1871-LB: Phase 1 Topline Safety, Efficacy, and Pharmacokinetics of Oral Ecnoglutide

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2024-06-21 DOI:10.2337/db24-1871-lb

ZHIYI ZHU, YAO LI, GUO WANJUN, QING ZHENG, JIANHUI DENG, ERIC ADEGBITE, STEPHEN ROSS, LIBNIR TELUSCA, CATHERINE L. JONES, MARTIJN FENAUX, SUSAN XU, MOHAMMED K. JUNAIDI

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引用次数: 0

Abstract

Introduction & Objective: Ecnoglutide is a cAMP-biased, long-acting GLP-1RA being developed for the treatment of type 2 diabetes mellitus and obesity. Oral ecnoglutide (XW004) is formulated with an absorption enhancer, PNAC (T2026). The objective of this study was to evaluate the safety and tolerability of oral ecnoglutide in healthy adults. Methods: We conducted a randomized, double-blind, placebo-controlled Phase 1 study in healthy (Cohorts 1 to 3) and healthy obese (Cohort 4) adults. Participants (n = 56) were randomized to receive oral ecnoglutide at target doses of 7, 15, or 30 mg QD for up to 6 weeks, with dose escalation. Safety, tolerability, PK, and body weight were assessed. The results of Cohorts 1 to 4 are presented, the study is ongoing to evaluate additional dosing schemes. Results: Oral ecnoglutide was generally safe and well tolerated. The most common AEs were mild to moderate gastrointestinal events that occurred during dose escalation. There were no serious AEs. One participant experienced a Grade 3 AE of diarrhea that led to study drug discontinuation. At baseline, participants had a mean BMI of 25.8 to 26.1 kg/m2 (Cohorts 1 to 3) and 32.9 kg/m2 (Cohort 4). At end of treatment, participants in Cohorts 1 to 3 receiving up to 7, 15, or 30 mg QD oral ecnoglutide for 2 weeks had body weight change from baseline of -3.63, -3.38, and -6.55%, respectively vs -0.85% for placebo. Participants in Cohort 4 receiving up to 30 mg QD for 6 weeks had a body weight reduction of -6.76% vs -0.85% for placebo. At steady state, oral ecnoglutide 30 mg QD resulted in a plasma AUC0-24h of 12,470 h*ng/mL and calculated weekly AUC 0-168h of 87,290 h*ng/mL. Conclusion: Oral ecnoglutide was safe and well tolerated and resulted in pronounced weight loss after 6 weeks of dosing. Improved oral bioavailability enables a daily dose of 30 mg oral ecnoglutide to match or exceed the plasma exposure of weekly subcutaneous GLP-1 analogs. Oral ecnoglutide has a potential to be a best-in-class oral GLP-1RA. Disclosure Z. Zhu: None. Y. Li: Employee; Sciwind Biosciences. G. Wanjun: Employee; Sciwind Biosciences. Q. Zheng: Employee; Sciwind Biosciences. J. Deng: Employee; Sciwind Biosciences. E. Adegbite: Employee; Sciwind Biosciences. S. Ross: None. L. Telusca: None. C.L. Jones: Employee; Sciwind Biosciences. M. Fenaux: None. S. Xu: None. M.K. Junaidi: None. Funding Sciwind Biosciences

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1871-LB：口服埃克诺鲁肽的安全性、疗效和药代动力学第一阶段初步研究

引言和目的：埃克诺鲁肽是一种基于 cAMP 的长效 GLP-1RA 药物，目前正在开发用于治疗 2 型糖尿病和肥胖症。口服埃克诺鲁肽（XW004）与吸收促进剂 PNAC（T2026）配伍。本研究旨在评估健康成年人口服埃克诺鲁肽的安全性和耐受性。研究方法我们在健康成人（群组 1 至 3）和健康肥胖成人（群组 4）中开展了一项随机、双盲、安慰剂对照的第一阶段研究。参与者（n = 56）被随机分配接受口服ecnoglutide，目标剂量为7、15或30 mg QD，疗程长达6周，剂量可递增。对安全性、耐受性、PK 和体重进行了评估。本文介绍了第 1 至第 4 组的研究结果，该研究仍在进行中，以评估其他剂量方案。研究结果口服埃克诺鲁肽总体上安全且耐受性良好。最常见的不良反应是剂量递增过程中出现的轻度至中度胃肠道反应。没有出现严重的不良反应。一名参与者出现了 3 级腹泻 AE，导致研究药物停用。基线时，参与者的平均体重指数为 25.8 至 26.1 kg/m2（队列 1 至 3）和 32.9 kg/m2（队列 4）。在治疗结束时，组群1至组群3的参与者连续2周每天口服7、15或30毫克ecnoglutide，体重与基线相比的变化分别为-3.63%、-3.38%和-6.55%，而安慰剂的变化为-0.85%。队列 4 中的参与者连续 6 周接受高达 30 毫克的 QD，体重减轻了-6.76%，而安慰剂的体重减轻幅度为-0.85%。在稳定状态下，口服ecnoglutide 30 mg QD的血浆AUC0-24h为12,470 h*ng/mL，每周计算的AUC 0-168h为87,290 h*ng/mL。结论口服ecnoglutide安全且耐受性良好，服药6周后体重明显减轻。口服生物利用度的提高使每天 30 毫克的口服ecnoglutide 剂量能够达到或超过每周皮下注射 GLP-1 类似物的血浆暴露量。口服ecnoglutide有望成为同类最佳的口服GLP-1RA。披露 Z. Zhu：无。Y. Li: 科风生物员工。G. Wanjun：员工；Sciwind Biosciences。Q. Zheng：Q. Zheng：员工；晨风生物。J. Deng: Employee; Sciwind Biosciences.E. Adegbite：员工；科风生物。S. Ross：L. Telusca: None.L. Telusca: None.C.L. Jones：员工；Sciwind 生物科学公司。M. Fenaux: None.S. Xu：无：无。M.K. Junaidi：无。资助科风生物

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.