Abstract：
Indolent systemic mastocytosis (ISM) is characterized by excessive mast cell (MC) accumulation and MC-driven signs and symptoms. Currently used therapies are not approved and have limited efficacy. Lirentelimab (AK002) is a monoclonal antibody against sialic acid-binding immunoglobulin-like lectin (Siglec)-8 that inhibits MC activation.
To determine the safety, tolerability and efficacy of lirentelimab in reducing the symptoms of ISM.
At a specialty centre for mastocytosis in Germany, we conducted a phase I first-in-human single-ascending and multidose clinical trial of lirentelimab in patients with ISM. Eligible adults had World Health Organization-confirmed ISM and an unsatisfactory response to available treatment. In part A, patients received a single dose of lirentelimab 0.0003, 0.001, 0.003, 0.01 or 0.03 mg kg-1; in part B, patients received one lirentelimab dose of 0.3 mg kg-1 or 1.0 mg kg-1; and in part C, patients received either 1.0 mg kg-1 lirentelimab every 4 weeks for 6 months or ascending doses of lirentelimab (one dose of 1 mg kg-1 followed by five doses of 3-10 mg kg-1 every 4 weeks). The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in Mastocytosis Symptom Questionnaire (MSQ), Mastocytosis Activity Score (MAS) and Mastocytosis Quality of Life Questionnaire (MC-QoL) scores at 2 weeks after the final dose.
In 25 patients with ISM (13 in parts A + B and 12 in part C; median age 51 years, 76% female, median 4.6 years from diagnosis), the most common treatment-related adverse events (AEs) were feeling hot (76%) and experiencing a headache (48%). No serious AEs occurred. Median MSQ and MAS symptom severity scores in part C improved (vs. baseline) across all symptoms [MSQ: skin (38-56%), gastrointestinal (49-60%), neurological (47-59%), musculoskeletal (26-27%); MAS: skin (53-59%), gastrointestinal (72-85%), neurological (20-57%), musculoskeletal (25%)]. Median MC-QoL scores improved across all domains: symptoms (39%), social life/functioning (42%), emotions (57%) and skin (44%).
Lirentelimab was generally well tolerated and improved symptoms and quality of life in patients with ISM. The therapeutic potential of lirentelimab should be considered for ISM.
To determine the safety, tolerability and efficacy of lirentelimab in reducing the symptoms of ISM.
At a specialty centre for mastocytosis in Germany, we conducted a phase I first-in-human single-ascending and multidose clinical trial of lirentelimab in patients with ISM. Eligible adults had World Health Organization-confirmed ISM and an unsatisfactory response to available treatment. In part A, patients received a single dose of lirentelimab 0.0003, 0.001, 0.003, 0.01 or 0.03 mg kg-1; in part B, patients received one lirentelimab dose of 0.3 mg kg-1 or 1.0 mg kg-1; and in part C, patients received either 1.0 mg kg-1 lirentelimab every 4 weeks for 6 months or ascending doses of lirentelimab (one dose of 1 mg kg-1 followed by five doses of 3-10 mg kg-1 every 4 weeks). The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in Mastocytosis Symptom Questionnaire (MSQ), Mastocytosis Activity Score (MAS) and Mastocytosis Quality of Life Questionnaire (MC-QoL) scores at 2 weeks after the final dose.
In 25 patients with ISM (13 in parts A + B and 12 in part C; median age 51 years, 76% female, median 4.6 years from diagnosis), the most common treatment-related adverse events (AEs) were feeling hot (76%) and experiencing a headache (48%). No serious AEs occurred. Median MSQ and MAS symptom severity scores in part C improved (vs. baseline) across all symptoms [MSQ: skin (38-56%), gastrointestinal (49-60%), neurological (47-59%), musculoskeletal (26-27%); MAS: skin (53-59%), gastrointestinal (72-85%), neurological (20-57%), musculoskeletal (25%)]. Median MC-QoL scores improved across all domains: symptoms (39%), social life/functioning (42%), emotions (57%) and skin (44%).
Lirentelimab was generally well tolerated and improved symptoms and quality of life in patients with ISM. The therapeutic potential of lirentelimab should be considered for ISM.
