Global, multi-center, repeat-dose, phase 2 study of RZ358 (ersodetug), an insulin receptor antibody, for congenital hyperinsulinism.

IF 12.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Med Pub Date : 2025-03-12 DOI:10.1016/j.medj.2025.100611

Huseyin Demirbilek, Maria Melikyan, Violeta Iotova, Sonya Galcheva, Mehmet Nuri Ozbek, Antonia Dastamani, Nino Kheladze, Kineret Mazor-Aronovitch, Maria Clemente, Susann Empting, Klaus Mohnike, Henrik Thybo Christesen, Paul S Thornton, Diva D De Leon, Davelyn Hood, Erin O'Boyle, Brian K Roberts

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引用次数: 0

Abstract

Background: Congenital hyperinsulinism (cHI) is a rare, primarily pediatric disease characterized by dysregulated insulin secretion resulting in severe, persistent hypoglycemia, frequently leading to lifelong neurologic impairments. The safety, pharmacokinetics, and glycemic efficacy of ersodetug, a fully human monoclonal antibody that allosterically and reversibly binds the insulin receptor (INSR) and reduces excess insulin action, are being evaluated for the treatment of cHI-related hypoglycemia.

Methods: A global, open-label, phase 2b study (ClinicalTrials.gov: NCT04538989) was conducted in 23 patients with cHI with persistent hypoglycemia on standard-of-care (SOC) therapies. Eligible participants (age ≥2 years) received add-on ersodetug at dose levels between 3 and 9 mg/kg intravenously (i.v.) bi-weekly for 8 weeks in 4 sequential dose cohorts.

Findings: Enrolled participants (average age = 6.7 years) on SOC (87% medications; 17% previous pancreatectomy) experienced 13 events/week and 23% time in hypoglycemia at baseline. Ersodetug resulted in predictable, dose-proportional pharmacokinetics. No deaths, adverse drug reactions, study withdrawals, or dose-limiting toxicities occurred. Hypoglycemia (<70 mg/dL) events (self-monitored blood glucose) and time (continuous glucose monitoring) improved from baseline by medians of 59% (p < 0.001) and 54% (p < 0.001), respectively, across pooled dose levels and by 48%-84% (events) and 61%-65% (time) at doses of 6 or 9 mg/kg (p < 0.05) with a nearly universal individual patient response rate. Additional hypoglycemia metrics, including overnight hypoglycemia, similarly improved.

Conclusion: Ersodetug was generally well tolerated and significantly improved hypoglycemia in participants with cHI. Ersodetug represents a novel INSR-targeted mechanism of action with the potential to be an effective therapy for all forms of cHI, alone or in combination with other therapies.

Funding: Rezolute, Inc. (Redwood City, CA), provided funds.

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RZ358 （ersodetug）是一种胰岛素受体抗体，用于先天性高胰岛素血症的全球多中心、重复给药的2期研究。

背景：先天性高胰岛素血症（cHI）是一种罕见的儿童疾病，主要表现为胰岛素分泌失调，导致严重、持续的低血糖，经常导致终身神经系统损伤。ersodetug是一种全人源单克隆抗体，可变变和可逆结合胰岛素受体（INSR）并减少过量胰岛素作用，目前正在评估其治疗与胰岛素相关的低血糖的安全性、药代动力学和降糖功效。方法：一项全球性、开放标签、2b期研究（ClinicalTrials.gov: NCT04538989）纳入了23例接受标准护理（SOC）治疗的持续性低血糖cHI患者。符合条件的参与者（年龄≥2岁）在4个顺序剂量队列中，每两周接受剂量水平为3 - 9mg /kg的静脉注射（静脉注射），持续8周。结果：纳入的参与者（平均年龄= 6.7岁）使用SOC(87%的药物；17%的既往胰腺切除术)经历13次事件/周，23%的基线低血糖时间。Ersodetug导致可预测的剂量比例药代动力学。未发生死亡、药物不良反应、研究退出或剂量限制性毒性。结论：Ersodetug一般耐受性良好，可显著改善cHI患者的低血糖。Ersodetug代表了一种新的靶向insr的作用机制，有可能成为所有形式cHI的有效治疗方法，无论是单独治疗还是与其他疗法联合使用。资助：Rezolute， Inc. （Redwood City， CA）提供资金。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

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