中，评估了选择性甲状腺激素受体-β激动剂雷美替胺（MGL-3196）在经活检证实的非酒精性脂肪性肝炎（NASH）成人患者中的疗效。主要终点是通过 MRI 质子密度脂肪分数（MRI-PDFF）评估的相对肝脂肪减少，次要终点包括组织病理学。随后，在主要研究结束时持续存在轻度至显著升高的肝酶的 31 名同意参与的患者（包括 14 名前安慰剂患者）中进行了 36 周的活性治疗开放标签扩展（OLE）研究。在接受雷美替胺（每天口服 80 或 100mg）治疗的患者中，OLE 第 36 周时 MRI-PDFF 减少了-11.1%（平均减少[SE]；<0.0001）和-52.3%（平均相对减少，<0.0001）。低密度脂蛋白（LDL）胆固醇（-26.1%[4.5%]，<0.0001）、载脂蛋白 B（-23.8%[3.0%]，<0.0001）和甘油三酯（-19.6%[5.4%]，=0.0012；-46.1[14.5]mg/dL，=0.0031）从基线降低。纤维化标志物减少，包括通过瞬时弹性成像评估的肝硬度（-2.1[0.8]kPa[SE]，=0.015）和 N 端 III 型胶原前肽（PRO-C3）（-9.8[2.3]ng/mL，=0.0004（基线≥10ng/mL）。在主要和 OLE 研究中，雷美替胺治疗的患者中，网织纤维形成的标志物 PRO-C3/C3M（基质金属蛋白酶降解的 C3）减少（-0.76[-1.27，-0.24]，=0.0044 和-0.68，<0.0001，分别）。雷美替胺耐受性良好，不良事件较少且不严重。这项 36 周 OLE 研究支持雷美替胺在每日剂量 80mg 和 100mg 下的疗效和安全性，这些剂量正在进行的 III 期 NASH 研究 MAESTRO-NASH（NCT03900429）中使用。OLE 研究表明，非侵入性评估可能有助于监测每位 NASH 患者对雷美替胺的反应。
