From the University of North Carolina, Chapel Hill (E.S.D.); the University of Utah, Salt Lake City (K.A.P.); Mayo Clinic Rochester, Rochester, MN (J.A.M., A.C.B.); the University of Pennsylvania Perelman School of Medicine, Philadelphia (G.W.F.); Northwestern University, Chicago (N.G., I.H.); the Icahn School of Medicine at Mount Sinai, New York (M.C.); Baylor College of Medicine, Houston (R.M.G.); Tufts University, Boston (J.L.); the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (P.K., A.D.K.); Ventura Clinical Trials, Ventura (S.H.), and Allakos, Redwood City (C.S., A.T.C., B.S., A.P.K., H.S.R.) - both in California; Vanderbilt University, Nashville (M.V.); the Division of Allergy and Immunology, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati (S.R.D., M.E.R.); and Pharma Data Associates, Piscataway, NJ (C.W.).
N Engl J Med. 2020 Oct 22;383(17):1624-1634. doi: 10.1056/NEJMoa2012047.
BACKGROUND: Eosinophilic gastritis and duodenitis are characterized by gastrointestinal mucosal eosinophilia, chronic symptoms, impaired quality of life, and a lack of adequate treatments. Mast-cell activity may contribute to the pathogenesis of the conditions. AK002 (lirentelimab) is an anti-Siglec-8 antibody that depletes eosinophils and inhibits mast cells and that has shown potential in animal models as a treatment for eosinophilic gastritis and duodenitis. METHODS: In this phase 2 trial, we randomly assigned adults who had symptomatic eosinophilic gastritis, eosinophilic duodenitis, or both conditions in a 1:1:1 ratio to receive four monthly infusions of low-dose AK002, high-dose AK002, or placebo. The primary end point was the change in gastrointestinal eosinophil count from baseline to 2 weeks after the final dose; to maximize statistical power, we evaluated this end point in the placebo group as compared with the combined AK002 group. Secondary end points were treatment response (>30% reduction in total symptom score and >75% reduction in gastrointestinal eosinophil count) and the change in total symptom score. RESULTS: Of the 65 patients who underwent randomization, 43 were assigned to receive AK002 and 22 were assigned to receive placebo. The mean percentage change in gastrointestinal eosinophil count was -86% in the combined AK002 group, as compared with 9% in the placebo group (least-squares mean difference, -98 percentage points; 95% confidence interval [CI], -121 to -76; P<0.001). Treatment response occurred in 63% of the patients who received AK002 and in 5% of the patients who received placebo (difference, 58 percentage points; 95% CI, 36 to 74; P<0.001). The mean change in total symptom score was -48% with AK002 and -22% with placebo (least-squares mean difference, -26 percentage points; 95% CI, -44 to -9; P = 0.004). Adverse events associated with AK002 were similar to those with placebo, with the exception of higher percentages of patients having mild-to-moderate infusion-related reactions with AK002 (60% in the combined AK002 group and 23% in the placebo group). CONCLUSIONS: In patients with eosinophilic gastritis or duodenitis, AK002 reduced gastrointestinal eosinophils and symptoms. Infusion-related reactions were more common with AK002 than with placebo. (Funded by Allakos; ENIGMA ClinicalTrials.gov number, NCT03496571.).
背景：嗜酸性粒细胞性胃炎和十二指肠炎的特征为胃肠道黏膜嗜酸性粒细胞增多、慢性症状、生活质量受损，且缺乏有效治疗方法。肥大细胞活性可能与这些疾病的发病机制有关。AK002（利仑赛利单抗）是一种抗 Siglec-8 抗体，可消耗嗜酸性粒细胞并抑制肥大细胞，在动物模型中已显示出作为治疗嗜酸性粒细胞性胃炎和十二指肠炎的潜力。
方法：在这项 2 期临床试验中，我们按 1:1:1 的比例随机分配有症状的嗜酸性粒细胞性胃炎、嗜酸性粒细胞性十二指肠炎或两者并存的成年患者，分别接受 4 次每月的低剂量 AK002、高剂量 AK002 或安慰剂治疗。主要终点为末次剂量后 2 周时胃肠道嗜酸性粒细胞计数相对于基线的变化；为了最大限度地提高统计学效能，我们将安慰剂组相对于联合 AK002 组评估该终点。次要终点为治疗应答（总症状评分降低≥30%且胃肠道嗜酸性粒细胞计数降低≥75%）和总症状评分的变化。
结果：在接受随机分组的 65 例患者中，43 例被分配接受 AK002 治疗，22 例被分配接受安慰剂治疗。联合 AK002 组胃肠道嗜酸性粒细胞计数的平均百分比变化为-86%，而安慰剂组为 9%（最小二乘均数差值，-98 个百分点；95%置信区间 [CI]，-121 至 -76；P<0.001）。接受 AK002 治疗的患者中有 63%出现治疗应答，而接受安慰剂治疗的患者中仅有 5%出现治疗应答（差异，58 个百分点；95%CI，36 至 74；P<0.001）。接受 AK002 治疗的患者总症状评分的平均变化为-48%，而接受安慰剂治疗的患者为-22%（最小二乘均数差值，-26 个百分点；95%CI，-44 至 -9；P=0.004）。与安慰剂相比，AK002 相关的不良事件相似，只是 AK002 组出现更多的轻度至中度输注相关反应（联合 AK002 组为 60%，安慰剂组为 23%）。
结论：在嗜酸性粒细胞性胃炎或十二指肠炎患者中，AK002 降低了胃肠道嗜酸性粒细胞计数和症状。与安慰剂相比，AK002 组更常见轻度至中度输注相关反应。（由 Allakos 公司资助；ENIGMA 临床试验.gov 编号，NCT03496571。）
N Engl J Med. 2020-10-22
N Engl J Med. 2024-6-27
N Engl J Med. 2024-6-27
N Engl J Med. 2023-7-20
Lancet Gastroenterol Hepatol. 2025-7
Cochrane Database Syst Rev. 2021-4-19
Gastroenterol Hepatol (N Y). 2025-8
Front Allergy. 2025-8-8
Clin Rev Allergy Immunol. 2025-6-20
J Immunother Cancer. 2025-6-18
Int J Mol Sci. 2025-1-23
Hum Gene Ther. 2024-1
Clin Gastroenterol Hepatol. 2021-10
J Allergy Clin Immunol Pract. 2020-6
Clin Rev Allergy Immunol. 2019-10
Ann Allergy Asthma Immunol. 2018-6-22
Clin Res Hepatol Gastroenterol. 2018-3-31
Zotero 插件