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Abstract：
BACKGROUND: TG103, a glucagon-like peptide-1 analog, is being investigated as an option for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese without diabetes.
METHODS: In this randomized, double-blind, placebo-controlled, multiple-dose phase 1b study, participants aged 18-75 years with a body-mass index (BMI) ≥ 26.0 kg/m2 and body weight ≥ 60 kg were enrolled from three centers in China. The study included three cohorts, and in each cohort, eligible participants were randomly assigned (3:1) to one of three once-weekly subcutaneous TG103 groups (15.0, 22.5 and 30.0 mg) or matched placebo, without lifestyle interventions. In each cohort, the doses of TG103 were escalated in 1-week intervals to the desired dose over 1 to 4 weeks. Then participants were treated at the target dose until week 12 and then followed up for 2 weeks. The primary endpoint was safety and tolerability assessed by the incidence and severity of adverse events (AEs) from baseline to the end of the follow-up period. Secondary endpoints included pharmacokinetic and pharmacodynamic profiles of TG103 and the occurrence of anti-drug antibodies to TG103.
RESULTS: A total of 147 participants were screened, and 48 participants were randomly assigned to TG103 (15.0, 22.5 and 30.0 mg groups, n = 12 per group) or placebo (n = 12). The mean (standard deviation, SD) age of the participants was 33.9 (10.0) years; the mean bodyweight was 81.65 (10.50) kg, and the mean BMI was 29.8 (2.5) kg/m2. A total of 466 AEs occurred in 45 of the 48 participants, with 35 (97.2%) in the TG103 group and 10 (83.3%) in the pooled placebo group. Most AEs were grade 1 or 2 in severity, and there were no serious adverse events (SAEs), AEs leading to death, or AEs leading to discontinuation of treatment. The steady-state exposure of TG103 increased with increasing dose and was proportional to Cmax,ss, AUCss, AUC0-t and AUC0-inf. The mean values of Cmax,ss ranged from 951 to 1690 ng/mL, AUC0-t ranged from 150 to 321 μg*h/mL, and AUC0-inf ranged from 159 to 340 μg*h/mL. TG103 had a half-life of 110-116 h, with a median Tmax of 36-48 h. After treatment for 12 weeks, the mean (SD) values of weight loss from baseline in the TG103 15.0 mg, 22.5 mg and 30.0 mg groups were 5.65 (3.30) kg, 5.35 (3.39) kg and 5.13 (2.56) kg, respectively, and that in the placebo group was 1.37 (2.13) kg. The least square mean percent weight loss from baseline to D85 in all the TG103 groups was more than 5% with p < 0.05 for all comparisons with placebo.
CONCLUSIONS: In this trial, all three doses of once-weekly TG103 were well tolerated with an acceptable safety profile. TG103 demonstrated preliminary 12-week body weight loss without lifestyle interventions, thus showing great potential for the treatment of overweight and obesity.
BACKGROUND: ClinicalTrials.gov, NCT04855292. Registered on April 22, 2021.
METHODS: In this randomized, double-blind, placebo-controlled, multiple-dose phase 1b study, participants aged 18-75 years with a body-mass index (BMI) ≥ 26.0 kg/m2 and body weight ≥ 60 kg were enrolled from three centers in China. The study included three cohorts, and in each cohort, eligible participants were randomly assigned (3:1) to one of three once-weekly subcutaneous TG103 groups (15.0, 22.5 and 30.0 mg) or matched placebo, without lifestyle interventions. In each cohort, the doses of TG103 were escalated in 1-week intervals to the desired dose over 1 to 4 weeks. Then participants were treated at the target dose until week 12 and then followed up for 2 weeks. The primary endpoint was safety and tolerability assessed by the incidence and severity of adverse events (AEs) from baseline to the end of the follow-up period. Secondary endpoints included pharmacokinetic and pharmacodynamic profiles of TG103 and the occurrence of anti-drug antibodies to TG103.
RESULTS: A total of 147 participants were screened, and 48 participants were randomly assigned to TG103 (15.0, 22.5 and 30.0 mg groups, n = 12 per group) or placebo (n = 12). The mean (standard deviation, SD) age of the participants was 33.9 (10.0) years; the mean bodyweight was 81.65 (10.50) kg, and the mean BMI was 29.8 (2.5) kg/m2. A total of 466 AEs occurred in 45 of the 48 participants, with 35 (97.2%) in the TG103 group and 10 (83.3%) in the pooled placebo group. Most AEs were grade 1 or 2 in severity, and there were no serious adverse events (SAEs), AEs leading to death, or AEs leading to discontinuation of treatment. The steady-state exposure of TG103 increased with increasing dose and was proportional to Cmax,ss, AUCss, AUC0-t and AUC0-inf. The mean values of Cmax,ss ranged from 951 to 1690 ng/mL, AUC0-t ranged from 150 to 321 μg*h/mL, and AUC0-inf ranged from 159 to 340 μg*h/mL. TG103 had a half-life of 110-116 h, with a median Tmax of 36-48 h. After treatment for 12 weeks, the mean (SD) values of weight loss from baseline in the TG103 15.0 mg, 22.5 mg and 30.0 mg groups were 5.65 (3.30) kg, 5.35 (3.39) kg and 5.13 (2.56) kg, respectively, and that in the placebo group was 1.37 (2.13) kg. The least square mean percent weight loss from baseline to D85 in all the TG103 groups was more than 5% with p < 0.05 for all comparisons with placebo.
