Abstract：
OBJECTIVE: To determine whether a continuous infusion of a glucagon-like peptide receptor (GLP-1R)/glucagon receptor (GCGR) co-agonist, G3215 is safe and well tolerated in adults with overweight or obesity.
METHODS: A phase 1 randomized, double blind, placebo-controlled trial of G3215 in overweight or obese participants, with or without type 2 diabetes.
RESULTS: Twenty-six participants were recruited and randomized with 23 completing a 14-day subcutaneous infusion of G3215 or placebo. The most common adverse events were nausea or vomiting, which were mild in most cases and mitigated by real-time adjustment of drug infusion. There were no cardiovascular concerns with G3215 infusion. The pharmacokinetic characteristics were in keeping with a continuous infusion over 14 days. A least-squares mean body weight loss of 2.39 kg was achieved with a 14-day infusion of G3215, compared with 0.84 kg with placebo infusion (p < .05). A reduction in food consumption was also observed in participants receiving G3215 and there was no deterioration in glycaemia. An improved lipid profile was seen in G3215-treated participants and consistent with GCGR activation, a broad reduction in circulating amino acids was seen during the infusion period.
CONCLUSIONS: An adaptive continuous infusion of the GLP-1/GCGR co-agonist, G3215, is safe and well tolerated offering a unique strategy to control drug exposure. By allowing rapid, response-directed titration, this strategy may allow for mitigation of adverse effects and afford significant weight loss within shorter time horizons than is presently possible with weekly GLP-1R and multi-agonists. These results support ongoing development of G3215 for the treatment of obesity and metabolic disease.
METHODS: A phase 1 randomized, double blind, placebo-controlled trial of G3215 in overweight or obese participants, with or without type 2 diabetes.
RESULTS: Twenty-six participants were recruited and randomized with 23 completing a 14-day subcutaneous infusion of G3215 or placebo. The most common adverse events were nausea or vomiting, which were mild in most cases and mitigated by real-time adjustment of drug infusion. There were no cardiovascular concerns with G3215 infusion. The pharmacokinetic characteristics were in keeping with a continuous infusion over 14 days. A least-squares mean body weight loss of 2.39 kg was achieved with a 14-day infusion of G3215, compared with 0.84 kg with placebo infusion (p < .05). A reduction in food consumption was also observed in participants receiving G3215 and there was no deterioration in glycaemia. An improved lipid profile was seen in G3215-treated participants and consistent with GCGR activation, a broad reduction in circulating amino acids was seen during the infusion period.
CONCLUSIONS: An adaptive continuous infusion of the GLP-1/GCGR co-agonist, G3215, is safe and well tolerated offering a unique strategy to control drug exposure. By allowing rapid, response-directed titration, this strategy may allow for mitigation of adverse effects and afford significant weight loss within shorter time horizons than is presently possible with weekly GLP-1R and multi-agonists. These results support ongoing development of G3215 for the treatment of obesity and metabolic disease.
摘要：
目的：为了确定是否连续输注胰高血糖素样肽受体（GLP-1R）/胰高血糖素受体（GCGR）共激动剂，G3215在超重或肥胖的成年人中安全且耐受性良好。
方法：第一阶段随机，双盲,G3215在超重或肥胖参与者中的安慰剂对照试验，有或没有2型糖尿病。
结果：招募了26名参与者，其中23名参与者完成了14天的G3215或安慰剂皮下输注。最常见的不良事件是恶心或呕吐，在大多数情况下是温和的，并通过实时调整药物输注来缓解。G3215输注没有心血管问题。药代动力学特征与连续输注14天保持一致。用14天输注G3215实现了2.39kg的最小二乘平均体重减轻,而安慰剂输注为0.84kg(p<.05)。在接受G3215的参与者中也观察到食物消耗减少，血糖没有恶化。在G3215治疗的参与者中观察到改善的脂质分布，并且与GCGR激活一致，在输注期间，循环氨基酸广泛减少。
结论：GLP-1/GCGR共激动剂的适应性连续输注，G3215是安全且耐受性良好的，提供了控制药物暴露的独特策略。通过允许快速，响应定向滴定，与目前使用每周一次的GLP-1R和多种激动剂相比,这种策略可以缓解不良反应,并在较短的时间范围内提供显著的体重减轻.这些结果支持G3215用于治疗肥胖和代谢疾病的持续发展。
方法：第一阶段随机，双盲,G3215在超重或肥胖参与者中的安慰剂对照试验，有或没有2型糖尿病。
结果：招募了26名参与者，其中23名参与者完成了14天的G3215或安慰剂皮下输注。最常见的不良事件是恶心或呕吐，在大多数情况下是温和的，并通过实时调整药物输注来缓解。G3215输注没有心血管问题。药代动力学特征与连续输注14天保持一致。用14天输注G3215实现了2.39kg的最小二乘平均体重减轻,而安慰剂输注为0.84kg(p<.05)。在接受G3215的参与者中也观察到食物消耗减少，血糖没有恶化。在G3215治疗的参与者中观察到改善的脂质分布，并且与GCGR激活一致，在输注期间，循环氨基酸广泛减少。
结论：GLP-1/GCGR共激动剂的适应性连续输注，G3215是安全且耐受性良好的，提供了控制药物暴露的独特策略。通过允许快速，响应定向滴定，与目前使用每周一次的GLP-1R和多种激动剂相比,这种策略可以缓解不良反应,并在较短的时间范围内提供显著的体重减轻.这些结果支持G3215用于治疗肥胖和代谢疾病的持续发展。
