Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1a, blinded, placebo-controlled, randomized, single- and multiple-ascending-dose study in healthy participants

被引:15
|
作者
Pratt, Edward [1 ,3 ]
Ma, Xiaosu [2 ]
Liu, Rong [2 ]
Robins, Deborah [2 ]
Haupt, Axel [2 ]
Coskun, Tamer [2 ]
Sloop, Kyle W. [2 ]
Benson, Charles [2 ]
机构
[1] Lilly Ctr Clin Pharmacol Pte Ltd, Singapore, Singapore
[2] Eli Lilly & Co, Indianapolis, IN USA
[3] Exploratory Med & Pharmacol EMP, Diabet Obes & Complicat, 3 Biopolis Dr,02 11 Synapse, Singapore 138623, Singapore
来源
DIABETES OBESITY & METABOLISM | 2023年 / 25卷 / 09期
关键词
antidiabetic drug; GLP-1; pharmacodynamics; pharmacokinetics; phase I-II study; weight control; GLP-1;
D O I
10.1111/dom.15184
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Aim: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of orforglipron (LY3502970), an oral, non-peptide glucagon-like peptide-1 receptor agonist (GLP-1RA) in healthy participants. Materials and Methods: This was a double-blind, placebo-controlled, Phase 1 study. Overtly healthy adults aged 18 to 65 years with body mass index of 20 to 40 kg/m(2) and glycated haemoglobin concentration of 47.5 mmol/mol (< 6.5%) were eligible. In Part A, participants received single-dose orforglipron, with four cohorts receiving escalating doses (0.3-6 mg). In Part B, participants received 4 weeks of daily repeated oral orforglipron with doses escalating weekly to four different final target doses (2-24 mg). Results: Ninety-two participants enrolled and received at least one study drug dose (32 in Part A [mean age 43.4 years] and 60 in Part B [mean age 42.5 years]). The most common adverse events were gastrointestinal tract-related. Pharmacokinetics were approximately dose proportional, and the mean t(1/2) was 24.6 to 35.3 hours after a single dose (0.3-6 mg). On Day 28, the mean t(1/2) was 48.1 to 67.5 hours across the dose range (2-24 mg). Substantial reductions in body weight of up to 5.4 kg were observed after 4 weeks in orforglipron-treated participants, compared to a reduction of 2.4 kg with placebo (P < 0.05). Orforglipron decreased fasting glucose levels across Days 1 to 28, and gastric emptying was delayed on Day 28. Conclusions: Orforglipron's long half-life (25-68 hours) allows once-daily oral dosing, without water and food restrictions. Orforglipron had a pharmacodynamic and safety profile similar to that of injectable GLP-1RAs, which supports continued clinical development.
引用
收藏
页码:2634 / 2641
页数:8
相关论文
empty
未找到相关数据