Department of Ophthalmology, University of California, San Francisco, San Francisco, California; Ophthalmology Section, Surgical Service, San Francisco Veterans Affairs Medical Center, San Francisco, California.
Department of Ophthalmology, University of California, San Francisco, San Francisco, California.
Ophthalmology. 2021 Nov;128(11):1627-1651. doi: 10.1016/j.ophtha.2021.04.024. Epub 2021 Apr 28.
Teprotumumab, a monoclonal antibody targeted against the insulin-like growth factor 1 (IGF-1) receptor, was recently approved by the United States Food and Drug Administration for the treatment of thyroid eye disease (TED). Phase 1 studies of teprotumumab for the treatment of malignancies demonstrated an acceptable safety profile but limited effectiveness. Basic research implicating the IGF-1 receptor on the CD-34+ orbital fibrocyte in the pathogenesis of TED renewed interest in the drug. Two multicenter, randomized, double-masked, clinical trials (phase 2 and 3) evaluated the efficacy of 8 infusions of teprotumumab every 3 weeks versus placebo in 170 patients with recent-onset active TED, as defined by a clinical activity score (CAS) of at least 4. Teprotumumab was superior to placebo for the primary efficacy end points in both studies: overall responder rate as defined by a reduction of 2 or more CAS points and a reduction of 2 mm or more in proptosis (69% vs. 20%; P < 0.001; phase 2 study) and proptosis responder rate as defined by a reduction of 2 mm or more in proptosis (83% vs. 10%; P < 0.001; phase 3 study). In both studies, treatment with teprotumumab compared with placebo achieved a significant mean reduction of proptosis (-3.0 mm vs. -0.3 mm, phase 2 study; -3.32 mm vs. -0.53 mm, phase 3 study) and CAS (-4.0 vs. -2.5, phase 2 study; -3.7 vs. -2.0, phase 3 study). Teprotumumab also resulted in a greater proportion of patients with a final CAS of 0 or 1, higher diplopia responder rate, and a larger improvement in the Graves' Ophthalmopathy Quality of Life overall score. More than half of patients (62%, phase 2 trial; 56%, phase 3 trial) who were primary end point responders maintained this response at 51 weeks after the last dose of therapy. The most common adverse events reported with teprotumumab included muscle spasms (25%), nausea (17%), alopecia (13%), diarrhea (13%), fatigue (10%), hearing impairment (10%), and hyperglycemia (8%). Teprotumumab is contraindicated for those with inflammatory bowel disease and who are pregnant. Although the current dosing regimen has proven effective for TED, dose-ranging studies including variable concentrations, infusion frequencies, and durations of teprotumumab therapy in the setting of TED have not been performed.
特罗替普单抗是一种针对胰岛素样生长因子 1（IGF-1）受体的单克隆抗体，最近被美国食品和药物管理局批准用于治疗甲状腺眼病（TED）。特罗替普单抗治疗恶性肿瘤的 1 期研究显示出可接受的安全性，但疗效有限。基础研究表明，TED 发病机制中的 IGF-1 受体位于 CD-34+眼眶成纤维细胞上，这重新引起了人们对该药物的兴趣。两项多中心、随机、双盲、临床试验（2 期和 3 期）评估了每 3 周 8 次输注特罗替普单抗与安慰剂在 170 例新近发病的活动性 TED 患者中的疗效，活动性 TED 定义为临床活动评分（CAS）至少为 4。特罗替普单抗在两项研究中的主要疗效终点均优于安慰剂：定义为 CAS 降低 2 个或更多点和眼球突出度降低 2 毫米或更多的总应答率（69%比 20%；P<0.001；2 期研究）和定义为眼球突出度降低 2 毫米或更多的眼球突出度应答率（83%比 10%；P<0.001；3 期研究）。在这两项研究中，与安慰剂相比，特罗替普单抗治疗可显著降低眼球突出度（-3.0 毫米比-0.3 毫米，2 期研究；-3.32 毫米比-0.53 毫米，3 期研究）和 CAS（-4.0 比-2.5，2 期研究；-3.7 比-2.0，3 期研究）。特罗替普单抗还导致更多患者最终 CAS 为 0 或 1，复视应答率更高，Graves 眼病生活质量总体评分改善更大。超过一半（62%，2 期试验；56%，3 期试验）的主要终点应答患者在治疗最后一剂后 51 周时仍保持此应答。特罗替普单抗最常见的不良反应包括肌肉痉挛（25%）、恶心（17%）、脱发（13%）、腹泻（13%）、疲劳（10%）、听力障碍（10%）和高血糖（8%）。特罗替普单抗禁用于炎症性肠病患者和孕妇。尽管目前的剂量方案已被证明对 TED 有效，但尚未在 TED 环境中进行包括特罗替普单抗不同浓度、输注频率和持续时间的剂量范围研究。