摘要：
背景：惰性系统性肥大细胞增多症（ISM）的特征是肥大细胞过度积聚和肥大细胞驱动的体征和症状。目前使用的疗法没有被批准并且具有有限的功效。Lirentelimab(AK002)是一种抗唾液酸结合免疫球蛋白样凝集素(Siglec)-8的单克隆抗体,其抑制肥大细胞活化。
目的：为了确定安全性，耐受性,以及lirentelimab在减轻ISM症状方面的功效。
方法：在德国的肥大细胞增多症专业中心，我们进行了第一阶段，人类第一，在ISM患者中使用lirentelimab的单次递增剂量和多剂量临床试验。符合条件的成年人患有WHO确认的ISM，对现有治疗的反应不令人满意。在A部分,患者接受单剂量的lirentelimab0.0003、0.001、0.003、0.01或0.03mg/kg；在B部分，患者接受了1次剂量为0.3mg/kg或1.0mg/kg的lirentelimab；在C部分，患者每4周接受1.0mg/kglirentelimab,共6个月或递增剂量的lirentelimab(1次1mg/kg剂量,然后每4周接受5次3~10mg/kg剂量).主要终点是安全性/耐受性。次要终点包括肥大细胞增多症症状问卷（MSQ）的基线变化，肥大细胞增多活动评分（MAS），最终剂量后2周的肥大细胞增多症生活质量问卷（MC-QoL）评分。
结果：共有25例ISM患者（n=13部分AB，n=12C部分；中位年龄51岁，76%为女性,自诊断起的中位数为4.6年)，最常见的治疗相关不良事件是发热(76%)和头痛(48%).无严重不良事件发生。C部分所有症状的平均MSQ和MAS症状严重程度评分均得到改善(MSQ:皮肤[与基线相比改善38%-56%],胃肠[49%-60%]，神经[47%-59%]，肌肉骨骼[26%-27%]；MAS：皮肤[53%-59%]，胃肠道[72%-85%]，神经[20%-57%]，肌肉骨骼[25%])。所有领域的MC-QoL得分中位数均有所改善：症状（39%），社交生活/功能（42%），情绪(57%)，皮肤（44%）。
结论：在ISM患者中，Lirentelimab的耐受性良好，症状和生活质量得到改善。对于ISM，应考虑lirentelimab的治疗潜力。
背景：ClinicalTrials.gov编号，NCT02808793。
目的：为了确定安全性，耐受性,以及lirentelimab在减轻ISM症状方面的功效。
方法：在德国的肥大细胞增多症专业中心，我们进行了第一阶段，人类第一，在ISM患者中使用lirentelimab的单次递增剂量和多剂量临床试验。符合条件的成年人患有WHO确认的ISM，对现有治疗的反应不令人满意。在A部分,患者接受单剂量的lirentelimab0.0003、0.001、0.003、0.01或0.03mg/kg；在B部分，患者接受了1次剂量为0.3mg/kg或1.0mg/kg的lirentelimab；在C部分，患者每4周接受1.0mg/kglirentelimab,共6个月或递增剂量的lirentelimab(1次1mg/kg剂量,然后每4周接受5次3~10mg/kg剂量).主要终点是安全性/耐受性。次要终点包括肥大细胞增多症症状问卷（MSQ）的基线变化，肥大细胞增多活动评分（MAS），最终剂量后2周的肥大细胞增多症生活质量问卷（MC-QoL）评分。
结果：共有25例ISM患者（n=13部分AB，n=12C部分；中位年龄51岁，76%为女性,自诊断起的中位数为4.6年)，最常见的治疗相关不良事件是发热(76%)和头痛(48%).无严重不良事件发生。C部分所有症状的平均MSQ和MAS症状严重程度评分均得到改善(MSQ:皮肤[与基线相比改善38%-56%],胃肠[49%-60%]，神经[47%-59%]，肌肉骨骼[26%-27%]；MAS：皮肤[53%-59%]，胃肠道[72%-85%]，神经[20%-57%]，肌肉骨骼[25%])。所有领域的MC-QoL得分中位数均有所改善：症状（39%），社交生活/功能（42%），情绪(57%)，皮肤（44%）。
结论：在ISM患者中，Lirentelimab的耐受性良好，症状和生活质量得到改善。对于ISM，应考虑lirentelimab的治疗潜力。
背景：ClinicalTrials.gov编号，NCT02808793。
