2型糖尿病(T2DM)仍然是治疗的挑战,尽管各种治疗类别的扩展。Visepegenatide(PB-119)是每周一次,皮下,胰高血糖素样肽-1受体激动剂(GLP-1RA)注射无需剂量滴定,在中国和美国进行的两项2期研究中显示了血糖控制和安全性,分别。本研究的目的是评估利培地肽作为单一疗法治疗初治T2DM患者的疗效和安全性。
■这是一个多中心,双盲,平行,安慰剂对照,在中国30个中心进行的3期试验。成年参与者(年龄18-75岁)患有T2DM,糖化血红蛋白(HbA1c)为7.5%-11.0%[58.47-96.73mmol/mol],体重指数(BMI)为18~40kg/m2,且在筛查访视前至少8周接受过饮食和运动治疗者符合纳入条件.经过4周的安慰剂注射磨合期,HbA1c为7.0%~10.5%[53.0~91.3mmol/mol]且空腹血糖(FPG)<15mmol/L的参与者以1∶1的比例随机分组,接受自拟肽(150μg)或安慰剂皮下注射,每周1次,共24周.治疗延长至28周,在此期间所有参与者都接受了异肽。主要结果是HbA1c从基线到第24周的变化。这项研究在ClinicalTrials.gov注册,作为NCT04504370。
■在2020年11月2日至2022年11月2日之间,我们将273名成年参与者随机分配到维生素组(n=137)和安慰剂组(n=136)。总的来说,257名(94.12%)参与者,131(95.6%),安慰剂和126(92.6%),完成双盲治疗期。在基线,平均(SD)HbA1c为8.47%(0.81)[69.07[8.81]mmol/mol],在治疗的第4周,使用可见生发肽迅速降低至7.63%(0.80)[59.94[8.70]mmol/mol],与基线相比的变化显著大于安慰剂组(-0.82%[-0.90至-0.74];[-8.99[-9.89至-8.10]mmol/mol]vs-0.30%[-0.41至-0.19];[-3.30[-4.50至-2.09]mmol/mol])。在第24周,当用治疗政策评估和评估治疗效果时,生发肽组的最小二乘平均值(HbA1c相对于基线的LSM变化为-1.36(95%置信区间[CI]-1.52~-1.20)[-14.84[-16.60~-13.08]mmol/mol],安慰剂组的最小二乘平均值为-0.63(-0.79~-0.46)[-6.84[-8.61~-5.07]mmol/mol].与安慰剂组相比,利培生肽组的HbA1c下降幅度明显更大(LSM差异-0.73,95%CI-0.96至-0.50;p<0.001)。在评估治疗估计和假设政策时,与基线相比,间肽组的HbA1c的LSM变化(-1.37[-1.53~-1.20])[-14.95[-16.76~-13.14]mmol/mol]显著大于安慰剂组(-0.63[-0.81~-0.45])[6.90(-8.89~-4.90)mmol/mol].LSM差异为(-0.74,95%CI-0.98至-0.49;[-8.00[-10.50至-5.50]mmol/mol];p<0.001]。与安慰剂组相比(50.4%vs14.2%;p<0.05)和严格的HbA1c水平≤6.5%(≤48mmol/mol)(26.7%vs7.9%),明显更多的前几肽组达到<7%(<53mmol/mol)的目标HbA1c水平,分别。FPG也有显著更大的改善,餐后2小时葡萄糖,β细胞功能的稳态模型评估(HOMA),餐后胰岛素,禁食,和餐后C-肽水平(p<0.05),与单肽治疗。与安慰剂组(17[12.5%])相比,在异孕肽组接受抢救治疗的参与者数量(3[2.2%])明显更低(p<0.05)。在延长治疗期间,通过上述所有终点确认,viepegenatide始终维持疗效至第52周。第52周时HbA1c的降低为-1.39%(-1.58至-1.19)[-15.14[-17.28至-13.01]mmol/mol],甚至比第24周的还要大。与基线值相比,第52周的HOMA-胰岛素抵抗(p=0.004)也有显着改善。对于安慰剂→可见生发肽组,在延长的治疗期接受了异丙肽,与基线相比,在第52周观察到HbA1c显著下降.HbA1c从基线的变化为-1.49%(-1.68至-1.30)[-16.27[-18.37至-14.16]mmol/mol]。结果与双盲治疗期的evepegenatide组的方向相同。viepegenatide的综合好处,包括减肥,脂质分布的改善,在这项研究中已经证明了血压的降低。Visepegenatide以BMI依赖性方式降低体重,在BMI=32kg/m2中表现突出,在第52周时平均(SD)降低-4.77(13.94)kg(p<0.05)。胃肠道不良事件的发生率不如市场上的其他每周GLP-1RA常见。大多数不良事件本质上是轻度和中度的,发生在治疗的第一周,是短暂的。研究期间未报告严重的低血糖或2级低血糖(血糖:≤3mmol/L)。
