Velocity Clinical Research, Los Angeles, CA, USA.
Velocity Clinical Research, Huntington Park, CA, USA.
Lancet. 2023 Aug 5;402(10400):472-483. doi: 10.1016/S0140-6736(23)01302-8. Epub 2023 Jun 24.
Orforglipron, an oral, non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist, is in development for type 2 diabetes and obesity. We assessed the efficacy and safety of orforglipron versus placebo or dulaglutide in participants with type 2 diabetes.
In this 26-week, phase 2, double-blind, randomised, multicentre study, participants were recruited from 45 centres (private clinics, hospitals, and research centers) in the USA, Hungary, Poland, and Slovakia. Adult participants aged 18 years or older with type 2 diabetes treated with diet and exercise, with or without metformin, and with a glycated haemoglobin (HbA) of 7·0-10·5%, and stable BMI of 23 kg/m or more, were randomly assigned (5:5:5:5:5:3:3:3:3) via an interactive web-response system to placebo, dulaglutide 1·5 mg once per week, or orforglipron 3 mg, 12 mg, 24 mg, 36 mg (group 1), 36 mg (group 2), 45 mg (group 1), or 45 mg (group 2) once per day with no food or water restrictions. Two different dose escalation regimens were evaluated for each of the 36 mg and 45 mg cohorts. Participants were masked to the study drug, dulaglutide, and placebo. The primary efficacy outcome The primary efficacy outcome was mean change in HbA from baseline with orforglipron versus placebo at week 26. Efficacy was analysed in all randomly assigned participants who received at least one dose of study drug and excluded data after the permanent discontinuation of study drug or initiation of rescue medication. Safety was analysed in all participants who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT05048719) and is completed.
Between Sept 15, 2021, and Sept 30, 2022, 569 participants were screened and 383 were enrolled and randomly assigned to a group. 352 (92%) completed the study and 303 (79%) completed 26 weeks of treatment. At baseline, the mean age was 58·9 years, HbA was 8·1%, BMI was 35·2 kg/m, 226 (59%) were men, and 157 (41%) were women. At week 26, mean change in HbA with orforglipron was up to -2·10% (-1·67% placebo adjusted), versus -0·43% with placebo and -1·10% with dulaglutide. HbA reduction was statistically superior with orforglipron versus placebo (estimated treatment difference -0·8% to -1·7%). Change in mean bodyweight at week 26 was up to -10·1 kg (95% CI -11·5 to -8·7; 7·9 kg placebo adjusted [-9·9 to -5·9]) with orforglipron versus -2·2 kg (-3·6 to -0·7) for placebo and -3·9 kg (-5·3 to -2·4) for dulaglutide. The incidence of treatment-emergent adverse events ranged from 61·8% to 88·9% in orforglipron-treated participants, compared with 61·8% with placebo and 56·0% with dulaglutide. The majority were gastrointestinal events (44·1% to 70·4% with orforglipron, 18·2% with placebo, and 34·0% with dulaglutide) of mild to moderate severity. Three participants receiving orforglipron and one participant receiving dulaglutide had clinically significant (<54 mg/dL [<3 mmol/L]) hypoglycaemia and no participants had severe hypoglycaemia. One death occurred in the placebo group and was not related to study treatment.
In this phase 2 trial the novel, oral, non-peptide GLP-1 receptor agonist orforglipron at doses of 12 mg or greater showed significant reductions in HbA and bodyweight compared with placebo or dulaglutide. The adverse event profile was similar to other GLP-1 receptor agonists in similar stage of development. Orforglipron might provide an alternative to injectable GLP-1 receptor agonists and oral semaglutide, with the prospect of less burdensome administration to achieve treatment goals in people with type 2 diabetes.
Eli Lilly and Company.
Orforglipron 是一种口服非肽类胰高血糖素样肽-1（GLP-1）受体激动剂，目前正在开发用于 2 型糖尿病和肥胖症。我们评估了 Orforglipron 与安慰剂或度拉糖肽在 2 型糖尿病患者中的疗效和安全性。
这是一项 26 周、双盲、随机、多中心的 2 期研究，参与者来自美国、匈牙利、波兰和斯洛伐克的 45 个中心（私人诊所、医院和研究中心）。年龄在 18 岁及以上的成年参与者患有 2 型糖尿病，接受饮食和运动治疗，可伴有或不伴有二甲双胍，糖化血红蛋白（HbA）为 7.0-10.5%，且稳定的体重指数（BMI）为 23kg/m2 或更高，通过交互式网络响应系统以 5:5:5:5:5:3:3:3:3:3 的比例随机分配（每组 5 人）至安慰剂、每周 1.5mg 度拉糖肽或 3mg、12mg、24mg、36mg（第 1 组）、36mg（第 2 组）、45mg（第 1 组）或 45mg（第 2 组）Orforglipron，每日一次，无食物或水限制。对于每个 36mg 和 45mg 队列，评估了两种不同的剂量递增方案。参与者对研究药物、度拉糖肽和安慰剂均不知情。主要疗效结局主要疗效结局是与安慰剂相比，Orforglipron 治疗 26 周后 HbA 的平均变化。在至少接受一剂研究药物且在永久停用研究药物或开始抢救药物后数据缺失的所有随机分配参与者中进行疗效分析。在至少接受一剂研究治疗的所有参与者中进行安全性分析。这项试验在 ClinicalTrials.gov（NCT05048719）上注册，现已完成。
2021 年 9 月 15 日至 2022 年 9 月 30 日，共有 569 名参与者接受了筛查，383 名参与者入选并随机分配至一组。352 名（92%）完成了研究，303 名（79%）完成了 26 周的治疗。基线时，平均年龄为 58.9 岁，HbA 为 8.1%，BMI 为 35.2kg/m2，226 名（59%）为男性，157 名（41%）为女性。在第 26 周时，Orforglipron 治疗组的 HbA 平均变化为-2.10%（安慰剂调整后为-1.67%），安慰剂组为-0.43%，度拉糖肽组为-1.10%。与安慰剂相比，Orforglipron 治疗 HbA 的降低具有统计学意义（估计治疗差异为-0.8%至-1.7%）。第 26 周时平均体重变化为最多-10.1kg（95%CI-11.5 至-8.7；7.9kg 安慰剂调整后为-9.9 至-5.9）与安慰剂组的-2.2kg（-3.6 至-0.7）相比，度拉糖肽组为-3.9kg（-5.3 至-2.4）。在接受 Orforglipron 治疗的参与者中，治疗期出现的不良事件发生率为 61.8%至 88.9%，安慰剂组为 61.8%，度拉糖肽组为 56.0%。大多数为胃肠道事件（44.1%至 70.4%的 Orforglipron，18.2%的安慰剂，34.0%的度拉糖肽），其严重程度为轻度至中度。3 名接受 Orforglipron 治疗的参与者和 1 名接受度拉糖肽治疗的参与者发生了临床显著（<54mg/dL [<3mmol/L]）的低血糖，无严重低血糖事件发生。安慰剂组有 1 人死亡，但与研究治疗无关。
在这项 2 期试验中，新型口服非肽类 GLP-1 受体激动剂 Orforglipron 的剂量为 12mg 或更高，与安慰剂或度拉糖肽相比，可显著降低 HbA 和体重。与处于类似开发阶段的其他 GLP-1 受体激动剂相比，其不良事件谱相似。与注射用 GLP-1 受体激动剂和口服 semaglutide 相比，Orforglipron 可能为 2 型糖尿病患者提供了一种替代治疗方案，其治疗效果相似，但给药负担可能更小，更容易达到治疗目标。
礼来公司。
