美国洛杉矶雪松西奈山医疗中心Raymond S. Douglas课题组的一项最新研究发现Teprotumumab可治疗活动性甲状腺眼病。该项研究成果发表在2020年1月23日出版的《新英格兰医学杂志》上。

甲状腺眼病是一种使人虚弱、毁容和可能致盲的眼周疾病，目前食品和药物管理局尚无批准的药物可治疗。强有力的证据表明胰岛素样生长因子I受体（IGF-IR）与本病的发病有关。

研究组进行了一项随机、双盲、安慰剂对照、临床3期的多中心试验，招募患有活动性甲状腺眼病的患者，并按1：1将其分组，其中41名患者接受静脉注射胰岛素样生长因子-胰岛素抵抗抑制剂Teprotumumab，42名接受安慰剂治疗，每3周1次，持续21周。

第24周时，Teprotumumab组有83%的患者突眼程度减少超过2mm，显著高于安慰剂组（10%），即每1.36例患者中有1例缓解。Teprotumumab组的总体有效率为78%，显著高于安慰剂组（7%），临床活动评分0或1占59%，显著高于对照组（21%），突眼程度平均减少了2.82mm，显著大于对照组（0.54mm），复视缓解率为68%，显著高于安慰剂组（29%），GO-QOL的平均变化为13.79分，显著大于对照组（4.43分），差异均具有统计学意义。

在Teprotumumab组中接受眼眶影像学检查的6名患者中，眼外肌或眼眶脂肪体积减少。大多数不良事件均为轻中度，Teprotumumab组发生两起严重事件，其中一起导致治疗中止。

总之，Teprotumumab治疗活动性甲状腺眼病患者在突眼、临床活动评分、复视和生活质量方面的疗效均优于安慰剂，且严重不良事件较少。

附：英文原文

Title: Teprotumumab for the Treatment of Active Thyroid Eye Disease

Author: Raymond S. Douglas, M.D., Ph.D.,, George J. Kahaly, M.D., Ph.D.,, Amy Patel, M.D.,, Saba Sile, M.D.,, Elizabeth H.Z. Thompson, Ph.D.,, Renee Perdok, M.S.,, James C. Fleming, M.D.,, Brian T. Fowler, M.D.,, Claudio Marcocci, M.D.,, Michele Marinò, M.D.,, Alessandro Antonelli, M.D.,, Roger Dailey, M.D.,, Gerald J. Harris, M.D.,, Anja Eckstein, M.D.,, Jade Schiffman, M.D.,, Rosa Tang, M.D.,, Christine Nelson, M.D.,, Mario Salvi, M.D.,, Sara Wester, M.D.,, Jeffrey W. Sherman, M.D.,, Thomas Vescio, M.D.,, Robert J. Holt, Pharm.D.,, and Terry J. Smith, M.D.

Issue&Volume: 2020-01-22

Abstract:

Background
Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration–approved medical therapy is available. Strong evidence has implicated the insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of this disease.

Methods

In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, we assigned patients with active thyroid eye disease in a 1:1 ratio to receive intravenous infusions of the IGF-IR inhibitor teprotumumab (10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions) or placebo once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24. The primary outcome was a proptosis response (a reduction in proptosis of ≥2 mm) at week 24. Prespecified secondary outcomes at week 24 were an overall response (a reduction of ≥2 points in the Clinical Activity Score plus a reduction in proptosis of ≥2 mm), a Clinical Activity Score of 0 or 1 (indicating no or minimal inflammation), the mean change in proptosis across trial visits (from baseline through week 24), a diplopia response (a reduction in diplopia of ≥1 grade), and the mean change in overall score on the Graves’ ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire across trial visits (from baseline through week 24; a mean change of ≥6 points is considered clinically meaningful).

Results

A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group. At week 24, the percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001), with a number needed to treat of 1.36. All secondary outcomes were significantly better with teprotumumab than with placebo, including overall response (78% of patients [32] vs. 7% [3]), Clinical Activity Score of 0 or 1 (59% [24] vs. 21% [9]), the mean change in proptosis (?2.82 mm vs. ?0.54 mm), diplopia response (68% [19 of 28] vs. 29% [8 of 28]), and the mean change in GO-QOL overall score (13.79 points vs. 4.43 points) (P≤0.001 for all). Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging. Most adverse events were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation.

Conclusions

Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon.

DOI: 10.1056/NEJMoa1910434

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1910434