■作为单一疗法,viepegenatide迅速提供而没有低血糖的风险,重要的,通过改善胰岛β细胞功能和胰岛素抵抗来持续控制血糖。利培生肽治疗可诱导早期治疗反应,降低HbA1c并维持血糖控制52周。同时,Visepegenatide在减肥方面提供了全面的益处,脂质,和降低血压。即使不需要剂量滴定,在T2DM患者中,与其他每周GLP-1RA相比,Visepegenatide具有更好的安全性。Visepegenatide将以其高效益和低风险平衡提供最佳治疗方法。
■佩格生物公司,Ltd.
UNASSIGNED: Type 2 diabetes (T2DM) remains a challenge to treat despite the expansion of various therapeutic classes. Visepegenatide (PB-119) is a once a week, subcutaneous, glucagon-like peptide-1 receptor agonist (GLP-1 RA) injection without the requirement of dose titration that has shown glycaemic control and safety profile in two phase 2 studies conducted in China and the United States, respectively. The aim of this study was to evaluate the efficacy and safety of visepegenatide as a monotherapy in treatment-naïve patients with T2DM.
UNASSIGNED: This was a multicentre, double-blind, parallel, placebo-controlled, phase 3 trial conducted in 30 centres in China. Adult participants (aged 18-75 years) with T2DM, glycated haemoglobin (HbA1c) of 7.5%-11.0% [58.47-96.73 mmol/mol], body mass index (BMI) of 18-40 kg/m2, and who had been treated with diet and exercise alone for at least 8 weeks before the screening visit were eligible for enrolment. After a 4-week placebo injection run-in period, participants with HbA1c of 7.0%-10.5% [53.0-91.3 mmol/mol] and fasting plasma glucose (FPG) < 15 mmol/L were randomised in a ratio of 1:1 to receive visepegenatide (150 μg) or placebo subcutaneous injections once a week for 24 weeks. The treatment was extended to another 28 weeks during which all participants received visepegenatide. The primary outcome was a change in HbA1c from baseline to week 24. This study was registered with ClinicalTrials.gov, as NCT04504370.