CONCLUSIONS: In this trial, all three doses of once-weekly TG103 were well tolerated with an acceptable safety profile. TG103 demonstrated preliminary 12-week body weight loss without lifestyle interventions, thus showing great potential for the treatment of overweight and obesity.
BACKGROUND: ClinicalTrials.gov, NCT04855292. Registered on April 22, 2021.
摘要：
背景：TG103，胰高血糖素样肽-1类似物，正在研究作为体重管理的一种选择。我们的目标是确定安全性，耐受性,药代动力学，和TG103注射在超重或肥胖但没有糖尿病的参与者中的药效学。
方法：在本随机分组中，双盲,安慰剂对照,多剂量1b期研究，纳入中国3个中心的18~75岁体重指数(BMI)≥26.0kg/m2,体重≥60kg的参与者.该研究包括三个队列，在每个队列中，符合条件的参与者被随机分配(3:1)到三个每周一次皮下TG103组(15.0,22.5和30.0mg)或匹配的安慰剂组,没有生活方式干预。在每个队列中，TG103的剂量在1~4周内以1周的间隔递增至所需剂量.然后以目标剂量治疗参与者直到第12周，然后随访2周。主要终点是通过从基线到随访期结束的不良事件（AE）的发生率和严重程度评估的安全性和耐受性。次要终点包括TG103的药代动力学和药效学谱以及针对TG103的抗药物抗体的出现。
结果：共筛选了147名参与者，48名参与者被随机分配到TG103（15.0、22.5和30.0mg组，每组n=12）或安慰剂（n=12）。平均值(标准偏差，SD）参与者的年龄为33.9（10.0）岁；平均体重为81.65（10.50）kg，平均BMI为29.8(2.5)kg/m2。48名参与者中有45名发生了466次不良事件，TG103组35例（97.2%），合并安慰剂组10例（83.3%）。大多数不良事件的严重程度为1级或2级，并且没有严重不良事件（SAE），导致死亡的AE，或导致停止治疗的AE。TG103的稳态暴露随着剂量的增加而增加，并且与Cmax成正比，ss,AUCss,AUC0-t和AUC0-inf。Cmax的平均值，SS范围从951到1690纳克/毫升，AUC0-t范围为150至321μg*h/mL，和AUC0-inf的范围为159至340μg*h/mL。TG103的半衰期为110-116小时，中位Tmax为36-48小时。治疗12周后，TG10315.0mg的体重从基线损失的平均值（SD），22.5mg和30.0mg组分别为5.65(3.30)kg,5.35（3.39）kg和5.13（2.56）kg，分别,安慰剂组为1.37（2.13）kg。在所有TG103组中从基线至D85的最小二乘平均重量损失百分比大于5%,对于与安慰剂的所有比较,p〈0.05。
结论：在本试验中，所有3种剂量的每周1次TG103均耐受良好,安全性可接受.TG103在没有生活方式干预的情况下显示出初步的12周体重减轻，因此显示出治疗超重和肥胖的巨大潜力。
背景：ClinicalTrials.gov，NCT04855292。2021年4月22日注册。
方法：在本随机分组中，双盲,安慰剂对照,多剂量1b期研究，纳入中国3个中心的18~75岁体重指数(BMI)≥26.0kg/m2,体重≥60kg的参与者.该研究包括三个队列，在每个队列中，符合条件的参与者被随机分配(3:1)到三个每周一次皮下TG103组(15.0,22.5和30.0mg)或匹配的安慰剂组,没有生活方式干预。在每个队列中，TG103的剂量在1~4周内以1周的间隔递增至所需剂量.然后以目标剂量治疗参与者直到第12周，然后随访2周。主要终点是通过从基线到随访期结束的不良事件（AE）的发生率和严重程度评估的安全性和耐受性。次要终点包括TG103的药代动力学和药效学谱以及针对TG103的抗药物抗体的出现。
结果：共筛选了147名参与者，48名参与者被随机分配到TG103（15.0、22.5和30.0mg组，每组n=12）或安慰剂（n=12）。平均值(标准偏差，SD）参与者的年龄为33.9（10.0）岁；平均体重为81.65（10.50）kg，平均BMI为29.8(2.5)kg/m2。48名参与者中有45名发生了466次不良事件，TG103组35例（97.2%），合并安慰剂组10例（83.3%）。大多数不良事件的严重程度为1级或2级，并且没有严重不良事件（SAE），导致死亡的AE，或导致停止治疗的AE。TG103的稳态暴露随着剂量的增加而增加，并且与Cmax成正比，ss,AUCss,AUC0-t和AUC0-inf。Cmax的平均值，SS范围从951到1690纳克/毫升，AUC0-t范围为150至321μg*h/mL，和AUC0-inf的范围为159至340μg*h/mL。TG103的半衰期为110-116小时，中位Tmax为36-48小时。治疗12周后，TG10315.0mg的体重从基线损失的平均值（SD），22.5mg和30.0mg组分别为5.65(3.30)kg,5.35（3.39）kg和5.13（2.56）kg，分别,安慰剂组为1.37（2.13）kg。在所有TG103组中从基线至D85的最小二乘平均重量损失百分比大于5%,对于与安慰剂的所有比较,p〈0.05。
结论：在本试验中，所有3种剂量的每周1次TG103均耐受良好,安全性可接受.TG103在没有生活方式干预的情况下显示出初步的12周体重减轻，因此显示出治疗超重和肥胖的巨大潜力。
背景：ClinicalTrials.gov，NCT04855292。2021年4月22日注册。