UNASSIGNED: Between November 2, 2020, and November 2, 2022, we randomly assigned 273 adult participants to the visepegenatide (n = 137) and placebo (n = 136) groups. In total, 257 (94.12%) participants, 131 (95.6%) on visepegenatide, and 126 (92.6%) on placebo, completed the double-blinded treatment period. At baseline, the mean (SD) HbA1c was 8.47% (0.81) [69.07 [8.81] mmol/mol], which rapidly decreased to 7.63% (0.80) [59.94 [8.70] mmol/mol] with visepegenatide by week 4 of treatment, and the change from baseline was significantly greater than that in the placebo group (-0.82% [-0.90 to -0.74]; [-8.99 [-9.89 to -8.10] mmol/mol] vs -0.30% [-0.41 to -0.19]; [-3.30 [-4.50 to -2.09] mmol/mol]). At week 24, when evaluating the effects of treatment with treatment policy estimand, the least square mean (LSM change in HbA1c from baseline was -1.36 (95% confidence interval [CI] -1.52 to -1.20) [-14.84 [-16.60 to -13.08] mmol/mol] in the visepegenatide group vs -0.63 (-0.79 to -0.46) [-6.84 [-8.61 to -5.07] mmol/mol] in the placebo group. The reduction in HbA1c was significantly greater with visepegenatide than placebo (LSM difference -0.73, 95% CI -0.96 to -0.50; p < 0.001). When evaluating the treatment estimand with hypothetic policy, the LSM change in HbA1c from baseline in the visepegenatide group (-1.37 [-1.53 to -1.20]) [-14.95 [-16.76 to -13.14] mmol/mol] was significantly greater than the placebo group (-0.63 [-0.81 to -0.45]) [6.90 (-8.89 to -4.90) mmol/mol]. The LSM difference was (-0.74, 95% CI -0.98 to -0.49; [-8.00 [-10.50 to -5.50] mmol/mol]; p < 0.001]. A significantly greater proportion of the visepegenatide group achieved a target HbA1c level of <7% (<53 mmol/mol) than the placebo (50.4% vs 14.2%; p < 0.05) and stringent HbA1c level of ≤6.5% (≤48 mmol/mol) (26.7% vs 7.9%), respectively. There was also a significantly greater improvement in FPG, 2-h postprandial glucose, homeostasis model assessment (HOMA) of beta cell function, post-prandial insulin, fasting, and post-prandial C-peptide level (p < 0.05) with visepegenatide treatment. The number (3 [2.2%]) of participants who received rescue therapy in the visepegenatide group was remarkably lower compared with those (17 [12.5%]) in the placebo group (p < 0.05). During the extended treatment period, visepegenatide consistently maintained the efficacy till week 52 confirmed by all the above endpoints. The reduction in HbA1c at week 52 was -1.39% (-1.58 to -1.19) [-15.14 [-17.28 to -13.01] mmol/mol], which was even greater than that at week 24. There was also a significant improvement in HOMA-insulin resistance (p = 0.004) at week 52 compared with the baseline value. For the placebo→visepegenatide group, which received visepegenatide in the extended treatment period, a notable decrease in HbA1c at week 52 compared to baseline was observed. The change from baseline in HbA1c was -1.49% (-1.68 to -1.30) [-16.27 [-18.37 to -14.16] mmol/mol]. The outcome was in the same direction as the visepegenatide group from the double-blind treatment period. Comprehensive benefits of visepegenatide including weight loss, improvement in lipid profile, and reduction in blood pressure have been demonstrated in this study. Visepegenatide reduced the body weight in a BMI-dependent manner that was prominent in BMI ˃32 kg/m2 with a mean (SD) reduction of -4.77 (13.94) kg at week 52 (p < 0.05). Incidences of gastrointestinal adverse events were less common than other weekly GLP-1 RA in the market, and most of the adverse events were mild and moderate in nature, occurring in the first weeks of the treatment, and were transient. No serious hypoglycaemia or grade 2 hypoglycaemia (blood glucose: ≤3 mmol/L) was reported during the study.
UNASSIGNED: As a monotherapy, visepegenatide provided rapid without the risk of hypoglycaemia, significant, and sustainable glycaemic control by improving islet β-cell function and insulin resistance. Treatment with visepegenatide induced early treatment response in reducing HbA1c and maintaining glycaemic control for 52 weeks. Meanwhile, visepegenatide provided a comprehensive benefit in body weight loss, lipids, and blood pressure reduction. Visepegenatide had a better safety profile than other weekly GLP-1 RA in participants with T2DM even without the requirement of dose titration. Visepegenatide would provide an optimal treatment approach with its high benefit and low-risk balance.
UNASSIGNED: PegBio Co., Ltd.